WO1996020930A1 - Acetylenes disubstituted with a 5 or 8 substituted tetrahydronaphthyl or dihydronaphthyl group and with an aryl or heteroaryl groups having retinoid-like biological activity - Google Patents

Acetylenes disubstituted with a 5 or 8 substituted tetrahydronaphthyl or dihydronaphthyl group and with an aryl or heteroaryl groups having retinoid-like biological activity Download PDF

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Publication number
WO1996020930A1
WO1996020930A1 PCT/US1995/016367 US9516367W WO9620930A1 WO 1996020930 A1 WO1996020930 A1 WO 1996020930A1 US 9516367 W US9516367 W US 9516367W WO 9620930 A1 WO9620930 A1 WO 9620930A1
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WO
WIPO (PCT)
Prior art keywords
carbons
compound
alkyl
group
phenyl
Prior art date
Application number
PCT/US1995/016367
Other languages
French (fr)
Inventor
Vidyasagar Vuligonda
Min Teng
Richard L. Beard
Alan T. Johnson
Yuan Lin
Roshantha A. Chandraratna
Tae K. Song
Harold N. Wong
Tien T. Duong
Samuel J. Gillett
Original Assignee
Allergan
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US08/366,167 external-priority patent/US5618943A/en
Priority claimed from US08/366,182 external-priority patent/US5489584A/en
Priority claimed from US08/366,193 external-priority patent/US5648514A/en
Priority claimed from US08/366,168 external-priority patent/US5514825A/en
Priority claimed from US08/366,172 external-priority patent/US5543534A/en
Priority claimed from US08/366,169 external-priority patent/US5599967A/en
Priority claimed from US08/366,183 external-priority patent/US5618931A/en
Application filed by Allergan filed Critical Allergan
Priority to AU45204/96A priority Critical patent/AU698527B2/en
Priority to EP95943828A priority patent/EP0800517A1/en
Priority to JP52102396A priority patent/JP2002504066A/en
Publication of WO1996020930A1 publication Critical patent/WO1996020930A1/en

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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the present invention relates to novel compounds having retinoid-like activity. More specifically, the present invention relates to compounds having an acetylene portion which is substituted with a 5 or 8 substituted tetrahydronaphthyl or dihydronaphthyl and by a substituted aryl or substituted heteroaryl group having an acid function.
  • the acid function may also be converted to an alcohol, aldehyde or ketone or
  • retinoid-like activity is well known in the art, and are described in numerous United States and other patents and in scientific publications. It is generally known and accepted in the art that retinoid-like activity is useful for treating animals of the mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous diseases and conditions. In other words, it is generally accepted in the art that pharmaceutical compositions having a retinoid-like compound or compounds as the active ingredient are useful as regulators of cell proliferation and
  • skin-related diseases including, actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of
  • glucocorticoid damage (steroid atrophy), as a topical anti-microbial, as skin anti-pigmentation agents and to treat and reverse the effects of age and photo damage to the skin.
  • Retinoid compounds are also useful for the prevention and treatment of cancerous and
  • precancerous conditions including, premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of Kaposi's sarcoma.
  • retinoid compounds can be used as agents to treat diseases of the eye, including, without
  • proliferative vitreoretinopathy PVR
  • retinal detachment dry eye and other corneopathies
  • cardiovascular diseases including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of post-angioplasty
  • retinoid compounds include the prevention and treatment of conditions and diseases associated with human papilloma virus (HPV), including warts and genital warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn's disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and stroke, improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis and inhibition of T- Cell activated apoptosis, restoration of hair growth, including combination therapies with the present compounds and other agents such as Minoxidil R , diseases associated with the immune system, including use of the present compounds as immunosuppressants and
  • immunostimulants modulation of organ transplant rejection and facilitation of wound healing, including modulation of chelosis.
  • the present invention covers compounds of Formula
  • X is S or O
  • R 1 is hydrogen or alkyl of 1 to 10 carbons
  • R 2 and R 3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the tetrahydronaphthalene nucleus; m is an integer having the value of 0 - 3;
  • o is an integer having the value 0 - 4;
  • R 4 is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C 1 - C 10 -alkylphenyl, naphthyl, C 1 - C 10 -alkylnaphthyl, phenyl-C 1 - C 10 alkyl, napthyl-C 1 - C 10 alkyl; CN, or (CH 2 ) p CO 2 R 8 where p is an integer between 0 to 10;
  • R 5 is hydrogen, alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C 1 - C 10 -alkylphenyl, naphthyl, C 1 - C 10 -alkylnaphthyl, phenyl-C 1 - C 10 alkyl, napthyl-C 1 - C 10 alkyl; Si(R 2 ) 3 , COR 14 , camphanoyl, C(R 15 ) (R 16 )XR 17 ;
  • Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl,
  • A is (CH 2 ) n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds, and
  • B is hydrogen, COOH or a pharmaceutically
  • CH 2 OR 1:L CH 2 OCOR 11 , CHO, CH(OR 12 ) 2 , CHOR 13 O, -COR 7 , CR 7 (OR 12 ) 2 , CR 7 OR 13 O, or tri-lower alkylsilyl, where R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R 8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or R 8 is phenyl or lower alkylphenyl, R 9 and R 10
  • R 11 is lower alkyl, phenyl or lower alkylphenyl
  • R 12 is lower alkyl
  • R 13 is divalent alkyl radical of 2-5 carbons
  • R 14 is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C 1 - C 10 -alkylphenyl, naphthyl, C 1 - C 10 -alkylnaphthyl, phenyl-C 1 - C 10 alkyl, napthylC 1 - C 10 alkyl; R 15 and R 16 are hydrogen or lower alkyl of 1 to 6 carbons, R 17
  • R 16 and R 17 jointly form a ring having a total of 4 to 5 carbons and the X heteroatom;
  • R 1 is hydrogen or alkyl of 1 to 10
  • R 2 and R 3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the tetrahydronaphthalene nucleus; m is an integer having the value of 0 - 3;
  • o is an integer having the value 0 - 4;
  • Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl,
  • A is (CH 2 ) n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
  • B is hydrogen, COOH or a pharmaceutically
  • R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons
  • R 8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons
  • R 8 is phenyl or lower alkylphenyl
  • R 9 and R 10 independently are hydrogen, an alkyl group of l to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl
  • R 11 is lower alkyl, phenyl or
  • X is O or S
  • R 1 is hydrogen or alkyl of 1 to 10
  • R 2 and R 3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the tetrahydronaphthalene nucleus; m is an integer having the value of 0 - 3;
  • o is an integer having the value 0 - 4;
  • Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl,
  • A is (CH 2 ) n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6
  • B is hydrogen, COOH or a pharmaceutically
  • R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons
  • R 8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl
  • R 9 and R 10 independently are hydrogen, an alkyl group of l to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl
  • R 11 is lower alkyl, phenyl or lower alkylphenyl
  • R 12 is lower alkyl
  • R 13 is divalent alkylsilyl
  • R 19 is independently hydrogen, alkyl of l to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group
  • phenyl consisting of phenyl, C 1 - C 10 -alkylphenyl, naphthyl, C 1 - C 10 -alkylnaphthyl, phenyl-C 1 - C 10 alkyl, naphthylC 1 - C 10 alkyl; CN, CHO, CH(OR 12 ) 2 , CHOR 13 O,
  • R 1 is hydrogen or alkyl of 1 to 10
  • R 2 and R 3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the tetrahydronaphthalene nucleus; m is an integer having the value of 0 - 3;
  • o is an integer having the value 0 - 4;
  • Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl,
  • A is (CH 2 ) n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6
  • B is hydrogen, COOH or a pharmaceutically
  • R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons
  • R 8 is an alkyl group of 1 tt 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl
  • R 9 and R 10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl
  • R 11 is lower alkyl, phenyl or lower alkylphenyl
  • R 12 is lower alkyl
  • R 13 is di
  • the wavy line represents a single valence bond around which the configuration can be syn or anti
  • Z is OR 1 , R 1 is phenyl, benzyl, lower alkyl or lower alkoxy substituted phenyl, OSi(R 2 ) 3 , OCOR 14 , OC(R 15 )(R 16 )XR 17 , N(R 14 ) 2 , NHCON(R 14 ) 2 , NHCSN(R 14 ) 2 , where X is O or S; R 14 is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C 1 - C 10 -alkylphenyl, naphthyl, C 1 - C 10 -alkylnaphthyl, phenyl-C 1 - C 10 alkyl, naphthylC 1 - C 10 alkyl; R 15 and R 16 are hydrogen
  • R 16 and R 17 jointly form a ring having a total of 4 to 5 carbons and the X heteroatom;
  • R 1 is hydrogen or alkyl of 1 to 10
  • R 2 and R 3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the tetrahydronaphthalene nucleus; m is an integer having the value of 0 - 3;
  • o is an integer having the value 0 - 4;
  • Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl,
  • A is (CH 2 ) n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6
  • B is hydrogen, COOH or a pharmaceutically
  • R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons
  • R 8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl
  • R 9 and R 10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl
  • R 11 is lower alkyl, phenyl or lower alkylphenyl
  • R 12 is lower alkyl
  • R 13 is divalent alkyl
  • R 14 is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C 1 - C 10 -alkylphenyl, naphthyl, C 1 - C 10 -alkylnaphthyl, phenyl-C 1 - C 10 alkyl, naphthyl-C 1 - C 10 alkyl, or R 14 is COR 8 , or the two R 14 groups together with the N jointly form a 5 or 6 membered ring,
  • R 1 is hydrogen or alkyl of 1 to 10
  • R 2 and R 3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the dihydronaphthalene nucleus; m is an integer having the value of 0 - 3;
  • o is an integer having the value 0 - 3;
  • Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R 2 groups;
  • A is (CH 2 ) n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
  • B is hydrogen, COOH or a pharmaceutically
  • R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons
  • R 8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl
  • R 9 and R 10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl
  • R 11 is lower alkyl, phenyl or lower alkylphenyl
  • R 12 is lower alkyl
  • R 13 is divalent
  • X is O, S, SO or SO 2 and
  • R 20 is Si(R 2 ) 3 , R 14 , COR 14 , SO 2 R 21 , where R 14 is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bond, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C 1 - C 10 -alkylphenyl, naphthyl, C 1 - C 10 -alkylnaphthyl, phenylC 1 - C 10 alkyl, napthyl-C 1 - C 10 alkyl, or R 20 is
  • R 21 is alkyl of 1 to 10 carbons
  • fluoroalkyl of 1 to 10 carbons or carbocyclic aryl selected from the group consisting of phenyl, C 1 - C 10 -alkylphenyl and phenyl-C 1 - C 10 alkyl, and
  • R 1 is hydrogen or alkyl of 1 to 10
  • R 2 and R 3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the dihydronaphthalene nucleus; m is an integer having the value of 0 - 3;
  • o is an integer having the value 0 - 3;
  • Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl,
  • A is (CH 2 ) n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6
  • B is hydrogen, COOH or a pharmaceutically
  • R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons
  • R 8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl
  • R 9 and R 10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl
  • R 11 is lower alkyl, phenyl or lower alkylphenyl
  • R 12 is lower alkyl
  • R 13 is divalent alkyl
  • R 22 is hydrogen, alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C 1 - C 10 -alkylphenyl, naphthyl, C 1 - C 10 -alkylnaphthyl, phenyl-C 1 - C 10 alkyl, naphthyl-C 1 - C 10 alkyl, C 1 - C 10 -alkenylphenyl having 1 to 3 double bonds, C 1 - C 10 -alkynylphenyl having 1 to 3 triple bonds, phenyl-C 1 - C 10 alkenyl having 1 to 3 double bonds, phenyl-C 1 - C 10 alkynyl having 1 to 3 triple bonds, hydroxy alky
  • this invention relates to the use of the compounds of Formula 1 through Formula 7 for the treatment of skin-related diseases, including, without limitation, actinic keratoses, arsenic
  • keratoses inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage
  • the compounds are also useful for the prevention and treatment of cancerous and precancerous conditions, including, premalignant and malignant
  • hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias,
  • the present compounds can be used as agents to treat diseases of the eye, including, without limitation, proliferative vitreoretinopathy (PVR), retinal detachment, dry eye and other corneopathies, as well as in the treatment and prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of post-angioplasty
  • PVR proliferative vitreoretinopathy
  • retinal detachment retinal detachment
  • dry eye and other corneopathies as well as in the treatment and prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of post-angioplasty
  • TPA tissue plasminogen activator
  • Krohn's disease neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and stroke, improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis and
  • Minoxidil diseases associated with the immune system, including use of the present compounds as
  • immunosuppressants and immunostimulants modulation of organ transplant rejection and facilitation of wound healing, including modulation of chelosis.
  • This invention also relates to a pharmaceutical formulation
  • a pharmaceutical formulation comprising a compound of Formula l through Formula 7 in admixture with a pharmaceutically
  • this invention relates to processes for making a compound of Formula 1 through Formula 7 which process comprises reacting a compound of Formula 8 with a compound of Formula 9, in the presence of cuprous iodide and Pd(PQ 3 ) 2 Cl 2 (Q is phenyl) or a similar complex, or reacting the zinc salt of the compound shown in Formula 8 with a compound of Formula 9 in the presence of Pd(PQ 3 ) 4 (Q is phenyl) or similar complex.
  • the symbol STHN the symbol STHN
  • Formulas 1 through 7 or said tetrahydronaphthalene or dihydronaphthalene nucleus is appropriately substituted to provide such precursors of compounds of the Formulas 1 through 7 from which the target compounds can be readily obtained by organic reactions well known in the art.
  • X 1 is halogen
  • B 1 is H
  • B' is either the desired B group of Formulas 1 through 7, or B' is a precursor from which the B group can be readily obtained by reactions well known in the art.
  • the present invention relates to such reactions performed on the compounds of Formula 1 through 7 which cause transformations of the A-B group or of the substituents on the tetrahydro- or
  • alkyl refers to and covers any and all groups which are known as normal alkyl, branched-chain alkyl and cycloalkyl.
  • alkenyl refers to and covers normal alkenyl, branch chain alkenyl and
  • alkynyl refers to and covers normal alkynyl, and branch chain alkynyl groups having one or more triple bonds.
  • alkyl groups having 1 to 6 carbons in case of normal lower alkyl, and as applicable 3 to 6 carbons for lower branch chained and cycloalkyl groups.
  • Lower alkenyl is defined similarly having 2 to 6 carbons for normal lower alkenyl groups, and 3 to 6 carbons for branch chained and cyclo- lower alkenyl groups.
  • Lower alkynyl is also defined similarly, having 2 to 6 carbons for normal lower alkynyl groups, and 4 to 6 carbons for branch chained lower alkynyl groups.
  • esters refers to and covers any compound falling within the definition of that term as classically used in organic chemistry. It includes organic and inorganic esters. Where B (of Formula 1 through 7) is -COOH, this term covers the products derived from treatment of this function with alcohols or thiols preferably with aliphatic alcohols having 1-6 carbons.
  • ester is derived from compounds where B is -CH 2 OH
  • this term covers compounds derived from organic acids capable of forming esters including phosphorous based and sulfur based acids, or compounds of the formula -CH 2 OCOR 11 where R 11 is any substituted or unsubstituted aliphatic, aromatic, heteroaromatic or aliphatic aromatic group, preferably with 1-6 carbons in the aliphatic portions.
  • esters are derived from the saturated
  • Particularly preferred aliphatic esters are those derived from lower alkyl acids and alcohols. Also preferred are the phenyl or lower alkyl phenyl esters.
  • amides include the unsubstituted amides and all aliphatic and aromatic mono- and di- substituted amides.
  • preferred amides are the mono- and di-substituted amides derived from the saturated aliphatic radicals of ten or fewer carbon atoms or the cyclic or saturated aliphatic-cyclic radicals of 5 to 10 carbon atoms.
  • amides are those derived from substituted and unsubstituted lower alkyl amines. Also preferred are mono- and disubstituted amides derived from the
  • Acetals and ketals include the radicals of the formula-CK where K is (-OR) 2 .
  • R is lower alkyl.
  • K may be -OR 7 O- where R 7 is lower alkyl of 2-5 carbon atoms, straight chain or branched.
  • a pharmaceutically acceptable salt may be prepared for any compounds in this invention having a
  • a pharmaceutically acceptable salt is any salt which retains the activity of the parent compound and does not impart any deleterious or
  • salts may be derived from organic or inorganic bases.
  • the salt may be a mono or polyvalent ion.
  • the inorganic ions sodium, potassium, calcium, and
  • Organic salts may be made with amines, particularly ammonium salts such as mono-, di- and trialkyl amines or ethanol amines. Salts may also be formed with caffeine, tromethamine and similar
  • salts are those formed with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid. Any of a number of simple organic acids such as mono-, di- or tri- acid may also be used.
  • the compounds of the present invention may have trans and cis (E and Z) isomers.
  • the compounds of the present invention may contain one or more chiral centers and therefore may exist in
  • oxime and related compounds of the present invention may exist in syn and anti isomeric forms.
  • the scope of the present invention is intended to cover all such isomers per se, as well as mixtures of cis and trans isomers, mixtures of syn and anti isomers, mixtures of diastereomers and racemic mixtures of enantiomers
  • the preferred compounds of the invention are those where Y is phenyl, pyridyl, thienyl or furyl. Even more preferred are compounds where Y is phenyl or pyridyl. As far as substititutions on the Y (phenyl) and Y (pyridyl) groups are concerned, compounds are preferred where the phenyl group is 1,4 (para)
  • the A-B group of the preferred compounds is
  • the aromatic portion of the tetrahydronaphthalene or dihydronaphthalene moiety is preferably substituted only by the acetylene function.
  • R 2 substituent other than hydrogen
  • R 3 substituent other than hydrogen
  • the R 1 substituent of the compounds of the invention is preferably lower alkyl, and even more preferably methyl.
  • R 4 substituent is preferably hydrogen, CN or CH 2 COOR 8 where R 8 is
  • R 5 substituent is preferably hydrogen, alkyl, cycloalkyl, of the
  • R 5 is hydrogen, cyclohexyl, trimethylsilyl, -CH 2 OCH 3 (methoxymethyl), 2'-tetrahydropyranyl, acetyl, benzoyl or camphanoyl.
  • Specific preferred compounds in accordance with Formula 1 and their synthesis are described below in the section of this application titled "Specific Examples”. The presently roost
  • X is sulphur and R 18 is an alkyl group; even more preferably X is sulphur and the two R 18 groups jointly represent methylene groups which together with the two sulphur atoms and the C 5 carbon of the tetrahydronaphthalene nucleus form a 6 membered ring.
  • Specific preferred compounds in accordance with Formula 2 and their synthesis are described below in the section of this application titled "Specific Examples”. The
  • the R 19 groups preferably are hydrogen, alkyl of 1 to 10 carbons, cyano (CN) or COOR 8 . Even more preferably the R 19 groups are H, CN, COOEt or lower alkyl.
  • the two R 19 groups jointly form a -(CH 2 ) q - radical, (q is an integer having the values of 3 to 7) whereby a cycloalkyl ring is formed, most preferably a
  • the Z group preferably represents OR 1 , where the R 1 group is preferably hydrogen or lower alkyl.
  • R 1 group is preferably hydrogen or lower alkyl.
  • Z is
  • R 14 groups are hydrogen or lower alkyl, even more
  • R 20 group is preferably R 14 , COR 14 , SO 2 R 21 or Si(R 2' ) 3 where R 14 is preferably phenyl, benzyl or lower alkyl, even more preferably ethyl, R 21 is preferably
  • fluorinated lower alkyl even more preferably CF 3 , and R 2 , is preferably lower alkyl, even more preferably methyl.
  • Specific preferred compounds in accordance with Formula 6 and their synthesis are described below in the section of this application titled "Specific Examples”. The presently most preferred compounds of the invention in accordance with Formula 6 are
  • R 22 is preferably hydrogen, alkyl of 1 - 10 carbons, alkynyl of 2 to 10 carbons having 1 triple bond, alkylphenyl having 1 to 10 carbons in the alkyl group, phenylalkyl having 1 to 10 carbons in the alkyl group,
  • phenylalkynyl having 2 to 10 carbons in the alkynyl group CH 2 CO 2 R 8 , hydroxyalkyl having 1 to 10 carbons in the alkyl group, hydroxyalkynyl having 2 to 10 carbons in the alkynyl group, cyano (CN), CONH 2 or heteroaryl.
  • heteroaryl groups 5 or 6 membered rings having 1 or 2 heteroatoms are particularly preferred.
  • Compounds where the R 22 group is 2-thiazolyl, 2-furyl, 2-thienyl or 2-pyridyl are especially preferred.
  • the compounds of this invention may be any organic compound having the same properties as the compounds of this invention.
  • the compound will be prepared as a solution or suspension capable of being administered by injection. In certain cases, it may be useful to formulate these compounds by injection. In certain cases, it may be useful to formulate these compounds in suppository form or as extended release formulation for deposit under the skin or intramuscular injection.
  • medicaments can be added to such topical formulation for such secondary purposes as treating skin dryness; providing protection against light; other medications for treating dermatoses; medicaments for preventing infection, reducing irritation, inflammation and the like.
  • Treatment of dermatoses or any other indications known or discovered to be susceptible to treatment by retinoic acid-like compounds will be effected by administration of the therapeutically effective dose of one or more compounds of the instant invention.
  • a therapeutic concentration will be that concentration which effects reduction of the particular condition, or retards it expansion.
  • the compound potentially may be used in prophylactic manner to prevent onset of a particular condition.
  • a useful therapeutic or prophylactic concentration will vary from condition to condition and in certain instances may vary with the severity of the condition being treated and the patient's susceptibility to treatment. Accordingly, no single concentration will be uniformly useful, but will require modification depending on the particularities of the disease being treated. Such concentrations can be arrived at through routine experimentation. However, it is anticipated that in the treatment of, for example, acne, or similar dermatoses, that a formulation containing between 0.01 and 1.0 milligrams per milliliter of formulation will constitute a therapeutically effective concentration for total application. If administered systemically, an amount between 0.01 and 5 mg per kg per day of body weight would be expected to effect a therapeutic result in the treatment of many diseases for which these compounds are useful.
  • retinoic acid-like activity of these compounds is confirmed through the classic measure of retinoic acid activity involving the effects of retinoic acid on ornithine decarboxylase.
  • the original work on the correlation between retinoic acid and decrease in cell proliferation was done by Verma & Boutwell, Cancer Research, 1977, 37,2196-2201. That reference discloses that ornithine decarboxylase (ODC) activity increased precedent to polyamine biosynthesis. It has been established elsewhere that increases in polyamine synthesis can be correlated or associated with cellular proliferation. Thus, if ODC activity could be
  • TPA 12-0-tetradecanoylphorbol-13-acetate
  • IC 80 is that concentration of the test compound which causes 80% inhibition in the
  • IC 60 concentration of the test compound which causes 60% inhibition in the ODC assay.
  • the compounds of this invention can be made by the synthetic chemical pathways illustrated here.
  • the synthetic chemist will readily appreciate that the conditions set out here are specific embodiments which can be generalized to any and all of the compounds represented by Formulas 1 through 7.
  • a zinc salt (or other suitable metal salt) of the compounds of Formula 12 can be coupled with the reagents of Formula 9 in the presence of Pd(PPh 3 ) 4 or similar complex.
  • the coupling reaction with the reagent X 1 -Y(R 2 )-A-B' (Formula 9) is conducted at room or moderately elevated temperature.
  • coupling between an ethynylaryl derivative or its zinc salt and a halogen substituted aryl or heteroaryl compound, such as the reagent of Formula 9, is described in United States Patent No. 5,264,456, the specification of which is expressly incorporated herein by reference.
  • compounds of Formula 13 are compounds of the invention within the scope of Formula 2, or a derivative thereof protected in the B' group, from which the protecting group can be readily removed by reactions well known in the art.
  • the compounds of Formula 13 can also be converted into ketals or thioketals, within the scope of Formula 2, by reactions generally well known in the art.
  • the compounds of Formula 13 can also be converted into further compounds of the invention by such
  • the halogen substitituted aryl or heteroaryl compounds of Formula 9 can, generally speaking, be obtained by reactions well known in the art.
  • An example of such compound is ethyl 4-iodobenzoate which is obtainable, for example, by esterification of 4-iodobenzoic acid.
  • Another example is ethyl 6-iodonicotinate which can be obtained by conducting a halogen exchange reaction on 6-chloronicotinic acid, followed by esterification.
  • derivatization of compounds of Formula 13 and/or the synthesis of aryl and heteroaryl compounds of Formula 9 which can thereafter be reacted with compounds of Formula 12 to yield compounds of the invention the following well known and published general principles and synthetic methodology can be employed.
  • Carboxylic acids are typically esterified by refluxing the acid in a solution of the appropriate alcohol in the presence of an acid catalyst such as hydrogen chloride or thionyl chloride.
  • an acid catalyst such as hydrogen chloride or thionyl chloride.
  • the carboxylic acid can be condensed with the
  • aromatic or heteroaromatic carboxylic acids are subjected to homologation by successive treatment under Arndt-Eistert conditions or other homologation
  • derivatives which are not carboxylic acids may also be homologated by appropriate procedures.
  • the homologated acids can then be
  • Compounds of Formula 9, (or of the invention as set forth in Formulas 1 through 7, as applicable) where A is an alkenyl group having one or more double bonds can be made for example, by synthetic schemes well known to the practicing organic chemist; for example by Wittig and like reactions, or by introduction of a double bond by elimination of halogen from an alpha-halo-arylalkyl-carboxylic acid, ester or like carboxaldehyde.
  • Compounds of Formula 9 (or of the invention as set forth in Formulas 1 through 7, as applicable) where the A group has a triple (acetylenic) bond can be made by reaction of a corresponding aromatic methyl ketone with strong base, such as lithium diisopropyl amide, reaction with diethyl chlorophosphate and subsequent addition of lithium diisopropylamide.
  • strong base such as lithium diisopropyl amide
  • an ester of Formula 13 (or other compounds of the invention as set forth in Formulas 1 through 7, as applicable) may be dissolved in a polar solvent such as an alkanol, preferably under an inert atmosphere at room temperature, with about a three molar excess of base, for example, lithium hydroxide or potassium hydroxide.
  • a polar solvent such as an alkanol
  • base for example, lithium hydroxide or potassium hydroxide
  • the amide may be formed by any appropriate
  • amidation means known in the art from the corresponding esters or carboxylic acids.
  • One way to prepare such compounds is to convert an acid to an acid chloride and then treat that compound with ammonium hydroxide or an appropriate amine.
  • the ester is treated with an alcoholic base solution such as ethanolic KOH (in approximately a 10% molar excess) at room
  • Alcohols are made by converting the corresponding acids to the acid chloride with thionyl chloride or other means (J. March, "Advanced Organic Chemistry", 2nd Edition, McGraw-Hill Book Company), then reducing the acid chloride with sodium borohydride (March, Ibid, pg. 1124), which gives the corresponding alcohols.
  • esters may be reduced with lithium aluminum hydride at reduced temperatures. Alkylating these alcohols with appropriate alkyl halides under Williamson reaction conditions (March, Ibid, pg. 357) gives the corresponding ethers. These alcohols can be converted to esters by reacting them with appropriate acids in the presence of acid catalysts or dicyclohexylcarbodiimide and dimethylaminopyridine.
  • Aldehydes can be prepared from the corresponding primary alcohols using mild oxidizing agents such as pyridinium dichromate in methylene chloride (Corey, E. J., Schmidt, G., Tet. Lett.. 399, 1979). or dimethyl sulfoxide/oxalyl chloride in methylene chloride (Omura, K., Swern, D., Tetrahedron. 1978. 34, 1651).
  • mild oxidizing agents such as pyridinium dichromate in methylene chloride (Corey, E. J., Schmidt, G., Tet. Lett.. 399, 1979). or dimethyl sulfoxide/oxalyl chloride in methylene chloride (Omura, K., Swern, D., Tetrahedron. 1978. 34, 1651).
  • Ketones can be prepared from an appropriate aldehyde by treating the aldehyde with an alkyl
  • Acetals or ketals can be prepared from the
  • halogenated aromatic or heteroaromatic compounds preferably where the halogen is I.
  • the 7,8-dihydro-naphthalen-5(6H)-one derivatives of Formula 13 are reduced with a mild reducing agent such as sodium borohydride, to yield the corresponding 5-hydroxy-5,6,7,8-tetrahydronaphthalene derivatives of Formula 14.
  • the 5-hydroxy function of the compounds of Formula 14 is then acylated with a suitable acylating agent (such as a carboxylic acid chloride or anhydride), or converted into an ether with a suitable reagent (such as an alkyl bromide under basic conditions, or
  • the compounds of Formula 15 are compounds of the invention (or protected derivatives thereof) within the scope of Formula 1.
  • Formula 15 can be "deprotected” or otherwise converted into further compounds of the invention by reactions well known in the art, as described above.
  • the compounds of Formula 13 can also be reacted with a Reformatsky reagent derived from an a halocarboxylic acid ester (such as ethyl bromoacetate), or with a Grignard reagent, optionally followed by acylation or ether formation on the resulting tertiary hydroxyl group on the 5-position of the tetrahydronaphthalene nucleus, to yield compounds of Formula 16.
  • a Reformatsky reagent derived from an a halocarboxylic acid ester (such as ethyl bromoacetate), or with a Grignard reagent, optionally followed by acylation or ether formation on the resulting tertiary hydroxyl group on the 5-position of the tetrahydronaphthalene nucleus, to yield compounds of Formula 16.
  • the compounds of Formula 13 are reacted with cyanotrimethylsilane in the presence of boron trifluoroetherate to yield compounds in accordance with Formula 16.
  • the compounds of Formula 16 are compounds of the invention within the scope of Formula 1, (or protected derivatives thereof) and can be converted into further homologs and derivatives within the scope of the invention.
  • Reaction Scheme 2 illustrates another synthetic route to the compounds of the invention in accordance with Formula 1. 6- or 7-Bromo substituted 1,2,3,4-tetrahydro naphthalene derivatives of Formula 17
  • the zinc salts of the compounds of Formula 18 can also be coupled with the reagents of Formula 9, in the presence of Pd(PPh 3 ) 4 or similar complex.
  • Compounds of Formula 19 are then reacted with a suitable brominating agent (such as N-bromosuccinimide (NBS) and benzoyl peroxide in carbontetrachloride) to yield the corresponding 5-bromo-5,6,7,8-tetrahydronaphthalene derivatives of Formula 20.
  • a suitable brominating agent such as N-bromosuccinimide (NBS) and benzoyl peroxide in carbontetrachloride
  • the 5-bromo substituent of the compounds of Formula 20 can be subjected to nucleophilic substitution reactions with nucleophilic reagents having the formula R 5 XH, in the presence of base.
  • the R 5 and X groups are defined as in connection with Formula 1, typically R 5 XH is the salt of a thiocarboxylic acid (such as potassium thioacetate) or the sodium derivative of an alcohol or thiol.
  • R 5 XH is the salt of a thiocarboxylic acid (such as potassium thioacetate) or the sodium derivative of an alcohol or thiol.
  • the compounds of Formula 21 can be converted into further homologs and derivatives, as is described above in connection with compounds of Formulas 13, 15 and 16.
  • Compound F is brominated with a suitable brominating agent (such as N.-bromosuccinimide (NBS) and benzoyl peroxide in carbontetrachloride) to yield the
  • R 5 and X groups are defined as in connection with Formula 1; typically R 5 XH is the salt of a thiocarboxylic acid (such as potassium thioacetate) or the sodium derivative of an alcohol (such as the sodium salt of cyclohexanol), or thiol.
  • R 5 XH is the salt of a thiocarboxylic acid (such as potassium thioacetate) or the sodium derivative of an alcohol (such as the sodium salt of cyclohexanol), or thiol.
  • the product of the latter reaction is a 6- or 7-bromo tetrahydronaphthalene derivative of Formula 23 which has the desired R 5 X substituent in the 4-position.
  • the 6- or 7- bromo compound of Formula 23 is then reacted with trimethylsilylacetylene, followed by base (such as potassium carbonate) to yield the 6- or 7-ethynyl-1,2,3,4-tetrahydronaphthalene derivatives of Formula 24.
  • base such as potassium carbonate
  • the latter two reactions involving introduction of the ethynyl group into the 6 or 7 position of the tetrahydronaphthalene nucleus are conducted under conditions substantially similar to the analogous reactions described above in connection with Reaction Schemes 1 and 2.
  • the ethynyl compounds of Formula 24 are then coupled with the reagent X 1 -Y(R 2 )-A-B'
  • this coupling reaction can be conducted with 6- or 7- substituted ethynyl compounds which either already have a substituent desired for the present invention in the 4- position (as in Reaction Scheme 3) or have a precursor suitable for introduction of such desired substituent (as in Reaction Schemes 1 and 2).
  • reaction step determines the nature of the R 1
  • Compound E is then treated with acid to cyclize it and to form 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F).
  • Compound F is in the scope of Formula 17, and in accordance with Reaction Schemes 2 and 3 serves as the starting material in the synthesis of several preferred compounds of the
  • Compound F is oxidized with chromium
  • Compound G is covered by Formula 10 and in accordance with
  • Reaction Scheme 1 serves as a starting material in the synthesis of several preferred compounds of the
  • Formula 27 are then coupled with the aromatic or heteroaromatic reagent X 1 -Y(R 2 )-A-B « (Formula 9) in the presence of cuprous iodide, a suitable catalyst, typically Pd(PPh 3 ) 2 Cl 2 , an acid acceptor, such as diethylamine, under inert gas (argon) atmosphere, as described above in connection with Reaction Scheme 1, to yield compounds of Formula 28.
  • a suitable catalyst typically Pd(PPh 3 ) 2 Cl 2
  • an acid acceptor such as diethylamine
  • Reaction Scheme 7 illustrates synthesis of those compounds of Formula 3 wherein one of the R 19 groups is hydrogen and the other is a carboxylic acid ester (or derivative thereof).
  • the starting compounds for these syntheses are compounds of Formula 30, which are within the scope of Formula 1 and can be obtained in
  • Formula 13 are reacted with a reagent of the formula H 2 N-Z (Formula 32), where Z is defined as in connection with Formula 4 , to yield compounds of Formula 4.
  • a reagent of the formula H 2 N-Z (Formula 32), where Z is defined as in connection with Formula 4 , to yield compounds of Formula 4.
  • reagent H 2 N-Z is a primary amine (Z is R 1 , phenyl or benzyl) then the reaction between the compounds of Formula 13 and the primary amine is the formation of an imine. The latter reaction is usually conducted in a polar (alcoholic) solvent.
  • Further reagents, in accordance with Formula 32 are those where Z is NHCON(R 14 ) 2 (formation of semicarbazone), NHCSN(R 14 ) 2 (formation of
  • the semicarbazones, thiosemicarbazones and hydrazones corresponding to Formula 4 can be prepared under conditions which are well known in the art for the formation of such derivatives of ketone compounds. Usually these
  • the hydrochloride salt of of the reagent is reacted with the compound of Formula 13 in an alcoholic solvent, in the presence of sodium acetate.
  • an oxime derivative of the Formula 33 is first prepared in accordance with the reaction described above.
  • the oxime derivative of Formula 33 is thereafter reacted with 3,4-dihydro-2H-pyran (DHP) in an inert solvent (such as
  • tetrahydrothiopyranyl can be prepared in reaction steps analogous to the ones described above for the preparation of compounds of Formula 34.
  • the oxime derivatives of Formula 33 can also be reacted with an appropriate reagent (such as an acyl chloride R 14 COCl) to introduce the R 14 CO group, to provide the compounds of Formula 35.
  • an appropriate reagent such as an acyl chloride R 14 COCl
  • the compounds of Formula 4 can also be obtained, generally speaking, by first forming an oxime, alkoxyoxime, imine, hydrazone, semicarbazone etc. from the ketone compounds of Formula 10 (see Reaction Scheme 1) and thereafter performing the synthetic steps of replacing the 6 or 7-bromo
  • Compounds of Formula 36 where the NH 2 group is not substituted comprise the presently preferred compounds of Formula 5.
  • Compounds of Formula 5 where R 14 is an alkyl, alkenyl, alkynyl or aryl group (as such groups are defined in connection with Formula 5) are prepared by reaction of compounds of Formula 36 with a reagent of the formula R 14 -X 1 , where X 1 is halogen. When R 14 is an alkyl group then the reagent R 14 -X 1 is an alkyl halide.
  • alkenyl, alkynyl or aryl group (as such groups are defined in connection with Formula 5) can also be obtained from the 5-oxo 2- or 3- (aryl or
  • R 14 NH 2 corresponding amine
  • R 8 CO acyl
  • the compounds of Formula 5 can also be obtained, generally speaking, by first forming the 5-amino, 5-alkylamino or 5-acylamido derivative from the ketone compounds of Formula 10 (see Reaction Scheme 1) and thereafter performing the synthetic steps of replacing the 6 or 7-bromo substituents in these compounds with an ethynyl group, and subsequently coupling the ethynyl compounds with the reagent X 1 -Y(R 2 )-A-B' (Formula 9).
  • the ketone derivatives of Formula 13 are reacted with a reagent which "enolizes” the ketone function of the tetrahydronaphthalene nucleus.
  • the resulting "enol” compound then reacts with a reagent which introduces the R 20 group into the enol function.
  • the group R 20 is defined in connection with Formula 6.
  • Suitable reagents for the purpose of introducing the R 20 function include a reactive leaving group L.
  • the reagents used in this reaction have the general formula R 20 -L, R 14 -CO-L, R 14 -L, and R 21 -L, where the R 14 and R 21 groups are defined as in connection with Formula 6.
  • Examples of the reagents, and/or reaction conditions which are used for the synthesis of the preferred compounds of the invention within the scope of Formula 6 include: reacting compounds of Formula 13 with sodium bis (trimethylsilyl) amide and 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine in an inert ether type solvent such as tetrahydrofuran at low temperatures (-78 °C and 0 °C) to obtain the 5-trifluoromethylsulfonyloxy-7,8-dihydronaphthalene derivative; reacting compounds of Formula 13 with acetic anhydride and p-toluenesulfonic acid at elevated temperature (80 °C) to obtain the 5-acetoxy-7,8-dihydronaphthalene derivative; and reacting compounds of Formula 13 with cyanotrimethylsilane in the presence of zinc iodide at ambient temperature to obtain the 5-trimethylsilyloxy-7,8-dihydron
  • Compounds of Formula 38, obtained in the above- described manner are such compounds of Formula 6 where the X is oxygen.
  • Compounds of Formula 6 where X is sulfur can be obtained by analogous reactions of the 5-thio analogs of the oxo compounds of Formula 13.
  • Compounds of Formula 6 where X is S and R 20 is R 14 are preferably obtained by reacting compounds of Formula 13 with titanium tetrachloride and a thiol of the formula R 14 SH in an inert ether type solvent (such as
  • the thienol ether compounds of Formula 38A can be oxidized to sulfoxides or with a suitable oxidizing agent, such as 3-chloroperoxybenzoic acid (MCPBA) to the corresponding sulfones of Formula 38B.
  • MCPBA 3-chloroperoxybenzoic acid
  • the compounds of Formula 6 can also be obtained, generally speaking, by first forming the "enolized” and acylated, alkylated or sulfonylated etc. derivative from the ketone compounds of Formula 10 (see Reaction Scheme 1) and thereafter performing the synthetic steps of replacing the 6 or 7-bromo substituents in these compounds with an ethynyl group, and subsequently coupling the ethynyl compounds with the reagent X 1 -Y(R 2 )-A-B' (Formula 9).
  • Reaction Scheme 11 discloses synthetic steps for the preparation of those compounds of Formula 7 where the R 22 group is alkyl, alkenyl, alkynyl, carbocyclic aryl or heteroaryl, as these groups are broadly defined in Formula 7.
  • R 22 group is alkyl, alkenyl, alkynyl, carbocyclic aryl or heteroaryl, as these groups are broadly defined in Formula 7.
  • 5-trifluoromethylsulfonyloxy 2- or 3- (aryl or heteroaryl) ethynyl 7,8-dihydronaphthalene compounds of Formula 39 serve as starting materials.
  • the compounds of Formula 39 can be obtained from the 5-oxo 2- or 3- (aryl or heteroaryl) ethynyl 5,6,7,8-tetrahydronaphthalene compounds of Formula 13 by reaction with sodium
  • Formula 39 are reacted with an organometal derivative derived from the alkane, alkene, alkyne, or aryl or heteroaryl compound R 22 H, such that the formula of the organometal derivative is R 22 Met (Met stands for metal), preferably R 22 Li.
  • the reaction with the organometal derivative, preferably lithium derivative of the formula R 22 Li is usually conducted in an inert ether type solvent (such as tetrahydrofuran) in the presence of either (1) cuprous cyanide (cuCN) and lithium chloride (Licl), or in the presence of zinc chloride (ZnCl 2 ) and tetrakis(triphenylphosphine)-palladium(O) (Pd(PPh 3 ) 4 ).
  • the organolithium reagent R 22 Li if not commercially available, can be prepared from the compound R 22 H (or its halogen derivative R 22 -X 1 where X 1 is halogen) in an ether type solvent in accordance with known practice in the art.
  • lithium salts derived from straight and branch chained alkanes such as methyl lithium, butyllithium, t-butyllithium
  • lithium salts derived from carbocyclic aryl compounds such as phenyl lithium
  • lithium salts derived from heteroaryl compounds such as 2-thiazolyllithium, 2-furyl lithium, 2-thienyllithium, and 2-pyridyllithium.
  • dimethylformamide or without solvent, in the presence of a mild base (such as diethylamine), cuprous iodide (CuI), and bis (triphenylphosphine) palladium(II)
  • a mild base such as diethylamine, cuprous iodide (CuI), and bis (triphenylphosphine) palladium(II)
  • the reaction is typically conducted in the temperature range of ambient to 70 °C.
  • 5,6,7,8-tetrahydronaphthalene compounds of Formula 42 serve as the starting materials.
  • Compounds of Formula 42 are within the scope of Formula 1, and can be prepared in accordance with the procedures set forth for the preparation of compounds of Formula l.
  • R 22 is defined as in connection with Formula 7, and R 24 is hydrogen, or trialkylsilyl (preferably trimethylsilyl), or any other group which is suitable to form a leaving group including the R 24 O- element, in the elimination
  • the product of the elimination reaction is a compound of Formula 7.
  • the reaction is conducted under conditions which are known in the art of organic chemistry to cause formation of double bonds by elimination, for example in refluxing pyridine in the presence of excess phosphorous oxychloride (POCl 3 ), or in a neutral hydrocarbon type solvent (such as benzene) in the presence of (methoxycarbonylsulfamoyl) triethylammonium hydroxide (Burgess reagent).
  • Reaction Scheme 12 is presently preferred for the preparation of compounds of Formula 7 where the R 22 group is hydrogen, cyano (CN) and CH 2 COOEt.
  • the elimination reaction which results in compounds where R 22 is CH 2 COOEt also gives rise to isomers where the double bond is exterior to the condensed 6-membered ring. The latter compounds are within the scope of Formula 3 and are not shown in this reaction scheme.
  • Compound B was converted into the title compound (oil) using 255 ml (255 mmol) of diisobutylaluminum hydride (DIBAL-H, 1M in hexane), 85.8 g (250 mmol) of (carbethoxymethylene) triphenylphosphorane and 1.7 g of 10% Pd/C.
  • DIBAL-H diisobutylaluminum hydride
  • reaction mixture was sealed in a pressure tube and placed in a preheated oil bath (100 °C) for 24 hours.
  • the reaction mixture was then filtered through Celite, washed with Et 2 O and the filtrate concentrated in vacuo to give crude 6-2-(trimethylsilyl)ethynyl-3, 4-dihydro-4,4-dimethylnaphthalen-1(2H)-one.
  • a solution of 2-lithiothiazole was prepared by the addition of 41.2 mg (0.42 ml, 0.63 mmol) of n-butyl-lithium (1.5M solution in hexanes) to a cold solution (-78 °C) of 53.4 mg (0.63 mmol) of thiazole in 1.0 ml of THF. The solution was stirred at for 30 minutes and then a solution of 113.9 mg (0.84 mmol) of zinc chloride in 1.5 ml of THF was added.
  • Ethyl 4-[(5-acetoxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 126) Employing the same general procedure as for the preparation of ethyl 4-[(5-acetoxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 105), 90.0 mg (0.26 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoate

Abstract

Acetylenes substituted with a phenyl or heteroaryl group and with a 5,6,7,8-tetrahydronaphthyl or 7,8-dihydronaphthyl group have retinoid-like biological activity. The 5,6,7,8-tetrahydronaphthyl or 7,8-dihydronaphthyl group is substituted in the 5 position.

Description

ACETYLENES DISUBSTITUTED WITH A 5 OR 8 SUBSTITUTED
TETRAHYDRONAPHTHYL OR D1HYDRONAPHTHYL GROUP AND WITH
AN ARYL OR HETEROARYL GROUPS HAVING RETINOID-LIKE
BIOLOGICAL ACTIVITY
1. Field of the Invention
The present invention relates to novel compounds having retinoid-like activity. More specifically, the present invention relates to compounds having an acetylene portion which is substituted with a 5 or 8 substituted tetrahydronaphthyl or dihydronaphthyl and by a substituted aryl or substituted heteroaryl group having an acid function. The acid function may also be converted to an alcohol, aldehyde or ketone or
derivatives thereof, or may be reduced to -CH3.
2. Background Art
Compounds which have retinoid-like activity are well known in the art, and are described in numerous United States and other patents and in scientific publications. It is generally known and accepted in the art that retinoid-like activity is useful for treating animals of the mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous diseases and conditions. In other words, it is generally accepted in the art that pharmaceutical compositions having a retinoid-like compound or compounds as the active ingredient are useful as regulators of cell proliferation and
differentiation, and particularly as agents for
treating skin-related diseases, including, actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of
glucocorticoid damage (steroid atrophy), as a topical anti-microbial, as skin anti-pigmentation agents and to treat and reverse the effects of age and photo damage to the skin. Retinoid compounds are also useful for the prevention and treatment of cancerous and
precancerous conditions, including, premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of Kaposi's sarcoma. In addition, retinoid compounds can be used as agents to treat diseases of the eye, including, without
limitation, proliferative vitreoretinopathy (PVR), retinal detachment, dry eye and other corneopathies, as well as in the treatment and prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of post-angioplasty
restenosis and as an agent to increase the level of circulating tissue plasminogen activator (TPA). Other uses for retinoid compounds include the prevention and treatment of conditions and diseases associated with human papilloma virus (HPV), including warts and genital warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn's disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and stroke, improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis and inhibition of T- Cell activated apoptosis, restoration of hair growth, including combination therapies with the present compounds and other agents such as MinoxidilR, diseases associated with the immune system, including use of the present compounds as immunosuppressants and
immunostimulants, modulation of organ transplant rejection and facilitation of wound healing, including modulation of chelosis.
United States Patent Nos. 4,740,519 (Shroot et al.), 4,826,969 (Maignan et al.), 4,326,055 (Loeliger et al.), 5,130,335 (Chandraratna et al.), 5,037,825 (Klaus et al.), 5,231,113 (Chandraratna et al.),
5,324,840 (Chandraratna),
Published European Patent Application Nos. 0 176 034 A (Wuest et al.), 0 350 846 A (Klaus et al.), 0 176 032 A (Frickel et al.), 0 176 033 A (Frickel et al.), 0 253 302 A (Klaus et al.), 0 303 915 A (Brvce et al.), UK Patent Application GB 2190378 A (Klaus et al.), German Patent Application Nos. DE 3715955 Al (Klaus et al.), DE 3602473 A1 (Wuest et al.), and the articles J. Amer. Acad. Derm. 15: 756 - 764 (1986) (Sporn et al.), Chem. Pharm. Bull. 33: 404-407 (1985) (Shudo et al.), J. Med Chem. 1988 31, 2182 - 2192 (Kagechika et al.), Chemistry and Biology of Synthetic Retinoids CRC Press Inc. 1990 p 334 - 335, 354 (Dawson et al.), describe or relate to compounds which include a tetrahydronaphthyl moiety and have retinoid-like or related biological activity. United States Patent No. 4,391,731 (Boiler et al.) describes tetrahydronaphthalene derivatives which are useful in liquid crystal compositions.
Several co-pending applications and recently issued patents which are assigned to the assignee of the present application, are directed to further compounds having retinoid-like activity.
SUMMARY OF THE INVENTION
The present invention covers compounds of Formula
Figure imgf000006_0001
wherein X is S or O;
R1 is hydrogen or alkyl of 1 to 10 carbons;
R2 and R3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the tetrahydronaphthalene nucleus; m is an integer having the value of 0 - 3;
o is an integer having the value 0 - 4;
R4 is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C1 - C10-alkylphenyl, naphthyl, C1 - C10-alkylnaphthyl, phenyl-C1 - C10alkyl, napthyl-C1 - C10alkyl; CN, or (CH2)pCO2R8 where p is an integer between 0 to 10;
R5 is hydrogen, alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C1 - C10-alkylphenyl, naphthyl, C1 - C10-alkylnaphthyl, phenyl-C1 - C10alkyl, napthyl-C1 - C10alkyl; Si(R2)3, COR14, camphanoyl, C(R15) (R16)XR17;
Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl,
pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl,
oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R2 groups;
A is (CH2)n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds, and
B is hydrogen, COOH or a pharmaceutically
acceptable salt thereof, COOR8, CONR9R10, -CH2OH,
CH2OR1:L, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, CR7OR13O, or tri-lower alkylsilyl, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10
independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons; and further wherein R14 is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C1 - C10-alkylphenyl, naphthyl, C1 - C10-alkylnaphthyl, phenyl-C1 - C10alkyl, napthylC1 - C10alkyl; R15 and R16 are hydrogen or lower alkyl of 1 to 6 carbons, R17 is lower alkyl of 1 to 6
carbons, or R16 and R17 jointly form a ring having a total of 4 to 5 carbons and the X heteroatom;
compounds of Formula 2
Figure imgf000008_0001
wherein R1 is hydrogen or alkyl of 1 to 10
carbons;
R2 and R3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the tetrahydronaphthalene nucleus; m is an integer having the value of 0 - 3;
o is an integer having the value 0 - 4;
Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl,
pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl,
oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R2 groups;
A is (CH2)n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
B is hydrogen, COOH or a pharmaceutically
acceptable salt thereof, COOR8, CONR9R10, -CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, CR7OR13O, or tri-lower alkylsilyl, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of l to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons;
X is O or S;
R18 is alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, or the two R18 groups jointly form a ring having a total of 3 to 6 carbons, or the two XR18 groups jointly symbolize an oxo (=O) or a thio (=S) function;
compounds of Formula 3
Figure imgf000009_0001
wherein R1 is hydrogen or alkyl of 1 to 10
carbons;
R2 and R3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the tetrahydronaphthalene nucleus; m is an integer having the value of 0 - 3;
o is an integer having the value 0 - 4;
Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl,
pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl,
oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R2 groups;
A is (CH2)n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6
carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
B is hydrogen, COOH or a pharmaceutically
acceptable salt thereof, COOR8, CONR9R10, -CH2OH,
CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7 , CR7(OR12)2, CR7OR13O, or tri-lower alkylsilyl, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of l to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons, and
R19 is independently hydrogen, alkyl of l to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group
consisting of phenyl, C1 - C10-alkylphenyl, naphthyl, C1 - C10-alkylnaphthyl, phenyl-C1 - C10alkyl, naphthylC1 - C10alkyl; CN, CHO, CH(OR12)2, CHOR13O,
(CH2)pCO2R8, (CH2)pCH2OH, (CH2)pCH2OR11,
(CH2)pCH2OCOR11, where p is an integer between 0 to 10, or the two R19 groups jointly represent 3 to 6
methylene groups which together with the alkylidene carbon complete a ring;
compounds of Formula 4
Figure imgf000011_0001
Formula 4
wherein R1 is hydrogen or alkyl of 1 to 10
carbons;
R2 and R3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the tetrahydronaphthalene nucleus; m is an integer having the value of 0 - 3;
o is an integer having the value 0 - 4; Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl,
pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl,
oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R2 groups;
A is (CH2)n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6
carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
B is hydrogen, COOH or a pharmaceutically
acceptable salt thereof, COOR8, CONR9R10, -CH2OH,
CH2ORχι, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7 , CR7(OR12)2, CR7OR13O, or tri-lower alkylsilyl, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 tt 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons;
the wavy line represents a single valence bond around which the configuration can be syn or anti, and
Z is OR1 , R1 is phenyl, benzyl, lower alkyl or lower alkoxy substituted phenyl, OSi(R2)3, OCOR14, OC(R15)(R16)XR17, N(R14)2, NHCON(R14)2, NHCSN(R14)2, where X is O or S; R14 is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C1 - C10-alkylphenyl, naphthyl, C1 - C10-alkylnaphthyl, phenyl-C1 - C10alkyl, naphthylC1 - C10alkyl; R15 and R16 are hydrogen or lower alkyl of 1 to 6 carbons, R17 is lower alkyl of 1 to 6
carbons, or R16 and R17 jointly form a ring having a total of 4 to 5 carbons and the X heteroatom;
compounds of Formula 5
Figure imgf000013_0001
Formula 5
wherein R1 is hydrogen or alkyl of 1 to 10
carbons;
R2 and R3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the tetrahydronaphthalene nucleus; m is an integer having the value of 0 - 3;
o is an integer having the value 0 - 4;
Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl,
pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl,
oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R2 groups;
A is (CH2)n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6
carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
B is hydrogen, COOH or a pharmaceutically
acceptable salt thereof, COOR8, CONR9R10, -CH2OH,
CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7 , CR7(OR12)2, CR7OR13O, or tri-lower alkylsilyl, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons, and
R14 is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C1 - C10-alkylphenyl, naphthyl, C1 - C10-alkylnaphthyl, phenyl-C1 - C10alkyl, naphthyl-C1 - C10alkyl, or R14 is COR8, or the two R14 groups together with the N jointly form a 5 or 6 membered ring,
compounds of Formula 6
Figure imgf000015_0001
wherein R1 is hydrogen or alkyl of 1 to 10
carbons;
R2 and R3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the dihydronaphthalene nucleus; m is an integer having the value of 0 - 3;
o is an integer having the value 0 - 3;
Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R2 groups;
A is (CH2)n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
B is hydrogen, COOH or a pharmaceutically
acceptable salt thereof, COOR8, CONR9R10, -CH2OH,
CH-jOR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, CR7OR13O, or tri-lower alkylsilyl, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons;
X is O, S, SO or SO2 and
R20 is Si(R2)3, R14, COR14, SO2R21, where R14 is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bond, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C1 - C10-alkylphenyl, naphthyl, C1 - C10-alkylnaphthyl, phenylC1 - C10alkyl, napthyl-C1 - C10alkyl, or R20 is
hydroxyalkyl, aminoalkyl or thioalkyl having 1 to 10 carbons; and R21 is alkyl of 1 to 10 carbons,
fluoroalkyl of 1 to 10 carbons, or carbocyclic aryl selected from the group consisting of phenyl, C1 - C10-alkylphenyl and phenyl-C1 - C10alkyl, and
compounds of Formula 7
wherein R1 is hydrogen or alkyl of 1 to 10
carbons;
R2 and R3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the dihydronaphthalene nucleus; m is an integer having the value of 0 - 3;
o is an integer having the value 0 - 3;
Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl,
pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl,
oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R2 groups;
A is (CH2)n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6
carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
B is hydrogen, COOH or a pharmaceutically
acceptable salt thereof, COOR8, CONR9R10, -CH2OH,
CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, CR7OR13O, or tri-lower alkylsilyl, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons, and
R22 is hydrogen, alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C1 - C10-alkylphenyl, naphthyl, C1 - C10-alkylnaphthyl, phenyl-C1 - C10alkyl, naphthyl-C1 - C10alkyl, C1 - C10-alkenylphenyl having 1 to 3 double bonds, C1 - C10-alkynylphenyl having 1 to 3 triple bonds, phenyl-C1 - C10alkenyl having 1 to 3 double bonds, phenyl-C1 - C10alkynyl having 1 to 3 triple bonds, hydroxy alkyl of 1 to 10 carbons, hydroxyalkynyl having 2 to 10 carbons and 1 to 3 triple bonds, acyloxyalkyl of 1 to 10 carbons or acyloxyalkynyl of 2 to 10 carbons and 1 to 3 triple bonds, where the acyl group is represented by COR14, CN, CON(R1)2, (CH2)pCO2R8 where p is an integer between 0 to 10, or R22 is aminoalkyl or thioalkyl of 1 to 10 carbons, or a 5 or 6 membered heteroaryl group optionally substituted with a C1 to C10 alkyl group and having 1 to 3 heteroatoms, said heteroatoms being selected from a group consisting of O, S, and N, or R22 is represented by (CH2)pXR1 or by (CH2)pNR1R2; where X is O or S, the R14 group is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bond, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C1 - C10-alkylphenyl, naphthyl, C1 - C10-alkylnaphthyl, phenyl- C1 - C10alkyl, or naphthyl-C1 - C10alkyl.
In a second aspect, this invention relates to the use of the compounds of Formula 1 through Formula 7 for the treatment of skin-related diseases, including, without limitation, actinic keratoses, arsenic
keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage
(steroid atrophy), as a topical anti-microbial, as skin anti-pigmentation agents and to treat and reverse the effects of age and photo damage to the skin. The compounds are also useful for the prevention and treatment of cancerous and precancerous conditions, including, premalignant and malignant
hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias,
neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of Kaposi's sarcoma. In addition, the present compounds can be used as agents to treat diseases of the eye, including, without limitation, proliferative vitreoretinopathy (PVR), retinal detachment, dry eye and other corneopathies, as well as in the treatment and prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of post-angioplasty
restenosis and as an agent to increase the level of circulating tissue plasminogen activator (TPA). Other uses for the compounds of the present invention include the prevention and treatment of conditions and diseases associated with Human papilloma virus (HPV), including warts and genital warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and
Krohn's disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and stroke, improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis and
inhibition of T-Cell activated apoptosis, restoration of hair growth, including combination therapies with the present compounds and other agents such as
Minoxidil", diseases associated with the immune system, including use of the present compounds as
immunosuppressants and immunostimulants, modulation of organ transplant rejection and facilitation of wound healing, including modulation of chelosis.
This invention also relates to a pharmaceutical formulation comprising a compound of Formula l through Formula 7 in admixture with a pharmaceutically
acceptable excipient.
In another aspect, this invention relates to processes for making a compound of Formula 1 through Formula 7 which process comprises reacting a compound of Formula 8 with a compound of Formula 9, in the presence of cuprous iodide and Pd(PQ3)2Cl2 (Q is phenyl) or a similar complex, or reacting the zinc salt of the compound shown in Formula 8 with a compound of Formula 9 in the presence of Pd(PQ3)4 (Q is phenyl) or similar complex. In Formula 8 the symbol STHN
represents a tetrahydronaphthalene or
dihydronaphthalene nucleus which is appropriately substituted to provide the compounds defined in
Formulas 1 through 7, or said tetrahydronaphthalene or dihydronaphthalene nucleus is appropriately substituted to provide such precursors of compounds of the Formulas 1 through 7 from which the target compounds can be readily obtained by organic reactions well known in the art. In Formula 9 X1 is halogen, B1 is H, or a
protected acid, alcohol, aldehyde, or ketone. In effect, B' is either the desired B group of Formulas 1 through 7, or B' is a precursor from which the B group can be readily obtained by reactions well known in the art.
Figure imgf000021_0001
Still further, the present invention relates to such reactions performed on the compounds of Formula 1 through 7 which cause transformations of the A-B group or of the substituents on the tetrahydro- or
dihydronaphthalene moiety, while the reaction product still remains within the scope of Formulas 1 through 7,
General Embodiments
Definitions
The term alkyl refers to and covers any and all groups which are known as normal alkyl, branched-chain alkyl and cycloalkyl. The term alkenyl refers to and covers normal alkenyl, branch chain alkenyl and
cycloalkenyl groups having one or more sites of
unsaturation. Similarly, the term alkynyl refers to and covers normal alkynyl, and branch chain alkynyl groups having one or more triple bonds.
Lower alkyl means the above-defined broad
definition of alkyl groups having 1 to 6 carbons in case of normal lower alkyl, and as applicable 3 to 6 carbons for lower branch chained and cycloalkyl groups. Lower alkenyl is defined similarly having 2 to 6 carbons for normal lower alkenyl groups, and 3 to 6 carbons for branch chained and cyclo- lower alkenyl groups. Lower alkynyl is also defined similarly, having 2 to 6 carbons for normal lower alkynyl groups, and 4 to 6 carbons for branch chained lower alkynyl groups.
The term "ester" as used here refers to and covers any compound falling within the definition of that term as classically used in organic chemistry. It includes organic and inorganic esters. Where B (of Formula 1 through 7) is -COOH, this term covers the products derived from treatment of this function with alcohols or thiols preferably with aliphatic alcohols having 1-6 carbons. Where the ester is derived from compounds where B is -CH2OH, this term covers compounds derived from organic acids capable of forming esters including phosphorous based and sulfur based acids, or compounds of the formula -CH2OCOR11 where R11 is any substituted or unsubstituted aliphatic, aromatic, heteroaromatic or aliphatic aromatic group, preferably with 1-6 carbons in the aliphatic portions.
Unless stated otherwise in this application, preferred esters are derived from the saturated
aliphatic alcohols or acids of ten or fewer carbon atoms or the cyclic or saturated aliphatic cyclic alcohols and acids of 5 to 10 carbon atoms.
Particularly preferred aliphatic esters are those derived from lower alkyl acids and alcohols. Also preferred are the phenyl or lower alkyl phenyl esters.
Amides has the meaning classically accorded that term in organic chemistry. In this instance it
includes the unsubstituted amides and all aliphatic and aromatic mono- and di- substituted amides. Unless stated otherwise in this application, preferred amides are the mono- and di-substituted amides derived from the saturated aliphatic radicals of ten or fewer carbon atoms or the cyclic or saturated aliphatic-cyclic radicals of 5 to 10 carbon atoms. Particularly
preferred amides are those derived from substituted and unsubstituted lower alkyl amines. Also preferred are mono- and disubstituted amides derived from the
substituted and unsubstituted phenyl or lower
alkylphenyl amines. Unsubstituted amides are also preferred.
Acetals and ketals include the radicals of the formula-CK where K is (-OR)2. Here, R is lower alkyl. Also, K may be -OR7O- where R7 is lower alkyl of 2-5 carbon atoms, straight chain or branched.
A pharmaceutically acceptable salt may be prepared for any compounds in this invention having a
functionality capable of forming a salt, for example an acid functionality. A pharmaceutically acceptable salt is any salt which retains the activity of the parent compound and does not impart any deleterious or
untoward effect on the subject to which it is
administered and in the context in which it is
administered.
Pharmaceutically acceptable salts may be derived from organic or inorganic bases. The salt may be a mono or polyvalent ion. Of particular interest are the inorganic ions, sodium, potassium, calcium, and
magnesium. Organic salts may be made with amines, particularly ammonium salts such as mono-, di- and trialkyl amines or ethanol amines. Salts may also be formed with caffeine, tromethamine and similar
molecules. Where there is a nitrogen sufficiently basic as to be capable of forming acid addition salts, such may be formed with any inorganic or organic acids or alkylating agent such as methyl iodide. Preferred salts are those formed with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid. Any of a number of simple organic acids such as mono-, di- or tri- acid may also be used.
Some of the compounds of the present invention may have trans and cis (E and Z) isomers. In addition, the compounds of the present invention may contain one or more chiral centers and therefore may exist in
enantiomeric and diastereomeric forms. Still further oxime and related compounds of the present invention may exist in syn and anti isomeric forms. The scope of the present invention is intended to cover all such isomers per se, as well as mixtures of cis and trans isomers, mixtures of syn and anti isomers, mixtures of diastereomers and racemic mixtures of enantiomers
(optical isomers) as well. In the present application when no specific mention is made of the configuration (cis, trans syn or anti or R or S) of a compound (or of an asymmetric carbon) then a mixture of such isomers, or either one of the isomers is intended. In a similar vein, when in the chemical structural formulas of this application a straight line representing a valence bond is drawn to an asymmetric carbon, then isomers of both R and S configuration, as well as their mixtures are intended. Defined stereochemistry about an asymmetric carbon is indicated in the formulas (where applicable) by a solid triangle showing β configuration, or by a hashed line showing a configuration.
Referring now to the nomenclature used in naming the compounds of the invention and intermediate
compounds leading thereto, two different systems for numbering the tetrahydronaphthalene ring are demonstrated as shown by the structural formulas of Compounds F, G and 1. Compound 1 is an exemplary compound of the invention and Compounds F and G are two exemplary intermediates utilized in the synthesis of the compounds of the invention. The numbering systems illustrated here will not only be readily apparent to those skilled in the art, but. will be readily
understood as it is applied in the ensuing description of the compounds of the invention and of intermediates utilized for obtaining the compounds of the invention.
Figure imgf000025_0001
With reference to the symbol Y in Formulas 1 through 7, the preferred compounds of the invention are those where Y is phenyl, pyridyl, thienyl or furyl. Even more preferred are compounds where Y is phenyl or pyridyl. As far as substititutions on the Y (phenyl) and Y (pyridyl) groups are concerned, compounds are preferred where the phenyl group is 1,4 (para)
substituted, and where the pyridine ring is 2,5
substituted. (Substitution in the 2,5 positions in the "pyridine" nomenclature corresponds to substitution in the 6-position in the "nicotinic acid" nomenclature.) In the preferred compounds of the invention there is no optional R2 substituent on the Y group.
The A-B group of the preferred compounds is
(CH2)n-COOH or (CH2)n-COOR8, where R8 is defined as above. Even more preferably n is zero and R8 is lower alkyl.
Referring still to the preferred compounds of Formulas 1 through 7, the aromatic portion of the tetrahydronaphthalene or dihydronaphthalene moiety is preferably substituted only by the acetylene function. In other words, in the preferred compounds there is no R2 substituent (other than hydrogen). Similarly, in the preferred compounds of the invention there is no R3 substituent (other than hydrogen). The R1 substituent of the compounds of the invention is preferably lower alkyl, and even more preferably methyl.
Referring now specifically to compounds in
accordance with Formula 1, the R4 substituent is preferably hydrogen, CN or CH2COOR8 where R8 is
preferably methyl or ethyl. The R5 substituent is preferably hydrogen, alkyl, cycloalkyl, of the
structure Si(R2)3, COR14, and C(R15)(R16)XR17 (as these are defined in connection with Formula 1). Even more preferably R5 is hydrogen, cyclohexyl, trimethylsilyl, -CH2OCH3 (methoxymethyl), 2'-tetrahydropyranyl, acetyl, benzoyl or camphanoyl. Specific preferred compounds in accordance with Formula 1 and their synthesis are described below in the section of this application titled "Specific Examples". The presently roost
preferred compounds of the invention in accordance with Formula 1 are indicated in Table 1 below, with
reference to Formula 1A.
Figure imgf000027_0001
Figure imgf000027_0002
Figure imgf000028_0001
Referring now specifically to compounds in accordance with Formula 2, the two X-R18 symbols preferably jointly represent an oxo (=O) function. Alternatively, in the preferred compounds of the invention in accordance with Formula 2, X is sulphur and R18 is an alkyl group; even more preferably X is sulphur and the two R18 groups jointly represent methylene groups which together with the two sulphur atoms and the C5 carbon of the tetrahydronaphthalene nucleus form a 6 membered ring. Specific preferred compounds in accordance with Formula 2 and their synthesis are described below in the section of this application titled "Specific Examples". The
presently most preferred compounds of the invention in accordance with Formula 2 are indicated in Table 2 below, with reference to Formula 2A.
Figure imgf000029_0001
Figure imgf000030_0001
Referring now specifically to compounds in
accordance with Formula 3, the R19 groups preferably are hydrogen, alkyl of 1 to 10 carbons, cyano (CN) or COOR8. Even more preferably the R19 groups are H, CN, COOEt or lower alkyl. Alternatively, in the preferred compounds of the invention in accordance with Formula 3 the two R19 groups jointly form a -(CH2)q- radical, (q is an integer having the values of 3 to 7) whereby a cycloalkyl ring is formed, most preferably a
cyclohexyl ring. Specific preferred compounds in accordance with Formula 3 and their synthesis are described below in the section of this application titled "Specific Examples". The presently most
preferred compounds of the invention in accordance with Formula 3 are indicated in Table 3 below, with
reference to Formula 3A.
Figure imgf000031_0001
Figure imgf000031_0002
Referring now specifically to compounds in accordance with Formula 4, the Z group preferably represents OR1, where the R1 group is preferably hydrogen or lower alkyl. Alternatively, Z is
preferably 2-tetrahydropyranyloxy. Specific preferred compounds in accordance with Formula 4 and their synthesis are described below in the section of this application titled "Specific Examples". The
presently most preferred compounds of the invention in accordance with Formula 4 are indicated in Table 4 below, with reference to Formula 4A.
Figure imgf000032_0001
Figure imgf000032_0002
Figure imgf000033_0003
Referring now specifically to compounds in
accordance with Formula 5, in the preferred compounds of the invention corresponding to this formula the R14 groups are hydrogen or lower alkyl, even more
preferably hydrogen. The presently most preferred compounds of the invention in accordance with Formula 5 are indicated in Table 5 below, with reference to
Formula 5A, and the synthesis of these compounds is described in the Specific Examples.
Figure imgf000033_0001
Figure imgf000033_0002
Referring now specifically to compounds in
accordance with Formula 6, in the preferred compounds of the invention which correspond to this formula the R20 group is preferably R14, COR14, SO2R21 or Si(R2')3 where R14 is preferably phenyl, benzyl or lower alkyl, even more preferably ethyl, R21 is preferably
fluorinated lower alkyl, even more preferably CF3, and R2, is preferably lower alkyl, even more preferably methyl. Specific preferred compounds in accordance with Formula 6 and their synthesis are described below in the section of this application titled "Specific Examples". The presently most preferred compounds of the invention in accordance with Formula 6 are
indicated in Table 6 below, with reference to Formula 6A.
Figure imgf000034_0001
Figure imgf000035_0001
Referring now specifically to compounds in
accordance with Formula 7, in the preferred compounds of the invention in accordance with this formula R22 is preferably hydrogen, alkyl of 1 - 10 carbons, alkynyl of 2 to 10 carbons having 1 triple bond, alkylphenyl having 1 to 10 carbons in the alkyl group, phenylalkyl having 1 to 10 carbons in the alkyl group,
phenylalkynyl having 2 to 10 carbons in the alkynyl group, CH2CO2R8, hydroxyalkyl having 1 to 10 carbons in the alkyl group, hydroxyalkynyl having 2 to 10 carbons in the alkynyl group, cyano (CN), CONH2 or heteroaryl. Among the heteroaryl groups 5 or 6 membered rings having 1 or 2 heteroatoms are particularly preferred. Compounds where the R22 group is 2-thiazolyl, 2-furyl, 2-thienyl or 2-pyridyl are especially preferred.
Specific preferred compounds in accordance with Formula 7 and their synthesis are described below in the section of this application titled "Specific Examples". The presently most preferred compounds of the invention in accordance with Formula 7 are indicated in Table 7 below, with reference to Formula 7A.
Figure imgf000036_0001
Figure imgf000036_0002
Figure imgf000037_0001
Modes of Adm n strat on
The compounds of this invention may be
administered systemically or topically, depending on such considerations as the condition to be treated, need for site-specific treatment, quantity of drug to be administered, and numerous other considerations.
In the treatment of dermatoses, it will generally be preferred to administer the drug topically, though in certain cases such as treatment of severe cystic acne or psoriasis, oral administration may also be used. Any common topical formulation such as a
solution, suspension, gel, ointment, or salve and the like may be used. Preparation of such topical
formulations are well described in the art of
pharmaceutical formulations as exemplified, for
example. Remington's Pharmaceutical Science, Edition 17, Mack Publishing Company, Easton, Pennsylvania. For topical application, these compounds could also be administered as a powder or spray, particularly in aerosol form. If the drug is to be administered systemically, it may be confected as a powder, pill, tablet or the like or as a syrup or elixir suitable for oral administration. For intravenous or
intraperitoneal administration, the compound will be prepared as a solution or suspension capable of being administered by injection. In certain cases, it may be useful to formulate these compounds by injection. In certain cases, it may be useful to formulate these compounds in suppository form or as extended release formulation for deposit under the skin or intramuscular injection.
Other medicaments can be added to such topical formulation for such secondary purposes as treating skin dryness; providing protection against light; other medications for treating dermatoses; medicaments for preventing infection, reducing irritation, inflammation and the like.
Treatment of dermatoses or any other indications known or discovered to be susceptible to treatment by retinoic acid-like compounds will be effected by administration of the therapeutically effective dose of one or more compounds of the instant invention. A therapeutic concentration will be that concentration which effects reduction of the particular condition, or retards it expansion. In certain instances, the compound potentially may be used in prophylactic manner to prevent onset of a particular condition.
A useful therapeutic or prophylactic concentration will vary from condition to condition and in certain instances may vary with the severity of the condition being treated and the patient's susceptibility to treatment. Accordingly, no single concentration will be uniformly useful, but will require modification depending on the particularities of the disease being treated. Such concentrations can be arrived at through routine experimentation. However, it is anticipated that in the treatment of, for example, acne, or similar dermatoses, that a formulation containing between 0.01 and 1.0 milligrams per milliliter of formulation will constitute a therapeutically effective concentration for total application. If administered systemically, an amount between 0.01 and 5 mg per kg per day of body weight would be expected to effect a therapeutic result in the treatment of many diseases for which these compounds are useful.
Assay of Retinoid-like Biological Activity
The retinoic acid-like activity of these compounds is confirmed through the classic measure of retinoic acid activity involving the effects of retinoic acid on ornithine decarboxylase. The original work on the correlation between retinoic acid and decrease in cell proliferation was done by Verma & Boutwell, Cancer Research, 1977, 37,2196-2201. That reference discloses that ornithine decarboxylase (ODC) activity increased precedent to polyamine biosynthesis. It has been established elsewhere that increases in polyamine synthesis can be correlated or associated with cellular proliferation. Thus, if ODC activity could be
inhibited, cell hyperproliferation could be modulated. Although all cases for ODC activity increases are unknown, it is known that 12-0-tetradecanoylphorbol-13-acetate (TPA) induces ODC activity. Retinoic acid inhibits this induction of ODC activity by TPA. An assay essentially following the procedure set out in Cancer Research: 1662-1670,1975 may be used to
demonstrate inhibition of TPA induction of ODC by compounds of this invention. Activity of exemplary compounds of the present invention in the above-described ODC assay is disclosed in Table 8 which provides the IC80 concentration for the respective exemplary compound. ("IC 80 is that concentration of the test compound which causes 80% inhibition in the
ODC assay. By analogy, "IC60, for example, is that concentration of the test compound which causes 60% inhibition in the ODC assay.)
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0002
SPECIFIC EMBODIMENTS
The compounds of this invention can be made by the synthetic chemical pathways illustrated here. The synthetic chemist will readily appreciate that the conditions set out here are specific embodiments which can be generalized to any and all of the compounds represented by Formulas 1 through 7.
Figure imgf000042_0001
Figure imgf000043_0001
Referring now to Reaction Scheme 1 a synthetic route leading to the compounds of Formula 1 and of Formula 2 is illustrated. In accordance with this scheme, a 6- or 7-bromo substituted 3,4-dihydronaphthalen-1(2H)-one (numbering as shown for Compound G) of Formula 10 is the starting material. The
compounds of Formula 10 already carry the desired R1 , R2 and R3 substituents, as these are defined above in connection with Formula 1. The compounds of Formula 10 are reacted with (trimethylsilyl) acetylene to provide the 6- or 7-trimethylsilylethynyl- substituted 3,4-dihydro-naphthalen-1(2H)-one compounds of Formula 11. The reaction with (trimethylsilyl) acetylene is
typically conducted under heat (approximately 100° C) in the presence of cuprous iodide, a suitable catalyst, typically having the formula Pd(PPh3)2Cl2, an acid acceptor (such as triethylamine) under an inert gas (argon) atmosphere. Typical reaction time is
approximately 24 hours. The 6- or 7-(trimethylsilyl)ethynyl- substituted 3,4-dihydronaphthalen-1(2H)-one compounds of Formula 11 are then reacted with base (potassium hydroxide or
potassium carbonate) in an alcoholic solvent, such as methanol, to provide the 6- or 7-ethynyl substituted 3,4-dihydro-1-naphthalen-1(2H) ones of Formula 12.
Compounds of Formula 12 are then coupled with the aromatic or heteroaromatic reagent X1-Y(R2)-A-B'
(Formula 9) in the presence of cuprous iodide, a suitable catalyst, typically Pd(PPh3)2Cl2, an acid acceptor, such as triethylamine, under inert gas
(argon) atmosphere. Alternatively, a zinc salt (or other suitable metal salt) of the compounds of Formula 12 can be coupled with the reagents of Formula 9 in the presence of Pd(PPh3)4 or similar complex. Typically, the coupling reaction with the reagent X1-Y(R2)-A-B' (Formula 9) is conducted at room or moderately elevated temperature. Generally speaking, coupling between an ethynylaryl derivative or its zinc salt and a halogen substituted aryl or heteroaryl compound, such as the reagent of Formula 9, is described in United States Patent No. 5,264,456, the specification of which is expressly incorporated herein by reference. The
compounds of Formula 13 are compounds of the invention within the scope of Formula 2, or a derivative thereof protected in the B' group, from which the protecting group can be readily removed by reactions well known in the art. The compounds of Formula 13 can also be converted into ketals or thioketals, within the scope of Formula 2, by reactions generally well known in the art. The compounds of Formula 13 can also be converted into further compounds of the invention by such
reactions and transformations which are well known in the art. Such reactions are indicated in Reaction Scheme 1 by conversion into "homologs and derivatives". One such conversion employed for the synthesis of several exemplary compounds of this invention is saponification of an ester group (when B or B' is an ester) to provide the free carboxylic acid or its salt.
The halogen substitituted aryl or heteroaryl compounds of Formula 9 can, generally speaking, be obtained by reactions well known in the art. An example of such compound is ethyl 4-iodobenzoate which is obtainable, for example, by esterification of 4-iodobenzoic acid. Another example is ethyl 6-iodonicotinate which can be obtained by conducting a halogen exchange reaction on 6-chloronicotinic acid, followed by esterification. Even more generally speaking, regarding derivatization of compounds of Formula 13 and/or the synthesis of aryl and heteroaryl compounds of Formula 9 which can thereafter be reacted with compounds of Formula 12 to yield compounds of the invention, the following well known and published general principles and synthetic methodology can be employed.
Carboxylic acids are typically esterified by refluxing the acid in a solution of the appropriate alcohol in the presence of an acid catalyst such as hydrogen chloride or thionyl chloride. Alternatively, the carboxylic acid can be condensed with the
appropriate alcohol in the presence of
dicyclohexylcarbodiimide and dimethylaminopyridine.
The ester is recovered and purified by conventional means. Acetals and ketals are readily made by the method described in March, "Advanced Organic
Chemistry," 2nd Edition, McGraw-Hill Book Company, p 810). Alcohols, aldehydes and ketones all may be protected by forming respectively, ethers and esters, acetals or ketals by known methods such as those described in McOmie, Plenum Publishing Press, 1973 and Protecting Groups, Ed. Greene, John Wiley & Sons, 1981.
To increase the value of n in the compounds of Formula 9 before affecting the coupling reaction of Reaction Scheme 1 (where such compounds corresponding to Formula 9 are not available from a commercial source) aromatic or heteroaromatic carboxylic acids are subjected to homologation by successive treatment under Arndt-Eistert conditions or other homologation
procedures. Alternatively, derivatives which are not carboxylic acids may also be homologated by appropriate procedures. The homologated acids can then be
esterified by the general procedure outlined in the preceding paragraph.
Compounds of Formula 9, (or of the invention as set forth in Formulas 1 through 7, as applicable) where A is an alkenyl group having one or more double bonds can be made for example, by synthetic schemes well known to the practicing organic chemist; for example by Wittig and like reactions, or by introduction of a double bond by elimination of halogen from an alpha-halo-arylalkyl-carboxylic acid, ester or like carboxaldehyde. Compounds of Formula 9 (or of the invention as set forth in Formulas 1 through 7, as applicable) where the A group has a triple (acetylenic) bond can be made by reaction of a corresponding aromatic methyl ketone with strong base, such as lithium diisopropyl amide, reaction with diethyl chlorophosphate and subsequent addition of lithium diisopropylamide.
The acids and salts derived from compounds of Formula 13 (or other compounds of the invention as set forth in Formulas 1 through 7, as applicable) are readily obtainable from the corresponding esters.
Basic saponification with an alkali metal base will provide the acid. For example, an ester of Formula 13 (or other compounds of the invention as set forth in Formulas 1 through 7, as applicable) may be dissolved in a polar solvent such as an alkanol, preferably under an inert atmosphere at room temperature, with about a three molar excess of base, for example, lithium hydroxide or potassium hydroxide. The solution is stirred for an extended period of time, between 15 and 20 hours, cooled, acidified and the hydrolysate
recovered by conventional means. The amide may be formed by any appropriate
amidation means known in the art from the corresponding esters or carboxylic acids. One way to prepare such compounds is to convert an acid to an acid chloride and then treat that compound with ammonium hydroxide or an appropriate amine. For example, the ester is treated with an alcoholic base solution such as ethanolic KOH (in approximately a 10% molar excess) at room
temperature for about 30 minutes. The solvent is removed and the residue taken up in an organic solvent such as diethyl ether, treated with a dialkyl formamide and then a 10-fold excess of oxalyl chloride. This is all effected at a moderately reduced temperature between about -10 degrees and +10 degrees C. The last mentioned solution is then stirred at the reduced temperature for 1-4 hours, preferably 2 hours. Solvent removal provides a residue which is taken up in an inert organic solvent such as benzene, cooled to about 0 degrees C and treated with concentrated ammonium hydroxide. The resulting mixture is stirred at a reduced temperature for 1 - 4 hours. The product is recovered by conventional means.
Alcohols are made by converting the corresponding acids to the acid chloride with thionyl chloride or other means (J. March, "Advanced Organic Chemistry", 2nd Edition, McGraw-Hill Book Company), then reducing the acid chloride with sodium borohydride (March, Ibid, pg. 1124), which gives the corresponding alcohols.
Alternatively, esters may be reduced with lithium aluminum hydride at reduced temperatures. Alkylating these alcohols with appropriate alkyl halides under Williamson reaction conditions (March, Ibid, pg. 357) gives the corresponding ethers. These alcohols can be converted to esters by reacting them with appropriate acids in the presence of acid catalysts or dicyclohexylcarbodiimide and dimethylaminopyridine.
Aldehydes can be prepared from the corresponding primary alcohols using mild oxidizing agents such as pyridinium dichromate in methylene chloride (Corey, E. J., Schmidt, G., Tet. Lett.. 399, 1979). or dimethyl sulfoxide/oxalyl chloride in methylene chloride (Omura, K., Swern, D., Tetrahedron. 1978. 34, 1651).
Ketones can be prepared from an appropriate aldehyde by treating the aldehyde with an alkyl
Grignard reagent or similar reagent followed by
oxidation.
Acetals or ketals can be prepared from the
corresponding aldehyde or ketone by the method
described in March, Ibid, p 810.
Compounds of Formula 9 (or of the invention as set forth in Formulas 1 through 7, as applicable) where B is H can be prepared from the corresponding
halogenated aromatic or heteroaromatic compounds, preferably where the halogen is I.
Referring still to Reaction Scheme 1, the 7,8-dihydro-naphthalen-5(6H)-one derivatives of Formula 13 (numbering as exemplified above for Compound 1) are reduced with a mild reducing agent such as sodium borohydride, to yield the corresponding 5-hydroxy-5,6,7,8-tetrahydronaphthalene derivatives of Formula 14. The 5-hydroxy function of the compounds of Formula 14 is then acylated with a suitable acylating agent (such as a carboxylic acid chloride or anhydride), or converted into an ether with a suitable reagent (such as an alkyl bromide under basic conditions, or
dihydropyran under acidic conditions) or converted into a trialkylsilyl ether (with trialkylsilyl chloride or other "silylating" agent) to provide compounds of
Formula 15. The compounds of Formula 15 are compounds of the invention (or protected derivatives thereof) within the scope of Formula 1. The compounds of
Formula 15 can be "deprotected" or otherwise converted into further compounds of the invention by reactions well known in the art, as described above.
Describing still the reactions outlined in
Reaction Scheme 1, the compounds of Formula 13 can also be reacted with a Reformatsky reagent derived from an a halocarboxylic acid ester (such as ethyl bromoacetate), or with a Grignard reagent, optionally followed by acylation or ether formation on the resulting tertiary hydroxyl group on the 5-position of the tetrahydronaphthalene nucleus, to yield compounds of Formula 16.
Alternatively, the compounds of Formula 13 are reacted with cyanotrimethylsilane in the presence of boron trifluoroetherate to yield compounds in accordance with Formula 16. The compounds of Formula 16 are compounds of the invention within the scope of Formula 1, (or protected derivatives thereof) and can be converted into further homologs and derivatives within the scope of the invention.
Figure imgf000051_0001
Reaction Scheme 2 illustrates another synthetic route to the compounds of the invention in accordance with Formula 1. 6- or 7-Bromo substituted 1,2,3,4-tetrahydro naphthalene derivatives of Formula 17
(numbering as exemplified for Compound F) are reacted with trimethylsilylacetylene as described above in connection with Reaction Scheme 1 (cuprous iodide, Pd(PPh3)2Cl2, catalyst and triethylamine under inert atmosphere) and thereafter with base (potassium
hydroxide or potassium carbonate in an alcoholic solvent, such as methanol) to provide the 6- or 7-ethynyl 1,2,3,4-tetrahydronaphthalene derivatives of Formula 18. Compounds of Formula 18 are coupled with the aromatic or heteroaromatic reagent X1-Y(R2)-A-B' (Formula 9) in the presence of cuprous iodide, a suitable catalyst, typically Pd(PPh3)2Cl2, an acid acceptor, such as diethylamine, under inert gas (argon) atmosphere, to yield compounds of Formula 19.
Alternatively, as is described in connection with the analogous coupling reaction of Reaction Scheme 1, the zinc salts of the compounds of Formula 18 can also be coupled with the reagents of Formula 9, in the presence of Pd(PPh3)4 or similar complex. Compounds of Formula 19 are then reacted with a suitable brominating agent (such as N-bromosuccinimide (NBS) and benzoyl peroxide in carbontetrachloride) to yield the corresponding 5-bromo-5,6,7,8-tetrahydronaphthalene derivatives of Formula 20. (numbering as shown for Compound 1) The 5-bromo substituent of the compounds of Formula 20 can be subjected to nucleophilic substitution reactions with nucleophilic reagents having the formula R5XH, in the presence of base. The R5 and X groups are defined as in connection with Formula 1, typically R5XH is the salt of a thiocarboxylic acid (such as potassium thioacetate) or the sodium derivative of an alcohol or thiol. The product of the latter nucleophilic
displacement reaction is a compound in accordance with Formula 21, which is within the scope of Formula 1.
The compounds of Formula 21 can be converted into further homologs and derivatives, as is described above in connection with compounds of Formulas 13, 15 and 16.
Figure imgf000053_0001
Figure imgf000054_0001
Reaction Scheme 3 discloses still another
synthetic route to the compounds of the invention within the scope of Formula 1. In accordance with this scheme, a 6- or 7-bromo-1,2,3,4-tetrahydronaphthalene derivative of Formula 17 (numbering as shown for
Compound F) is brominated with a suitable brominating agent (such as N.-bromosuccinimide (NBS) and benzoyl peroxide in carbontetrachloride) to yield the
corresponding 4- and 6- or 7- dibromo-1,2,3,4-tetrahydronaphthalene derivatives of Formula 22. The dibromo compounds of Formula 22 are then reacted with a nucleophilic reagent having the formula R5XH, in the presence of base. The R5 and X groups are defined as in connection with Formula 1; typically R5XH is the salt of a thiocarboxylic acid (such as potassium thioacetate) or the sodium derivative of an alcohol (such as the sodium salt of cyclohexanol), or thiol. The product of the latter reaction is a 6- or 7-bromo tetrahydronaphthalene derivative of Formula 23 which has the desired R5X substituent in the 4-position. The 6- or 7- bromo compound of Formula 23 is then reacted with trimethylsilylacetylene, followed by base (such as potassium carbonate) to yield the 6- or 7-ethynyl-1,2,3,4-tetrahydronaphthalene derivatives of Formula 24. The latter two reactions involving introduction of the ethynyl group into the 6 or 7 position of the tetrahydronaphthalene nucleus are conducted under conditions substantially similar to the analogous reactions described above in connection with Reaction Schemes 1 and 2. The ethynyl compounds of Formula 24 are then coupled with the reagent X1-Y(R2)-A-B'
(Formula 9) under conditions which are described above for the analogous reactions of Reaction Schemes l and 2, to provide compounds of Formula 21. The compounds of Formula 21 are within the scope of Formula 1 or are such protected derivatives thereof which can be readily converted into compounds of the invention by chemical reactions well known in the art. These and similar reactions of the compounds of Formula 21 within the state of the art, are symbolized in Reaction Scheme 3 by conversion into "homologs and derivatives".
With reference to the coupling reactions of the reagent X1-Y(R2)-A-B' (Formula 9) shown in the
foregoing three reaction schemes, it is noted that, generally speaking, this coupling reaction can be conducted with 6- or 7- substituted ethynyl compounds which either already have a substituent desired for the present invention in the 4- position (as in Reaction Scheme 3) or have a precursor suitable for introduction of such desired substituent (as in Reaction Schemes 1 and 2).
Figure imgf000057_0001
In the preferred compounds of the invention the two R1 substituents are methyl, and the R2 and R3 substituents are hydrogen. Reaction Scheme 4
illustrates a synthetic process for preparing 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1-one (Compound G) which serves as a starting material for the synthesis of several preferred compounds of the invention. Thus, referring now specifically to Reaction Scheme 4, ethyl 3-bromophenylacetate (Compound B, made by
esterification of 3-bromophenylacetic acid) is reduced with diisobutylaluminum hydride (DIBAL H) to yield (3-bromophenyl)acetaldehyde. (3-Bromophenyl)acetaldehyde is reacted in a Wittig reaction with
(carbethoxymethylene)triphenylphosphorane to provide a mixture of E and Z. ethyl 4-(3-bromophenyl)but-2-enoates. The latter compounds are hydrogenated to yield ethyl 4-(3-bromophenyl)butanoate (Compound D). Compound D is reacted with the Grignard reagent derived from methylbromide to give the tertiary alcohol 5-(3-bromophenyl)-2-methylpentan-2-ol (Compound E) (It should be apparent to those skilled in the art, that the choice of the Grignard reagent used in this
reaction step determines the nature of the R1
substituent in the resulting compounds of the
invention.) Compound E is then treated with acid to cyclize it and to form 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F). Compound F is in the scope of Formula 17, and in accordance with Reaction Schemes 2 and 3 serves as the starting material in the synthesis of several preferred compounds of the
invention. Compound F is oxidized with chromium
trioxide to yield 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G). Compound G is covered by Formula 10 and in accordance with
Reaction Scheme 1 serves as a starting material in the synthesis of several preferred compounds of the
invention.
6-Bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H) is isomeric with Compound G, and can be obtained, starting with ethyl (4-bromophenyl) acetate, in accordance with the sequence of reactions illustrated in Reaction scheme 4 for
Compound G.
6-Bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H) can also be obtained in accordance with the published literature procedure: Mathur et al.
Tetrahedron, 41, 1509-1516 (1985). Compound H is also covered by Formula 10 and in accordance with Reaction Scheme 1 serves as a starting material in the synthesis of several preferred compounds of the invention.
Starting materials for the synthetic routes outlined in Reaction Schemes 1-3 where the R2 and/or R3 groups are other than hydrogen, can be obtained
similarly to the synthesis of the starting materials demonstrated in Reaction Scheme 4 , and/or by
introducing the R2 by a Friedel-Crafts or like reaction into the aromatic portion of the tetrahydronaphthalene nucleus.
Synthesis of Compounds of Formula 3
Figure imgf000060_0001
Compounds of Formula 3 can be synthesized in accordance with the synthetic steps illustrated in Reaction Schemes 5, 6 and 7. Referring first to
Reaction Scheme 5, the 1-oxo 6- or 7-bromo 1,2,3,4-tetrahydronaphthalene derivative (numbering as
exemplified for Compound G) of Formula 10 is reacted with a ketone or aldehyde compound of Formula 25 wherein the R19 groups are defined as in connection with Formula 3. The reaction (McMurry coupling) is conducted at elevated temperature in the presence of lithium metal and titanium trichloride, in an inert ether type solvent, for example in refluxing 1,2-dimethoxyethane (DME). The resulting compounds of Formula 26 are then reacted with
trimethylsilylacetylene as described above in
connection with Reaction Scheme 1 (cuprous iodide, Pd(PPh3)2Cl2, catalyst and triethylamine under inert atmosphere) and thereafter with base (potassium
hydroxide or potassium carbonate in an alcoholic solvent, such as methanol) to provide the 6- or 7-ethynyl 1,2,3,4-tetrahydronaphthalene derivatives of Formula 27 which have the R19R19C= group attached to the tetrahydronaphthalene nucleus. Compounds of
Formula 27 are then coupled with the aromatic or heteroaromatic reagent X1-Y(R2)-A-B« (Formula 9) in the presence of cuprous iodide, a suitable catalyst, typically Pd(PPh3)2Cl2, an acid acceptor, such as diethylamine, under inert gas (argon) atmosphere, as described above in connection with Reaction Scheme 1, to yield compounds of Formula 28. Alternatively, as is also described in connection with the analogous
coupling reaction of Scheme 1, the zinc salts of the compounds of Formula 27 are coupled with the reagents of Formula 9, in the presence of Pd(PPh3)4 or similar complex. Compounds of Formula 28 are within the scope of Formula 3. They can be converted to further homologs and derivatives which are still within the scope of the invention, as is described above in connection with compounds of Formulas 13, 15 and 16.
Figure imgf000062_0001
Referring now to Reaction Scheme 6, synthesis of those compounds of Formula 3 is illustrated where one of the R19 groups represents hydrogen and the other is cyano (CN). These compounds are obtained by reacting a 5-oxo 2- or 3- (aryl or heteroaryl) ethynyl 5,6,7,8-tetrahydronaphthalene compound of Formula 13 (numbering as exemplified for Compound 1) with diethyl cyanomethylphosphonate and potassium bis (trimethylsilyl) amide in an inert ether type solvent, such as tetrahydrofuran. The resulting compounds of Formula 29 can be converted into further homologs and derivatives, as described above. Also, the cyano derivative (Formula 29) can be converted into the corresponding aldehyde by reduction with diisobutylaluminum hydride.
Figure imgf000063_0001
Reaction Scheme 7 illustrates synthesis of those compounds of Formula 3 wherein one of the R19 groups is hydrogen and the other is a carboxylic acid ester (or derivative thereof). The starting compounds for these syntheses are compounds of Formula 30, which are within the scope of Formula 1 and can be obtained in
accordance with the synthetic procedures leading to compounds of Formula 1. Dehydration (elimination of the hydroxy group) of compounds of Formula 30 with a suitable reagent such as
(methoxycarbonylsulfamoyl) triethylammonium hydroxide (Burgess reagent) by heating moderately (50 °C) in an inert solvent, such as benzene, provides compounds of Formula 31 and also compounds isomeric therewith where the newly formed double bond is within the ring. The latter isomeric compounds are not shown in Reaction Scheme 7. The mixtures of these isomers are separated by chromatography or other conventional methods known in the art, to yield the compounds of Formula 31. The compounds of Formula 31 are within the scope of Formula 3, and can also be converted into further homologs and derivatives still within the scope of the invention.
Figure imgf000065_0001
Compounds of Formula 4 are synthesized from the 5-oxo-2- or 3- (aryl or heteroaryl) ethynyl 5,6,7,8-tetrahydronaphthalene compounds of Formula 13 (numbering as exemplified for Compound 1) as is illustrated in Reaction Scheme 8. Thus, the 5-oxo compounds of
Formula 13 are reacted with a reagent of the formula H2N-Z (Formula 32), where Z is defined as in connection with Formula 4 , to yield compounds of Formula 4. Those skilled in the art will recognize that when the reagent H2N-Z is NH2OH or its salt, then the reaction is the formation of an oxime. These oximes are readily formed by reacting the compounds of Formula 13 with
hydroxylamine hydrochloride in a polar solvent, such as a lower alkanol, in the presence of a buffering agent, such as sodium acetate. The reaction can be conducted under similar conditions with a reagent of the formula NH2OR1 or its salt (such as methoxylamine hydrochloride or ethoxylamine hydrochloride) to yield compounds of Formula 4 where Z is OR1 (R1 is defined as in
connection with Formula 4). When the reagent H2N-Z is a primary amine (Z is R1, phenyl or benzyl) then the reaction between the compounds of Formula 13 and the primary amine is the formation of an imine. The latter reaction is usually conducted in a polar (alcoholic) solvent. Further reagents, in accordance with Formula 32 are those where Z is NHCON(R14)2 (formation of semicarbazone), NHCSN(R14)2 (formation of
thiosemicarbazone) and N(R14)2 (formation of a
hydrazone). (The symbol R14 is defined as in
connection with Formula 4.) The semicarbazones, thiosemicarbazones and hydrazones corresponding to Formula 4 can be prepared under conditions which are well known in the art for the formation of such derivatives of ketone compounds. Usually these
conditions are similar to the conditions leading to the oximes of compounds of Formula 13. Typically, the hydrochloride salt of of the reagent (semicarbazide, thiosemicarbazide or hydrazide) is reacted with the compound of Formula 13 in an alcoholic solvent, in the presence of sodium acetate.
Referring still to Reaction Scheme 8 synthesis of O-(2-tetrahydropyranyl) oxime derivatives of the
structure shown by Formula 34 is illustrated. To obtain these compounds, an oxime derivative of the Formula 33 is first prepared in accordance with the reaction described above. The oxime derivative of Formula 33 is thereafter reacted with 3,4-dihydro-2H-pyran (DHP) in an inert solvent (such as
dichloromethane) in the presence of acid, typically pyridinium p-tolunesulfonate (PPTS). This reaction is typically conducted in the cold, or at ambient
temperature. The resulting product of Formula 34 is usually isolated by chromatography. Compounds of
Formula 4 where the Z group represents OC(R15)(R16)XR17 other than tetrahydropyranyl, (for example
tetrahydrothiopyranyl) can be prepared in reaction steps analogous to the ones described above for the preparation of compounds of Formula 34. The oxime derivatives of Formula 33 can also be reacted with an appropriate reagent (such as an acyl chloride R14COCl) to introduce the R14CO group, to provide the compounds of Formula 35. The compounds of Formula 4, 33, 34 and 35 can be converted into further homologs and
derivatives as is described above for compounds of Formulas 13, 15 and 16, and shown in Reaction Scheme 8.
In addition to the synthetic steps shown in Reaction Scheme 8, the compounds of Formula 4 can also be obtained, generally speaking, by first forming an oxime, alkoxyoxime, imine, hydrazone, semicarbazone etc. from the ketone compounds of Formula 10 (see Reaction Scheme 1) and thereafter performing the synthetic steps of replacing the 6 or 7-bromo
substituents in the resulting oximes, alkoxyoxime etc. with an ethynyl group and subsequently coupling the ethynyl compounds with the reagent X1-Y(R2)-A-B'
(Formula 9).
Figure imgf000069_0001
Compounds of Formula 5 can be prepared by the reactions illustrated in Reaction Scheme 9. In
accordance with this scheme, the 5-oxo 2- or 3- (aryl or heteroaryl) ethynyl 5,6,7,8-tetrahydronaphthalene compounds of Formula 13 (numbering as exemplified for Compound 1) are reduced in the 5 position and aminated by reaction with ammonium acetate and sodium
cyanoborohydride (NaBH3CN). The latter reaction provides the 5-amino 2- or 3- (aryl or
heteroaryl) ethynyl 5,6,7,8-tetrahydronaphthalene compounds of Formula 36. Compounds of Formula 36 where the NH2 group is not substituted (R14 of Formula 5 is hydrogen) comprise the presently preferred compounds of Formula 5. Compounds of Formula 5 where R14 is an alkyl, alkenyl, alkynyl or aryl group (as such groups are defined in connection with Formula 5) are prepared by reaction of compounds of Formula 36 with a reagent of the formula R14-X1, where X1 is halogen. When R14 is an alkyl group then the reagent R14-X1 is an alkyl halide. Compounds of Formula 36 are reacted with an equal amount of an acylating agent, such as an acyl chloride (R8COCl) to yield compounds of Formula 5 which are amides (R14 represents R8CO in Formula 5). The compounds of Formula 36 and of Formula 5 can be converted into further homologs and derivatives by reactions well known to the practicing organic chemist, as is described above in connection with compounds of Formulas 13, 15 and 16.
Compounds of Formula 5 where R14 is alkyl,
alkenyl, alkynyl or aryl group (as such groups are defined in connection with Formula 5) can also be obtained from the 5-oxo 2- or 3- (aryl or
heteroaryl) ethynyl 5,6,7, 8-tetrahydronaphthalene compounds of Formula 13 by reacting compounds of
Formula 13 with the corresponding amine (R14NH2) and thereafter reducing the resulting imine compounds with hydrogen or other suitable reducing agent. A second R14 group which is alkyl, alkenyl, alkynyl or aryl, or which is R8CO (acyl) can be introduced into the latter compounds by reaction with the reagent R14-X1 (X1 is halogen), or R8COCl.
In addition to the synthetic steps described above, the compounds of Formula 5 can also be obtained, generally speaking, by first forming the 5-amino, 5-alkylamino or 5-acylamido derivative from the ketone compounds of Formula 10 (see Reaction Scheme 1) and thereafter performing the synthetic steps of replacing the 6 or 7-bromo substituents in these compounds with an ethynyl group, and subsequently coupling the ethynyl compounds with the reagent X1-Y(R2)-A-B' (Formula 9).
Figure imgf000072_0001
Compounds of Formula 6 are obtained in accordance with Reaction Scheme 10, starting with the 5-oxo 2- or 3- (aryl or heteroaryl) ethynyl 5,6,7,8-tetrahydronaphthalene compounds of Formula 13 (numbering as
exemplified for Compound 1). As the reaction scheme indicates, the ketone derivatives of Formula 13 are reacted with a reagent which "enolizes" the ketone function of the tetrahydronaphthalene nucleus. The resulting "enol" compound then reacts with a reagent which introduces the R20 group into the enol function. The group R20 is defined in connection with Formula 6. Suitable reagents for the purpose of introducing the R20 function include a reactive leaving group L. Thus, the reagents used in this reaction have the general formula R20-L, R14-CO-L, R14-L, and R21-L, where the R14 and R21 groups are defined as in connection with Formula 6. Examples of the reagents, and/or reaction conditions which are used for the synthesis of the preferred compounds of the invention within the scope of Formula 6 include: reacting compounds of Formula 13 with sodium bis (trimethylsilyl) amide and 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine in an inert ether type solvent such as tetrahydrofuran at low temperatures (-78 °C and 0 °C) to obtain the 5-trifluoromethylsulfonyloxy-7,8-dihydronaphthalene derivative; reacting compounds of Formula 13 with acetic anhydride and p-toluenesulfonic acid at elevated temperature (80 °C) to obtain the 5-acetoxy-7,8-dihydronaphthalene derivative; and reacting compounds of Formula 13 with cyanotrimethylsilane in the presence of zinc iodide at ambient temperature to obtain the 5-trimethylsilyloxy-7,8-dihydronaphthalene derivative.
Compounds of Formula 38, obtained in the above- described manner are such compounds of Formula 6 where the X is oxygen. Compounds of Formula 6 where X is sulfur can be obtained by analogous reactions of the 5-thio analogs of the oxo compounds of Formula 13.
Compounds of Formula 6 where X is S and R20 is R14 (as R14 is defined in connection with Formula 6) are preferably obtained by reacting compounds of Formula 13 with titanium tetrachloride and a thiol of the formula R14SH in an inert ether type solvent (such as
tetrahydrofuran) in the presence of base (such as triethylamine). Generally speaking the reaction is conducted at room temperature. The latter reaction is shown in Reaction Scheme 10, and gives rise to
compounds of Formula 38A. The thienol ether compounds of Formula 38A can be oxidized to sulfoxides or with a suitable oxidizing agent, such as 3-chloroperoxybenzoic acid (MCPBA) to the corresponding sulfones of Formula 38B.
The compounds of Formula 38, 38A and 38B can be converted into further homologs and derivatives still within the scope of the invention, as is descibed above in connection with compounds of Formulas 13, 15 and 16.
It is noted at this point that the present
invention is not intended to be limited or bound by the above-mentioned theory of "enolization", and other theories of reaction mechanisms. Brief description of theory of reaction mechanisms (where applicable) are given to further enable and facilitate the work of a skilled artisan in the field to modify and adjust the synthetic conditions to fit particular specific
intermediates and to make the several compounds of the invention, without departing from the scope and spirit of the invention. In addition to the synthetic steps described in connection with Reaction Scheme 10, the compounds of Formula 6 can also be obtained, generally speaking, by first forming the "enolized" and acylated, alkylated or sulfonylated etc. derivative from the ketone compounds of Formula 10 (see Reaction Scheme 1) and thereafter performing the synthetic steps of replacing the 6 or 7-bromo substituents in these compounds with an ethynyl group, and subsequently coupling the ethynyl compounds with the reagent X1-Y(R2)-A-B' (Formula 9).
Figure imgf000076_0001
Reaction Scheme 11 discloses synthetic steps for the preparation of those compounds of Formula 7 where the R22 group is alkyl, alkenyl, alkynyl, carbocyclic aryl or heteroaryl, as these groups are broadly defined in Formula 7. In accordance with the presently preferred method of synthesizing these compounds of the invention, 5-trifluoromethylsulfonyloxy 2- or 3- (aryl or heteroaryl) ethynyl 7,8-dihydronaphthalene compounds of Formula 39 (numbering as exemplified for Compound 1) serve as starting materials. The compounds of Formula 39 can be obtained from the 5-oxo 2- or 3- (aryl or heteroaryl) ethynyl 5,6,7,8-tetrahydronaphthalene compounds of Formula 13 by reaction with sodium
bis (trimethylsilyl) amide and 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine in an inert ether type solvent such as tetrahydrofuran at low temperatures (-78 °C and 0 °C). This is described in connection with Reaction Scheme 10. Compounds of
Formula 39 are reacted with an organometal derivative derived from the alkane, alkene, alkyne, or aryl or heteroaryl compound R22H, such that the formula of the organometal derivative is R22Met (Met stands for metal), preferably R22Li. The reaction with the organometal derivative, preferably lithium derivative of the formula R22Li is usually conducted in an inert ether type solvent (such as tetrahydrofuran) in the presence of either (1) cuprous cyanide (cuCN) and lithium chloride (Licl), or in the presence of zinc chloride (ZnCl2) and tetrakis(triphenylphosphine)-palladium(O) (Pd(PPh3)4). The organolithium reagent R22Li, if not commercially available, can be prepared from the compound R22H (or its halogen derivative R22-X1 where X1 is halogen) in an ether type solvent in accordance with known practice in the art. The
temperature range for the reaction between the reagent R22Li and the compounds of Formula 39 is, generally speaking in the range of approximately -78 °C to 50 °C. Examples of the lithium compounds which are used in the just described reaction are lithium salts derived from straight and branch chained alkanes, such as methyl lithium, butyllithium, t-butyllithium, lithium salts derived from carbocyclic aryl compounds, such as phenyl lithium, and lithium salts derived from heteroaryl compounds, such as 2-thiazolyllithium, 2-furyl lithium, 2-thienyllithium, and 2-pyridyllithium. The just described synthetic process is preferably used for the synthesis of compounds of the invention within the scope of Formula 7 where the triple bonded (alkynyl) carbon is not directly attached to the 5-position of the 7,8-dihydronaphthalene nucleus. These compounds are shown in Formula 40 as the products of the reaction of compounds of Formula 39 with the R22Li reagent.
Referring still to Reaction Scheme 11, the
presently preferred method for the synthesis of those compounds of Formula 7 is disclosed where a triple bonded (alkynyl) carbon is directly attached to the 5position of the 7, 8-dihydronaphthalene nucleus. These compounds are shown in Formula 41, where R23 is defined as R22 of Formula 7 minus a two carbon fragment, so that the alkyne reagent R23C≡CH is within the applicable definition of R22 of Formula 7; namely R23C≡CH is alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, phenyl-C1 - C10alkynyl having 1 to 3 triple bonds, hydroxyalkynyl having 2 to 10 carbons and 1 to 3 triple bonds, acyloxyalkynyl of 2 to 10 carbons and 1 to 3 triple bonds. Compounds of Formula 41 are obtained by the reaction compounds of Formula 39 with the reagent R23CsCH in an inert ether type solvent, or
dimethylformamide, or without solvent, in the presence of a mild base (such as diethylamine), cuprous iodide (CuI), and bis (triphenylphosphine) palladium(II)
chloride (Pd(PPh3)2Cl2) in an inert gas (argon)
atmoshere. The reaction is typically conducted in the temperature range of ambient to 70 °C.
Compounds of Formula 40 and 41 can be converted into further homologs and derivatives still within the scope of the invention, as is descibed above in
connection with compounds of Formulas 13, 15 and 16.
Referring now to Reaction Scheme 12 an alternative synthetic route for the preparation of compounds of Formula 7 is disclosed.
Figure imgf000080_0001
According to this reaction scheme, derivatives of 5-hydroxy, 2- or 3- (aryl or heteroaryl) ethynyl
5,6,7,8-tetrahydronaphthalene compounds of Formula 42 serve as the starting materials. Compounds of Formula 42 are within the scope of Formula 1, and can be prepared in accordance with the procedures set forth for the preparation of compounds of Formula l.
Specifically, in Formula 42 the group R22 is defined as in connection with Formula 7, and R24 is hydrogen, or trialkylsilyl (preferably trimethylsilyl), or any other group which is suitable to form a leaving group including the R24O- element, in the elimination
reaction which is shown in the reaction scheme. The product of the elimination reaction is a compound of Formula 7. The reaction is conducted under conditions which are known in the art of organic chemistry to cause formation of double bonds by elimination, for example in refluxing pyridine in the presence of excess phosphorous oxychloride (POCl3), or in a neutral hydrocarbon type solvent (such as benzene) in the presence of (methoxycarbonylsulfamoyl) triethylammonium hydroxide (Burgess reagent). Reaction Scheme 12 is presently preferred for the preparation of compounds of Formula 7 where the R22 group is hydrogen, cyano (CN) and CH2COOEt. The elimination reaction which results in compounds where R22 is CH2COOEt also gives rise to isomers where the double bond is exterior to the condensed 6-membered ring. The latter compounds are within the scope of Formula 3 and are not shown in this reaction scheme.
SPECIFIC EXAMPLES
Ethyl (4-bromophenyl) acetate (Compound A)
A solution of 43 g (200 mmol) of 4- bromophenylacetic acid and 0.2 g of cone. H2SO4 in 470 ml of ethanol was refluxed for 16 hours. The reaction mixture was cooled to ambient temperature, stirred with 6 g of solid K2CO3 for 30 minutes and then filtered. The filtrate was concentrated in vacuo. diluted with Et2O (200 ml), washed with 10% aqueous NaHCO3 (10 ml) and brine (10 ml), dried over MgSO4 and concentrated in vacuo to give the title compound as a colorless oil. PMR (CDCl3) : δ 1.25 (3H, t, J = 7.0 Hz), 3.56 (2H, s), 4.15 (2H, q, J = 7.0 Hz), 7.16 (2H, d, J = 8.4 Hz), 7.45 (2H, d, J = 8.4 Hz). Ethyl (3-bromophenyl) acetate (Compound B)
Employing the same general procedure as for the preparation of ethyl (4-bromophenyl) acetate (Compound A), 100 g (463 mmol) of 3-bromophenylacetic acid was converted into the title compound (yellow oil) using 2 g of cone. H2SO4 and 500 ml of ethanol.
PMR (CDCl3) : δ 1.26 (3H, t, J = 7.0 Hz), 3.56 (2H, s), 4.16 (2H, q, J = 7.0 Hz), 7.16-7.26 (2H, m), 7.38-7.46 (2H, m).
Ethyl 4-(4-bromophenyl)butanoate (Compound C)
To a cold solution (-78 °C) of 15 g (62 mmol) of ethyl (4-bromophenyl) acetate (Compound A) in 150 ml of CH2Cl2 was added dropwise (over a span of 1 hour) 65 ml (65 mmol) of diisobutylaluminum hydride (DIBAL-H, 1M solution in hexane). After the DIBAL-H addition was complete, the reaction was stirred at -78 °C for an additional hour. The reaction was quenched by the dropwise addition of methanol (10 ml), followed by water (10 ml) and 10% HCl (40 ml). The mixture was then warmed to 0 °C, stirred for 10 minutes and then washed with water (15 ml), 10% aqueous NaHCO3 (10 ml) and brine (10 ml). The organic phase was dried over MgSO4 and the solvent distilled off at ambient
temperature to give crude (4-bromophenyl) acetaldehyde. To a cold solution (0 °C) of this crude aldehyde in 150 ml of CH2Cl2 was added a solution of 26 g (74.6 mmol) of (carbethoxymethylene) triphenylphosphorane in 50 ml of CH2Cl2. The mixture was stirred for 16 hours, concentrated in vacuo and purified by flash
chromatography (silica, 10% EtOAc-hexane) to give ethyl 4-(4-bromophenyl)but-2-enoate as a mixture of E:Z isomers. This isomeric mixture was dissolved in 150 ml of EtOAc and hydrogenated over 1 g of 10% Pd/C for 6 hours. The catalyst was filtered off and the filtrate concentrated in vacuo to give the title compound as a white solid.
PMR (CDCl3) : δ 1.26 (3H, t, J = 7.1 Hz), 1.88-1.99
(2H, m), 2.31 (2H, t, J = 7.5 Hz), 2.61 (2H, t, J = 7.5 Hz), 4.28 (2H, q, J = 7.1 Hz), 7.05 (2H, d, J = 8.4
Hz), 7.40(2H, d, J = 8.4 Hz).
Ethyl 4-(3-bromophenyl)butanoate (Compound D)
Employing the same general multistep preparation as for ethyl 4-(4-bromophenyl)butanoate (Compound C), 60 g (246 mmol) of ethyl (3-bromophenyl) acetate
(Compound B) was converted into the title compound (oil) using 255 ml (255 mmol) of diisobutylaluminum hydride (DIBAL-H, 1M in hexane), 85.8 g (250 mmol) of (carbethoxymethylene) triphenylphosphorane and 1.7 g of 10% Pd/C.
PMR (CDCl3) : δ 1.26 (3H, t, J = 7.1 Hz), 1.89-2.00 (2H, m), 2.31 (2H, t, J = 7.5 Hz), 2.63 (2H, t, J = 7.2 Hz), 4.15 (2H, q, J = 7.1 Hz), 7.10-7.35 (4H, m).
5-(3-bromophenyl)-2-methylpentan-2-ol (Compound E)
To a cold solution (0 °C) of 17 g (63 mmol) of ethyl 4-(3-bromophenyl)butanoate (Compound D) in 40 ml of THF was added 63 ml (189 mmol) of methylmagnesium bromide (3.0M solution in THF). The reaction was stirred at 0 °C for 2 hours, quenched by the slow addition of ice cold water (30 ml) followed by 10% HCl (30 ml) and then extracted with Et2O (4 × 60 ml). The combined organic layer was washed with 10% aqueous NaHCO3 (10 ml), water (10 ml) and brine (10 ml), dried over MgSO4 and concentrated in vacuo. Purification by Kugelrohr distillation gave the title compound as a colorless oil.
PMR (CDCl3) : δ 1.20 (6H, s), 1.43-1.55 (2H, m), 1.62- 1.78 (2H, m), 2.60 (2H, t, J = 6.0 Hz), 7.10-7.41 (4H, m).
6-Bromo-1,2,3,4-tetrahydro-1,1-dimethylnaohthalene
(Compound F)
15.0 g (58.3 mmol) of 5-(3-bromophenyl)-2-methyl- pentan-2-ol (Compound E) was cooled to 0 °C and then 2.8 ml of cone. H2SO4 was added. The mixture was stirred for 2.5 hours, diluted with water (20 ml) and extracted with Et2O (3 × 40 ml). The combined organic layers were washed with water, sat. aqueous NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo.
Purification by Kugelrohr distillation gave the title compound as a colorless oil.
PMR (CDCl3) : δ 1.25 (6H, s), 1.61-1.66 (2H, m), 1.74-1.82 (2H, m), 2.73 (2H, t, J = 6.0 Hz), 7.16-7.26 (3H, m).
7-Bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G)
To a cold mixture (0 °C) of 209 g (200 mmol) of chromium trioxide, 100 ml (1.06 mol) of acetic
anhydride and 200 ml (3.5 mol) of acetic acid was added a solution of 10 g (41.8 mmol) of 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F) in 125 ml of benzene. The reaction mixture was stirred for 1 hour, quenched with ice cold water and extracted with Et2O (3 × 100 ml). The organic layer was dried over MgSO4, concentrated in vacuo. and purified by column chromatography (silica, 10% EtOAc-hexane) to give the title compound as a white solid.
PMR (CDCl3) : δ 1.28 (6H, s), 2.01 (2H, t, J = 6.0 Hz), 2.72 (2H, t, J = 6.0Hz), 7.31 (1H, d, J = 9.0 Hz), 7.61 (1H, dd, J = 3.0, 9.0 Hz), 8.11 (1H, d, J = 3.0 Hz). 6-Bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H)
Employing a published procedure (Mathur, N.C.; Snow, M.S. ; Young, K. M.; and Pincock, J. A. Tetrahedron, 41, 1509-1516 (1985) ), ethyl 4-(4-bromophenyl)butanoate (Compound C) was converted into the title compound. Alternatively, the title compound can be obtained using similar reactions that were used to convert ethyl 4-(3-bromophenyl)butanoate (Compound D) into 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G).
4.6-Dibromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound I)
To a solution of 1.2 g (5.0 mmol) of 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F) in 20 ml of CCl4 was added 0.97 g (5.5 mmol) of N-bromosuccinimide followed by 20 mg (0.08 mmol ) of benzoylperoxide. The mixture was refluxed for 3 hours, filtered and the filtrate washed with water (5 ml).
The organic phase was dried over MgSO4 and then
concentrated in vacuo to yield the title compound as a pale yellow oil.
PMR (CDCl3) : δ 1.20 (3H, s), 1.39 (3H, s), 1.60-1.72 (2H, m), 2.20-2.34 (2H, m), 5.45 (1H, br s), 7.21 (1H, d, J = 8.5 Hz), 7.36 (1H, dd, J = 2.1 , 8.5 Hz), 7.48 (1H, d, J =- 2.1 Hz).
6-Bromo-4-cyclohexyloxy-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound J)
To 9 g (89.9 mmol) of cyclohexanol was added 160 mg (7.0 mmol) of sodium metal and the mixture was stirred at 70 °C for 12 hours. After all of the sodium dissolved the reaction mixture was cooled to ambient temperature and then a solution of 1 g (3.2 mmol) of 4,6-dibromo-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene (Compound I) in 1 ml of cyclohexanol was added. The mixture was heated at 120 °C for 4 hours and thereafter the excess solvent distilled off under reduced
pressure. The product was dissolved in Et2O (75 ml), washed with water (5 ml) and brine (5 ml), dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (silica, 5% EtOAc-hexane) yielded the title compound as a colorless oil.
PMR (CDCl3) : δ 1.20 (3H, s), 1.26 (3H, s), 1.24-1.50 (4H, m), 1.51-1.64 (2H, m), 1.75-2.14 (8H, m), 3.45-3.55 (1H, m), 4.42 (1H, dd, J = 4.6, 4.6 Hz), 7.15 (1H, d, J = 8.5 Hz), 7.31 (1H, dd, J = 2.1 , 8.5 Hz), 7.51 (1H, d, J = 2.1 Hz).
6-Ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound K)
To a solution (flushed for 15 minutes with a stream of argon) of 13.55 g (53.8 mmol) of 6-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H) in 280 ml of triethylamine was added 1.87 g (2.66 mmol) of bis (triphenylphosphine) palladium(II) chloride and 0.53 g (2.66 mmol) of cuprous iodide. The solution mixture was flushed with argon for 5 minutes and then 100 ml (938.7 mmol) of (trimethylsilyl) acetylene was added. The reaction mixture was sealed in a pressure tube and placed in a preheated oil bath (100 °C) for 24 hours. The reaction mixture was then filtered through Celite, washed with Et2O and the filtrate concentrated in vacuo to give crude 6-2-(trimethylsilyl)ethynyl-3, 4-dihydro-4,4-dimethylnaphthalen-1(2H)-one. To a
solution of this crude TMS-acetylenic compound in 50 ml of methanol was added 2.8 g (20.3 mmol) of K2CO3. The mixture was stirred for 8 hours at ambient temperature and then filtered. The filtrate was concentrated in vacuo, diluted with Et2O (100 ml), washed with water (10 ml), 10% HCl (10 ml) and brine (10 ml), dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (silica, 10% EtOAc-hexane) yielded the title compound as a white solid.
PMR (CDCl3) : δ 1.38 (6H, s), 2.01 (2H, t, J = 7.1 Hz),
2.72 (2H, t, J = 7.1 Hz), 3.24 (1H, s), 7.39 (1H, dd, J - 1.5, 8.1 Hz), 7.54 (1H, d, J = 1.5 Hz), 7.91 (1H, d, J = 8.1 Hz).
7-Ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound L)
Employing the same general procedure as for the preparation of 6-ethynyl-3,4-dihydro-4,4-dimethyl-naphthalen-1(2H)-one (Compound K), 7 g (27.6 mmol) of 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G) was converted into the title compound using 39 ml (36.6 mmol) of (trimethylsilyl) acetylene, 0.97 g (1.3 mmol) of bis(triphenylphosphine)palladium(II) chloride, 0.26 g (1.3 mmol) of cuprous iodide and 0.6 g (4.3 mmol) of K2CO3.
PMR (CDCl3) : δ 1.39 (6H, s), 2.02 (2H, t, J = 7.0 Hz),
2.73 (2H, t, J = 7.0 Hz), 3.08 (1H, s), 7.39 (1H, d, J = 8.2 Hz), 7.61 (1H, dd, J = 1.8 , 8.2 Hz), 8.14 (1H, d, J = 9 1.8 Hz).
7-Ethynyl-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound M)
Employing the same general procedure as for the preparation of 6-ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound K), 2.1 g (8.8 mmol) of 7-bromo-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene was converted into the title compound using 10 ml (93.9 mmol) of trimethylsiiyl acetylene, 1.25 g (1.8 mmol) of bis (triphenylphosphine) palladium(II) chloride, 0.53 g (2.8 mmol) of cuprous iodide and 10 ml (20.0 mmol) of K2CO3 (2M solution in methanol).
PMR (CDCl3) : δ 1.25 (6H, s), 1.60-1.68 (2H, m), 1.75-1.85 (2H, m), 2.75 (2H, t, J = 6.4 Hz), 3.01 (1H, s), 6.98 (1H, d, J = 7.9 Hz), 7.19 (1H, dd, J = 1.7 , 7.9 Hz), 7.46 (1H, d, J = 1.7 Hz).
4-Cyclohexyloxy-6-ethynyl-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound N)
Employing the same general procedure as for the preparation of 6-ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-l(2H)-one (Compound K), 2.1 g (8.8 mmol) of 6-bromo-4-cyclohexyloxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene (Compound J) was converted into the title compound using 1 g (10.2 mmol) of trimethylsilyl acetylene, 0.14 g (0.20 mmol) of bis (triphenylphosphine) palladium(II) chloride, 19 mg (0.1 mmol) of cuprous iodide and 80 mg (0.6 mmol) of K2CO3.
PMR (CDCl3) : δ 1.25 (3H, s), 1.29 (3H, s), 1.20-1.50 (4H, m), 1.50-1.65 (2H, m), 1.75-2.15 (8H, m), 3.00 (1H, s), 3.47-3.55 (1H, m), 4.43 (1H, t, J = 6.0 Hz), 7.24 (1H, d, J = 7.8 Hz), 7.32 (1H, dd, J = 1.9 , 7.8 Hz), 7.52 (1H, d, J = 1.9 Hz).
6-Bromo-1(2H)-cyclohexylidene-3,4-dihydro-4,4-dimethylnaphthalene (Compound O)
To a slurry of 12.2 g (79 mmol) of titanium trichloride in 150 ml of 1,2-dimethoxyethane (DME) under argon atmosphere was added in small portions 1.92 g (227 mmol) of lithium wire. The mixture was refluxed for 1 hour, cooled to ambient temperature and then a mixture of 1.56 g (15.9 mmol) of cyclohexanone and 1.0 g (3.97 mmol) of 6-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H) in 50 ml of DME was added. The resultant reaction mixture was stirred at ambient temperature for 2 hours, refluxed for 16 hours, diluted with hexane (100 ml) and then filtered through florisil. Purification by flash chromatography
(silica, 100% hexane) to give the title compound as a pale yellow oil.
PMR (CDCl3) : δ 1.26 (6H, s), 1.52-1.64 (8H, br s), 2.30 (2H, t, J = 5.5 Hz), 2.42 (2H, t, J = 5.5 Hz), 2.53 (2H, t, J = 7.1Hz), 7.04 (1H, d, J = 8.2 Hz), 7.23 (1H, dd, J = 2.1 , 8.2 Hz), 7.41 (1H, d, J = 2.1 Hz). 7-Bromo-1(2H)-cyclohexylidene-3,4-dihydro-4,4-dimethylnaohthalene (Compound P)
Employing the same general procedure as for the preparation of 6-bromo-1(2H)-cyclohexylidene-3,4-dihydro-4,4-dimethylnaphthalene (Compound O), 1.0 g (3.97 mmol) of 7-bromo-3,4-dihydro-4,4-dimethyl-naphthalen-1(2H)-one (Compound G) was converted into the title compound using 1.56 g (15.9 mmol) of cyclohexanone, 1.92 g (277 mmol) of lithium and 12.2 g (79.4 mmol) of titanium trichloride.
PMR (CDCl3): δ 1.23 (6H, s), 1.50-1.65 (8H, m), 2.33 (2H, br s), 2.45 (2H, t, J = 5.5 Hz), 2.50 (2H, t, J = 7.1 Hz), 7.15 (d, J = 8.1 Hz), 7.26 (1H, d, J = 1.6 Hz), 7.29 (1H, br s).
6-Bromo-1-(3-pentylidene)-1,2,3,4-tetrahydro-4,4-dimethylnaphthalene (Compound Q)
Employing the same general procedure as for the preparation of 6-bromo-1(2H)-cyclohexylidene-3,4-dihydro-4,4-dimethylnaphthalene (Compound O), 1.0 g (3.97 mmol) of 6-bromo-3,4-dihydro-4,4-dimethyl-naphthalen-1(2H)-one (Compound H) was converted into the title compound using 1.37 g (15.9 mmol) of 3-pentanone, 1.92 g (277 mmol) of lithium and 12.2 g (79.4 mmol) of titanium trichloride. PMR (CDCl3) : δ 1.05 (3H, t, J = 7.3 Hz), 1.13 (3H, t, J = 7.2 Hz), 1.25 (6H, s), 1.64 (2H, t, J = 7.1Hz), 2.16-2.30 (4H, m), 2.50 (2H, t, J = 7.1Hz), 7.09 (1H, d, J = 8.2 Hz), 7.25 (1H, dd, J = 2.1 , 8.2 Hz), 7.41 (1H, d, J = 2.1 Hz).
7-Bromo-1-(3-pentylidene)-1,2,3,4-tetrahydro-4,4-dimethylnaphthalene (Compound R)
Employing the same general procedure as for the preparation of 6-bromo-1(2H)-cyclohexylidene-3,4-dihydro-4,4-dimethylnaphthalene (Compound O), 1.0 g (3.97 mmol) of 7-bromo-3,4-dihydro-4,4-dimethyl-naphthalen1(2H)-one (Compound G) was converted into the title compound using 1.37 g (15.9 mmol) of 3-pentanone, 1.92 g (277 mmol) of lithium and 12.2 g (79.4 mmol) of titanium trichloride.
PMR (CDCl3) : δ 1.04 (3H, t, J = 7.5 Hz), 1.14 (3H, t, J = 7.5 Hz), 1.23 (6H, s), 1.63 (2H, t, J = 7.1 Hz), 2.21 (2H, q, J = 7.5 Hz), 2.29 (2H, q, J = 7.5 Hz), 2.49 (2H, t, J = 7.1 Hz), 7.15 (1H, d, J = 8.3 Hz), 7.29 (1H, dd, J = 2.2 , 8.3 Hz), 7.36 (1H, d, J = 2.2 Hz). 6-Bromo-1,2,3,4-tetrahydro-1,1-dimethyl-4-thioacetylnaphthalene (Compound s)
Employing the above-described procedure for the conversion of 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F) to the dibromonaphthalene derivative (Compond I), 3.5 g (14.6 mmol) of (Compound F), 2.86 g (16.1 mmol) of N-bromosuccinimide and 150 mg (0.62 mmol ) of benzoylperoxide gave crude 4,6-dibromo¬1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound I). To a solution of this crude dibromonaphthalene derivative (Compound I) in 50 ml of THF was added 5.38 g (47.1 mmol) of potassium thioacetate. The mixture was refluxed for 6 hours under argon atmosphere. filtered through celite and concentrated in vacuo.
Purification by chromatography (silica, 10% EtOAc-hexane) yielded the title compound as red oil.
PMR (CDCl3): δ 1.20 (3H, s), 1.23 (3H, s), 1.65-1.68 (1H, m), 1.78-1.95 (2H, m), 2.20-2.25 (1H, m), 2.35 (3H, s), 4.88 (1H, t, J = 4.3 Hz), 7.18 (1H, d, J = 8.5 Hz), 7.27 (1H, dd, J = 2.1 , 8.5 Hz), 7.35 (1H, d, J = 2.1 Hz).
6-Bromo-1,2,3,4-tetrahydro-1,1-dimethyl-4-thio(2-tetrahydropyranyl)naphthalene (Compound T)
To a solution of 2.0 g (6.38 mmol) of 6-bromo-1,2,3,4-tetrahydro-1,1-dimethyl-4-thioacetylnaphthalene (Compound S) in 20 ml of MeOH was added 200 mg (1.45 mmol) of potassium carbonate. The reaction mixture was stirred for 16 hours at ambient temparature,
concentrated in vacuo and diluted with EtOAc (80 ml). The organic layer was washed with water (20 ml) and brine (10 ml), dried over MgSO4 and concentrated in vacuo to give crude thiol. To a solution of the crude thiol in 50 ml of dry THF was added 6.3 g (74.9 mmol) of 3,4-dihydro-2H-pyran and 35 mg (0.18 mmol) of p-toluenesulfonic acid. The reaction mixture was stirred for 48 hours at ambient temperature under argon
atmosphere, concentrated in vacuo and purified by flash chromatography (silica, 10% EtOAc-hexane) to give the title compound as a 1:1 mixture of two diastereomers that were used without further purification.
6-Ethynyl-1(2H)-cyclohexylidene-3,4-dihydro-4,4-dimethylnaphthalene (Compound U)
Employing the same general procedure as for the preparation of 6-ethynyl-3,4-dihydro-4,4-dimethyl- naphthalen-1(2H)-one (Compound K), 530 mg (1.66 mmol) of 6-bromo-1(2H)-cyclohexylidene-3,4-dihydro-4,4-di methylnaphthalene (Compound O) was converted into the title compound using 1.63 g (16.6 mmol) of trimethylsilylacetylene, 20 mg (0.08 mmol) of cuprous iodide, 60 mg (0.08 mmol) of bis (triphenylphosphine) palladium(II) chloride and 40 mg (0.3 mmol) of potassium carbonate. PMR (CDCl3) : δ 1.26 (6H, s), 1.54-1.64 (8H, br s), 2.33 (2H, br s), 2.43 (2H, t, J = 5.9 Hz), 2.53 (2H, t, J = 7.0 Hz), 3.07 (1H, s), 7.13 (1H, d, J = 7.9 Hz), 7.27 (1H, dd, J = 1.7 , 7.9 Hz), 7.44 (1H, d, J = 1.7 Hz).
7-Ethynyl-1(2H)-cyclohexylidene-3,4-dihydro-4,4-dimethylnaphthalene (Compound V)
Employing the same general procedure as for the preparation of 6-ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound K), 351 mg (1.1 mmol) of 7-bromo-1(2H)-cyclohexylidene-3,4-dihydro-4,4-dimethylnaphthalene (Compound P) was converted into the title compound using 1.1 g (11 mmol) of trimethylsilylacetylene, 10 mg (0.04 mmol) of cuprous iodide, 38 mg (0.05 mmol) of bis (triphenylphosphine) palladium (II) chloride and 35 mg (0.25 mmol) of potassium carbonate.
PMR (CDCl3): δ 1.25 (6H, s), 1.50-1.67 (8H, m), 2.32 (2H, br s), 2.45 (2H, t, J = 5.9 Hz), 2.51 (2H, t, J = 7.0 Hz), 3.00 (1H, s), 7.24 (1H, d, J = 7.0 Hz), 7.29 (1H, d, J = 1.8 Hz), 7.30 (1H, br s).
6-Ethynyl-3,4-dihydro-1(2H)-(3-pentylidene)-4,4-dimethylnaphthalene (Compound W)
Employing the same general procedure as for the preparation of 6-ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound K), 530 mg (1.66 mmol) of 6-bromo-3,4-dihydro-1(2H)-(3-pentylidene)-4,4-dimethylnaphthalene (Compound Q) was converted into the title compound using 1.63 g (16.6 mmol) of trimethylsi lylacetylene, 20 mg (0.08 mmol) of cuprous iodide, 60 mg (0.08 mmol) of bis (triphenylphosphine) palladium(II) chloride and 40 mg (0.3 mmol) of potassium carbonate. PMR (CDCl3): δ 1.04 (3H, t, J = 7.6 Hz), 1.13 (3H, t, J = 8.3 Hz), 1.24 (6H, s), 1.64 (2H, t, J = 7.0 Hz), 2.15-2.32 (4H, m), 2.50 (2H, t, J = 7.0 Hz), 3.07 (1H, s), 7.18 (1H, d, J = 8.0 Hz), 7.27 (1H, dd, J = 1.7 , 8.0 Hz), 7.43 (1H, d, J = 1.7 Hz).
7-Ethynyl-3.4-dihydro-1(2H)-(3-pentylidene)-4,4-dimethylnaphthalene (Compound X)
Employing the same general procedure as for the preparation of 6-ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound K), 384 mg (1.25 mmol) of 7-bromo-3,4-dihydro-1(2H)-(3-pentylidene)-4,4-dimethylnaphthalene (Compound R) was converted into the title compound using 2.1 g (21 mmol) of trimethylsilylacetylene, 12 mg (0.06 mmol) of cuprous iodide, 43 mg (0.06 mmol) of bis (triphenylphosphine) palladium(II) chloride and 70 mg (0.5 mmol) of potassium carbonate. PMR (CDCl3): δ 1.04 (3H, t, J = 7.6 Hz), 1.13 (3H, t, J = 7.4 Hz), 1.23 (6H, s), 1.63 (2H, t, J = 7.0 Hz), 2.21 (2H, q, J = 7.4 Hz), 2.27 (2H, q, J = 7.6 Hz), 2.48 (2H, t, J = 7.0 Hz), 3.00 (1H, s), 7.23 (1H, d, J = 8.0 Hz), 7.28 (1H, dd, J = 2.3 , 8.0 Hz), 7.35 (1H, d, J = 2.3 Hz).
6-Ethynyl-1,2,3,4-tetrahydro-1,1-dimethyl-4-thio( 2-tetrahydropyranyl)naphthalene (Compound Y)
Employing the same general procedure as for the preparation of 6-ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound K), 1.31 g (3.85 mmol) of 6-bromo-1,2,3,4-tetrahydro-1,1-dimethyl-4-thio(2-tetrahydroopyranyl)naphthalene (Compound T) was
converted into the title compound using 3.79 g (38.5 mmol) of trimethylsilylacetylene, 40 mg (0.19 mmol) of cuprous iodide, 140 mg (0.19 mmol) of bis (triphenylphosphine) palladium(II) chloride and 120 mg (0.87 mmol) of potassium carbonate. The mixture of diastereomers was used without further purification.
Ethyl-4-iodobenzoate
To a suspension of 10 g (40.32 mmol) of 4-iodobenzoic acid in 100 ml absolute ethanol was added 2 ml thionyl chloride and the mixture was then heated at reflux for 3 hours. Solvent was removed in vacuo and the residue was dissolved in 100 ml ether. The ether solution was washed with saturated NaHCO3 and saturated NaCl solutions and dried (MgSO4). Solvent was then removed in vacuo and the residue Kugelrohr distilled (100 degrees C; 0.55 mm) to give the title compound as a colorless oil, PMR (CDCl3) : δ 1.42 (3H, t, J-7 Hz), 4.4 (2H, q, J-7 Hz), 7.8 (4H).
Ethyl 6-chloronicotinate
A mixture of 15.75 g (0.1 mol) 6-chloronicotinic acid, 6.9 g (0.15 mol) ethanol, 22.7 g (0.11 mol) dicyclohexylcarbodiimide and 3.7 g dimethylaminopyridine in 200 ml methylene chloride was heated at reflux for 2 hours. The mixture was allowed to cool, solvent removed in vacuo and the residue subjected to flash chromatography to give the title compound as a lowmelting white solid. PMR (CDCl3) : δ 1.44 (3H, t, J-6.2 Hz) 4.44 (2H, q, J-4.4 Hz), 7.44 (1H, d, J-8.1 Hz), 8.27 (1H, dd, J-8.1 Hz, 3 Hz), 9.02 (1H, d, J-3 Hz). 6-Iodonicotinic acid
To 27.97 g (186.6 mmol) of sodium iodide cooled to -78*C was added 121.77 g (71.6 ml, 952.0 mmol) of hydriodic acid (57 wt %) . The reaction mixture was allowed to warm slightly with stirring for 5 minutes, and then 30.00 g (190.4 mmol) of 6-chloronicotinic acid was added. The resulting mixture was allowed to warm to room temperature with stirring and then heated at 120-125ºC in an oil bath for 42 hours. A dark brown layer formed above the yellow solid material. The reaction mixture was allowed to cool to room
temperature and then poured into acetone (chilled to O'C). The resultant yellow solid was collected by filtration, washed with 200 ml of 1N NaHSO3 solution, and dried in high vacuum (3 mm Hg) to give the title compound as a pale yellow solid.
PMR (DMSO-d6) : δ 7.90 (1H, dd, J = 8.1, 2 Hz), 7.99 (1H, d, J = 8.1 Hz), 8.80 (1H, d, J = 2.Hz).
Ethyl 6-iodonicotinate
To a suspension of 23.38 g (94.2 mmol) of 6-iodonicotinic acid in 100 ml of dichloromethane was added a solution of 19.86 g (103.6 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 250 ml of dichloromethane. To this suspension was added 12.40 g (15.8 ml, 269.3 mmol) of ethanol (95%) and 1.15 g (9.4 mmol) of 4-dimethylaminopyridine. The resulting solution mixture was then heated at 50ºC in an oil bath for 24.5 hours, concentrated in vacuo. partitioned between 200 ml of water and 250 ml of ethyl ether, and the layers were separated. The aqueous phase was washed with 2 × 150 ml portions of ethyl ether. All organic phases were combined, washed once with 75 ml of brine solution, dried over MgSO4, filtered and
concentrated in vacuo to a yellow solid. Purification by flash chromatography (silica, 10% ethyl acetate in hexane) yielded the title compound as a white solid. PMR (CDCl3): .5 1.41 (3H, t, J = 7.1 Hz), 4.41 (2H, q, J = 7.1 Hz), 7.85 (1H, d, J = 8.2 Hz), 7.91 (1H, dd, J = 8.2, 2.1 Hz), 8.94 (1H, d, J = 2.1 Hz).
Ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth- 2-yl)ethynyl]benzoate (Compound 1)
To a solution of 8.8 g (47.8 mmol) of 6-ethynyl-1,2,3,4-tetrahydro-4,4-dimethylnaphthalen-1-one
(Compound K) flushed for 15 minutes with a stream of argon, and 13.2 g (47.8 mmol) of ethyl 4-iodobenzoate in 200 ml of triethylamine was added 1.1 g (1.6 mmol) of bis(triphenylphosphine)palladiuum(II) chloride and 0.30 g (1.6 mmol) of cuprous iodide. The solution mixture was flushed with argon for 5 minutes and then stirred at ambient temperature for 18 hours. The reaction mixture was filtered through Celite and the filtrate concentrated in vacuo. Purification by flash chromatography (silica, 10% EtOAc-hexane) yielded the title compound as a white solid.
PMR (CDCl3) : δ 1.41 (3H, t, J = 7.2 Hz), 1.43 (6H, s), 2.04 (2H, t, J = 7.0 Hz), 2.75 (2H, t, J = 7.0 Hz), 4.40 (2H, q, J = 7.2 Hz), 7.46 (1H, dd, J = 1.5, 8.1 Hz), 7.60 (1H, d, J = 1.5 Hz), 7.63 (2H, d, J = 8.4 Hz), 8.01 (1H, d, J = 8.1 Hz), 8.05 (2H, d, J = 8.4 Hz).
Ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoate (Compound 2)
Employing the same general procedure as for the preparation of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound l), 4 g (21.7 mmol) of 7-ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound L) was converted into the title compound using 6 g (21.7 mmol) of ethyl 4-iodobenzoate, 5 g (7.2 mmol) of
bis(triphenylphosphine)palladium(II) chloride and 1.4 g (7.2 mmol) of cuprous iodide. PMR (CDCl3) : δ 1.41 (3H, t, J = 7.2 Hz), 1.41 (6H, s),
2.04 (2H, t, J = 6.5 Hz), 2.76 (2H, t, J = 6.5 Hz), 4.40 (2H, q, J = 7.2 Hz), 7.44 (1H, d, J = 8.2 Hz),
7.59 (2H, d, J = 8.4 Hz), 7.68 (1H, dd, J = 1.8, 8.2 Hz), 8.04 (2H, d, J = 8.4 Hz), 8.15 (1H, d, J = 1.8 Hz).
Ethyl 6-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]nicotinate (Compound 3)
Employing the same general procedure as for the preparation of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 1), 606 mg (3.48 mmol) of 7-ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound K) was converted into the title compound using 964 mg (3.48 mmol) of ethyl 6-iodonicotinate, 122 mg (0.17 mmol) of bis(triphenylphosphine)palladium(II) chloride and 9.5 mg (0.17 mmol) of cuprous iodide.
PMR (CDCl3) : δ 1.41 (6H, s), 1.43 (3H, t, J = 7.1 Hz),
2.05 (2H, t, J = 7.1 Hz), 2.76 (2H, t, J = 7.1 Hz), 4.43 (2H, q, J = 7.1 Hz), 7.46 (1H, d, J = 8.2 Hz),
7.60 (1H, d, J = 7.8 Hz), 7.75 (1H, dd, J = 1.9, 8.2 Hz), 8.27 (1H, d, J = 1.9 Hz), 8.30 (1H, dd, J = 2.0, 7.8 Hz), 9.22 (1H, br s).
Ethyl 6-[(5,6,7,8-tetrahydro-8,8-dimethylnaphth-2-yl)ethynyl]nicotinate (Compound 4)
Employing the same general procedure as for the preparation of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 1), 1.3 g (7.05 mmol) of 7-ethynyl-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound M) was converted into the title compound using 2.2 g (8.0 mmol) of ethyl 6-iodonicotinate, 1.2 g (1.7 mmol) of
bis(triphenylphosphine)palladium(II) chloride and 0.32 g (1.7 mmol) of cuprous iodide.
PMR (CDCl3) : δ 1.29 (6H, s), 1.42 (3H, t, J = 7.1 Hz), 1.62-1.68 (2H, m), 1.75-1.85 (2H, m), 2.78 (2H, t, J = 6.5 Hz), 4.42 (2H, q, J = 7.1 Hz), 7.05 (1H, d, J = 7.8 Hz), 7.31 (1H, dd, J = 1.7, 7.8 Hz), 7.58 (1H, d, J =
7.3 Hz), 7.61 (1H, d, J = 1.7 Hz), 8.27 (1H, dd, J = 2.1, 7.3 Hz), 9.20 (1H, d, J = 2.1 Hz).
Ethyl 6-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]nicotinate (Compound 5)
Employing the same general procedure as for the preparation of ethyl 4-[5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound l), 422 mg (2.1 mmol) of 6-ethynyl-3,4-dihydro-4,4-dimethyl-naphthalen-1(2H)-one (Compound L) was converted into the title compound using 202 mg (0.73 mmol) of ethyl 6iodonicotinate, 168mg (0.24 mmol) of bis(triphenylphosphine)palladium(II) chloride and 45.7 mg (0.24 mmol) of cuprous iodide.
PMR (CDCl3) : δ 1.40 (6H, s), 1.42 (3H, t, J = 7.1 Hz),
2.04 (2H, t, J = 6.0 Hz), 2.74 (2H, t, J = 6.0 Hz), 4.43 (2H, q, J = 7.1 Hz), 7.51 ( 1H , d, J = 8.4 Hz), 7.63 (1H, d, J = 8.4 Hz), 7.70 (1H, s), 8.01 (1H, d, J = 8.1 Hz), 8.30 (1H, d, J = 8.1 Hz), 9.22 (1H, s).
Ethyl 4-[(5-cyclohexyloxy-5,6,7,8-tetrahydro-8,8-dimethyl-naphth-3-yl)ethynyl]benzoate (Compound 6)
Employing the same general procedure as for the preparation of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 1), 90 mg (0.3 mmol) of 4-cyclohexyloxy-6-ethynyl-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound N) was converted into the title compound using 88 mg (0.32 mmol) of ethyl 4-iodobenzoate, 70 mg (0.1 mmol) of bis (triphenylphosphine) palladium(II) chloride and 19 mg (0.1 mmol) of cuprous iodide.
PMR (CDCl3) : δ 1.24 (3H, s), 1.27 (3H, s), 1.40 (3H, t, J = 7.1 Hz), 1.26-1.45 (5H, m), 1.55-1.66 (2H, m),
1.75-2.20 (7H, m), 3.45 (1H, m), 4.40 (2H, q, J = 7.1 Hz), 4.46 (1H, t, J = 6.4 Hz), 7.29 (1H, d, J = 8.2 Hz), 7.38 (1H, dd, J = 1.7, 8.2 Hz), 7.56 (1H, d, J =
1.7 Hz), 7.59 (2H, d, J = 8.2 Hz), 8.02 (2H, d, J = 8.2 Hz).
4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoic acid (Compound 7)
To a suspension of 0.30 g (0.87 mmol) of ethyl 4- [(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 1) in 4 ml of THF and 2 ml of ethanol was added 2 ml (2 mmol) of LiOH (1N aqueous solution). The reaction mixture was stirred at room temperature for 4 hours, concentrated in vacuo to near dryness, partitioned between EtOAc and 1 ml of water and acidified to pH 4 with 10% HCl. The aqueous layer was extracted with EtOAc and then the organic layer was dried over Na2SO4 and concentrated in vacuo to give the title compound as a light yellow solid.
PMR (DMSO-d6) : δ 1.39 (6H, s), 1.98 (2H, t, J = 7.0 Hz), 2.70 (2H, t, J = 7.0 Hz), 7.54 (1H, dd, J = 1.5 , 8.1 Hz), 7.73 (2H, d, J = 8.4 Hz), 7.77 (1H, d, J = 1.5 Hz), 7.90 (1H, d, J = 8.1 Hz), 8.00 (2H, d, J = 8.4 Hz).
4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoic acid (Compound 8)
Employing the same general procedure as for the preparation of 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoic acid (Compound 7), 500 mg (1.45 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoate (Compound 2) was converted into the title compound using 4 ml (4 mmol) of LiOH (1 N aqueous solution).
PMR (DMSO-d6) : δ 1.37 (6H, s), 1.99 (2H, t, J = 6.9
Hz), 2.71 (2H, t, J = 6.9 Hz), 7.64 (1H, d, J = 8.2
Hz), 7.70 (2H, d, J = 8.3 Hz), 7.80 (1H, dd, J = 2.0,
8.2 Hz), 7.98 (3H, m).
Ethyl 4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 9)
To a cold solution (0 °C) of 980 mg (2.8 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 1) in 5 ml of THF and 10 ml of ethanol was added 78 mg (2 mmol) of sodium borohydride. The mixture was stirred for 6 hours, diluted with water (10 ml) and extracted with Et2O (4 × 40 ml). The combined organic layers were washed with 10% HCl (5 ml), 10% aqueous NaHCO3 (10 ml) and brine (10 ml), dried over MgSO4 and concentrated in vacuo to give the title compound as a white solid.
PMR (CDCl3): δ 1.25 (3H, s), 1.32 (3H, s), 1.38 (3H, t, J = 7.2 Hz), 1.56-1.65 (1H, m), 1.78-2.15 (4H, m), 4.35 (2H, q, J = 7.2 Hz), 4.70 (1H, q, J = 4.0 Hz), 7.33 (1H, dd, J = 1.5 , 8.1 Hz), 7.41 (1H, d, J = 8.1 Hz), 7.49 (1H, d, J = 1.5 Hz), 7.56 (2H, d, J = 8.4 Hz), 7.98 (2H, d, J = 8.4 Hz).
Ethyl 4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 10)
Employing the same general procedure as for the preparation of ethyl 4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 9), 1 g (2.88 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoate (Compound 2) was converted into the title compound using 60 mg (1.6 mmol) of sodium borohydride. PMR (CDCl3) : δ 1.26 (3H, s), 1.33 (3H, s), 1.40 (3H, t, J = 7.1 Hz), 1.58-1.70 (1H, m), 1.80-1.95 (2H, m), 2.04-2.14 (1H, m), 4.38 (2H, q, J = 7.1 Hz), 4.72 (1H, q, J = 5.1 Hz), 7.32 (1H, d, J = 8.2 Hz), 7.41 (1H, dd, J = 1.8, 8.2 Hz), 7.56 (2H, d, J = 8.5 Hz), 7.65 (1H, d, J = 1.8 Hz), 8.01 (2H, d, J = 8.5 Hz).
Ethyl 6-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-3-yl)ethynyl]nicotinate (Compound 11)
Employing the same general procedure as for the preparation of ethyl 4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 9), 700 mg (2 mmol) of ethyl 6-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]nicotinate (Compound 4) was converted into the title compound using 60 mg (1.6 mmol) of sodium borohydride.
PMR (CDCl3) : δ 1.26 (3H, s), 1.33 (3H, s), 1.42 (3H, t, J = 7.1 Hz), 1.52-1.70 (1H, m), 1.70-1.95 (2H, m), 2.10-2.20 (1H, m), 4.40 (2H, q, J = 7.1 Hz), 4.70 (1H, br s), 7.32 (1H, d, J = 8.0 Hz), 7.48 (1H, d, J = 7.9 Hz), 7.55 (1H, d, J = 8.0 Hz), 7.84 (1H, s), 8.28 (1H, d, J = 7.9 Hz), 9.20 (1H, br s).
Ethyl 4-[(5,6,7,8-tetrahydro-5-(O-methoxymethyl)-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 12)
To a solution of 200 mg (0.57 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 10) in 10 ml of N,N-diisopropylethylamine and 3 ml of CH2Cl2 was added 88 mg (1.2 mmol) of chloromethyl methyl ether. The reaction mixture was stirred for 72 hours, diluted with water (5 ml) and Et2O (100 ml) and then washed with water (10 ml) and brine (10 ml). The organic phase was dried over MgSO4 and then concentrated in vacuo to a yellow oil. Purification by column chromatography (silica, 5% EtOAc-hexane) yielded the title compound as a white solid.
PMR (CDCl3): .5 1.25 (3H, s), 1.34 (3H, s), 1.40 (3H, t, J = 7.5 Hz), 1.55-1.68 (1H, m), 1.88-2.10 (3H, m), 3.50 (3H, s), 4.38 (2H, q, J = 7.5 Hz), 4.63 (1H, t, J = 5.9 Hz), 4.84 (2H, ABq, J = 7.0 , 18 Hz), 7.34 (1H, d, J = 8.2 Hz), 7.42 (1H, dd, J = 1.9, 8.2 Hz), 7.53 (1H, d, J = 1.9 Hz), 7.57 (2H, d, J = 8.2 Hz), 8.01 (2H, d, J = 8.2 Hz).
Ethyl 4-[[5,6,7,8-tetrahydro-5(SR)-(2'(RS)-tetrahydropyranyloxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoate (Compound 13) and Ethyl
4-[[5,6,7,8-tetrahydro-5(SR)-(2'(SR)-tetrahydropyranyloxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoate
(Compound 14)
To a cold solution (0°C) of 680 mg (1.95 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 9) in 25 ml of CH2Cl2 was added 400 mg (4.8 mmol) of
3,4-dihydro-2H-pyran (DHP) followed by 50 mg (0.2 mmol) of pyridinium p-toluenesulfonate (PPTS). The reaction mixture was stirred at ambient temperature for 16 hours and then 1 g of K2CO3 was added. The mixture was stirred for 5 minutes, washed with water (5 ml) and brine (5 ml), dried over MgSO4 and concentrated in vacuo to a gummy mixture of two diastereomers.
Purification by column chromatography (silica, 10% EtOAc-hexane) followed by reverse phase HPLC separation (ODS-2, 5% water-acetonitrile) gave the title compounds as a white solid (RT = 62 minutes) and as a colorless oil (RT = 70 minutes), respectively.
Ethyl 4-[[5,6,7,8-tetrahydro-5(SR)-(2'(RS)-tetrahydropyranyloxy)-8,8-dimethylnaphth-2- yl]ethynyl]benzoate (Compound 13): PMR (CDCl3) : (RT = 62 minutes) δ 1.29 (3H, s), 1.31 (3H, s), 1.41 (3H, t, J = 7.1 Hz), 1.55-1.70 (4H, m), 1.72-1.94 (5H,m), 2.00-2.10 (1H, m), 3.55-3.65 (1H, m), 3.98-4.10 (1H, m), 4.39 (2H, q, J = 7.1 Hz), 4.79 (1H, t, J = 6.3 Hz), 4.90 (1H, d, J = 4.3 Hz), 7.36 (1H, dd, J = 1.7, 8.0 Hz), 7.51 (1H, d, J = 1.7 Hz), 7.53 (1H, d,J = 8.0Hz), 7.60 (2H, d, J = 8.4 Hz), 8.03 (2H, d, J = 8.4 Hz).
Ethyl 4-[[5,6,7,8-tetrahydro-5(SR)-(2'(SR)-tetrahydropyranyloxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoate (Compound 14): PMR (CDCl3) : (RT = 70 minutes) δ 1.28 (3H, s), 1.35 (3H, s), 1.41 (3H, t, J = 7.1 Hz), 1.50-2.20 (10H, m), 3.55-3.62 (1H, m), 3.95-4.05 (1H, m), 4.39 (2H, q, J = 7.1 Hz), 4.66 (1H, t, J = 6.4 Hz), 4.86 (1H, d, J = 3.2 Hz), 7.29 (1H, d, J = 8.2 Hz), 7.33 (1H, dd, J = 1.5 , 8.2 Hz), 7.53 (1H, d, J = 1.5 Hz), 7.60 (2H, d, J = 8.5 Hz), 8.03 (2H, d, J = 8.5 Hz).
Ethyl 4-[[5,6,7,8-tetrahydro-5(RS)-(2'(RS)-tetrahydropyranyloxy)-8,8-dimethylnaphth-3-yl]ethynyl]benzoate (Compound 15) and Ethyl
4-[[5,6,7,8-tetrahydro-5(RS)-(2'(SR)-tetrahydropyranyloxy)-8,8-dimethylnaphth-3-yl]ethynyl]benzoate
(Compound 16)
Employing the same general procedure as for the preparation of ethyl 4-[[5,6,7,8-tetrahydro-5(SR)-(2'(RS)-tetrahydropyranoxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoate (Compound 13) and ethyl
4-[[5,6,7,8-tetrahydro-5(SR)-(2'(SR)-tetrahydropyranoxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoate (Compound 14), 500 mg (1.44 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 10) was converted to a mixture of diastereomers using 400 mg
(4.8 mmol) of 3,4-dihydro-2H-pyran and 50 mg (0.2 mmol) of pyridinium p-toluenesulfonate. HPLC separation
(Partisil 10, 10% EtOAc-hexane) of the diastereomers gave the title compounds (RT = 65 and 70 minutes), respectively.
Ethyl 4-[[5,6,7,8-tetrahydro-5(RS)-(2'(RS)-tetrahydropyranyloxy)-8,8-dimethylnaphth-3-yl]ethynyl]benzoate (Compound 15): PMR (CDCl3) : (RT =
65 minutes) δ 1.26 (3H,s), 1.32 (3H,s), 1.43 (3H, t, J
= 7.1Hz), 1.51-2.20 (10H, m), 3.55-3.62 (1H, m), 3.95- 4.05 (1H, m), 4.39 (2H, q, j = 7.1 Hz), 4.64 (1H, t, J
= 5.9 Hz), 4.89 (1H, t, J = 2.9 Hz), 7.33 (1H, d, J =
8.2 Hz), 7.41 (1H, dd, J = 1.8, 8.2 Hz), 7.46 (1H, d, J
= 1.8 Hz), 7.57 (2H, d, J = 8.2 Hz), 8.01 (2H, d, J =
8.2 Hz).
Ethyl 4-[[5,6,7,8-tetrahydro-5(RS)-(2'(SR)-tetrahydropyranyloxy)-8,8-dimethylnaphth-3-yl]ethynyl]benzoate (Compound 16) : PMR (CDCl3) : (RT =
70 minutes) δ 1.26 (3H,s), 1.32 (3H,s), 1.40 (3H, t, J
= 7.1Hz), 1.52-1.68 (5H, m), 1.72-1.95 (4H, m), 1.96- 2.10 (1H, m), 3.55-3.65 (1H, m), 4.00-4.10 (1H, m),
4.38 (2H, q, j = 7.1 Hz), 4.77 (1H, t, J = 6.1 Hz),
4.89 (1H, t, J = 2.5 Hz), 7.30 (1H, d, J = 8.2 Hz),
7.40 (1H, dd, J = 1.8, 8.2 Hz), 7.57 (2H, d, J = 8.5
Hz), 7.68 (1H, d, J = 1.8 Hz),8.01 (2H, d, J = 8.5 Hz).
Ethyl 6-[[5,6,7,8-tetrahydro-5(RS)-(2'(RS)-tetrahydropyranyloxy)-8,8-dimethylnaphth-3-yl]ethynyl]nicotinate (Compound 17) and Ethyl 4- [[5,6,7,8-tetrahydro-5(RS)-(2'(SR)-tetrahydropyranoxy)-8,8-dimethylnaphth-3-yl]ethynyl]nicotinate (Compound
18)
Employing the same general procedure as for the preparation of ethyl 4-[[5,6,7,8-tetrahydro-5(SR)- (2'(RS)-tetrahydropyranoxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoate (Compound 13) and ethyl
4-[[5,6,7,8-tetrahydro-5(SR)-(2'(SR)-tetrahydropyranoxy)-8,8-dimethyl]naphth-2-yl]ethynyl]benzoate (Compound 14), 600 mg (1.39 mmol) of ethyl 6-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-3-yl)ethynyl]nicotinate (Compound 11) was converted to a mixture of diastereomers using 440 mg (5.3 mmol) of 3,4-dihydro-2H-pyran and 50 mg (0.2 mmol) of pyridinium p-toluenesulfonate. Normal phase HPLC separation (Partisil 10, 10% EtOAc-hexane) gave the title compounds (RT = 82 minutes and 88 minutes) respectively.
Ethyl 6-[[5,6,7,8-tetrahydro-5(RS)-(2'(RS)-tetrahydropyranyloxy)-8,8-dimethylnaphth-3-yl]ethynyl]nicotinate (Compound 17) : PMR (CDCl3) :
(RT = 82 minutes) δ 1.24 (3H,s), 1.31 (3H,s), 1.40 (3H, t, J = 7.2 Hz), 1.50-2.25 (10H, m), 3.52-3.61 (1H, m), 3.92-4.02 (1H, m), 4.41 (2H, q, J = 7.2 Hz), 4.62 (1H, t, J = 6.2 Hz), 4.87 (1H, t, J = 2.5 Hz), 7.32 (1H, d, J = 8.0 Hz), 7.47 (1H, dd, J = 1.8, 8.0 Hz), 7.54 (1H,br s), 7.56 (1H, d, J = 8.3 Hz), 8.25 (1H, dd, J = 2.2 , 8.3 Hz), 9.18 (1H, d, J = 2.2 Hz).
Ethyl 4-[[5,6,7,8-tetrahydro-5(RS)-(2'(SR)-tetrahydropyranyloxy)-8,8-dimethylnaphth-3-yl]ethynyl]nicotinate (Compound 18): PMR (CDCl3) :
(RT = 82 minutes) δ 1.26 (3H,s), 1.32 (3H,s), 1.42 (3H, t, J = 7.1 Hz), 1.50-1.68 (5H, m), 1.73-1.80 (1H, m), 1.80-1.95 (3H, m), 1.95-2.00 (1H, m), 3.55-3.65 (1H, m), 4.00-4.10 (1H, m), 4.42 (2H, q, J = 7.1 Hz), 4.78 (1H, t, J = 5.8 Hz), 4.90 (1H,br s), 7.32 (1H, d, J = 8.2 Hz), 7.48 (1H, dd, J = 1.7, 8.2 Hz), 7.59 (1H, dd, J = 1.7 , 8.2 Hz), 7.76 (1H, br s), 8.27 (1H, dd, J = 2.2 , 8.2 Hz), 9.20 (1H, d, J = 2.2 Hz).
Ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-(oxime)naphth-3-yl)ethynyl]benzoate (Compound 19)
A solution of 500 mg (1.44 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3¬yl)ethynyl]benzoate (Compound 2), 110 mg (1.6 mmol) of hydroxylamine hydrochloride and 431 mg (3.2 mmol) of sodium acetate in 5 ml of EtOH was stirred at ambient temperature for 16 hours. The mixture was diluted with water (10 ml) and extracted with EtOAc (3 × 30 ml). The organic layer was washed with water (5 ml) and brine (10 ml), dried over MgSO4 and concentrated in vacuo. Recrystallization from EtOAc-hexane yielded the title compound as a white solid.
PMR (CDCl3) : δ 1.30 (6H, s), 1.41 (3H, t, J = 7.2 Hz), 1.75 (2H, t, J = 7.0 Hz), 2.90 (2H, t, J = 7.0 Hz),
4.39 (2H, q, J = 7.2 Hz), 7.35 (1H, d, J = 8.1 Hz), 7.48 (1H, d, J = 8.1 Hz), 7.57 (2H, d, J = 8.2 Hz), 8.02 (2H, d, J = 8.2 Hz), 8.08 (1H, d, J = 1.5 Hz).
Ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5- (oxime)naphth-2-yl)ethynyl]benzoate (Compound 20)
Employing the same general procedure as for the preparation of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-(oxime)naphth-3-yl)ethynyl]benzoate
(Compound 19), 346 mg (1.0 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 1) was converted into the title compound using 125 mg (1.8 mmol) of hydroxylamine hydrochloride and 485 mg (3.6 mmol) of sodium acetate trihydrate.
PMR (CDCl3) : δ 1.34 (6H, s), 1.42 (3H, t, J = 7.1 Hz), 1.78 (2H, t, J = 6.2 Hz), 2.89 (2H, t, J = 6.2 Hz),
4.40 (2H, q, J = 7.1 Hz), 7.37 (1H, dd, J = 1.9, 7.9 Hz), 7.56 (1H, d, J = 1.9 Hz), 7.60 (2H, d, J = 8.2 Hz), 7.91 (1H, d, J = 7.9 Hz), 8.04 (2H, d, J = 8.2 Hz).
Ethyl 6-[(5,6,7,8-tetrahydro-8,8-dimethyl-5- (oxime)naphth-2-yl)ethynyl]nicotinate (Compound 21)
Employing the same general procedure as for the preparation of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-(oxime)naphth-3-yl)ethynyl]benzoate
(Compound 19), 200 mg (0.58 mmol) of ethyl 6-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]nicotinate (Compound 5) was converted into the title
compound using 126 mg (1.8 mmol) of hydroxylamine hydrochloride and 286 mg (2.1 mmol) of sodium acetate trihydrate.
PMR (CDCl3) : δ 1.31 (6H, s), 1.43 (3H, t, J = 7.1 Hz), 1.77 (2H, t, J = 7.0 Hz), 2.88 (2H, t, J = 7.0 Hz), 4.44 (2H, q, J = 7.1 Hz), 7.41 (1H, d, J = 8.1 Hz), 7.62 (1H, d, J = 8.5Hz), 7.65 (1H, s), 7.90 (1H, d, J = 8.1 Hz), 8.31 (1H, dd, J = 2.2, 8.5 Hz), 9.23 (1H, d, J = 2.2 Hz).
Ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-anti-(O-methyl oxime)naphth-2-yl)ethynyl]benzoate (Compound 22) and Ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-syn-(O-methyl oxime)naphth-2-yl)ethynyl]benzoate (Compound 23)
Employing the same general procedure as for the preparation of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-(oxime)naphth-3-yl)ethynyl]benzoate
(Compound 19), 1 g (2.9 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 1) was converted into a mixture of isomers using 1.02 g (12 mmol) of O-methyl-hydroxylamine hydrochloride and 2.34 g (18 mmol) of sodium acetate trihydrate. Purification by column chromatography (silica, 5 % EtOAc-hexane) gave a 6:1 ratio of the title compounds, respectively.
Ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-anti-(O-methyl oxime)naphth-2-yl)ethynyl)benzoate (Compound 22): PMR (CDCl3) : δ 1.31 (6H, s), 1.41 (3H, t, J = 7.1 Hz), 1.73 (2H, t, J = 6.3 Hz), 2.79 (2H, t, J = 6.3 Hz), 4.02 (3H, s), 4.39 (2H, q, J = 7.1 Hz), 7.36 (1H, dd, J = 1.7 , 8.3 Hz), 7.54 (1H, d, J = 1.7 Hz), 7.60 (2H, d, J = 8.3 Hz), 7.98 (1H, d, J = 8.3 Hz), 8.03 (2H, d, J = 8.3 Hz).
Ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-syn-(O-methyl oxime)naphth-2-yl)ethynyl]benzoate (Compound 23): PMR (CDCl3) : δ 1.36 (6H, s), 1.42 (3H, t, J = 7.1 Hz), 1.90 (2H, t, J = 6.5 Hz), 2.56 (2H, t, J = 6.5 Hz), 3.97 (3H, s), 4.40 (2H, q, J = 7.1 Hz), 7.37 (1H, dd, J = 1.5 , 8.3 Hz), 7.57 (1H, d, J = 1.5 Hz), 7.61 (2H, d, J = 8.6 Hz), 8.04 (2H, d, J = 8.6 Hz), 8.40 (1H, d, J = 8.3 Hz).
Ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-anti-(O-ethyl oxime)naphth-2-yl)ethynyl]benzoate (Compound 24) and Ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-syn-(O-ethyl oxime)naphth-2-yl)ethynyl]benzoate (Compound 25)
Employing the same general procedure as for the preparation of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-(oxime)naphth-3-yl)ethynyl]benzoate
(Compound 19), 200 mg (0.6 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 1) was converted into a mixture of isomers using 185 mg (1.9 mmol) of O-ethylhydroxylamine hydrochloride and 290 mg (2.2 mmol) of sodium acetate trihydrate. Purification by column chromatography (silica, 5% EtOAc-hexane) gave a 9:1 ratio of the title compounds, respectively. Ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-anti-(O-ethyl oxime)naphth-2-yl)ethynyl]benzoate (Compound 24): PMR (CDCl3): δ 1.31 (6H, s), 1.35 (3H, t, J = 7.1 Hz),
1.41 (3H, t, J = 7.1 Hz), 1.74 (2H, t, J = 6.9 Hz), 2.80 (2H, t, J = 6.9 Hz), 4.27 (2H, q, J = 7.1 Hz), 4.40 (2H, q, J = 7.1 Hz), 7.35 (1H, dd, J = 1.7 , 8.2 Hz), 7.56 (1H, d, J = 1.7 Hz), 7.60 (2H, d, J = 8.3 Hz), 8.00 (1H, d, J = 8.2 Hz), 8.04 (2H, d, J = 8.3 Hz).
Ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-syn-(O-ethyl oxime)naphth-2-yl)ethynyl]benzoate (Compound 25): PMR (CDCl3) : δ 1.35 (6H, s), 1.35 (3H, t, J = 7.1 Hz),
1.42 (3H, t, J = 7.1 Hz), 1.89 (2H, t, J = 6.2 Hz), 2.58 (2H, t, J = 6.2 Hz), 4.22 (2H, q, J = 7.1 Hz), 4.40 (2H, q, J = 7.1 Hz), 7.37 (1H, dd, J = 1.8, 8.3 Hz), 7.58 (1H, d, J = 1.8 Hz), 7.61 (2H, d, J = 8.2 Hz), 8.04 (2H, d, J = 8.2 Hz), 8.47 (1H, d, J = 8.3 Hz).
Ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-anti-(O-methyl oxime)naphth-3-yl)ethynyl]benzoate (Compound 26) and Ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-syn-(O-methyl oxime)naphth-3-yl)ethynyl]benzoate (Compound 27)
Employing the same general procedure as for the preparation of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-(oxime)naphth-2-yl)ethynyl]benzoate
(Compound 19), 200 mg (0.6 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzo- ate (Compound 2) was converted into a mixture of isomers using 510 mg (6 mmol) of O-methylhydroxylamine hydrochloride and 1.17 g (9 mmol) of sodium acetate trihydrate. Purification by column chromatography (silica, 5% EtOAc-hexane) followed by HPLC separation (Partisil 10, 5% EtOAc-hexane) gave a 7:1 ratio of the title compounds (tR = 12 minutes and 25 minutes), respectively.
Ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-anti-(O-methyl oxime)naphth-3-yl)ethynyl]benzoate (Compound 26): PMR (CDCl3): (tR = 12 minutes) δ 1.28 (6H, s), 1.41 (3H, t, J = 7.1 Hz), 1.72 (2H, t, J = 6.4 Hz), 2.79 (2H, t, J = 6.4 Hz), 4.03 (3H, s), 4.39 (2H, q, J = 7.1 Hz), 7.33 (1H, d, J = 8.1 Hz), 7.46 (1H, dd, J = 1.8, 8.1 Hz), 7.58 (2H, d, J = 8.3 Hz), 8.03 (2H, d, J = 8.3 Hz), 8.17 (1H, d, J = 1.8 Hz).
Ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-syn-(O-methyl oxime)naphth-3-yl)ethynyl]benzoate (Compound 27): PMR (acetone-d6) : (tR - 25 minutes) δ 1.33 (6H, s), 1.34 (3H, t, J = 7.1 Hz), 1.86 (2H, t, J = 6.3 Hz), 2.53 (2H, t, J = 6.3 Hz), 3.90 (3H, s), 4.37 (2H, q, J = 7.1 Hz), 7.56 (2H, s), 7.66 (2H, d, J = 8.4 Hz), 8.02 (2H, d, J = 8.4 Hz), 8.57 (1H, s).
Ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-anti-(O-ethyl oxime)naphth-3-yl)ethynyl]benzoate (Compound 28) andEthyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-syn-(O-ethyl oxime)naphth-3-yl)ethynyl]benzoate (Compound 29)
Employing the same general procedure as for the preparation of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-(oxime)naphth-3-yl)ethynyl]benzoate
(Compound 19), 200 mg (0.6 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoate (Compound 2) was converted into a mixture of isomers using 185 mg (1.9 mmol) of O- ethylhydroxylamine hydrochloride and 290 mg (2.2 mmol) of sodium acetate trihydrate. Purification by column chromatography (silica, 5% EtOAc-hexane) followed by HPLC separation (Partisil 10, 5% EtOAc-hexane) gave a 6.6 : 1 ratio of the title compounds (tR = 15 minutes and 20 minutes), respectively.
Ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-anti-(O-ethyl oxime)naphth-3-yl)ethynyl]benzoate (Compound 28) : PMR (CDCl3) : (tR = 15 minutes) δ 1.30 (6H, s), 1.36 (3H, t, J = 7.1 Hz), 1.41 (3H, t, J = 7.1 Hz), 1.73 (2H, t, J = 7.0 Hz), 2.81 (2H, t, J = 7.0 Hz), 4.28 (2H, q, J = 7.1 Hz), 4.40 (2H, q, J = 7.1 Hz), 7.34 (1H, d, J = 8.2 Hz), 7.46 (1H, dd, J = 1.8 , 8.2 Hz), 7.59 (2H, d, J = 8.6 Hz), 8.02 (2H, d, J = 8.6 Hz), 8.17 (1H, d, J = 1.8 Hz).
Ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-syn-(O-ethyl oxime)naphth-3-yl)ethynyl]benzoate (Compound 29): PMR (acetone-d6) : (tR = 20 minutes) δ 1.30 (3H, t, J = 7.1 Hz), 1.33 (6H, s), 1.37 (3H, t, J = 7.1 Hz), 1.86 (2H, t, J = 6.3 Hz), 2.53 (2H, t, J = 6.3 Hz), 4.16 (2H, q, J = 7.1 Hz), 4.35 (2H, q, J = 7.1 Hz), 7.56 (2H, s), 7.66 (2H, d, J = 7.6 Hz), 8.03 (2H, d, J = 7.6 Hz), 8.65 (1H, s).
Ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-anti-(O-(2-tetrahydropyranyl) oxime)naphth-3-yl)ethynyl]benzoate (Compound 30)
Employing the same general procedure as for the preparation of ethyl 4-[[5,6,7,8-tetrahydro-5(SR)-(2'(RS)-tetrahydropyranoxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoate (Compound 13) and ethyl
4-[[5,6,7,8-tetrahydro-5(SR)-(2'(SR)-tetrahydropyranoxy)-8,8-dimethyl]naphth-2-yl]ethynyl]benzoate (Compound 14), 200 mg (0.55 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-(oxime)naphth-3-yl)ethynyl]benzoate (Compound 19) was converted into the title compound using 84 mg (1 mmol) of 3,4-dihydro-2H-pyran and 14 mg (0.06 mmol) of pyridinium p.-toluenesulfonate. PMR (CDCl3) : δ 1.29 (3H, s), 1.30 (3H, s), 1.40 (3H, t, J = 7.1 Hz), 1.55-1.70 (4H, m), 1.75 (2H, t, J = 6.0 Hz), 1.80-1.92 (2H, m), 2.80-3.00 (2H, m), 3.55-3.72 (1H, m), 3.90-4.00 (1H, m), 4.38 (2H, q, J = 7.1 Hz), 5.44 (1H, t, J = 4.6 Hz), 7.33 (1H, d, J = 7.8 Hz), 7.46 (1H, dd, J = 1.9, 7.8 Hz), 7.57 (2H, d, J = 8.1 Hz), 8.01 (2H, d, J = 8.1 Hz), 8.24 (1H, d, J = 1.9 Hz).
Ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-anti-(O-(2-tetrahydropyranyl) oxime)naphth-2-yl)ethynyl]benzoate (Compound 31)
Employing the same general procedure as for the preparation of ethyl 4-[[5,6,7,8-tetrahydro-5(SR)-(2'(RS)tetrahydropyranoxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoate (Compound 13) and ethyl
4-[[5,6,7,8-tetrahydro-5(SR)-(2'(SR)-tetrahydropyranoxy)-8,8-dimethyl]naphth-2-yl]ethynyl]benzoate (Compound 14), 346 mg (1 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-(oxime)naphth-2-yl)ethynyl]benzoate (Compound 20) was converted into the title compound using 420 mg (5 mmol) of 3,4-dihydro-2H-pyran and 10 mg (0.04 mmol) of pyridinium p-toluenesulfonate.
PMR (CDCl3): 5 1.32 (3H, s), 1.33 (3H, s), 1.41 (3H, t, J = 7.1 Hz), 1.56-1.70 (3H, m), 1.75 (2H, t, J = 6.0 Hz), 1.80-1.95 (3H, m), 2.80-3.05 (2H, m), 3.65-3.74 (1H, m), 3.90-4.00 (1H, m), 4.40 (2H, q, J = 7.1 Hz), 5.42 (1H, t, J = 3.0 Hz), 7.34 (1H, dd, J = 1.9, 8.0 Hz), 7.53 (1H, d, J = 1.9 Hz), 7.60 (2H, d, J = 8.2 Hz), 8.03 (2H, d, J = 8.2 Hz), 8.06 (1H, d, J = 8.0 Hz).
4-[[5,6,7,8-tetrahydro-5(SR)-(2'(RS)-tetrahydropyranyloxy)-8,8-dimethylnaphth-2- yl]ethynyl]benzoic acid (Compound 32)
To a solution of 75 mg ( 0.17mmol) of ethyl 4- [[5,6,7,8-tetrahydro-5(SR)-(2'(RS)-tetrahydropyranoxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoate (Compound 13) in 3 ml of THF and 1 ml of methanol was added 0.5 ml (0.5 mmol) of LiOH (1M aqueous solution). The mixture was refluxed for 2 hours, cooled to ambient
temperature, diluted with 100 ml of Et2O:EtOAc (1:1, v/v) and acidified to pH 5 with ice-cold 10% HCl. The organic phase was washed with water ( 10 ml) and brine ( 10 ml ) , dried with MgSO4 and concentrated in vacuo to yield the title compound as a white solid.
PMR (CDCl3) : δ 1.29 (3H, s), 1.34 (3H, s), 1.55-1.70 (4H, m), 1.72-1.95 (5H, m), 2.00-2.10 (1H, m), 3.55-3.65 (1H, m), 4.00-4.10 (1H, m), 4.78 (1H, t, J = 6.3 Hz), 4.92 (1H, s), 7.34 (1H, dd, J = 1.5, 8.0 Hz), 7.51 (1H, d, J = 1.5 Hz), 7.53 (1H, d, J = 8.0 Hz), 7.63 (2H, d, J = 8.3 Hz), 8.09 (2H, d, J = 8.3 Hz).
4-[[5,6,7,8-tetrahydro-5(RS)-(2'(RS)-tetrahydropyranyloxy)-8,8-dimethylnaphth-3-yl]ethynyl]benzoic acid (Compound 33)
Employing the same general procedure as for the preparation of 4-[[5,6,7,8-tetrahydro-5(SR)-(2'(RS)-tetrahydropyranoxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoic acid (Compound 32), 80 mg (0.19 mmol) of ethyl 4-[[5,6,7,8-tetrahydro-5(RS)-(2'(RS)-tetrahydropyranoxy)-8,8-dimethylnaphth-3-yl]ethynyl]benzoate (Compound 15) was converted into the title compound using 1 ml (1 mmol) of LiOH (1M aqueous solution).
PMR (CDCl3) : δ 1.26 (3H, s), 1.33 (3H, s), 1.60-2.10 (10H, m), 3.55-3.65 (1H, m), 3.95-4.05 (1H, m), 4.65 (1H, t, J = 5.5 Hz), 4.90 (1H, t, J = 2.9 Hz), 7.34 (1H, d, J = 8.2 Hz), 7.42 (1H, dd, J = 1.8 , 8.2 Hz), 7.46 (1H, d, J = 1.8 Hz), 7.61 (2H, d, J = 8.2 Hz), 8.07 (2H, d, J = 8.2 Hz).
4-[[5,6,7,8-tetrahydro-5(RS)-(2'(SR)-tetrahydropyranyloxy)-8,8-dimethylnaphth-3-yl]ethynyl]benzoic acid (Compound 34)
Employing the same general procedure as for the preparation of 4-[[5,6,7,8-tetrahydro-5(SR)-(2'(RS)-tetrahydropyranoxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoic acid (Compound 32), 100 mg (0.23 mmol) of ethyl 4-[[5,6,7,8-tetrahydro-5(RS)-(2'(SR)-tetrahydropyranoxy)-8,8-dimethylnaphth-3-yl]ethynyl]benzoate (Compound 16) was converted into the title compound using 0.6 ml (0.6 mmol) of LiOH (1M aqueous solution).
PMR (DMSO-d6) : δ 1.22 (3H, s), 1.27 (3H, s), 1.40-1.60 (5H, m), 1.62-1.86 (4H, m), 1.90-2.05 (1H, m), 3.50-3.60 (1H, m), 3.87-4.00 (1H, m), 4.68 (1H, t, J = 5.5 Hz), 4.80-4.85 (1H, m), 7.45 (2H, s), 7.54 (1H, s), 7.67 (2H, d, J = 8.4 Hz), 7.97 (2H, d, J = 8.4 Hz).
4-[[5,6,7,8-tetrahydro-5(SR)-(2'(SR)-tetrahydropyranyloxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoic acid (Compound 35)
Employing the same general procedure as for the preparation of 4-[[5,6,7,8-tetrahydro-5(SR)-(2'(RS)-tetrahydropyranoxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoic acid (Compound 32), 70 mg (0.16 mmol) of ethyl 4-[[5,6,7,8-tetrahydro-5(SR)-(2'(SR)-tetrahydropyranoxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoate (Compound 14) was converted into the title compound using 0.5 ml (0.5 mmol) of LiOH (1M aqueous solution).
PMR (CDCl3) : δ 1.29 (3H, s), 1.35 (3H, s), 1.50-2.15 (10H, m), 3.55-3.65 (1H, m), 3.95-4.05 (1H, m), 4.66 (1H, t, J = 5.1 Hz), 4.87 (1H, br, s), 7.29 (2H, d, J = 8.1 Hz), 7.34 (1H, dd, J = 1.6, 8.1 Hz), 7.53 (1H, br s), 7.63 (2H, d, J = 8.2 Hz), 8.10 (2H, d, J = 8.2 Hz) 6-[[5,6,7,8-tetrahydro-5(RS)-(2'(RS)-tetrahydropyranyloxy)-8,8-dimethylnaphth-3-yl]ethynyl]nicotinic acid (Compound 36)
Employing the same general procedure as for the preparation of 4-[[5,6,7,8-tetrahydro-5(SR)-(2'(RS)-tetrahydropyranoxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoic acid (Compound 32), 150 mg (0.38 mmol) of ethyl 6-[[5,6,7,8-tetrahydro-5(RS)-(2'(RS)-tetrahydropyranoxy)-8,8-dimethylnaphth-3-yl]ethynyl]nicotinate (Compound 17) was converted into the title compound using 1 ml (1 mmol) of LiOH (1M aqueous solution).
PMR (CDCl3) : δ 1.26 (3H, s), 1.33 (3H, s), 1.50-2.25 (10H, m), 3.55-3.65 (1H, m), 3.95-4.05 (1H, m), 4.65 (1H, t, J = 6.0 Hz), 4.90 (1H, t, J = 2.2 Hz), 7.34 (1H, d, J = 8.2 Hz), 7.50 (1H, dd, J = 1.9 , 8.2 Hz), 7.55 (1H, d, J = 1.9 Hz), 7.61 (1H, d, J = 8.0 Hz), 8.35 (1H, dd, J = 2.2 , 8.0 Hz), 9.29 (1H, d, J = 2.2 Hz).
6-[[5,6,7,8-tetrahydro-5(RS)-(2'(SR)-tetrahydropyranyloxy)-8,8-dimethylnaphth-2-yl]ethynyl]nicotinic acid (Compound 37)
Employing the same general procedure as for the preparation of 4-[[5,6,7,8-tetrahydro-5(SR)-(2'(RS)-tetrahydropyranoxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoic acid (Compound 32), 166 mg (0.38 mmol) of ethyl 6-[[5,6,7,8-tetrahydro-5(RS)-(2'(RS)-tetrahydropyranoxy)-8,8-dimethylnaphth-3-yl]ethynyl]nicotinate (Compound 18) was converted into the title compound using 1 ml (1 mmol) of LiOH (1M aqueous solution).
PMR (CDCl3) : δ 1.26 (3H, s), 1.32 (3H, s), 1.50-1.68 (5H, m), 1.73-1.80 (1H, m), 1.80-1.95 (3H, m), 1.95-2.00 (1H, m), 3.57-3.68 (1H, m), 4.05-4.15 (1H, m), 4.80 (1H, t, J = 5.8 Hz), 4.90 (1H, br s), 7.32 (1H, d, J = 8.2 Hz), 7.48 (1H, dd, J = 1.7, 8.2 Hz), 7.56 (1H, d, J = 8.2 Hz), 7.76 (1H, br s), 8.34 (1H, dd, J = 2.2 , 8.2 Hz), 9.28 (1H, d, J = 2.2 Hz).
4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-anti-(O-(2-tetrahydropyranyl) oxime)naphth-3-yl)ethynyl]benzoic acid (Compound 38)
Employing the same general procedure as for the preparation of 4-[[5,6,7,8-tetrahydro-5(SR)-(2'(RS)-tetrahydropyranoxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoic acid (Compound 32), 124 mg (0.34 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-anti-(O-(2-tetrahydropyranyl) oxime)naphth-3-yl)ethynyl]benzoate (Compound 30) was converted into the title compound using 1 ml (1 mmol) of LiOH (1M aqueous solution).
PMR (DMS0-d6) : δ 1.25 (6H, s), 1.50-1.80 (8H, m), 2.65-2.90 (2H, m), 3.50-3.60 (1H, m), 3.70-3.80 (1H, m), 5.36 (1H, br s), 7.49 (1H, d, J = 8.0 Hz), 7.56 (1H, dd, J = 1.9, 8.0 Hz), 7.68 (2H, d, J = 8.2 Hz), 7.94 (2H, d, J = 8.2 Hz), 8.01 (1H, d, J = 1.9 Hz).
4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-anti-(O-(2-tetrahydropyranyl) oxime)naphth-2-yl)ethynyl]benzoic acid (Compound 39)
Employing the same general procedure as for the preparation of 4-[[5,6,7,8-tetrahydro-5(SR)-(2'(RS)-tetrahydropyranoxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoic acid (Compound 32), 160 mg (0.37 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-anti-(O-(2-tetrahydropyranyl) oxime)naphth-2-yl)ethynyl]benzoate (Compound 31) was converted into the title compound using 1 ml (1 mmol) of LiOH (1M aqueous solution).
PMR (CDCl3): δ 1.32 (3H, s), 1.33 (3H, s), 1.56-1.95
(8H, m), 2.78-3.02 (2H, m), 3.65-3.75 (1H, m), 3.93- 4.02 (1H, m), 5.45 (1H, br s), 7.31 (1H, dd, J = 1.5 ,
8.1 Hz), 7.53 (1H, d, J = 1.5 Hz), 7.62 (2H, d, J = 8.2 Hz), 8.04 (1H, d, J = 8.1 Hz), 8.06 (2H, d, J = 8.2 Hz).
6-[(5,6,7,8-tetrahydro-8,8-dimethylnaphth-2-yl)ethynyl]nicotinic acid (Compound 40)
Employing the same general procedure as for the preparation of 4-[[5,6,7,8-tetrahydro-5(SR)-(2'(RS)-tetrahydropyranoxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoic acid (Compound 32), 306 mg (0.92 mmol) of ethyl 6-[(5,6,7,8-tetrahydro-8,8-dimethylnaphth-2-yl)ethynyl]nicotinate (Compound 4) was converted into the title compound using 2 ml (2 mmol) of LiOH (1M aqueous solution).
PMR (DMSO-d6) : δ 1.27 (6H, s), 1.60-1.66 (2H, m), 1.70-1.80 (2H, m), 2.76 (2H, t, J = 6.3 6z), 7.13 (1H, d, J = 8.0 Hz), 7.32 (1H, dd, J = 1.7, 8.0 Hz), 7.62 (1H, d, J = 1.7 Hz), 7.74 (1H, d, J = 8.0 Hz), 8.28 (1H, dd, J = 2.1 , 8.1 Hz), 9.06 (1H, d, J = 2.1 Hz). 4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-3-yl)ethynyl]benzoic acid (Compound 41)
Employing the same general procedure as for the preparation of 4-[[5,6,7,8-tetrahydro-5(SR)-(2'(RS)-tetrahydropyranoxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoic acid (Compound 32), 272 mg (0.78 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8- dimethylnaphth-3-yl)ethynyl]benzoate (Compound 10) was converted into the title compound using 2 ml (2 mmol) of LiOH (1M aqueous solution).
PMR (acetone-d6) : δ 1.28 (3H, s), 1.31 (3H, s), 1.60-1.70 (1H, m), 1.80-1.96 (2H, m), 2.00-2.12 (1H, m), 4.67 (1H, t, J = 7.1 Hz), 7.42 (2H, br s), 7.67 (1H, d, J = 8.2 Hz), 7.69 (1H, br S), 8.07 (2H, d, J = 8.2 Hz). 4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-2-yl)ethynyl]benzoic acid (Compound 42)
Employing the same general procedure as for the preparation of 4-[[5,6,7,8-tetrahydro-5(SR)-(2'(RS)-tetrahydropyranoxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoic acid (Compound 32), 110 mg (0.31 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 9) was converted into the title compound using 1 ml (1 mmol) of LiOH (1M aqueous solution).
PMR (acetone-d6) : δ 1.28 (3H, s), 1.31 (3H, s), 1.58-1.70 (1H, m), 1.76-1.92 (2H, m), 1.98-2.10 (1H, m), 4.66 (1H, t, J = 5.1 Hz), 7.35 (1H, dd, J = 1.6, 7.9 Hz), 7.53 (1H, d, J = 7.9 Hz), 7.65 (2H, d, J = 8.1 Hz), 8.05 (2H, d, J = 8.1 Hz).
4-[(5,6,7,8-tetrahydro-5-(O-methoxymethyl)-8,8-dimethylnaphth-3-yl)ethynyl]benzoic acid (Compound 43)
Employing the same general procedure as for the preparation of 4-[[5,6,7,8-tetrahydro-5(SR)-(2'(RS)-tetrahydropyranoxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoic acid (Compound 32), 150 mg (0.38 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-5-(O-methoxymethyl)-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 12) was converted into the title compound using 1 ml (1 mmol) of LiOH (1M aqueous solution).
PMR (CDCl3) : δ 1.25 (3H, s), 1.34 (3H, s), 1.55-1.68 (1H, m), 1.88-2.10 (3H, m), 3.50 (3H, s), 4.64 (1H, t, J = 5.9 Hz), 4.84 (2H, ABq, J = 7.0 , 18 Hz), 7.34 (1H, d, J = 8.2 Hz), 7.43 (1H, dd, J = 1.9, 8.2 Hz), 7.53 (1H, d, J = 1.9 Hz), 7.60 (2H, d, J = 8.2 Hz), 8.07 (2H, d, J = 8.2 Hz).
6-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]nicotinic acid (Compound 44)
Employing the same general procedure as for the preparation of 4-[[5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl]ethynyl]benzoic acid (Compound 7), 300 mg (0.86 mmol) of ethyl 6-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]nicotinate (Compound 3) was converted into the title compound (pale yellow solid) using 8.6 ml (8.6 mmol) of LiOH (1M aqueous solution).
PMR (DMSO-d6) : PMR δ 1.38 (6H, s), 1.99 (2H, t, J = 6 Hz), 2.72 (2H, t, J = 6 Hz), 7.68 (1H, d, J = 8.2 Hz), 7.82 (1H, d, J = 8.5 Hz), 7.86 (1H, dd, 3 = 2 , 8.2 Hz), 8.04 (1H, d, J = 2 Hz), 8.30 (1H, dd, J = 1.9, 7.9 Hz), 9.07 (1H, d, 1.9 Hz).
4-[(5-cyclohexyloxy-5,6,7,8-tetrahydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoic acid (Compound 45)
Employing the same general procedure as for the preparation of 4-[[5,6,7,8-tetrahydro-5(SR)-(2'(RS)-tetrahydropyranoxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoic acid (Compound 32), 10 mg (0.02 mmol) of ethyl 4-[(5-cyclohexyloxy-5,6,7,8-tetrahydro-8,8-dimethyl-naphth-3-yl)ethynyl]benzoate (Compound 6) was converted into the title compound using 0.6 ml (0.6 mmol) of LiOH (1M aqueous solution).
PMR (CDCl3) : 5 1.27 (3H, s), 1.32 (3H, s), 1.25-1.50 (5H, m), 1.52-1.62 (3H, m), 1.75-2.20 (6H, m), 3.45-3.58 (1H, m), 4.46 (1H, t, J = 6.5 Hz), 7.30 (1H, d, J = 8.2 Hz), 7.39 (1H, dd, J = 1.9, 8.2 Hz), 7.57 (1H, d, J = 1.9 Hz), 7.62 (2H, d, J = 8.5 Hz), 8.08 (2H, d, J = 8.5 Hz).
4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-(oxime)naphth-3-yl)ethynyl]benzoic acid (Compound 46)
Employing the same general procedure as for the preparation of 4-[[5,6,7,8-tetrahydro-5(SR)-(2'(RS)-tetrahydropyranoxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoic acid (Compound 32), 217 mg (0.6 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-(oxime)naphth-3-yl)ethynyl]benzoate (Compound 19) was converted into the title compound using 2 ml (2 mmol) of LiOH (1M aqueous solution).
PMR (CD3OD) : δ 1.30 (6H, s), 1.74 (2H, t, J = 7.0 Hz), 2.82 (2H, t, J = 7.0 Hz), 4.92 (1H, br s), 7.41-7.48 (2H, m), 7.60 (2H, d, J = 8.2 Hz), 8.02 (2H, d, J = 8.2 Hz), 8.06 (1H, d, J = 1.5 Hz).
4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-(oxime)naphth-2-yl)ethynyl]benzoic acid (Compound 47)
Employing the same general procedure as for the preparation of 4-[[5,6,7,8-tetrahydro-5(SR)-(2'(RS)-tetrahydropyranoxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoic acid (Compound 32), 150 mg (0.4 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-(oxime)naphth-2-yl)ethynyl]benzoate (Compound 20) was converted into the title compound using 2 ml (2 mmol) of LiOH (1M aqueous solution).
PMR (CD3OD) : δ 1.11 (6H, s), 1.54 (2H, t, J = 6.0 Hz), 2.62 (2H, t, J = 6.0 Hz), 7.10 (1H, d, J = 8.2 Hz), 7.31 (2H, d, J = 6.8 Hz), 7.33 (1H, s), 7.70 (1H, d, J = 8.2 Hz), 7.78 (2H, d, J = 6.8 Hz).
6-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-(oxime)naphth-2-yl)ethynyl]nicotinic acid (Compound 48) Employing the same general procedure as for the preparation of 4-[[5,6,7,8-tetrahydro-5(SR)-(2'(RS)-tetrahydropyranoxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoic acid (Compound 32), 36 mg (0.1 mmol) of ethyl 6-[(5,6,7,8-tetrahydro-8,8-dimethyl-5- (oxime)naphth-2-yl)ethynyl]nicotinate (Compound 21) was converted into the title compound using 0.5 ml (0.5 mmol) of LiOH (1M aqueous solution).
PMR (acetone-d6) : δ 1.33 (6H, s), 1.76 (2H, t, J = 6.8 Hz), 2.85 (2H, t, J = 6.8 Hz), 7.41 (1H, d, J = 8.1 Hz), 7.68 (1H, s), 7.74 (1H, d, J = 8.1 Hz), 8.00 (1H, d, J = 8.2 Hz), 8.35 (1H, d, J = 8.2 Hz), 9.16 (1H, s). 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-anti-(O-methyl oxime)naphth-2-yl)ethynyl]benzoic acid (Compound 49)
Employing the same general procedure as for the preparation of 4-[[5,6,7,8-tetrahydro-5(SR)-(2'(RS)-tetrahydropyranoxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoic acid (Compound 32), 130 mg (0.35 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-anti-(O-methyl oxime)naphth-2-yl)ethynyl]benzoate
(Compound 22) was converted into the title compound using 1 ml (1.0 mmol) of LiOH (1M aqueous solution). PMR (CDCl3) : δ 1.32 (6H, s), 1.74 (2H, t, J = 6.3 Hz), 2.79 (2H, t, J = 6.3 Hz), 4.03 (3H, s), 7.38 (1H, dd, J = 1.7, 8.3 Hz), 7.55 (1H, d, J = 1.7 Hz), 7.64 (2H, d, J = 8.4 Hz), 7.99 (1H, d, J = 8.3 Hz), 8.10 (2H, d, J = 8.4 Hz).
4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-syn-(O-methyl oxime)naphth-3-yl)ethynyl]benzoic acid (Compound 50)
Employing the same general procedure as for the preparation of 4-[[5,6,7,8-tetrahydro-5(SR)-(2'(RS)-tetrahydropyranoxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoic acid (Compound 32), 40 mg (0.15 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-syn-(O-methyl oxime)naphth-3-yl)ethynyl]benzoate
(Compound 23) was converted into the title compound using 0.5 ml (0.5 mmol) of LiOH (1M aqueous solution). PMR (CDCl3) : δ 1.36 (6H, s), 1.90 (2H, t, J = 6.3 Hz), 2.58 (2H, t, J = 6.3 Hz), 3.97 (3H, s), 7.38 (1H, d, J = 8.3 Hz), 7.59 (1H, s), 7.65 (2H, d, J = 8.3 Hz), 8.10 (2H, d, J = 8.3 Hz), 8.41 (1H, d, J = 8.3 Hz).
4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-anti-(O-ethyl oxime)naphth-2-yl)ethynyl]benzoic acid (Compound 51)
Employing the same general procedure as for the preparation of 4-[[5,6,7,8-tetrahydro-5(SR)-(2'(RS)-tetrahydropyranoxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoic acid (Compound 32), 40 mg (0.15 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-anti-(O-ethyl oxime)naphth-2-yl)ethynyl]benzoate
(Compound 24) was converted into the title compound using 0.5 ml (0.5 mmol) of LiOH (1M aqueous solution). PMR (CDCl3) : δ 1.32 (6H, s), 1.36 (3H, t, J = 7.1 Hz), 1.74 (2H, t, J = 6.4 Hz), 2.82 (2H, t, J = 6.4 Hz), 4.27 (2H, q, J = 7.1 Hz), 7.37 (1H, dd, J = 1.6 , 8.2 Hz), 7.55 (1H, d, J = 1.6 Hz), 7.64 (2H, d, J = 8.4 Hz), 8.01 (1H, d, J = 8.2 Hz), 8.11 (2H, d, J = 8.4 Hz).
4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-syn-(O-ethyl oxime)naphth-2-yl)ethynyl]benzoic acid (Compound 52)
Employing the same general procedure as for the preparation of 4-[[5,6,7,8-tetrahydro-5(SR)-(2'(RS)-tetrahydropyranoxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoic acid (Compound 32), 10 mg (0.03 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-syn-(O-ethyl oxime)naphth-2-yl)ethynyl]benzoate (Compound 25) was converted into the title compound using 1 ml (1.0 mmol) of LiOH (1M aqueous solution).
PMR (CDCl3) : δ 1.31 (6H, s), 1.35 (3H, t, J = 7.1 Hz),
1.74 (2H, t, J = 6.9 Hz), 2.80 (2H, t, J = 6.9 Hz),
4.27 (2H, q, J = 7.1 Hz), 7.35 (1H, d, J = 8.3 Hz),
7.59 (1H, s), 7.65 (2H, d, J = 8.3 Hz), 8.10 (2H, d, J
= 8.3 Hz), 8.41 (1H, d, J = 8.3 Hz).
4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-anti-(O-methyl oxime)naphth-3-yl)ethynyl]benzoic acid (Compound 53)
Employing the same general procedure as for the preparation of 4-[[5,6,7,8-tetrahydro-5(SR)-(2'(RS)-tetrahydropyranoxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoic acid (Compound 32), 85 mg (0.23mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-anti-(O-methyl oxime)naphth-3-yl)ethynyl]benzoate (Compound 26) was converted into the title compound using 1 ml (1.0 mmol) of LiOH (1M aqueous solution).
PMR (acetone-d6) : δ 1.31 (6H, s), 1.74 (2H, t, J = 6.3 Hz), 2.80 (2H, t, J = 6.3 Hz), 4.04 (3H, s), 7.36 (1H, d, J = 8.2 Hz), 7.48 (1H, dd, J = 1.8 , 8.2 Hz), 7.62 (2H, d, J = 8.3 Hz), 8.10 (2H, d, J = 8.3 Hz), 8.17 (1H, d, J = 1.8 Hz).
4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-syn-(O-methyl oxime)naphth-3-yl)ethynyl]benzoic acid (Compound 54)
Employing the same general procedure as for the preparation of 4-[[5,6,7,8-tetrahydro-5(SR)-(2'(RS)-tetrahydropyranoxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoic acid (Compound 32), 20 mg (0.05 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-syn-(O-methyl oxime)naphth-2-yl)ethynyl]benzoate (Compound 27) was converted into the title compound using 0.2 ml (0.2 mmol) of LiOH (1M aqueous solution).
PMR (acetone-d6) : δ 1.34 (6H, s), 1.87 (2H, t, J = 6.3
Hz), 2.53 (2H, t, J = 6.3 Hz), 3.90 (3H, s), 7.57 (2H, s), 7.67 (2H, d, J = 8.2 Hz), 8.06 (2H, d, J = 8.2 Hz),
8.57 (1H, s).
4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-anti-(O-ethyl oxime)naphth-3-yl)ethynyl]benzoic acid (Compound 55)
Employing the same general procedure as for the preparation of 4-[[5,6,7,8-tetrahydro-5(SR)-(2'(RS)-tetrahydropyranoxy)-8,8-dimethylnaphth-2¬yl]ethynyl]benzoic acid (Compound 32), 80 mg (0.21 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-anti-(O-ethyl oxime)naphth-3-yl)ethynyl]benzoate
(Compound 26) was converted into the title compound using 0.6 ml (0.6 mmol) of LiOH (1M aqueous solution). PMR (CDCl3) : δ 1.31 (6H, s), 1.37 (3H, t, J = 7.1 Hz), 1.74 (2H, t, J = 6.8 Hz), 2.81 (2H, t, J = 6.8 Hz), 4.28 (2H, q, J = 7.1 Hz), 7.35 (1H, d, J = 8.2 Hz), 7.47 (1H, dd, J = 1.7, 8.2 Hz), 7.63 (2H, d, J = 8.4 Hz), 8.10 (2H, d, J = 8.4 Hz), 8.18 (1H, d, J = 1.7 Hz).
Ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-aminonaphth-3-yl)ethynyl]benzoate (Compound 56)
To a solution of 100 mg (0.3 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoate (Compound 2) in 5 ml of MeOH was added 922 mg (12 mmol) of ammonium acetate and then 188 mg (3 mmol) of sodium cyanoborohydride. The reaction mixture was refluxed for 1 hour, stirred at ambient temperature for 12 hours; and then diluted with water (10 ml) and extracted with Et2O (3 × 30 ml). The organic layer was washed with water (5 ml) and brine (5 ml), dried over MgSO4 and concentrated in vacuo to an oil. Recrystallization from EtOAc-hexane yielded the title compound as a white solid.
PMR (CDCl3) : δ 1.26 (3H, s), 1.31 (3H, s), 1.40 (3H, t, J = 7.1 Hz), 1.60-1.78 ( 2H, m), 1.80-1.90 (3H, m),
2.00-2.12 (1H, m), 3.94 (1H, t, J = 6.0 Hz), 4.38 (2H, q, J = 7.1 Hz), 7.30 (1H, d, J = 8.2 Hz), 7.37 (1H, dd,
J = 1.7 , 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.62 (1H, br s), 8.01 (2H, d, J = 8.2 Hz).
4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-aminonaphth-3-yl)ethynyl]benzoic acid (Compound 57)
Employing the same general procedure as for the preparation of 4-[[5,6,7,8-tetrahydro-5(SR)-(2'(RS)-tetrahydropyranoxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoic acid (Compound 32), 100 mg (0.29 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-aminonaphth-3-yl)ethynyl]benzoate (Compound 56) was converted into the title compound using 0.5 ml (0.5 mmol) of LiOH (1M aqueous solution).
PMR (DMSO-d6) : δ 1.26 (3H, s), 1.31 (3H, s), 1.55-1.65( 2H, m), 1.80-2.00 (3H, m), 2.05-2.20 (1H, m), 4.20 (1H, br s), 7.50 (2H, br s), 7.55 (2H, d, J = 8.2 Hz), 7.80 (1H, s), 7.95 (2H, d, J = 8.2 Hz).
Ethyl 4-[[5,6,7,8-tetrahydro-8,8-dimethyl-5-(2-(1,3-dithiane))naphth-3-yl]ethynyl]benzoate (Compound 58)
To a cold solution (0 °C) of 180 mg (0.29 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoate (Compound 2) in 5 ml of CH2Cl2 was added 141 mg (1 mmol) of propane dithiol and then 108 mg (1 mmol) of boron trifluoride etherate. The reaction mixture was left in the freezer for 48 hours, diluted with sat. aqueous Na2CO3 (5 ml) and extracted with Et2O (70 ml). The organic layer was washed with water (5 ml), sat. aqueous Na2CO3 (5 ml) and brine (5 ml), dried over MgSO4 and concentrated in vacuo.
Recrystallization from acetonitrile yielded the title compound as a white solid.
PMR (CDCl3) : δ 1.31 (6H, s), 1.40 (3H, t, J = 7.1 Hz), 1.80-1.86 (2H, m), 1.90-2.06 (1H, m), 2.15-2.24 (1H, m), 2.58-2.65 (2H, m), 2.71 (1H, t, J = 3.6 Hz), 2.76 (1H, t, J = 3.6 Hz), 3.15-3.26 ( 2H, m), 4.38 (2H, q, J = 7.1 Hz), 7.30 (1H, d, J = 8.0 Hz), 7.38 (1H, dd, J = 2.0 , 8.0 Hz), 7.58 (2H, d, J = 8.2 Hz), 8.02 (2H, d, J = 8.2 Hz), 8.19 (1H, d, J = 2.0 Hz).
Ethyl 4-[[5,6,7,8-tetrahydro-8,8-dimethyl-5-(2-(1,3-dithiane))naohth-2-yl]ethynyl]benzoate (Compound 59)
Employing the same general procedure as for the preparation of ethyl 4-[[5,6,7,8-tetrahydro-8,8-dimethyl-5-(2-(1,3-dithiane))naphth-3-yl]ethynyl]benzoate (Compound 58), 100 mg (0.29 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxo-naphth-2-yl)ethynyl]benzoate (Compound 1) was converted into the title compound using 120 mg (1.1 mmol) of propane dithiol and 0.1 ml of boron trifluoride
etherate.
PMR (CDCl3) : 5 1.33 (6H, s), 1.41 (3H, t, J = 7.1 Hz), 1.81-1.87 (2H, m), 1.88-2.06 (1H, m), 2.15-2.25 (1H, m), 2.58-2.66 (2H, m), 2.71 (1H, t, J = 3.5 Hz), 2.76 (1H, t, J = 3.5 Hz), 3.15-3.29 ( 2H, m), 4.38 (2H, q, J = 7.1 Hz), 7.36 (1H, dd, J = 1.6, 8.2 Hz), 7.49 (1H, d, J = 1.6 Hz), 7.59 (2H, d, J = 8.2 Hz), 7.98 (1H, d, J = 8.2 Hz), 8.03 (2H, d, J = 8.2 Hz).
4-[[5,6,7,8-tetrahydro-8,8-dimethyl-5-(2-(1,3-dithiane))naphth-3-yl]ethynyl]benzoic acid (Compound 60)
Employing the same general procedure as for the preparation of 4-[[5,6,7,8-tetrahydro-5(SR)-(2'(RS)- tetrahydropyranoxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoic acid (Compound 32), 100 mg (0.23 mmol) of ethyl 4-[[5,6,7,8-tetrahydro-8,8-dimethyl-5- (2-(1,3-dithiane))naphth-3-yl]ethynyl]benzoate
(Compound 58) was converted into the title compound using 1 ml (1.0 mmol) of LiOH (1M aqueous solution). PMR (DMSO-d6) : δ 1.26 (6H, s), 1.73-1.82 (2H, m), 2.10-2.20 (1H, m), 2.55-2.62 (1H, m), 2.70-2.80 (1H, m), 3.16-3.38 ( 5H, m), 7.47 (2H, br s), 7.70 (2H, d, . = 8.2 Hz), 7.97 (2H, d, J = 8.2 Hz), 8.01 (1H, br s). 4-[[5,6,7,8-tetrahydro-8,8-dimethyl-5-(2-(1,3-dithiane))naphth-2-yl]ethynyl]benzoic acid (Compound 61)
Employing the same general procedure as for the preparation of 4-[[5,6,7,8-tetrahydro-5(SR)-(2'(RS)-tetrahydropyranoxy)-8,8-dimethylnaphth-2-yl]ethynyl]benzoic acid (Compound 32), 180 mg (0.4 mmol) of ethyl 4-[ [5,6,7,8-tetrahydro-8,8-dimethyl-5-(2-(1,3-dithiane))naphth-2-yl]ethynyl]benzoate (Compound 59) was converted into the title compound using 1 ml (1.0 mmol) of LiOH (1M aqueous solution).
PMR (CDCl3) : δ 1.34 (6H, s), 1.82-1.88 (2H, m), 1.90-2.25 (2H, m), 2.58-2.68 (2H, m), 2.69-2.80 (2H, m), 3.18-3.30 ( 2H, m), 7.37 (1H, dd, J = 1.9, 8.0 Hz), 7.51 (1H, d, J = 1.9 Hz), 7.63 (2H, d, J = 8.2 Hz), 8.00 (1H, d, J = 8.0 Hz), 8.11 (2H, d, J = 8.2 Hz). Ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 66)
To a cold solution (-78 ° C) of 291.6 mg (1.59 mmol) of sodium bis (trimethylsily) amide in 5.6 ml of THF was added a solution of 500.0 mg (1.44 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth- 3-yl) ethynyl]benzoate (Compound 2) in 4.0 ml of THF. The reaction mixture was stirred at -78 °C for 35 minutes and then a solution of 601.2 mg (1.59 mmol) of 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine in 4.0 ml of THF was added. After stirring at -78 ° C for 1 hour, the solution was warmed to 0 °C and stirred for 2 hours. The reaction was quenched by the addition of sat. aqueous NH4Cl. The mixture was extracted with EtOAc (50 ml) and the combined organic layers were washed with 5% aqueous NaOH, water, and brine. The organic phase was dried over Na2SO4 and then concentrated in vacuo to a yellow oil. Purification by column chromatography (silica, 7% EtOAc-hexanes) yielded the title compound as a
colorless waxy solid.
PMR (CDCl3): δ 1.33 (6H, s), 1.43 (3H, t, J = 7.1 Hz), 2.44 (2H, d, J = 5.0 Hz), 4.40 (2H, q, J = 7.1 Hz), 6.02 (1H, t, J = 5.0 Hz), 7.32 (1H, d, J = 8.0 Hz), 7.51 (2H, m), 7.60 (2H, dd, J = 1.8, 8.4 Hz), 8.04 (2H, dd, J = 1.8, 8.4 Hz).
Ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl]benzoate (Compound 67)
A solution of 2-lithiothiazole was prepared by the addition of 41.2 mg (0.42 ml, 0.63 mmol) of n-butyl-lithium (1.5M solution in hexanes) to a cold solution (-78 °C) of 53.4 mg (0.63 mmol) of thiazole in 1.0 ml of THF. The solution was stirred at for 30 minutes and then a solution of 113.9 mg (0.84 mmol) of zinc chloride in 1.5 ml of THF was added. The resulting solution was warmed to room temperature, stirred for 30 minutes and then the organozinc was added via cannula to a solution of 200.0 mg (0.42 mmol) of ethyl 4-[(8-trifluoromethylsulfonyloxy-7,8-dihydro-8,8- dimethylnaphth-3-yl) ethynyl]benzoate (Compound 66) and 12.4 mg (0.01 mmol) of
tetrakis (triphenylphosphine) palladium(O) in 1.5 ml of THF. The resulting solution was heated at 50 °C for 45 minutes, cooled to room temperature and diluted with sat. aqueous NH4Cl. The mixture was extracted with EtOAc (40 ml) and the combined organic layers were washed with water and brine. The organic phase was dried over Na2SO4 and concentrated in vacuo to a yellow oil. Purification by column chromatography (silica, 20% EtOAc-hexanes) yielded the title compound as a colorless oil.
PMR (CDCl3): δ 1.35 (6H, s), 1.40 (3H, t, J = 7.1 Hz), 2.42 (2H, d, J = 4.8 Hz), 4.38 (2H, q, J = 7.1 Hz), 6.57 (1H, t, J = 4.8 Hz), 7.33 (1H, d, J = 3.3 Hz), 7.36 (1H, d, J = 8.0 Hz), 7.46 (1H, dd, J = 1.7 , 8.1 Hz), 7.55 (2H, d, J = 8.4 Hz), 7.87 (1H, d, J = 1.7 Hz), 7.92 (1H, d, J = 3.3 Hz), 8.00 (2H, d, J = 8.4 Hz).
Ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-phenylnaphth-3-yl)ethynyl)benzoate (Compound 68)
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl]benzoate (Compound 67), 203.8 mg (0.43 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 66) was converted into the title compound (colorless solid) using 58.2 mg (0.36 ml, 0.69 mmol) of phenyllithium (1.8M solution in cyclohexane/Et2O), 116.1 mg (0.85 mmol) of zinc chloride and 13.8 mg (0.01 mmol) of tetrakis (triphenylphosphine) palladium(0).
PMR (CDCl3): δ 1.36 (6H, s), 1.40 (3H, t, J = 7.1HH), 2.37 (2H, d, J = 4.7 Hz), 4.38 (2H, q, J = 7.1 Hz), 6.02 (1H, t, J = 4.7 Hz), 7.20 (1H, d, J = 1.5 Hz), 7.27 (1H, m), 7.39 (6H, m), 7.52 (2H, d, J = 8.2 Hz), 7.98 (2H, d, J = 8.2 Hz).
Ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(4-(1,1-dimethylethyl)phenyl)naphth-3-yl)ethynyl]benzoate
(Compound 69)
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl]benzoate (Compound 67), 250.0 mg (0.52 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 66) was converted into the title compound (colorless solid) using 142.4 mg (1.045 mmol) of zinc chloride, 24.1 mg
(0.02 mmol) of tetrakis (triphenylphosphine) palladium(O) and 4-tert-butylphenyllithium (prepared by adding 100.6 mg (0.97 mL, 1.57 mmol) of tert-butyllithium (1.5M solution in pentane) to a cold solution (-78 °C) of 167.0 mg (0.78 mmol) of 4-tert-butylbromobenzene in 1.0 mL of THF).
PMR (CDCl3): δ 1.35 (6H, s), 1.39 (9H, s), 1.40 (3H, t, J = 7.2 Hz), 1.59 (3H, s), 2.36 (2H, d, J = 4.9 Hz),
4.38 (2H, q, J = 7.2 Hz), 6.02 (1H, t, J = 4.9 Hz), 7.28-7.45 (7H, m), 7.55 (2H, d, J = 8.4 Hz), 7.99 (2H, d, J = 8.4 Hz).
Ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-pyridyl)naphth-3-yl)ethynyl]benzoate (Compound 70)
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-2-yl)ethynyl]benzoate (Compound 67), 250.0 mg (0.52 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8- dimethylnaphth-3-yl)ethynyl]benzoate (Compound 66) was converted into the title compound (colorless solid) using 142.4 mg (1.045 mmol) of zinc chloride, 24.1 mg (0.02 mmol) of tetrakis (triphenylphosphine) palladium(O) and 2-lithiopyridine (prepared by the addition of 100.6 mg (0.97 ml, 1.57 mmol) of tert-butyllithium (1.5M solution in pentane) to a cold solution (-78 °C) of 123.8 mg (0.784 mmol) of 2-bromopyridine in 1.0 mL of THF).
PMR (d6-acetone) : δ 1.35 (6H, s), 1.35 (3H, t, J = 7.1 Hz), 2.42 (2H, d, J = 4.7 Hz), 4.34 (2H, q, J = 7.1 Hz), 6.32 (1H, t, J = 4.7 Hz), 7.35 (2H, m), 7.47 (2H, d, J = 1.1 Hz), 7.50 (1H, d, J = 7.7 Hz), 7.58 (2H, d, J = 8.4 Hz), 7.85 (1H, ddd, J = 1.8, 7.7, 9.5 Hz), 7.99 (2H, d, J = 8.4 Hz), 8.64 (1H, m).
Ethyl 4-[(7.8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl]benzoate (Compound 71)
and Ethyl 4-[(7.8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 72)
A mixture of 35.1 mg (0.39 mmol) of cuprous cyanide and 16.6 mg (0.39 mmol) of lithium chloride was flame dried under vacuum, cooled to room temperature and dissolved in 1.5 ml of THF. This solution was cooled to -78 °C and 50.2 mg (0.46 mL, 0.784 mmol) of tert-butyllithium (1.7M solution in pentane) was added forming a clear yellow solution. The reaction mixture was stirred at -78 °C for 15 minutes and then 125.0 mg (0.26 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 66) was added as a solution in 0.5 ml of THF. After 10 minutes the reaction was quenched at -78 °C with 1.5 ml of a 2:1 (v/v) mixture of sat. aqueous NH4Cl and 5% NaOH. The mixture was extracted with EtOAc and the combined organic layers were washed with water and brine. The organic phase was dried over MgSO4, concentrated in vacuo and purified by column chromatography (silica, 5% EtOAc-hexanes) to give a clear yellow oil (7:5 ratio of title compounds). The two compounds were separated by HPLC (partisil 10, 2% EtOAc-hexanes) to give the title compounds as colorless oils.
Ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl]benzoate (Compound 71) PMR (CDCl3): δ 1.23 (6H, s), 1.39 (9H, s), 1.42 (3H, t J = 7.2 Hz), 2.16 (2H, d, J = 4.9 Hz), 4.40 (2H, q, J = 7.2 Hz), 6.01 (1H, t, J = 4.9 Hz), 7.34 (2H; m, J = 1.6, 7.3 Hz), 7.61 (2H, d, J = 8.2 Hz), 7.81 (1H, d, J = 1.6 Hz), 8.03 (2H, d, J = 8.2 Hz).
Ethyl 4-[(7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 72) PMR (CDCl3): δ 1.28 (6H, s), 1.43 (3H, t, J = 7.2 Hz), 2.27 (2H, dd, J = 1.9, 4.4 Hz), 4.39 (2H, q, J = 7.2 Hz), 5.99 (1H, dt, J = 4.4, 9.3 Hz), 6.44 (1H, dt, J = 1.9, 9.3 Hz), 7.22 (1H, d, J = 1.3 Hz), 7.26-7.39 (2H, m), 7.57 (2H, d, J = 8.4 Hz), 8.02 (2H, d, J = 8.2 Hz).
Ethyl 4-[(7,8-dihydro-5,8,8-trimethylnaphth-3-yl)ethynyl]benzoate (Compound 73)
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl]benzoate
(Compound 71), 250 mg (0.52 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 66) was converted into the title compound (HPLC Partisil 10, 0.5% EtOAC-hexanes) using 70.2 mg (0.78 mmol) of cuprous cyanide, 33.2 mg (0.78 mmol) of lithium
chloride and 34.5 mg (1.28 ml, 1.57 mmol) of methyl-lithium (1.22M solution in Et2O).
PMR (CDCl3): δ 1.27 (6H, s), 1.41 (3H, t, J = 7.1 Hz), 2.09 (3H, d, J = 1.7 Hz), 2.21 (2H, dd, J = 1.8, 4.1 Hz), 4.39 (2H, q, J = 7.1 Hz), 5.82 (1H, br m), 7.30 (1H, d, J = 7.7 Hz), 7.40 (2H, d, J = 8.3 Hz), 7.60 (2H, d, J = 7.3 Hz), 8.03 (2H, d, J = 8.3 Hz).
4-[(5-butyl-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 74)
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5- (1,1-dimethylethyl)naphth-3-yl)ethynyl]benzoate
(Compound 71), 98.1 mg (0.205 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 66) was converted into the title compound (HPLC Partisil 10, 1% tBuOMe-hexanes) using a mixture of 27.5 mg (0.31 mmol) of cuprous cyanide and 13.0 mg (0.31 mmol) of lithium chloride in 1.5 ml of Et2O treated with 39.4 mg (0.41 ml, 0.62 mmol) of n-butyllithium (1.5M solution in hexane).
PMR (CDCl3): δ 0.96 (3H, t) , 1.26 (6H, s), 1.42 (3H, t, J = 7.1 Hz), 1.43 (2H, m), 1.55 (2H, m), 2.20 (2H, d, J - 4.5 Hz), 2.47 (2H, t, J = 6.5 Hz), 4.39 (2H, q, J = 7.1 Hz), 5.80 (1H, t, J = 4.5 Hz), 7.31 (1H, d, J = 8.0 Hz), 7.39 (1H, dd, J = 1.8, 8.0 Hz), 7.43 (1H, br s), 7.61 (2H, d, J = 8.2 Hz), 8.03 (2H, d, J = 8.2 Hz).
Ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)-naphth-3-yl)ethynyl]benzoate (Compound 75)
A solution (flushed with argon) of 201.3 mg (0.42 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 66), 286.5 mg (4.21 mmol) of 1-pentyne, 59.5 mg (0.08 mmol) of bis (triphenylphosphine) palladium(II) chloride and 32.0 mg (0.17 mmol) of cuprous iodide in 2.5 ml of diethylamine was heated to 70 °C in a
pressure vial for 6 hours. After stirring overnight at room temperature, the mixture was diluted with EtOAc (25 ml) and washed with water and brine. The organic phase was dried over MgSO4, concentrated in vacuo and purified by column chromatography (silica, 5% Et2O-hexanes) to give the title compound as a colorless, air-sensitive oil.
PMR (CDCl3): δ 1.10 (3H, t, J = 7.2 Hz), 1.28 (6H, s), 1.42 (3H, t, J = 7.2 Hz), 1.69 (2H, sextet, J = 7.2 Hz), 2.31 (2H, d, J = 4.7 Hz), 2.46 (2H, t, J = 7.0 Hz), 4.39 (2H, q, J = 7.2 Hz), 6.35 (1H, t, J = 4.7 Hz), 7.30 (1H, s), 7.42 (1H, dd, J = 1.5, 7.8 Hz), 7.59 (2H, d, J = 8.3 Hz), 7.82 (1H, d, J = 1.5 Hz), 8.03 (2H, d, J = 8.3 Hz).
Ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1-(3,3-dimethyl)butynyl)naphth-3-yl)ethynyl]benzoate (Compound 76)
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)naphth-3-yl)ethynyl]benzoate (Compound 75), 184.3 mg (0.39 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 66) was
converted into the title compound (pale yellow oil) using 316.4 mg (3.85 mmol) 3,3-dimethyl-1-butyne, 54.5 mg (0.08 mmol) of bis (triphenylphosphine) palladium(II) chloride and 29.3 mg (0.15 mmol) of cuprous iodide.
PMR (CDCl3): δ 1.28 (6H, s), 1.39 (9H, s), 1.41 (3H, t, J = 7.2 Hz) 2.31 (2H, d, J = 4.9 Hz), 4.39 (2H, q, J = 7.2 Hz), 6.33 (1H, t, J = 4.9 Hz), 7.29 (1H, s), 7.41 (1H, dd, J = 1.7, 8.0 Hz), 7.59 (2H, d, J = 8.4 Hz), 7.76 (1H, d, J = 1.7 Hz), 8.03 (2H, d, J = 8.4 Hz). Ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1-propynyl)naphth-3-yl)ethynyl]benzoate (Compound 77)
Into a solution of 263.7 mg (0.55 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 66), 4.2 mg (0.02 mmol) cuprous iodide and 7.8 mg (0.11 mmol) bis (triphenylphosphine) palladium(II) chloride in 2.0 ml of DMF and 1.0 ml of diethylamine was bubbled propyne. The initial blue solution turned brown in color after 45 minutes of stirring at room temperature. The reaction mixture was diluted with EtOAc (40 ml) and washed with water and brine. The organic phase was dried over MgSO4, concentrated in vacuo and purified by column chromatography (silica, 5% Et2O-hexanes) to give the title compound as a colorless solid.
PMR (CDCl3): δ 1.38 (6H, s), 1.42 (3H, t, J = 7.2 Hz), 2.12 (3H, s), 2.31 (2H, d, J = 4.8 Hz), 4.40 (2H, q, J = 7.2 Hz), 6.34 (1H, t, J = 4.8 Hz), 7.30 (1H, s), 7.42 (1H, dd, J = 1.5 , 7.6 Hz), 7.61 (2H, d, J = 8.6 Hz) 7.78 (1H, d, J = 1.5 Hz), 8.03 (2H, d, J = 8.6 Hz).
4-[(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl]benzoic acid (Compound 78)
A solution of 33.9 mg (0.08 mmol) of ethyl
4-[(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl]benzoate (Compound 67) and 8.5 mg (0.20 mmol) of LiOH-H2O in 3 ml of THF/water (3:1, v/v), was stirred overnight at room temperature. The reaction was quenched by the addition of sat. aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid.
PMR (d6-DMSO) : δ 1.29 (6H, s), 2.42 (2H, d, J = 4.6 Hz), 6.68 (1H, t, J = 4.6 Hz), 7.51 (2H, m), 7.62 (2H, d, J = 8.2 Hz), 7.77 (1H, d, J = 3.3 Hz), 7.93 (2H, d,
J = 8.2 Hz), 7.98 (1H, d, J = 3.3 Hz).
4-[(7,8-dihydro-8,8-dimethyl-5-phenylnaphth-2-yl)ethynyl]benzoic acid (Compound 79)
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-(2¬thiazolyl)naphth-3-yl)ethynyl]benzoic acid (Compound 78), 27.0 mg (0.07 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-phenylnaphth-3-yl)ethynyl]benzoate (Compound 68) was converted into the title compound (colorless solid) using 5.9 mg (0.14 mmol) of LiOH in H2O.
PMR (d6-DMSO) : δ 1.31 (6H, s), 2.35 (2H, d, J = 4.5 Hz), 6.05 (1H, t, J = 4.5 Hz), 7.00 (1H, s), 7.33 (2H, d, J = 6.2 Hz), 7.44 (4H, m), 7.59 (2H, d, J = 8.1 Hz), 7.90 (2H, d, J = 8.1 Hz).
4-[(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl]benzoic acid
(Compound 80)
A solution of 24.0 mg (0.06 mmol) of ethyl
4-[(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl]benzoate (Compound 71) and 6.5 mg (0.16 mmol) of LiOH-H2O in 3 mL THF/water (3:1, v/v) was stirred overnight (22 hours) at room temperature. The reaction mixture was extracted with Et2O and the layers were separated. The aqueous layer was acidified with HCl (1M aqueous solution) and then extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid. PMR (d6-DMSO) : δ 1.23 (6H, s), 1.37 (9H, s), 2.16 (2H, d, J = 4.9 q 1Hz), 6.07 (1H, t, J = 4.9 Hz), 7.40 (2H, s), 7.66 (2H, d, J = 8.1 Hz), 7.84 (1H,s), 8.06 (2H, d, J = 8.1 Hz).
4-[(7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoic acid (Compound 81)
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl]benzoic acid
(Compound 80), 25.3 mg (0.08 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate
(Compound 72) was converted into the title compound (colorless solid) using 8.0 mg (0.14 mmol) of LiOH in H2O.
PMR (d6-DMSO) : δ 1.26 (6H, s), 2.27 (2H, dd, J = 2.9, 4.4 Hz), 6.03 (1H, dt, J = 4.4, 9.6 Hz), 6.51 (1H, ddd, J = 1.9, 3.6, 9.6 Hz), 7.27 (1H, s), 7.39 (2H, m), 7.67 (2H, d, J = 7.6 Hz), 8.07 (2H, J = 7.6 Hz).
4-[(5,8,8-trimethyl-7,8-dihydronaphth-3-yl)ethynyl]benzoic acid (Compound 82)
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl]benzoic acid
(Compound 80), 33.7 mg (0.10 mmol) of ethyl 4-[(7,8-dihydro-5,8,8-trimethylnaphth-3-yl)ethynyl]benzoate (Compound 73) was converted into the title compound (colorless solid) using 10.2 mg (0.25 mmol) of LiOH in H2O.
PMR (d6-DMSO) : δ 1.22 (6H, s), 2.06 (3H, d, J = 1.4 Hz), 2.18 (2H, dd, J = 2.1, 4.5 Hz), 5.87 (1H, br m), 7.42 (3H, m), 7.67 (2H, d, J = 8.4 Hz), 7.97 (2H, d, J = 8.4 Hz).
4-[(5-butyl-8,8-dimethyl-7,8-dihydronaphth-3- yl)ethynyl]benzoic acid (Compound 83)
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl]benzoic acid
(Compound 80), 22.6 mg (0.06 mmol) of ethyl
4-[(5-butyl-7,8-dihydro-8,8-dimethylnaphth-3-yl)-ethynyl]benzoate (Compound 74) was converted into the title compound using 6.1 mg (0.146 mmol) of LiOH in H2O.
PMR (d6-DMSO) : δ 0.90 (3H, t, J = 7.1 Hz), 1.20 (6H, s), 1.35 (2H, m), 1.45 (2H, m), 2.16 (2H, d, J = 4.2 Hz), 2.43 (2H, t), 5.82 (1H, t, J = 4.2 Hz), 7.36 (1H, m), 7.43 (2H, d), 7.84 (2H, d).
4-[(7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)naohth-3-yl)ethynyl]benzoic acid (Compound 84)
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl]benzoic acid
(Compound 80), 42.0 mg (0.106 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)naphth-3-yl)ethynyl]benzoate (Compound 75) was converted into the title compound (colorless solid) using 11.1 mg (0.27 mmol) of LiOH in H2O in 3 mL of THF/water (3:1, v/v, flushed with argon).
PMR (d6-DMSO) : δ 1.04 (3H, br t), 1.22 (6H, s), 1.59 (2H, m), 2.30 (2H, m), 2.45 (2H, m), 6.37 (1H, br t), 7.38 (1H, m), 7.48 (1H, m), 7.60 (2H, d, J = 7.4 Hz), 7.67 (1H, s), 7.96 2H, d, J = 7.4 Hz).
4-((7,8-dihydro-8,8-dimethyl-5-(1-(3,3-dimethyl)butynyl)naphth-3-yl)ethynyl]benzoic acid
(Compound 85)
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-(1- pentynyl)naphth-3-yl)ethynyl]benzoic acid (Compound
84), 34.7 mg (0.085 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1-(3,3-dimethyl)butynyl)naphth-3-yl)ethynyl]benzoate (Compound 76) was converted into the title compound (colorless solid) using 9.6 mg (0.23 mmol) of LiOH in H2O.
PMR (d6-DMSO) : δ 1.21 (6H, s), 1.32 (9H, s), 2.29 (2H, d, J = 4.8 Hz), 6.34 (1H, t, J = 4.8 Hz), 7.39 (1H, d,
J = 8.0 Hz), 7.48 (1H, dd, J = 1.8, 8.0 Hz), 7.61 (1H, d, J = 1.8 Hz), 7.65 (2H, d, J = 8.3 Hz), 7.96 (2H, d,
J = 8.3 Hz).
4-[(7,8-dihydro-8,8-dimethyl-5-(1-propynyl)naphth-3-yl)ethynyl]benzoic acid (Compound 86)
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)naphth-3-yl)ethynyl]benzoic acid (Compound 84), 75.0 mg (0.204 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1-propynyl)naphth-3-yl)ethynyl]benzoate (Compound 77) was converted into the title compound (colorless solid) using 21.4 mg (0.51 mmol) of LiOH in H2O.
PMR (d6-DMSO) : δ 1.22 (6H, s), 2.10 (3H, s), 2.30 (2H, d, J = 4.5 Hz), 6.38 (1H, t, J = 4.5 Hz), 7.39 (2H, d, J = 8.2 Hz), 7.47 (2H, d, J = 7.7 Hz), 7.54 (2H, d, J = 7.7 Hz), 7.61 (1H, s), 7.89 (2H, d, J = 7.7 Hz).
Ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 87)
Employing the same general procedure as for the preparation of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 66), 800 mg (2.31 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 1) in 2 ml of THF was converted into the title compound (white solid) using 466 mg (2.5 ml, 2.54 mmol) of sodium bis (trimethylsilyl) amide (1.0M solution in THF) and a solution of 961 mg (2.54 mmol) of 2-[N,N-bis(trifluoromethylsulfonyloxy)amino]-5-chloropyridine in 2 ml of THF.
PMR (CDCl3): δ 1.34 (6H, s), 1.41 (3H, t, J = 7.2 Hz),
2.44 (2H, d, J = 4.8 Hz), 4.39 (2H, q, J = 7.2 Hz), 6.01 (1H, t, J = 4.8 Hz), 7.37 (1H, d, J = 8.0 Hz),
7.45 (1H, dd, J = 1.5 , 8.0 Hz), 7.48 (1H, d, J = 1.5 Hz), 7.60 (2H, d, J = 8.3 Hz), 8.04 (2H, d, J = 8.3 Hz).
Ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-2-yl)ethynyl]benzoate (Compound 88) Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)napth-3-yl)ethynyl]benzoate (Compound 67),400 mg (0.84 mmol) of ethyl 4-[(5¬trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 87) in 2 ml of THF was converted into the title compound (white solid) using a solution of 82 mg (1.26 mmol) of
thiazole in 2 ml of THF, 81 mg (0.84 ml, 1.26 mmol) of n-butyllithium (1.5M solution in hexanes), 228 mg (3.36 ml, 1.68 mmol) of zinc chloride (0.5M solution in THF) and 10 mg (0.01 mmol) of
tetrakis (triphenylphosphine) palladium (O).
PMR (CDCl3): δ 1.36 (6H, s), 1.41 (3H, t, J = 7.2 Hz), 2.42 (2H, d, J = 4.9 Hz), 4.39 (2H, q, J = 7.2 Hz), 6.58 (1H, t, J = 4.9 Hz), 7.32 (1H, d, J = 3.4 Hz), 7.38 (1H, dd, J = 1.7, 8.1 Hz), 7.54 (1H, d, J = 1.7 Hz), 7.60 (2H, d, J = 8.2 Hz), 7.72 (1H, d, J = 8.1 Hz), 7.87 (1H, d, J = 3.4 Hz), 8.02 (2H, d, J = 8.2 Hz). Ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-phenylnaphth-2-yl)ethynyl]benzoate (Compound 89)
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl]benzoate (Compound 67), 200 mg (0.42 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy)-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 87) in 1 ml of THF was converted into the title compound (white solid) using 53 mg (0.35 ml, 0.63 mmol) of phenyl-lithium (1.8M in cyclohexane/Et2O), 81 mg (0.84 ml,
1.26 mmol) of n-butyllithium (1.5M solution in
hexanes), 86 mg (1.26 ml, 0.63 mmol) of zinc chloride (0.5M solution in THF) and 10 mg (0.01 mmol) of
tetrakis (triphenylphosphine) palladium (O).
PMR (CDCl3): δ 1.36 (6H, s), 1.40 (3H, t, J = 7.2 Hz), 2.37 (2H, d, J = 4.9 Hz), 4.38 (2H, q, J = 7.2 Hz), 6.03 (1H, t, J = 4.9 Hz), 7.01 (1H, d, J = 8.0 Hz),
7.27 (1H, dd, J = 1.7, 8.0 Hz), 7.31-7.41 (5H, m), 7.53 (1H, d, J = 1.7 Hz), 7.59 (2H, d, J = 8.2 Hz), 8.02 (2H, d, J = 8.2 Hz).
Ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(phenylethyn-1-yl)naphth-2-yl)ethynyl]benzoate (Compound 90)
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)naphth-3-yl)ethynyl]benzoate (Compound 75), 200 mg (0.42 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 87) was converted into the title compound (pale yellow oil) using 429 mg (4.2 mmol) of phenylacetylene, 60 mg (0.08 mmol) of bis (triphenylphosphine) palladium (II) chloride and 20 mg (0.11 mmol) of cuprous iodide. PMR (CDCl3) : δ 1.32 (6H, s), 1.40 (3H, t, J = 7.1 Hz), 2.38 (2H, d, J = 5.0 Hz), 4.38 (2H, q, J = 7.1 Hz), 6.53 (1H, t, J = 5.0 Hz), 7.32-7.38 (3H, m), 7.43 (1H, dd, J = 1.6, 7.9 Hz), 7.50 (1H, d, J = 1.6 Hz), 7.54 (1H, d, J = 1.6 Hz), 7.56 (1H, d, J = 4.8), 7.61 (2H, d, J = 8.2 Hz), 7.70 (1H, d, J = 7.9 Hz), 8.03 (2H, d, J = 8.2 Hz).
Ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1-(3-hydroxy-3- methyl)butynyl)naphth-2-yl)ethynyl]benzoate (Compound 91)
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(l¬pentynyl)naphth-3-yl)ethynyl]benzoate (Compound 75), 200 mg (0.42 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 87) was converted into the title compound (pale yellow solid) using 353 mg (4.2 mmol) of 2-methyl-3-butyn-2-ol, 60 mg (0.08 mmol) of bis (triphenylphosphine) palladium (II) chloride and 20 mg (0.11 mmol) of cuprous iodide.
PMR (CDCl3): δ 1.28 (6H, s), 1.40 (3H, t, J = 7.1 Hz), 1.65 (6H, s), 2.31 (2H, d, J = 4.8 Hz), 4.38 (2H, q, J = 7.1 Hz), 6.39 (1H, t, J = 4.8 Hz), 7.38 (1H, dd, J = 1.6 , 7.9 Hz), 7.46 (1H, d, J = 1.6 Hz), 7.56 (1H, d, J = 7.9 Hz), 7.58 (2H, d, J = 8.2 Hz), 8.02 (2H, d, J = 8.2 Hz).
Ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1-propynyl)-naphth-2-yl)ethynyl]benzoate (Compound 92)
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)naphth-3-yl)ethynyl]benzoate (Compound 75), 200 mg (0.42 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8- dimethylnaphth-2-yl)ethynyl]benzoate (Compound 87) was converted into the title compound (pale yellow oil) using 168 mg (4.2 mmol) of propyne, 60 mg (0.08 mmol) of bis (triphenylphosphine) palladium (II) chloride and
20 mg (0.11 mmol) of cuprous iodide.
PMR (CDCl3): δ 1.28 (6H, s), 1.40 (3H, t, J = 7.1 Hz),
2.08 (3H, s), 2.30 (2H, d, J = 4.8 Hz), 4.38 (2H, q, J
- 7.1 Hz), 6.33 (1H, t, J = 4.8 Hz), 7.40 (1H, dd, J =
1.6 , 7.9 Hz), 7.45 (1H, d, J = 1.6 Hz), 7.59 (1H, d, J
= 7.9 Hz), 7.61 (2H, d, J = 8.2 Hz), 8.02 (2H, d, J =
8.2 Hz).
Ethyl
4-[(7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)naohth-2-yl)ethynyl]benzoate (Compound 93)
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)naphth-3-yl)ethynyl]benzoate (Compound 75), 200 mg (0.42 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 87) was converted into the title compound (pale yellow oil) using 286 mg (4.2 mmol) of pentyne, 60 mg (0.08 mmol) of bis (triphenylphosphine)palladium (II) chloride and 20 mg (0.11 mmol) of cuprous iodide.
PMR (CDCl3): δ 1.06 (3H, t, J = 7.3 Hz), 1.28 (6H, s),
1.39 (3H, t, J = 7.1 Hz), 1.65 (2H, sext, J = 7.3 Hz), 2.30 (2H, d, J = 4.8 Hz), 2.41 (2H, t, J = 7.3 Hz), 4.37 (2H, q, J = 7.1 Hz), 6.34 (1H, t, J = 4.8 Hz),
7.40 (1H, dd, J = 1.6 , 7.9 Hz), 7.45 (1H, d, J = 1.6 Hz), 7.59 (2H, d, J = 8.1 Hz), 7.62 (1H, d, J = 7.9 Hz), 8.01 (2H, d, J = 8.1 Hz).
Ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1-(3,3-dimethyl)butynyl)naphth-2-yl)ethynyl]benzoate (Compound 94)
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)naphth-3-yl)ethynyl]benzoate (Compound 75), 200 mg (0.42 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 87) was converted into the title compound (pale yellow oil) using 70 mg (0.84 mmol) of 3,3-dimethyl-1-butyne, 60 mg (0.08 mmol) of bis (triphenylphosphine) palladium (II) chloride and 20 mg (0.11 mmol) of cuprous iodide.
PMR (CDCl3): δ 1.28 (6H, s), 1.35 (9H, s), 1.40 (3H, t, J = 7.1 Hz), 2.29 (2H, d, J = 4.8 Hz), 4.38 (2H, q, J = 7.1 Hz), 6.32 (1H, t, J = 4.8 Hz), 7.40 (1H, dd, J = 1.6 , 7.9 Hz), 7.45 (1H, d, J = 1.6 Hz), 7.59 (3H, d, J = 8.1 Hz), 8.01 (2H, d, J = 8.1 Hz).
Ethyl 4-[(7,8-dihydro-5,8,8-trimethylnaphth-2-yl)ethynyl]benzoate (Compound 95)
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl]benzoate
(Compound 71), 300 mg (0.63 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8¬dimethylnaphth-2-yl)ethynyl]benzoate (Compound 87) was converted into the title compound (colorless oil) using 84 mg (0.94 mmol) of cuprous cyanide, 40 mg (0.94 mmol) of lithium chloride and 41 mg (1.54 ml, 1.88 mmol) of methyllithium (1.22M solution in Et2O) .
PMR (CDCl3): δ 1.27 (6H, s), 1.40 (3H, t, J = 7.1 Hz), 2.05 (3H, d, J = 1.9 Hz), 2.21 (2H, dd, J = 1.9, 4.8 Hz), 4.38 (2H, q, J = 7.1 Hz), 5.81 (1H, dt, J = 1.9, 4.8 Hz), 7.21 (1H, d J = 8.0 Hz), 7.38 (1H, dd, J = 1.6, 8.0 Hz), 7.47 (1H, d, J = 1.6 Hz), 7.59 (2H, d, J = 8.1 Hz), 8.02 (2H, d, J = 8.1 Hz).
Ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-2-yl)ethynyl]benzoate (Compound 96)
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-diraethyl-5- (1,1-dimethylethyl)naphth-3-yl)ethynyl]benzoate
(Compound 71), 300 mg (0.63 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 87) was converted into the title compound (colorless oil) using 84 mg (0.94 mmol) of cuprous cyanide, 40 mg (0.94 mmol) of lithium chloride and 120 mg (1.1 ml, 1.88 mmol) of tert-butyllithium (1.7M solution in pentane).
PMR (CDCl3) : δ 1.24 (6H, s), 1.35 (9H, s), 1.40 (3H, t, J = 7.1 Hz), 2.15 (2H, d, J = 4.9 Hz), 4.38 (2H, q, J = 7.1 Hz), 6.00 (1H, t, J = 4.9 Hz), 7.34 (1H, dd J = 2.0, 8.1 Hz), 7.48 (1H, d, J = 2.0 Hz), 7.59 (2H, d, J = 8.2 Hz), 7.63 (1H, d, J = 8.1 Hz), 8.02 (2H, d, J = 8.2 Hz).
4-[(7,8-dihydro-8,8-dimethyl-5-Phenylnaphth-2-yl)ethynyl]benzoic acid (Compound 97)
To a solution of 50 mg (0.13 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-phenylnaphth-2-yl)ethynyl]benzoate (Compound 89) in 1 ml of argon saturated THF was added 27 mg (1.3 ml, 0.65 mmol) of argon saturated LiOH (0.5M aqueous solution). The reaction mixture was stirred at room temperature for 24 hours under an atmosphere of argon, concentrated in vacuo and the resulting residue partitioned between water and hexanes. The layers were separated and the aqueous fraction was acidified to pH 1 with 2N HCl.
The product was extracted into Et2O, dried over MgSO4, and concentrated in vacuo to give the title compound as a pale yellow solid.
PMR (DMSO-d6) : δ 1.37 (6H, s), 2.38 (2H, d, J = 4.7 Hz), 6.03 (1H, t, J = 4.7 Hz), 6.99 (1H, d, J = 8.1
Hz), 7.26 (1H, dd, J = 1.7 , 8.1 Hz), 7.30-7.42 (5H, m), 7.52 (1H, d, J = 1.7 Hz), 7.58 (2H, d, J = 8.2 Hz),
8.00 (2H, d, J = 8.2 Hz).
4-[(7,8-dihydro-8,8-dimethyl-5-(phenylethyn-1-yl)naphth-2-yl)ethynyl]benzoic acid (Compound 98)
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-phenylnaphth-2-yl)ethynyl]benzoic acid (Compound 97), 22 mg (0.05 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(phenylethyn-1-yl)naphth-2-yl)ethynyl]benzoate (Compound 90) was converted to the title compound (pale yellow solid) using 11 mg (0.5 ml, 0.26 mmol) of LiOH (0.5 M aqueous solution).
PMR (CDCl3): δ 1.33 (6H, s), 2.40 (2H, d, J = 4.9 Hz), 6.54 (1H, t, J = 4.9 Hz), 7.33-7.40 (3H,m), 7.45 (1H, dd, J = 1.6, 7.9 Hz), 7.51 (1H, d, J = 1.6 Hz), 7.55 (1H, d, J = 1.6 Hz), 7.57 (1H, d, J = 4.8), 7.65 (2H, d, J = 8.2 Hz), 7.72 (1H, d, J = 7.9 Hz), 8.12 (2H, d, J = 8.2 Hz).
4-[(7,8-dihydro-8,8-dimethyl-5-(1-(3-hydroxy-3-methyl)butynyl)naphth-2-yl)ethynyl]benzoic acid
(Compound 99)
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-phenylnaphth-2-yl)ethynyl]benzoic acid (Compound 97), 79 mg (0.19 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1-(3-hydroxy-3-methyl)butynyl)naphth-2-yl)ethynyl]benzoate (Compound 91) was converted to the title compound (pale yellow solid) using 40 mg (1.92 ml, 0.96 mmol) of LiOH (0.5 M aqueous solution).
PMR (acetone-d6) : δ 1.29 (6H, s), 1.56 (6H, s), 2.35 (2H, d, J = 5.1 Hz), 6.39 (1H, t, J = 5.1 Hz), 7.45 (1H, dd, J = 1.6, 7.9 Hz), 7.46 (1H, d, J = 1.6 Hz), 7.64 (1H, d, J = 7.9 Hz), 7.68 (2H, d, J = 8.2 Hz), 8.06 (2H, d, J * 8.2 Hz).
4-[(7,8-dihydro-8,8-dimethyl-5-(1-propynyl)naphth-2-yl)ethynyl]benzoic acid (Compound 100)
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-phenylnaphth-2-yl)ethynyl]benzoic acid (Compound 97), 75 mg (0.20 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1-propynyl)naphth-2-yl)ethynyl]benzoate (Compound 92) was converted to the title compound (pale yellow solid) using 42 mg (2 ml, 1.0 mmol) of LiOH (0.5 M aqueous solution).
PMR (DMSO-d6) : δ 1.21 (6H, s), 2.05 (3H, s), 2.28 (2H, d, J = 4.7 Hz), 6.36 (1H, t, J = 4.7 Hz), 7.46 (1H, dd, J = 1.6 , 7.9 Hz), 7.48 (1H, d, J = 1.6 Hz), 7.55 (1H, d, J = 7.9 Hz), 7.66 (2H, d, J = 8.2 Hz), 7.96 (2H, d, J = 8.2 Hz).
4-[(7,8-dihydro-8,8-dimethyl-5-(1-(3,3-dimethyl)butynyl)naphth-2-yl)ethynyl]benzoic acid
(Compound 101)
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-phenylnaphth-2-yl)ethynyl]benzoic acid (Compound 97), 52 mg (0.13 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1-(3,3-dimethyl)butynyl)naphth-2-yl)ethynyl]benzoate (Compound 94) was converted to the title compound (pale yellow solid) using 26 mg (1.25 ml, 0.63 mmol) of LiOH (0.5 M aqueous solution).
PMR (acetone-d6) : δ 1.29 (6H, s), 1.33 (9H, s), 2.34 , (2H, d, J = 4.8 Hz), 6.33 (1H, t, J = 4.8 Hz), 7.45
(1H, dd, J = 1.6 , 7.9 Hz), 7.52 (1H, d, J = 1.6 Hz),
7.64 (1H, d, J = 8.1 Hz), 7.67 (2H, d, J = 8.0 Hz),
8.06 (2H, d, J = 8.0 Hz).
4-[(7,8-dihydro-5,8,8-trimethylnaphth-2-yl)ethynyl]benzoic acid (Compound 102)
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-phenylnaphth-2-yl)ethynyl]benzoic acid (Compound 97), 37 mg (0.11 mmol) of ethyl 4-[(7,8-dihydro-5,8,8-trimethylnaphth-2-yl)ethynyl]benzoate (Compound 95) was converted to the title compound (white solid) using 23 mg (1.1 ml, 0.54 mmol) of LiOH (0.5 M aqueous
solution).
PMR (DMSO-d6) : δ 1.21 (6H, s), 2.02 (3H, br s), 2.17 (2H, br s), 5.87 (1H, br s), 7.26 (1H, d, J = 8.2 Hz), 7.40 (1H, d, J = 8.2), 7.47 (1H, s), 7.65 (2H, d, J = 8.1 Hz), 7.67 (2H, d, J = 8.1 Hz).
4- [ (7 , 8-dihydro-8 , 8-dimethyl-5- ( 1 , 1-dimethylethyl)naphth-2-yl)ethynyl]benzoic acid
(Compound 103)
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-phenylnaphth-2-yl)ethynyl]benzoic acid (Compound 97), 51 mg (0.13 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-2-yl)ethynyl]benzoate (Compound 96) was converted to the title compound (white solid) using 28 mg (1.3 ml, 0.66 mmol) of LiOH (0.5 M aqueous solution).
PMR (acetone-d6) : δ 1.24 (6H, s), 1.35 (9H, s), 2.16 (2H, d, J = 4.9 Hz), 6.06 (1H, t, J = 4.9 Hz), 7.40 (1H, dd, J = 2.0 , 8.1 Hz), 7.50 (1H, d, J = 2.0 Hz), 7.64 (2H, d, J = 8.2 Hz), 7.71 (1H, d, J = 8.1 Hz), 8.03 (2H, d, J = 8.2 Hz).
4-[(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-2-yl)ethynyl]benzoic acid (Compound 104)
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-phenylnaphth-2-yl)ethynyl]benzoic acid (Compound 97), 177 mg (0.43 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-2-yl)ethynyl]benzoate (Compound 88) was converted to the title compound
(white solid) using 91 mg (4.3 ml, 2.14 mmol) of LiOH (0.5M aqueous solution).
PMR (acetone-d6): δ 1.34 (6H, s), 2.45 (2H, d, J = 4.9 Hz), 6.61 (1H, t, J = 4.9 Hz), 7.42 (1H, dd, J = 1.7, 8.1 Hz), 7.61 (2H, d, J = 3.4 Hz), 7.67 (2H, d, J = 8.2 Hz), 7.87 (1H, d, J = 8.1 Hz), 7.92 (1H, d, J = 1.7 Hz), 8.02 (2H, d, J = 8.2 Hz).
Ethyl 4-[(5-acetoxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 105)
To 200 mg (0.51 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonapth-2-yl)ethynyl]benzoate (Compound 1) was added 0.13 ml (1.5 mmol) of acetic anhydride and 10 mg (0.05 mmol) of p-toluenesulfonic acid. The mixture was heated at 80 °C for 12 hours, cooled to room temperature and
concentrated in vacuo to an oil. Purification by flash chromatography (silica, 10% EtOAc-hexane) yielded the title compound as a light yellow powder.
PMR (CDCl3) : δ 1.36 (6H, s), 1.41 (3H, t, J = 7.1 Hz), 2.31 (3H, s), 2.80 (2H, d, J = 4.7 Hz), 4.39 (2H, q, J = 7.1 Hz), 5.69 (1H, t, J = 1.1 Hz), 7.11 (1H, d, J = 7.9 Hz), 7.35 (1H, d, J = 1.7 Hz), 7.38 (1H, d, J = 1.7 Hz), 7.47 (1H, d, J = 1.5 Hz), 7.59 (2H, d, J = 6.7 Hz), 8.03 (2H, d, J = 8.4 Hz). 4-[(5-acetoxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoic acid (Compound 106)
Employing the same general procedure as for the preparation of ethyl 4-[(5-acetoxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 105), 274 mg (0.86 mmol) of 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonapth-2-yl)ethynyl]benzoic acid (Compound 7) was converted into the title compound (light yellow solid) using 0.22 ml (2.58 mmol) acetic anhydride and 84 mg (0.43 mmol) of p-toluenesulfonic acid.
PMR (CDCl3): δ 1.37 (6H, s), 2.32 (3H, s), 2,40 (2H, d, J = 4.8 Hz), 5.70 (1H, t, J = 1.1 Hz), 7.12 (1H, d, J = 8.1 Hz), 7.37 (1H, d, J = 8.1 Hz), 7.48 (1H, s), 7.64 (2H, d, J = 8.3 Hz), 8.1 (2H, d, J = 8.3 Hz).
Ethyl 4-[(5-cyano-5,6,7,8-tetrahydro-8,8-dimethyl-5-trimethylsiloxynaphth-2-yl)ethynyl]benzoate (Compound 107)
To 500 mg (1.28 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 1) was added 0.21 ml (1.40 mmol) of cyanotrimethylsilane and 6 drops of boron trifluoride etherate. The resulting dark mixture was heated at 60 °C for 30 minutes, cooled to room temperature and purified by flash chromatography
(silica, 25% EtOAc-hexane) to yield the title compound as a clear oil.
PMR (CDCl3): δ 0.25 (9H, s), 1.34 (6H, s), 1.41 (3H, t, J = 7.1 Hz), 1.90 (2H, m), 2.25 (1H, m), 2.35 (1H, m), 4.39 (2H, q, J = 7.1 Hz), 7.44 (1H, dd, J = 1.6, 8.4 Hz), 7.51 (1H, s), 7.61 (2H, d, J = 8.4 Hz), 7.64 (1H, d, J = 8.4 Hz), 8.04 (2H, d, J = 8.3 Hz).
Ethyl 4-[(5-cyano-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 108) To 215 mg (0.48 mmol) of ethyl
4- [(5-cyano-5,6,7,8-tetrahydro-8,8-dimethyl-5-trimethylsiloxynaphth-2-yl)ethynyl]benzoate (Compound 107) was added 0.5 ml of pyridine and 3 drops of phosphorous oxychloride. The resulting dark mixture was gently refluxed at 115 °C for 30 minutes, cooled to room temperature and poured into crushed ice. The mixture was extracted with Et2O and the combined organic layers were washed with water, dilute HCl and water. The organic phase was concentrated in vacuo to a gummy residue which was purified by flash chromatography (silica, 20% EtOAc-hexane) to yield the title compound as a pale yellow solid.
PMR (CDCl3): δ 1.31 (6H, s), 1.41 (3H, t, J = 7.2 Hz), 2.44 (2H, d, J = 4.8 Hz), 4.39 (2H, q, J = 7.2 Hz), 6.89 (1H, t, J = 4.8 Hz), 7.49 (3H, m), 7.60 (2H, d, J = 8.4 Hz), 8.03 (2H, d, J = 8.4 Hz).
Ethyl 4-[(5-carboxamido-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 109)
To a solution of 50 mg (0.14 mmol) of ethyl 4-[(5-cyano-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 108) in 1 ml of ethanol was added 1 ml of H2SO4 (1M aqueous solution) . This reaction mixture was heated at 80 °C overnight, 2 ml of water was added and the solution was extracted with EtOAc (3 × 2 ml). The combined organic layers were washed with sat. aqueous NaHCO3 and brine, dried over MgSO4, concentrated in vacuo and the residue purified by column chromatography (silica, 20% EtOAc-hexane) to yield the title compound as a colorless oil.
PMR (CDCl3): δ 1.31 (6H, s), 1.38 (3H, t, J = 7.2 Hz), 2.46 (2H, d, J = 4.8 Hz), 4.33-4.38 (4H, m), 6.98 (1H, t, J = 4.8 Hz), 7.35 (2H, d, J = 8.2 Hz), 7.56-7.59 (1H, d, J = 8.0 Hz), 7.91 (1H, d, J = 8.0 Hz), 7.97
(1H, s), 8.02 (2H, d, J = 8.2 Hz).
Ethyl 4-[(7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 110)
To a solution of 0.13 g (0.38 mmol) of ethyl 4- [(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 9) in 15 ml of dry benzene was added 0.67 g (2.90 mmol) of (methoxy carbonylsulfamoyl) triethylammonium hydroxide (Burgess Reagent). The resulting mixture was heated at 50 °C for 30 minutes, cooled to room temperature, partitioned between water (10 ml) and EtOAc (20 ml) and the layers separated. The organic layer was dried over Na2SO4, concentrated in vacuo and purified by flash
chromatography (silica, 10% EtOAc-hexane) to yield the title compound as a clear oil.
PMR (CDCl3): δ 1.28 (6H, s), 1.40 (3H, t, J = 7.1 Hz), 2.25 (2H, dd, J = 1.8 , 2.6 Hz), 4.37 (2H, q, J = 7.1 Hz), 5.99 (1H, q, J = 4.8 Hz), 6.45 (1H, d, J = 9.7 Hz), 7.00 (1H, d, J = 7.8 Hz), 7.32 (1H, dd, J = 1.6 , 6.2 Hz), 7.46 (1H, s), 7.57 (2H, d, J = 8.3 Hz), 8.02
(2H, d, J = 8.5 Hz).
Ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-trimethylsiloxynaphth-2-yl)ethynyl]benzoate (Compound
111)
To a solution of 0.23 g (0.54 mmol) of ethyl 4- [(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-2-yl)ythynyl]benzoate (Compound 9) in 4 ml of dry CH2Cl2 was added 0.06 ml of triethylamine (0.81 mmol). The solution was flushed with nitrogen and then 0.12 g
(0.81 mmol) of chlorotrimethylsilane was slowly added by syringe. The mixture was stirred at room
temperature (flushed with nitrogen) for 30 minutes. concentrated in vacuo to an oil and purified by flash chromatography (silica, 10% EtOAc-hexane) to yield the title compound as a clear oil.
PMR (CDCl3): δ 0.23 (9H, s), 1.32 (6H, s), 1.41 (3H, t, J = 7.1 Hz), 1.65 (1H, m), 1.84 (2H, m), 2.00 (1H, m),
4.37 (2H, q, J = 7.1 Hz), 4.75 (1H, dd, J = 3.24 , 5.2 Hz), 7.37 (2H, s), 7.49 (1H, s) , 7.60 (2H, d, J = 8.42 Hz), 8.03 (2H, d, J = 8.5 Hz).
4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-trimethylsiloxynaphth-2-yl)ethynyl]benzoic acid
(Compound 112)
Employing the same general procedure as for the preparation of ethyl 4-[ (5,6,7,8-tetrahydro-8,8-dimethyl-5-trimethylsiloxynaphth-2-yl)ethynyl]benzoate (Compound 111), 83 mg (0.26 mmol) of 4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-2-yl)ethynyl]benzoic acid (Compound 42) was converted into the title compound (white solid) using 0.07 ml (0.65 mmol) of triethylamine and 0.08 ml (0.65 mmol) of chlorotrimethylsilane.
PMR (CDCl3): δ 0.18 (9H, s), 1.26 (6H, d, J = 5.1 Hz), 1.65 (1H, m), 1.80 (2H, m), 2.01 (1H, m), 4.77 (1H, s), 7.33 (1H, q, J = 3.3 Hz), 7.57 (1H, s), 7.62 (2H, d, J = 8.3 Hz), 8.05 (2H, d, J =• 8.3 Hz).
Ethyl 4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethyl-5-carboethoxymethylnaphth-2-yl)ethynyl]benzoate (Compound 113)
To a refluxing solution of 1.00 g (15.30 mmol) of 20 mesh, granular zinc (activated prior to use by washing with 2% HCl, water, 95% ethanol, acetone, anhydrous Et2O and then dried in vacuum for several hours) in 20 ml of dry benzene was slowly added a mixture of 0.23 ml (1.62 mmol) of ethyl bromoacetate, 0.28 g (0.81 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 1) in 10 ml of dry benzene. The resulting mixture was refluxed for 2 hours, cooled to room temperature and the precipitate filtered through Celite. The filtrate was washed with cold 15% H2SO4, sat. aqueous NaHCO3 and brine. The organic phase was dried over Na2SO4 and concentrated in vacuo to a yellow oil. Purification by flash
chromatography (silica, 10% EtOAc-hexane) yielded the title compound as a light yellow solid.
PMR (CDCl3): 6 1.30 (6H, s), 1.42 (3H, t, J = 7.1 Hz), 1.75 (2H, m), 2.08 (2H, m), 2.77 (2H, s), 4.22 (3H, m), 4.39 (2H, q, J = 7.1 Hz), 7.38 (1H, dd, J = 1.7 , 6.5 Hz), 7.49 (1H, d, J = 1.6 Hz), 7.59 (3H, m), 8.02 (2H, d, J = 8.4 Hz).
Ethyl 4-[(7.8-dihydro-8,8-dimethyl-5-carboethoxymethylnaphth-2-yl)ethynyl]benzoate (Compound 114) and Ethyl 4-[(5-carboethoxymethylidene- 7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate
(Compound 115)
To a solution of 0.50 g (1.15 mmol) of ethyl 4-[(7,8-dihydro-5-hydroxy-8,8-dimethyl-5-carboethoxymethylnaphth-2-yl)ethynyl]benzoate (Compound 113) in 25 ml of dry benzene was added 2.12 g (8.90 mmol) of (methoxycarbonylsulfamoyl) triethylammonium hydroxide (Burgess Reagent). The reaction mixture was heated at 50 °C for 30 minutes, cooled to room
temperature and concentrated in vacuo. The residue was diluted with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated in vacuo to an oil.
Purification by flash chromatography (silica, 25%
EtOAc-hexane) yielded the title compounds as solids in a ratio of 5 to 1, respectively. Ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-carboethoxymethylnaphth-2-yl)ethynyl]benzoate (Compound 114): PMR (CDCl3): δ 1.17 (3H, t, J = 2.8 Hz), 1.30 (6H, s), 1.41 (3H, t, J = 7.1 Hz), 2.26 (2H, d, J = 4.6 Hz), 3.46 (2H, s), 4.12 (2H, q, J = 7.2 Hz), 4.38 (2H, q, J = 7.1 Hz), 5.96 (1H, s), 7.17 (1H, d, J = 8.0 Hz), 7.36 (1H, dd, J = 1.7, 6.4 Hz) . 7.48 (1H, d, J = 1.7 Hz), 7.58 (2H, d, J = 6.5 Hz), 8.01 (2H, d, J = 6.5 Hz).
Ethyl 4-[(5-carboethoxymethylidene-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 115): PMR (CDCl3) : δ 1.32 (6H, s), 1.41 (3H, t, J = 7.1 Hz), 1.73 (3H, t, J = 6.7 Hz), 3.22 (2H, m), 4.22 (2H, q, J = 7.1 Hz), 4.39 (2H, q, J = 7.1 Hz), 6.30 (1H, d, J = 1.8 Hz), 7.35 (1H, dd, J = 1.7, 6.6 Hz), 7.55 (1H, d, J = 1.6 Hz), 7.60 (3H, dd, J = 2.0, 6.4 Hz), 8.04 (2H, d, J = 6.5 Hz).
(Trimethylsilyl)ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 116)
To a solution of 0.24 g (0.73 mmol) of
4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoic acid (Compound 7) in 10 ml of dry CH2Cl2 was added 0.09 g (0.74 mmol) of dimethylaminopyridine, 0.115 ml (0.80 mmol) of
trimethylsilylethanol and 0.17 g (0.88 mmol) of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide
hydrochloride. The reaction mixture was stirred at 25 °C for 5 hours, washed with sat. aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo to an oil. Purification by flash chromatography (silica, 10% EtOAc-hexane) yielded the title compound as a white solid. PMR (CDCl3): 0.09 (9H, s), 1.14 (2H, m), 1.42 (6H, s), 2.03 (2H, t, J = 7.1 Hz), 2.74 (2H, t, J = 6.5 Hz),
4.43 (2H, t, J - 8.5 Hz), 7.45 (1H, dd, J = 1.5 , 6.7
Hz), 7.61 (3H, d, J = 7.0 Hz), 8.03 (3H, t, J = 6.7 Hz).
(Trimethylsilyl)ethyl 4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethyl-5-carboethoxymethylnaphth-2-yl)ethynyl]benzoate (Compound 117)
Employing the same general procedure as for the preparation of ethyl 4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethyl-5-carboethoxymethylnaphth-2-yl)ethynyl]benzoate (Compound 113), 0.38 g (0.89 mmol) of trimethylsilylethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 116), was converted into the title compound (yellow solid) using 0.50 g (7.65 mmol) of zinc, 0.20 ml (1.78 mmol) of ethyl bromoacetate and 20 ml of dry benzene. PMR (CDCl3) : δ 0.09 (9H, s), 1.14 (2H, m), 1.28 (8H, m), 1.74 (2H, m), 2.07 (2H, m), 2.77 (2H, s), 4.20 (3H, m), 4.42 (3H, t, J = 8.4 Hz), 7.37 (1H, dd, J = 1.6 , 6.7 Hz), 7.49 (1H, s), 7.58 (3H, dd, J = 3.8 , 7.0 Hz), 8.01 (2H, d, J = 8.4 Hz).
4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethyl-5-carboethoxymethylnaphth-2-yl)ethynyl]benzoic acid
(Compound 118)
To a solution of 0.25 g (0.49 mmol) of
trimethylsilylethyl 4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethyl-5-carboethoxy-methylnaphth-2-yl)ethynyl]benzoate (Compound 117) in 5 ml of dry THF (flushed with argon) was added 1.48 ml (1.5 mmol) of tetrabutylammonium fluoride (1M solution in THF). The reaction mixture was stirred at room temperature for 12 hours, concentrated in vacuo to an oil and slowly diluted with water. The solution was acidified to pH 4 with 10% HCl and extracted with Et2O. The organic layer was dried over Na2SO4, concentrated in vacuo to an oil and purified by flash chromatography (silica, 90% EtOAc-hexane) to give the title compound as a white solid.
PMR (CDCl3) : δ 1.30 (9H, m), 1.72 (2H, m), 2.08 (2H, m), 2.78 (2H, s), 4.21 (2H, q, J = 7.0 Hz), 7.38 (1H, dd, J = 1.5, 6.6 Hz), 7.50 (1H, s), 7.58 (1H, d, J = 8.2 Hz), 7.62 (2H, d, J = 8.4 Hz), 8.10 (2H, d, J = 8.4 Hz).
Ethyl 4-[(5-hydroxy-8,8-dimethyl-5-carboethoxymethyl-5,6,7,8-tetrahydronaphth-3-yl)ethynyl]benzoate
(Compound 119)
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-5-hydroxy-8,8-dimethyl-5-carboethoxymethylnaphth-2-yl)ethynyl]benzoate (Compound 113), 1.00 g (2.88 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoate (Compound 2) was converted into the title compound (light yellow solid) using 1.00 g (15.30 mmol) of zinc, 0.639 ml (5.76 mmol) of ethyl bromoacetate and 70 ml of dry benzene.
PMR (CDCl3): δ 1.30 (9H, m), 1.40 (3H, t, J = 7.1 Hz), 1.75 (2H, m), 2.04 (2H, m), 2.80 (2H, d, J = 3.1 Hz), 4.21 (2H, m), 4.38 (2H, q, J = 7.2 Hz), 7.30 (1H, d, J = 8.3 Hz), 7.41 (1H, dd, J = 1.8, 6.4 Hz), 7.57 (2H, d, J = 6.7 Hz), 7.81 (1H, d, J = 1.8 Hz), 8.03 (2H, d, J = 8.4 Hz).
Ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-carboethoxymethylnaphth-3-yl)ethynyl]benzoate (Compound 120) and Ethyl 4-[(5-carboethoxymethylidene-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 121)
Employing the same general procedure as for the preparations of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-carboethoxymethylnaphth- 2-yl)ethynyl]benzoate
(Compound 114) and ethyl 4-[(5-carboethoxymethylidene-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 115), 0.57 g (1.31 mmol) of ethyl
4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethyl-5-carboethoxymethylnaphth-3-yl)ethynyl]benzoate (Compound 119) was converted into the title compounds (yellow solid and white solid, respectively) using 15 ml of dry benzene, 6 ml of dry THF and 2.42 g (10.1 mmol) of (methoxycarbonylsulfamoyl) triethylammonium hydroxide (Burgess Reagent).
Ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-carboethoxymethylnaphth-3-yl)ethynyl]benzoate (Compound 120) :
PMR (CDCl3): δ 1.22 (3H, t, J = 7.1 Hz), 1.29 (6H, s), 2.70 (2H, d, J = 4.4 Hz), 3.49 (2H, s), 4.17 (2H, q, J = 7.1 Hz), 4.00 (2H, q, J = 7.1 Hz), 5.96 (1H, t, J = 4.5 Hz), 7.35 (3H, m), 7.58 (2H, d, J = 8.4 Hz), 8.02 (2H, d, J = 7.9 Hz).
Ethyl 4-[(5-carboethoxymethylidene-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 121):
PMR (CDCl3) δ 1.31 (9H, m), 1.74 (2H, q, J = 6.7 Hz), 3.24 (2H, t, J = 3.3 Hz), 4.22 (2H, q, J = 7.1 Hz), 4.40 (2H, q, J = 7.1 Hz), 6.33 (1H, s), 7.37 (1H, d, J = 7.9 Hz), 7.50 (1H, d, J = 8.3 Hz), 7.59 (2H, d, J = 7.7 Hz), 7.79 (1H, s), 8.04 (2H, d, J = 8.4 Hz). Ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-furyl)naphth-3-yl)ethynyl]benzoate (Compound 122)
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2 thiazolyl)naphth-3-yl)ethynyl]benzoate (Compound 67),
250.0 mg (0.52 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth- 3-yl)ethynyl]benzoate (Compound 66) was converted into the title compound (colorless solid) using 142.4 mg (1.045 mmol) of zinc chloride, 24.1 mg
(0.02 mmol) of tetrakis (triphenylphosphine) palladium(0) and 2-lithiofuran (prepared by the addition of 53.4 mg
(0.52 ml, 0.78 mmol) of n-butyllithium (1.5M solution in hexane) to a cold solution (-78 °C) of 53.4 mg
(0.784 mmol) of furan in 1.0 mL of THF).
PMR (CDCl3): δ 1.32 (6H, s), 1.41 (3H, t, J = 7.1 Hz),
2.35 (2H, d, J = 5.0 Hz), 4.39 (2H, q, J = 7.1 Hz),
6.41 (1H, t, J = 5.0 Hz), 6.50 (2H, s), 7.36 (1H, d, J
= 8.0 Hz), 7.45 (1H, dd, J = 1.7, 8.0 Hz), 7.49 (1H, s), 7.57 (2H, d, J = 8.2 Hz), 7.63 (1H, d, J = 1.7 Hz),
8.02 (2H, d, J = 8.2 Hz).
Ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-thienyl)naphth- 3-yl)ethynyl]benzoate (Compound 123)
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl]benzoate (Compound 67), 328.0 mg (0.685 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 66) was converted into the title compound (colorless solid) using 186.8 mg (1.37 mmol) of zinc chloride 37.1 mg (0.03 mmol) of tetrakis (triphenylphosphine) palladium(O) and 2-lithiothiophene (prepared by the addition of 65.9 mg (0.69 ml, 1.03 mmol) of n-butyllithium (1.5M
solution in hexane) to a cold solution (-78 °C) of 86.5 mg (1.03 mmol) of thiophene in 1.0 mL of THF).
PMR (CDCl3): δ 1.33 (6H, s), 1.36 (3H, t, J = 7.1 Hz), 2.38 (2H, d, J = 4.7 Hz), 4.34 (2H, q, J = 7.2 Hz), 6.25 (1H, t, J = 4.7 Hz), 7.13 ( 2H, m), 7.47 (4H, m), 7.62 ( 2H, d, J = 8.5 Hz), 8.00 (2H, d, J = 8.5 Hz). 4-[(7,8-dihydro-8,8-dimethyl-5-(2-furyl)naphth-3-yl)ethynyl]benzoic acid (Compound 124)
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)naphth-3-yl)ethynyl]benzoic acid (Compound 84), 60.3 mg (0.15 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-furyl)naphth-3-yl)ethynyl]benzoate
(Compound 122) was converted into the title compound (colorless solid) using 16.0 mg (0.38 mmol) of LiOH in H2O.
PMR (d6-DMSO) : δ 1.26 (6H, s), 2.33 ( 2H, d, J = 4.9 Hz), 6.41 (1H, t, J - 4.9 Hz), 6.60 (2H, m), 7.45-7.53 (3H, m), 7.64 (2H, d, J = 8.3 Hz), 7.75 (1H, d, J = 1.6 Hz), 7.93 (2H, d, J = 8.3 Hz).
4-[(7,8-dihydro-8,8-dimethyl-5-(2-thienyl)naphth-3-yl)ethynyl)benzoic acid (Compound 125)
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)naphth-2-yl)ethynyl]benzoic acid (Compound 84), 70.0 mg (0.17 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-thienyl)naphth-3-yl)ethynyl]benzoate (Compound 123) was converted into the title compound (colorless solid) using 17.8 mg (0.42 mmol) of LiOH in H2O.
PMR (d6-DMSO) : δ 1.27 (6H, s), 2.33 (2H, d, J = 4.9 Hz), 6.23 (1H, t, J = 4.9 Hz), 7.14 (2H, m), 7.38 - 7.56 (4H, m), 7.61 (2H, d, J = 8.3 Hz), 7.92 (2H, d, J = 8.3 Hz).
Ethyl 4-[(5-acetoxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 126) Employing the same general procedure as for the preparation of ethyl 4-[(5-acetoxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 105), 90.0 mg (0.26 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoate
(Compound 2) was converted into the title compound (light yellow powder) using 0.06 ml (0.78 mmol) of acetic anhydride and 5 mg (0.03 mmol) of p-toluenesulfonic acid.
PMR (CDCl3): δ 1.34 (6H, s), 1.40 (3H, t, J = 7.2 Hz), 2.34 (3H, s), 2.37 (2H, d, J = 4.7 Hz), 4.38 (2H, q, J = 7.1 Hz), 5.68 (2H, t, J = 4.7 Hz), 7.28 (2H, d, J = 5.1 Hz), 7.43 (1H, dd, J = 1.7, 8.0 Hz), 7.59 (2H, d, J = 8.4 Hz), 8.03 (2H, d, J = 8.4 Hz).
4-[(5-acetoxy-7.8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoic acid (Compound 127)
Employing the same general procedure as for the preparation of ethyl 4-[(5-acetoxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 105), 100.0 mg (0.31 mmol) of 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoic acid
(Compound 8) was converted into the title compound (white solid) using 0.08 ml (0.94 mmol) of acetic anhydride and 30 mg (0.16 mmol) of p-toluenesulfonic acid.
PMR (CDCl3): .5 1.35 (6H, s), 2.36 (3H, s), 2.38 (2H, d, J = 4.8 Hz), 5.69 (2H, t, J = 4.8 Hz), 7.29 (2H, d, J = 7.6 Hz), 7.45 (1H, dd, J = 1.7, 8.0 Hz), 7.63 (2H, d, J = 8.4 Hz), 8.10 (2H, d, J = 8.4 Hz).
4-[(7,8-dihydro-8,8-dimethyl-5-trimethylsiloxynaphth-3-yl)ethynyl]benzoic acid (Compound 128)
To a cold solution (0 °C) of 50 mg (0.07 mmol) of zinc iodide (dried in vacuo over P2O5 for several hours) in 2 ml of dry THF (flushed with argon) was added a solution of 0.110 g (0.34 mmol) of
4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)-ethynyl]benzoic acid (Compound 8) in 2 ml of THF followed by 0.14 ml (1.03 mmol) of
cyanotrimethylsilane. The resulting mixture was stirred at 25 ° C for 12 hours and purified by flash chromatography (silica, 50% EtOAc-hexane) to yield the title compound as a white solid.
PMR (CDCl3): δ 0.165 (9H, s), 1.17 (6H, s), 2.16 (2H, d, J = 5.30 Hz), 5.06 (1H, t, J = 4.7 Hz), 7.19 (1H, d,
J = 7.9 Hz), 7.28 (1H, dd, J = 1.8, 7.9 Hz), 7.41 (1H, s), 7.49 (2H, d, J = 8.5 Hz), 7.91 (2H, d, J = 8.21
Hz).
4-[(5-cyano-7.8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoic acid (Compound 129)
To 76 mg (0.24 mmol) of 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoic acid (Compound 8) was added 0.06 ml (0.48 mmol) of
cyanotrimethylsilane and 6 drops of boron trifluoride etherate. The resulting dark mixture was heated at 80 °C for 45 minutes, cooled to room temperature and purified by flash chromatography (silica, 50% EtOAc-hexane) to yield the title compound as a yellow solid. PMR (CDCl3): δ 1.31 (6H, s), 2.45 (2H, d, J = 4.8 Hz), 6.91 (1H, t, J = 4.8 Hz), 7.36 (1H, d, J = 8.0 Hz), 7.51 (1H, dd, J = 1.8, 8.0 Hz), 7.65 (2H, d, J = 8.4 Hz), 7.69 (1H, s), 8.10 (2H, d, J = 8.4 Hz).
4-[(5-cyano-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoic acid (Compound 130)
Employing the same general procedure as for the preparation of 4-[(8-cyano-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoic acid (Compound 129), 63 mg (0.26 mmol) of 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoic acid
(Compound 7) was converted into the title compound
(yellow powder) using 0.06 ml (0.54 mmol) of
cyanotrimethylsilane and 6 drops of boron trifluoride etherate.
PMR (CDCl3): δ 1.32 (6H, s), 2.45 (2H, d, J = 4.8 Hz),
6.90 (1H, t, J = 4.8 Hz), 7.49 (3H, m), 7.65 (2H, d, J
= 8.4 Hz), 8.10 (2H, d, J = 8.4 Hz).
Ethyl 4-[(5(6H)-cyclohexylidene-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 131)
Employing the same general procedure as for the preparation of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 1), 289 mg (1.22 mmol) of 6-ethynyl-1(2H)-cyclohexylidene-3,4-dihydro-4,4-dimethylnaphthalene (Compound ϋ) was converted into the title compound using 337 mg (1.22 mmol) of ethyl 4-iodobenzoate, 77 mg (0.4 mmol) of cuprous iodide and 286 mg (0.41 mmol) of bis (triphenylphosphine) palladium(II) chloride.
PMR (CDCl3): δ 1.28 (6H, s), 1.38 (3H, t, J = 7.1 Hz), 1.54-1.65 (8H, br s), 2.32 (2H, br s), 2.46 (2H, t, J = 6.4 Hz), 2.51 (2H, t, J = 7.1 Hz), 4.37 (2H, q, J = 7.1Hz), 7.16 (1H, d, J = 8.0 Hz), 7.29 (1H, dd, J = 1.7, 8.0 Hz), 7.47 (1H, d, J - 1.7 Hz), 7.57 (2H, d, J = 8.3 Hz), 8.00 (2H, d, J = 8.3 Hz).
Ethyl 4-[(5(6H)-cyclohexylidene-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl)benzoate (Compound 132)
Employing the same general procedure as for the preparation of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 1), 289 mg (1.22 mmol) of 7-ethynyl-1(2H)-cyclohexylidene-3,4-dihydro-4,4-dimethylnaphthalene (Compound V) was converted into the title compound using 337 mg (1.22 mmol) of ethyl 4-iodobenzoate, 77 mg
(0.4 mmol) of cuprous iodide and 286 mg (0.41 mmol) of bis (triphenylphosphine) palladium(II) chloride.
PMR (CDCl3): .5 1.27 (6H, s), 1.40 (3H, t, J = 7.1 Hz), 1.52-1.69 (8H, m), 2.33 (2H, br s), 2.46 (2H, t, J = 6.2 Hz), 2.53 (2H, t, J = 7.4 Hz), 4.38 (2H, q, J = 7.1 Hz), 7.27 (1H, d, J = 8.5 Hz), 7.33 (2H, m), 7.56 (2H, d, J = 8.4 Hz), 8.00 (2H, d, J = 8.4 Hz).
Ethyl 4-[(7,8-dihydro-8,8-dimethyl-5(6H)-(3-pentylidene)naphth -2-yl)ethynyl ] benzoate (Compound 133)
Employing the same general procedure as for the preparation of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 1), 143 mg (0.57 mmol) of 6-ethynyl-3,4-dihydro-1(2H)- (3-pentylidene)-4,4-dimethylnaphthalene (Compound W) was converted into the title compound using 142 mg
(0.51 mmol) of ethyl 4-iodobenzoate, 36 mg (0.19 mmol) of cuprous iodide and 130 mg (0.19 mmol) of
bis (triphenylphosphine) palladium(II) chloride.
PMR (CDCl3): δ 1.05 (3H, t, J = 7.4 Hz), 1.13 (3H, t,
J = 7.3 Hz), 1.27 (6H, s), 1.40 (3H, t, J = 7.1 Hz),
1.65 (2H, t, J = 6.9 Hz), 2.17-2.32 (4H, m), 2.51 (2H, t, J = 6.9 Hz), 4.38 (2H, q, J = 7.1 Hz), 7.21 (1H, d,
J = 8.0 Hz), 7.32 (1H, dd, J = 1.7, 8.0 Hz), 7.47 (1H, d, J = 1.7 Hz), 7.58 (2H, d, J = 8.2 Hz), 8.02 (2H, d,
J = 8.2 Hz).
Ethyl 4-[(7,8-dihydro-8,8-dimethyl-5(6H)-(3-pentylidene)-naphth-3-yl)ethynyl]benzoate (Compound
134)
Employing the same general procedure as for the preparation of ethyl 4-[(5,6,7,8-tetrahydro-8,8- dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound
1), 235 mg (0.94 mmol) of 7-ethynyl-3,4-dihydro-1(2H)- (3-pentylidene)-4,4-dimethylnaphthalene (Compound X) was converted into the title compound using 236 mg
(0.85 mmol) of ethyl 4-iodobenzoate, 57 mg (0.3 mmol) of cuprous iodide and 220 mg (0.31 mmol) of
bis (triphenylphosphine) palladium(II) chloride.
PMR (CDCl3): δ 1.07 (3H, t, J = 7.5 Hz), 1.15 (3H, t,
J = 7.5 Hz), 1.25 (6H, s), 1.40 (3H, t, J = 7.1 Hz),
1.65 (2H, t, J = 7.0 Hz), 2.22 (2H, q, J = 7.5 Hz),
2.31 (2H, q, J = 7.5 Hz), 2.50 (2H, t, J = 7.0 Hz),
4.38 (2H, q, J = 7.1 Hz), 7.28 (1H, d, J = 8.0 Hz),
7.35 (1H, dd, J = 1.7, 8.0 Hz), 7.39 (1H, d, J = 1.7
Hz), 7.56 (2H, d, J = 8.5 Hz), 8.01 (2H, d, J = 8.5 Hz).
4-[(5(6H)-cyclohexylidene-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoic acid (Compound 135)
Employing the same general procedure as for the preparation of 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoic acid (Compound 7), 95 mg (0.23 mmol) of ethyl 4-[(5(6H)-cyclohexylidene-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate
(Compound 131) was converted to the title compound using 1 ml (1 mmol) of LiOH (1M aqueous solution).
PMR (CDCl3) : δ 1.24 (6H, s), 1.50-1.61 (8H, br s), 2.30 (2H, br s), 2.39 (2H, br s), 2.47 (2H, br s), 7.16 (1H, d, J = 8.1 Hz), 7.34 (1H, dd, J = 1.7 , 8.1 Hz), 7.48 (1H, d, J = 1.7 Hz), 7.65 (2H, d, J = 8.4 Hz), 7.96 (2H, d, J = 8.4 Hz).
4-[(5(6H)-cyclohexylidene-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoic acid (Compound 136)
Employing the same general procedure as for the preparation of 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5- oxonaphth-2-yl)ethynyl]benzoic acid (Compound 7), 95 mg (0.23 mmol) of ethyl 4-[(5(6H)-cyclohexylidene-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate
(Compound 132) was converted to the title compound using 1 ml (1 mmol) of LiOH (1M aqueous solution).
PMR (Acetone-d6) : δ 1.27 (6H, s), 1.50-1.70 (8H, m), 2.33 (2H, br s), 2.49 (2H, br s), 2.53 (2H, t, J = 7.1 Hz), 7.29 (1H, d, J = 8.4 Hz), 7.35 (2H, br s), 7.61 (2H, d, J = 8.1 Hz), 8.08 (2H, d, J = 8.1 Hz).
4-[(7,8-dihydro-8,8-dimethyl-5(6H)-(3-pentylidene)naphth-2-yl)ethynyl]benzoic acid (Compound 137)
Employing the same general procedure as for the preparation of 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoic acid (Compound 7), 90 mg (0.23 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5(6H)-(3-pentylidene)naphth-2-yl)ethynyl]benzoate
(Compound 133) was converted to the title compound using 0.5 ml (0.5 mmol) of LiOH (1M aqueuos solution). PMR (CDCl3) : δ 1.05 (3H, t, J = 7.6 Hz), 1.34 (3H, t, J = 7.4 Hz), 1.27 (6H, s), 1.67 (2H, t, J = 7.1 Hz), 2.20-2.34 (4H, m), 2.54 (2H, t, J = 7.1 Hz), 7.27 (1H, d, J = 7.9 Hz), 7.36 (1H, dd, J = 1.7 , 7.9 Hz), 7.53 (1H, d, J = 1.7 Hz), 7.66 (2H, d, J = 8.4 Hz), 8.05 (2H, d, J = 8.4 Hz).
4-[(7,8-dihydro-8,8-dimethyl-5(6H)-(3-pentylidene)naphth-3-yl)ethynyl]benzoic acid (Compound 138)
Employing the same general procedure as for the preparation of 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoic acid (Compound 7), 90 mg (0.23 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5(6H)-(3-pentylidene)naphth-3-yl)ethynyl]benzoate (Compound 134) was converted to the title compound using 1 ml (1.0 mmol) of LiOH (1M aqueous solution).
PMR (CDCl3) : δ 1.05 (3H, t, J = 7.6 Hz), 1.16 (3H, t, J = 7.5 Hz), 1.25 (6H, s), 1.65 (2H, t, J = 6.9 Hz), 2.22 (2H, q, J = 7.5 Hz), 2.31 (2H, q, J = 7.6 Hz), 2.50 (2H, t, J = 6.9 Hz), 7.28 (1H, d, J = 8.1 Hz), 7.36 (1H, dd, J = 1.7, 8.1 Hz), 7.41 (1H, d, J = 1.7 Hz), 7.61 (2H, d, J = 8.5 Hz), 8.08 (2H, d, J = 8.5 Hz).
Ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5(S or R)-thio{2'(S or R)-tetrahydropyranyl}naphth-3-yl)ethynyl]benzoate (Compound 139)
Ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5(S or R)-thio{2'(S or R)-tetrahydropyranyl}naphth-3-yl)ethynyl]benzoate (Compound 140)
Employing the same general procedure as for the preparation of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxo-naphth-2-yl)ethynyl]benzoate (Compound 1), 900 mg (3.0 mmol) of 6-ethynyl-1,2,3,4-tetrahydro-1,1-dimethyl-4-thio(2-tetrahydropyranyl)naphthalene (Compound Y) was converted into a mixture of
diastereomers using 850 mg (3.07 mmol) of ethyl 4-iodobenzoate, 210 mg (1.2 mmol) of cuprous iodide and 790 mg (1.2 mmol) of bis(triphenyl-phosphine)palladium(II) chloride. Separation by normal phase HPLC (Partisil 10, 5% EtOAc-hexane) gave the title compounds (RT = 90 minutes and 96 minutes), respectively. The relative stereochemistry about the two asymmetric carbons has not yet been determined and the stereochemistry about the first asymmetric center has been assigned arbitrarily.
Ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5(S or R)-thio{2'(S or R)-tetrahydropyranyl}naphth-3- yl)ethynyl]benzoate (Compound 139):
PMR (CDCl3): (RT = 90 minutes) δ 1.21 (3H, s), 1.35
(3H, s), 1.39 (3H, t, J = 7.1 Hz), 1.52-1.64 (3H, m),
1.64-1.85 (3H, m), 1.89-1.99 (1H, m), 2.05-2.25 (3H, m), 3.54-3.64 (1H, m), 4.10-4.19 (1H, m), 4.27 (1H, br s), 4.37 (2H, q, J = 7.1 Hz), 4.95-5.03 (1H, m), 7.31
(1H, d, J = 8.2 Hz), 7.35 (1H, dd, J = 1.6, 8.2 Hz),
7.44 (1H, br s), 7.56 (2H, d, J = 8.4 Hz), 8.01 (2H, d,
J = 8.4 Hz).
Ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5(S or R)-thio(2'(S or R)-tetrahydropyranyl)naphth-3-yl)ethynyl]benzoate (Compound 140)
PMR (CDCl3): (RT = 96 minutes) δ 1.23 (3H, s), 1.34
(3H, s), 1.40 (3H, t, J = 7.2 Hz), 1.54-1.78 (5H, m),
1.80-2.20 (5H, m), 3.35-3.65 (1H, m), 4.20-4.30 (1H, m), 4.29 (1H, br s), 4.38 (2H, q, J = 7.2 Hz), 4.94- 4.99 (1H, m), 7.28 (1H, d, J = 8.2 Hz), 7.33 (1H, dd, J
= 1.7 , 8.2 Hz), 7.56 (2H, d, J = 8.4 Hz), 7.57 (1H, d,
J = 1.7 Hz), 8.01 (2H, d, J = 8.4 Hz).
4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5(S or R)-thio(2'(S or R)-tetrahydropyranyl)naphth-3-yl)ethynyl]benzoic acid (Compound 141)
Employing the same general procedure as for the preparation of 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoic acid (Compound 7), 60 mg (0.14 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5(S or R)-thio(2'(S or R)-tetrahydropyranyl)naphth-3-yl)ethynyl]benzoate
(Compound 139) was converted to the title compound using 3 ml (3.0 mmol) of LiOH (1M aqueous solution). PMR (CDCl3): δ 1.22 (3H, s), 1.36 (3H, s), 1.53-1.68 (3H, m), 1.68-1.89 (3H, m), 1.90-2.00 (1H, m), 2.07-2.22 (3H, m), 3.55-3.65 (1H, m), 4.12-4.70 (1H, m), 4.28 (1H, br s), 5.00-5.04 (1H, m), 7.32 (1H, d, J =
8.2 Hz), 7.37 (1H, dd, J - 1.6, 8.2 Hz), 7.45 (1H, d, J
= 1.6 Hz), 7.59 (2H, d, J - 8.4 Hz), 8.09 (2H, d, J =
8.4 Hz).
Ethyl 4-[(5,6,7,8-Tetrahydro-8,8-dimethyl-5(S or R)-thio{2'(S or R)-tetrahydropyranyl}naphth-3-yl)ethynyl]benzoic acid (Compound 142)
Employing the same general procedure as for the preparation of 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoic acid (Compound 7), 60 mg (0.14 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5(S or R)-thio(2'(S or R)-tetrahydropyranyl}naphth-3-yl)ethynyl]benzoate
(Compound 139) was converted to the title compound using 3 ml (3.0 mmol) of LiOH (1M aqueous solution). PMR (CDCl3): δ 1.23 (3H, s), 1.34 (3H, s), 1.55-1.75 (5H, m), 1.78-2.25 (5H, m), 3.57-3.68 (1H, m), 4.22-4.35 (1H, m), 4.32 (1H, br s), 4.85-4.99 (1H, m), 7.29 (1H, d, J = 8.2 Hz), 7.35 (1H, dd, J = 1.5, 8.2 Hz), 7.58 (2H, d, J = 8.4 Hz), 7.58 (1H, d, J = 1.5 Hz), 8.09 (2H, d, J = 8.4 Hz).
Ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-thioacetylnaphth-2-yl)ethynyl]benzoate (Compound 143)
To a solution of 543 mg (1.64 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate in 20 ml of CCl4 was added 320 mg (1.81 mmol) of N-bromosuccinimide and 26 mg (0.11 mmol) of benzoyl peroxide. The mixture was refluxed for 3 hours under argon atmosphere, cooled, filtered through celite and concentrated in vacuo to a dark brown syrup. The syrup was taken up in 20 ml of dry THF and 780 mg (6.9 mmol) of potassium thioacetate was added. The mixture was refluxed for 4 hours under argon atmosphere, concentrated in vacuo and purified by chromatography (silica, 10% EtOAc-hexane) to yield the title compound as a pale yellow solid.
PMR (CDCl3): δ 1.25 (3H, s), 1.35 (3H, s), 1.39 (3H, t, J = 7.1 Hz), 1.68-1.69 (1H, m), 1.82-1.97 (2H, m), 2.20-2.27 (1H, m), 2.35 (3H, s), 4.34 (2H, q, J = 7.1 Hz), 4.94 (1H, t, J = 3.9 Hz), 7.20 (1H, d, J = 8.1 Hz), 7.27 (1H, dd, J = 1.6, 8.1 Hz), 7.49 (1H, d, J = 1.6 Hz), 7.57 (2H, d, J = 8.5 Hz), 8.02 (2H, d, J = 8.5 Hz).
Ethyl 4-[[(5,6,7,8-tetrahydro-8,8-dimethyl-5-thiol)naphth-2-yl]ethynyl]benzoate (Compound 144)
A solution of 88mg (0.2 mmol) of ethyl
4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-thioacetyl-naphth-2-yl)ethynyl]benzoate (Compound 143) and 100 mg (0.53 mmol) of p-toluenesulfonic acid in 3 ml of THF and 3 ml of EtOH was heated at 55 °C for 72 hours. The reaction was diluted with EtOAc (50 ml), washed with water (5 ml) and brine (5 ml), dried over MgSO4 and concentrated in vacuo. Purification by chromatography (silica, 10% EtOAc-hexane) yielded the title compound as a pale yellow oil.
PMR (CDCl3): δ 1.25 (3H, s), 1.39 (3H, s), 1.43 (3H, t, J = 7.1 Hz), 1.58-1.65 (1H, m), 1.89-1.99 (1H, m), 2.10-2.20 (1H, m), 2.24-2.31 (1H, m), 4.33-4.43 (3H, m), 7.28-7.34 (2H, m), 7.50 (1H, br s), 7.58 (2H, d, J = 8.5 Hz), 8.04 (2H, d, J = 8.5 Hz).
Ethyl 4-[[7,8-dihydro-8,8-dimethyl-5(E)(6H)-(cyanomethylidene)naphth-2-yl]ethynyl]benzoate
(Compound 145)
Ethyl 4-[[7,8-dihydro-8,8-dimethyl-5(Z)(6H)-(cyanomethylidene)naphth-2-yl]ethynyl]benzoate
(Compound 146) To a cold solution (0 °C) of 442 mg (2.5 mmol) of diethyl cyanomethylphosphonate in 8 ml of THF was added 450 mg (2.25 mmol) of potassium
bis (trimethylsilyl) amide. The mixture was stirred for 15 minutes and then a solution of 366 mg (1.08 mmol) of ethyl-4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 1) in 7 ml of THF was added via syringe. The mixture was stirred for 8 hours, diluted with Et2O (100 ml), washed with water (10 ml) and brine (10 ml), dried over MgSO4 and
concentrated in vacuo. Purification by chromatography (silica, 5% EtOAc-hexane) gave a 6:1 ratio of E:Z isomers. Separation by normal phase HPLC (Partisil 10, 5% EtOAc-hexane) gave the title compounds (RT = 64 minutes and 70 minutes), respectively.
Ethyl 4-[[7,8-dihydro-8,8-dimethyl-5(E)(6H)- (cyanomethylidene)naphth-2-yl]ethynyl]benzoate
(Compound 145) :
PMR (CDCl3): (RT = 64 minutes) δ 1.35 (6H, s), 1.41 (3H, t, J = 7.1 Hz), 1.82 (2H, t, J = 6.4 Hz), 2.94 (2H, t, J = 6.4 Hz), 4.39 (2H, q, J = 7.1Hz), 5.72 (1H, d, J = 1.7 Hz), 7.36 (1H, dd, J = 1.6 , 8.3 Hz), 7.50 (1H, d, J = 8.3 Hz), 7.58 (1H, d, J = 1.6 Hz), 7.61 (2H, d, J = 8.4 Hz), 8.05 (2H, d, J = 8.4 Hz).
Ethyl 4-[[7,8-dihydro-8,8-dimethyl-5(Z)6(H)-(cyanomethylidene)naohth-2-yl]ethynyl]benzoate
(Compound 146) :
PMR (CDCl3) : (RT = 70 minutes) δ 1.35 (6H, s), 1.42 (3H, t, J = 7.1Hz), 1.84 (2H, t, J = 6.5 Hz), 2.64 (2H, t, J = 6.5Hz), 4.40 (2H, q, J = 7.1 Hz), 5.32 (1H, d, J = 1.4 Hz), 7.43 (1H, dd, J = 1.6, 8.2 Hz), 7.57 (1H, d, J = 1.6 Hz), 7.62 (2H, d, J = 8.4 Hz), 8.05 (2H, d, J = 8.4 Hz), 8.18 (2H, d, J = 8.2 Hz). Ethyl 4-[[5,6,7,8-tetrahydro-8,8-dimethyl-5(R)-{1(S)-O-camphanoate)naphth-3-yl)ethynyl]benzoate (Compound 147) Ethyl 4-[[5,6,7,8-tetrahydro-8,8-dimethyl-5(S)-(1(S)-O-camphanoate)naphth-3-yl]ethynyl]benzoate (Compound 148)
To a solution of 40 mg (0.15 mmol) of racemic ethyl-4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-hydroxy-naphth-3-yl)ethynyl]benzoate (Compound 10) in 2 ml of pyridine was added 147 mg (0.66 mmol) of 1-(S)-camphanic chloride and 30 mg (0.24 mmol) of 4-dimethylaminopyridine. The mixture was heated at 100 °C for 12 hours, cooled and diluted with Et2O (70 ml). The organic phase was washed with 10% HCl (2 × 5 ml), water (5 ml), 10% aqueous NaHCO3 solution (10 ml) and brine (10 ml), dried over MgSO4 and concentrated in vacuo. Purification by chromatography (silica, 15% EtOAc-hexane) gave a 1:1 mixture of two diastereomers (colorless oil). Separation by HPLC separation
(Partisil 10, 10% EtOAc-hexane) gave the title
compounds (RT = 58 minutes and 64 minutes),
respectively.
Ethyl 4-[[5,6,7,8-tetrahydro-8,8-dimethyl-5(R)-(1(S)-O-camphanoate)naphth-3-yl]ethynyl]benzoate (Compound
147) :
PMR (CDCl3): (RT = 58 minutes) δ 0.92 (3H, s), 1.05 (3H, s), 1.10 (3H, s), 1.27 (3H, s), 1.37 (3H, s), 1.41 (3H, t, J = 7.1 Hz), 1.58-1.72 (3H, m), 1.85-2.20 (4H, m), 2.38-2.50 (1H, m), 4.39 (2H, q, J = 7.1 Hz), 6.11 (1H, t, J = 4.6 Hz), 7.37 (1H, d, J = 8.2 Hz), 7.45 (1H, br s), 7.46 (1H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.5 Hz), 8.02 (2H, d, J = 8.5 Hz).
Ethyl 4-[[5,6,7,8-tetrahydro-8,8-dimethyl-5(S)-(1(S)-O-camohanoate)naphth-3-yl]ethynyl]benzoate (Compound
148) : PMR (CDCl3): (RT = 64 minutes) δ 0.95 (3H, s), 0.97 (3H, s), 1.09 (3H, s), 1.26 (3H, s), 1.38 (3H, s), 1.40 (3H, t, J = 7.1 Hz), 1.58-1.74 (3H, m), 1.85-2.20 (4H, m), 2.39-2.50 (1H, m), 4.38 (2H, q, J = 7.1 Hz), 6.12 (1H, t, J = 4.4 Hz), 7.36 (1H, d, J = 8.8 Hz), 7.45 (1H, d, J = 1.6 Hz), 7.46 (1H, dd, J = 1.6 , 8.8 Hz), 7.56 (2H, d, J = 8.6 Hz), 8.02 (2H, d, J = 8.6 Hz).
4-[(7,8-Dihydro-8,8-dimethyl-5-ethylthionaphth-2-yl)ethynyl]benzoic acid (Compound 149)
To a stirring solution of 500 mg (1.44 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 1) in 25 ml of THF at room temperature under argon was added 273 mg (1.44 mmol) of titanium tetrachloride. The resulting orange solution was treated dropwise with a solution of 99 mg (1.59 mmol) of ethanethiol, 291 mg (2.88 mmol) of triethylamine and 8.4 ml of THF, stirred at room temperature for 5 hours and carefully diluted with water. The organic products were extracted with diethyl ether (3X), combined, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was column chromatographed (silica, 2% EtOAc-hexane) to isolate the unstable, impure thioenol ether. A
solution of the impure thioenol ether in 4 ml of ethanol was treated with 1 ml of KOH (2N aqueous solution) and then heated to 50°C for two hours. The solution was cooled to room temperature, concentrated in vacuo. diluted with dichloromethane (5 ml) and acidified with 10% aqueous HCl at 0°C. The layers were separated and the aqueous layer was extracted with dichloromethane (2X). The organic layers were
combined, washed with brine, dried over MgSO4 and concentrated in vacuo. Recrystallization from acetonitrile gave the title compound as a white solid. PMR (CDCl3): δ 1.19 (3H, t, J = 7.5 Hz), 1.23 (6H, s),
2.28 (2H, d, J = 4.5 Hz), 2.71 (2H, q, J = 7.5 Hz), 6.17 (1H, t, J = 4.5 Hz), 7.45 (1H, d, J = 7.5 Hz), 7.51 (1H, s), 7.59 (1H, d, J = 7.5 Hz), 7.66 (2H, d, J = 8.0 Hz), 7.97 (2H, d, J = 8.0 Hz).
4-(7,8-Dihydro-8,8-dimethyl-5-ethylsulfonylnaphth-2-ylethynyl)benzoic acid (Compound 150)
To a stirring solution of 10 mg (0.03 mmol) of 4-[(7,8-dihydro-8,8-dimethyl-5-ethylthionaphth-2-yl)ethynyl]benzoic acid (Compound 149) in 2.5 ml of diethyl ether at room temperature was added 50 mg
(0.145 mmol) of 50 % 3-chloroperoxybenzoic acid. The resulting colorless solution was stirred overnight at room temperature during which time a white precipitate formed. The solution was diluted with water and dichloromethane, the layers separated and the aqueous layer extracted with dichloromethane (3X). All organic layers were collected, washed with brine, dried over MgSO4 and concentrated in vacuo. Recrystallization from acetonitrile gave the title compound as a white solid.
PMR (CDCl3): 5 1.31 (3H, t, J = 7.4 Hz), 1.33 (6H, s), 2.51 (2H, d, J = 4.8 Hz), 3.15 (2H, q, J = 7.4 Hz),
7.29 (1H, t, J = 4.8 Hz), 7.46 (1H, dd, J = 1.6, 8.2 Hz), 7.57 (1H, d, J = 1.6 Hz), 7.65 (2H, d, J = 8.3 Hz), 8.06 (1H, d, J = 8.2 Hz), 8.11 (2H, d, J = 8.3 Hz).
Ethyl 4-[(7,8-dihydro-9,8-dimethyl-5-ethylthionaphth-3-yl)ethynyl]benzoate (Compound 151)
To a stirring solution of 500 mg (1.44 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoate (Compound 2) in 25 ml of THF at room temperature under argon was added 268 mg (1.42 mmol) of titanium tetrachloride. The resulting orange solution was treated dropwise with a solution of 96 mg (1.56 mmol) of ethanethiol, 291 mg (2.88 mmol) of triethylamine and 8.4 ml of THF, stirred at room temperature for 5 hours and carefully diluted with water. The organic products were extracted with diethyl ether (3X), combined, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was column chromatographed (silica, 2% EtOAc-hexane) to give the title compound as a colorless solid.
PMR (CDCl3): δ 1.28 (6H, s), 1.29 (3H, t, J = 7.3 Hz), 1.41 (3H, t, J = 7.2 Hz), 2.30 (2H, d, J = 4.8 Hz), 2.74 (2H, q, J = 7.3 Hz), 4.38 (2H, q, J = 7.2 Hz), 6.21 (1H, t, J = 4.8 Hz), 7.29 (1H, d, J = 8.1 Hz), 7.41 (1H, dd, J = 1.8, 8.1 Hz), 7.59 (2H, d, J = 8.4 Hz), 7.90 (1H, d, J = 1.8 Hz), 8.03 (2H, d, J = 8.4 Hz).
4-[(7 ,8-dihydro-8,8-dimethyl-5-ethylthionaphth-3-yl)ethynyl]benzoic acid (Compound 152)
To a solution of 150 mg (0.38 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-ethylthionaphth-3-yl)ethynyl]benzoate (Compound 151) in 4 ml of ethanol was added 1 ml of KOH (2N aqueous solution). The solution was heated to 50 °C for two hours, cooled to room temperature, concentrated in vacuo. diluted with dichloromethane (5 ml) and acidified with 10% aqueous HCl at 0 °C. The layers were separated and the aqueous layer was extracted with dichloromethane (2X). The organic layers were combined, washed with brine, dried over MgSO4 and concentrated in vacuo.
Recrystallization from acetonitrile gave the title compound as a white solid. PMR (CDCl3): δ 1.29 (3H, t, J = 7.3 Hz), 1.29 (6H, s), 2.32 (2H, d, J = 4.8 Hz), 2.75 (2H, q, J = 7.3 Hz), 6.23 (1H, t, J = 4.5 Hz), 7.32 (1H, d, J = 8.0 Hz), 7.42 (1H, dd, J = 1.7, 8.0 Hz), 7.63 (2H, d, J = 8.4 Hz), 7.90 (1H, d, J = 1.7 Hz), 8.10 (2H, d, J = 8.4 Hz).
Ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-ethylsulfonylnaphth-3-yl)ethynyl]benzoate (Compound 153)
To a stirring solution of 25 mg (0.06 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-ethylthionaphth-3-yl)ethynyl]benzoate (Compound 151) in 3 ml of diethyl ether at room temperature was added 88 mg (0.26 mmol) of 50 % 3-chloroperoxybenzoic acid. The resulting colorless solution was stirred overnight at room temperature during which time a white precipitate formed. The solution was diluted with sat. aqueuos NaHCO3 solution and dichloromethane, the layers
separated and the aqueous layer extracted with
dichloromethane (3X). All organic layers were
collected, washed with brine, dried over MgSO4 and concentrated in vacuo. Recrystallization from ethyl alcohol gave the title compound as a white solid.
PMR (CDCl3): δ 1.30 (6H, s), 1.31 (3H, t, J = 7.4 Hz), 1.41 (3H, t, J = 7.1 Hz), 2.49 (2H, d, J = 4.8 Hz), 3.19 (2H, q, J = 7.4 Hz), 4.39 (2H, q, J = 7.1 Hz), 7.30 (1H, t, J = 4.8 Hz), 7.39 (1H, d, J = 8.1 Hz), 7.51 (1H, dd, J = 1.7, 8.1 Hz), 7.60 (2H, d, J = 8.4 Hz), 8.03 (2H, d, J = 8.4 Hz), 8.22 (1H, d, J = 1.7 Hz).
4-[(7,8-dihydro-8,8-dimethyl-5-ethylsulfonylnaphth-3-yl)ethynyl]benzoic acid (Compound 154)
Employing the same general procedure as for the preparation of 4-(7,8-dihydro-8,8-dimethyl-5-ethylsulfonylnaphth-2-ylethynyl)benzoic acid (Compound 150), 25 mg (0.07 mmol) of 4-[(7,8-dihydro-8,8-dimethyl-5-ethylthionaphth-3-yl)ethynyl]benzoic acid (Compound 152) was converted to the title compound (white solid, recrystallized from ethyl alcohol) using 95 mg (0.28 mmol) of 50 % 3-chloroperoxybenzoic acid. PMR (CDCl3): δ 1.31 (6H, s), 1.32 (3H, t, J = 7.5 Hz), 2.50 (2H, d, J = 4.9 Hz), 3.20 (2H, q, J = 7.5 Hz), 7.30 (1H, t, J = 4.9 Hz), 7.40 (1H, d, J = 8.1 Hz), 7.53 (1H, dd, J = 1.8, 8.1 Hz), 7.64 (2H, d, J = 8.5 Hz), 8.09 (2H, d, J = 8.5 Hz), 8.23 (1H, d, J = 1.8 Hz).
Ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-phenylthionaphth-3-yl)ethynyl]benzoate (Compound 155)
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-ethylthionaphth-3-yl)ethynyl]benzoate (Compound 151), 500 mg (1.44 mmol) of ethyl 4-[ (5,6,7,8-tetrahydro-5,5-dimethyl-8-oxonaphth-3-yl)ethynyl]benzoate (Compound 2) was converted into the title compound (colorless flakes, recrystallized from hexane) using 0.268 g (1.42 mmol) of titanium tetrachloride, 172 mg (1.56 mmol) of thiophenol and 291 mg (2.88 mmol) of triethylamine.
PMR (CDCl3) : δ 1.34 (6H, s), 1.40 (3H, t, J = 7.1 Hz),
2.39 (2H, d, J = 4.8 Hz), 4.38 (2H, q, J = 7.1 Hz), 6.52 (1H, t, J = 4.8 Hz), 7.14-7.32 (6H, several d's),
7.40 (1H, dd, J = 1.7, 8.0 Hz), 7.53 (2H, d, J = 8.6 Hz), 7.84 (1H, d, J = 1.7 Hz), 7.99 (2H, d, J = 8.6 Hz).
4-[(7,8-dihydro-8,8-dimethyl-5-phenylthionaphth-3-yl)ethynyl]benzoic acid (Compound 156)
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-ethylthionaphth-3-yl)ethynyl]benzoic acid (Compound
153), 100 mg (0.38 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-phenylthionaphth-3-yl)ethynyl]benzoate
(Compound 155) was converted into the title compound
(white solid, recrystallized from acetonitrile) using 2 ml of KOH (2N aqueous solution).
PMR (CDCl3): δ 1.35 (6H, s), 2.41 (2H, d, J = 4.8 Hz),
6.54 (1H, t, J = 4.8 Hz), 7.15-7.34 (6H, several d's),
7.42 (1H, dd, J = 1.7, 7.9 Hz), 7.59 (2H, d, J = 8.5
Hz), 7.85 (1H, d, J = 1.7 Hz), 7.06 (2H, d, J = 8.5 Hz).
Ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-phenylsulfonylnaphth-3-yl)ethynyl]benzoate (Compound
157)
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-ethylsulfonylnaphth-3-yl)ethynyl]benzoate (Compound 153), 50 mg (0.11 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-phenylthionaphth-3-yl)ethynyl]benzoate
(Compound 155) was converted into the title compound (white solid, recrystallized from ethyl alcohol) using 157 mg (0.46 mmol) of 50 % 3-chloroperoxybenzoic acid. PMR (CDCl3): δ 1.19 (6H, s), 1.41 (3H, t, J = 7.1 Hz), 2.49 (2H, d, J = 5.0 Hz), 4.40 (2H, q, J = 7.1 Hz), 7.27 (1H, d, J = 8.1 Hz), 7.41 (1H, dd, J = 1.7, 8.1 Hz), 7.46-7.58 (4H, several d's), 7.60 (2H, d, J = 8.4 Hz), 7.96 (1H, dd, J = 1.8, 8.1 Hz), 8.04 (2H, d, J = 8.4 Hz), 8.18 (1H, d, J = 1.7 Hz).
4-[(7,8-dihydro-8,8-dimethyl-5-phenylsufonylnaphth-3-yl)ethynyl]benzoic acid (Compound 158)
Employing the same general procedure as for the preparation of 4-(7,8-dihydro-8,8-dimethyl-5- ethylsulfonylnaphth-2-ylethynyl)benzoic acid (Compound 150), 25 mg (0.06 mmol) of 4-[(7,8-dihydro-8,8-dimethyl-5-phenylthionaphth-3-yl)ethynyl]benzoic acid (Compound 156) was converted into the title compound (white solid, recrystallized from acetonitrile) using 84 mg (0.24 mmol) of 50 % 3-chloroperoxybenzoic acid. PMR (CDCl3): δ 1.20 (6H, s), 2.50 (2H, d, J = 4.9 Hz), 7.28 (1H, d, J = 8.1 Hz), 7.40-7.57 (5H, several d's), 7.63 (2H, d, J = 8.3 Hz), 7.97 (2H, dd, J = 1.6, 8.1 Hz), 8.11 (2H, d, J = 8.3 Hz), 8.19 (1H, d, J = 1.6 Hz).
Ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-methyl-2-propylthio)naphth-3-yl)ethynyl)benzoate (Compound 159)
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-ethylthionaphth-2-yl)ethynyl]benzoate (Compound 151), 500 mg (1.44 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoate (Compound 2) was converted into the title compound (colorless flakes, recrystallized from ethyl alcohol) using 268 mg (1.42 mmol) of titanium tetrachloride, 134 mg (1.49 mmol) of 2-methyl-2-propanethiol and 271 mg (2.82 mmol) of triethylamine.
PMR (CDCl3): δ 1.31 (15H, s), 1.41 (3H, t, J = 7.1 Hz), 2.36 (2H, d, J = 4.5 Hz), 4.39 (2H, q, J = 7.1 Hz), 6.55 (1H, t, J = 4.5 Hz), 7.27 (1H, d, J = 7.9 Hz), 7.39 (1H, d, J = 7.9 Hz), 7.60 (2H, d, J = 8.2 Hz), 8.02 (2H, d, J = 8.2 Hz), 8.17 (1H, s).
4-[(7,8-dihydro-8,8-dimethyl-5-(2-methyl-2-propylthio)naphth-3-yl)ethynyl]benzoic acid (Compound 160)
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5- ethylthionaphth-3-yl)ethynyl]benzoic acid (Compound 152), 100 mg (0.38 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-methyl-2-propylthio)naphth-2-yl)ethynyl]benzoate (Compound 159) was converted into the title compound (light yellow crystals,
recrystallized from a 50 % solution of acetonitrile and ethyl acetate) using 2 ml of KOH (2N aqueous solution). PMR (d6-DMSO) : .5 1.23 (9H, s), 1.25 (6H, s), 2.35 (2H, d, J = 4.6 Hz), 6.54 (1H, t, J = 4.6 Hz), 7.37 (1H, d, J = 8.1 Hz), 7.45 (1H, dd, J = 1.8, 8.1 Hz), 7.66 (2H, d, J = 8.4 Hz), 7.95 (2H, d, J = 8.4 Hz), 8.01 (1H, d, J = 1.8 Hz).
Ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-benzylthionaphth-3-yl)ethynyl]benzoate (Compound 161)
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-ethylthionaphth-3-yl)ethynyl]benzoate (Compound 151), 500 mg (1.44 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoate (Compound 2) was converted into the title compound (colorless crystals, recrystallized from methyl alcohol) using 268 mg (1.42 mmol) of titanium tetrachloride, 184 mg (1.49 mmol) of benzyl mercaptan and 271 mg (2.82 mmol) of triethylamine.
PMR (CDCl3): δ 1.71 (6H, s), 1.41 (3H, t, J = 7.1 Hz), 2.21 (2H, d, J = 4.8 Hz), 3.93 (2H, s), 4.49 (2H, q, J = 7.1 Hz), 6.12 (1H, t, J = 4.8 Hz), 7.22-7.27 (5H, several d's), 7.29 (1H, d, J = 8.0 Hz), 7.43 (1H, dd, J = 1.8, 8.0 Hz), 7.60 (2H, d, J = 8.3 Hz), 7.93 (1H, d, J = 1.8 Hz), 8.01 (2H, d, J = 8.3 Hz).
4-((7,8-dihydro-8,8-dimethyl-5-benzylthionaphth-3-yl)ethynyl]benzoic acid (Compound 162)
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-ethylthionaphth-3-yl)ethynyl]benzoic acid (Compound 152), 100 mg (0.38 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-benzylthionaphth-3-yl)ethynyl]benzoate
(Compound 161) was converted into the title compound (white needles, recrystallized from a 50 % solution of acetonitrile and ethyl acetate) using 2 ml of KOH (2N aqueous solution).
PMR (d6-DMSO) : δ 1.13 (6H, s), 2.21 (2H, d, J = 4.7 Hz), 4.00 (2H, s), 6.14 (1H, t, J = 4.7 Hz), 7.20-7.28 (5H, several d's), 7.38 (1H, d, J = 8.0 Hz), 7.48 (1H, dd, J = 1.8, 8.0 Hz), 7.67 (2H, d, J = 8.3 Hz), 7.70 (1H, d, J = 1.8 Hz), 7.96 (2H, d, J = 8.3 Hz).
Ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(4-methylphenyl)naphth-3-yl)ethynyl]benzoate (Compound 163)
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl]benzoate (Compound 67), 200.0 mg (0.42 mmol) of ethyl 4-[(5-triflouromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 66) was converted into the title compound (colorless solid) using 113.8 mg (0.835 mmol) of zinc chloride and 4-methylphenyllithium (prepared by adding 40.4 mg (0.42 ml, 0.63 mmol) of n-butyllithium (1.5 M solution in hexane) to a cold solution (-78 °C) of 108.0 mg (0.63 mmol) of 4-bromotoluene in 1.0 ml of THF).
PMR (CDCl3): δ 1.36 (6H, s), 1.41 (3H, t, J = 7.2 Hz), 2.36 (2H, d, J = 4.7 Hz), 2.43 (3H, s), 4.39 (2H, q, J = 7.2 Hz), 6.01 (1H, t, J = 4.7 Hz), 7.26 (4H, m), 7.40 (2H, m ), 7.53 (2H, d, J = 8.4 Hz), 7.90 (2H, d, J=8.4 Hz). 4-[(7,8-dihydro-8,8-dimethyl-5-(4-methylphenyl)naphth-2-yl)ethynylIbenzoic acid (Compound 164)
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl]benzoic acid (Compound 78), 26.0 mg (0.06 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(4-methylphenyl)naphth-3-yl)ethynyl]benzoate (Compound 163) was converted into the title compound (colorless solid) using 6.5 mg (0.16 mmol) of LiOH in H2O.
PMR (dg-DMSO) : .5 1.28 (6H, s), 2.31 (2H, d, J = 4.7 Hz), 2.33 (3H, s) 5.98 (1H, t, J = 4.5 Hz), 7.00 (1H, s), 7.20 (4H, m), 7.44 (2H, m), 7.58 (2H, d, J = 8.5 Hz), 7.90 (2H, d, J = 8.3 Hz).

Claims

WHAT IS CLAIMED IS:
1. A compound of the formula
Figure imgf000183_0001
wherein X is S or O;
R1 is hydrogen or alkyl of 1 to 10 carbons;
R2 and R3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the tetrahydronaphthalene nucleus; m is an integer having the value of 0 - 3;
o is an integer having the value 0 - 4;
R4 is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C1 - C10-alkylphenyl, naphthyl, C1 - C10-alkylnaphthyl, phenyl-C1 - C10alkyl, napthyl-C1 - C10alkyl; CN, or (CH2)pCO2R8 where p is an integer between 0 to 10;
R5 is hydrogen, alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds. carbocyclic aryl selected from the group consisting of phenyl, C1 - C10-alkylphenyl, naphthyl, C1 - C10-alkylnaphthyl, phenyl-C1 - C10alkyl, napthyl-C1 - C10alkyl; Si(R2)3, COR14, camphanoyl, C(R15) (R16)XR17;
Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl,
pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl,
oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R2 groups;
A is (CH2)n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6
carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds, and
B is hydrogen, COOH or a pharmaceutically
acceptable salt thereof, COOR8, CONR9R10, -CH2OH,
CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, CR7OR13O, or tri-lower alkylsilyl, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or
trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons; and further wherein R14 is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bond, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group
consisting of phenyl, C1 - C10-alkylphenyl, naphthyl. C1 - C10-alkylnaphthyl, phenyl-C1 - C10alkyl, napthyl-C1 - C10alkyl; R15 and R16 are hydrogen or lower alkyl of 1 to 6 carbons, R17 is lower alkyl of 1 to 6 carbons, or R16 and R17 jointly form a ring having a total of 4 to 5 carbons and the X heteroatom.
2. A compound of Claim 1 where Y is phenyl, pyridyl, thienyl or furyl.
3. A compound of Claim 1 where Y is phenyl.
4. A compound of Claim 3 where the phenyl ring is 1,4 (para) substituted.
5. A compound of Claim 1 where Y is pyridyl.
6. A compound of Claim 5 where the pyridyl ring is substituted in the 2 and 5 positions.
7. A compound of Claim 1 where Y is thienyl or furyl.
8. A compound of Claim 1 where R2 is hydrogen.
9. A compound of Claim 1 where R3 is hydrogen.
10. A compound of Claim 1 where R4 is hydrogen, CN, or CH2COOR8.
11. A compound of Claim 1 where R5 is hydrogen, alkyl of 1 to 10 carbons, Si(R2)3, COR14 or
C(R15)(R16)XR17.
12. A compound of Claim 11 where R5 is hydrogen, cyclohexyl, trimethylsilyl, -CH2OCH3 (methoxymethyl), CH2SCH3 (methylthiomethyl), tetrahydropyranyl, acetyl or camphanoyl.
13. A compound of Claim 1 where X is O.
14. A compound of Claim 1 where X is S.
15. A compound of the formula
Figure imgf000186_0001
wherein X is S or O;
R1 is hydrogen or alkyl of 1 to 10 carbons;
R2 and R3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the tetrahydronaphthalene nucleus; m is an integer having the value of 0 - 3;
o is an integer having the value 0 - 4;
R4 is hydrogen, alkyl of 1 to 10 carbons, CN, or
R5 is hydrogen, alkyl of 1 to 10 carbons, Si(R2)3, COR14, camphanoyl, CH2OCH3, 2-tetrahydropyranyl or 2-tetrahydrothiopyranyl;
Y is phenyl or pyridyl said groups being
optionally substituted with one or two R2 groups;
A is (CH2)n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6
carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds, and
B is hydrogen, COOH or a pharmaceutically
acceptable salt thereof, COOR8, CONR9R10, -CH2OH,
CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, CR7OR13O, or tri-lower alkylsilyl, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or
trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R^ is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons; and further wherein R14 is hydrogen, alkyl of 1 to 10 carbons, or phenyl.
16. A compound of Claim 15 where X is O.
17. A compound of Claim 16 where A is (CH2)n where n is 0-5 and where B is COOH or a
pharmaceutically acceptable salt thereof, COOR8, or CONR9R10.
18. A compound of Claim 15 where X is S.
19. A compound of Claim 18 where A is (CH2)n where n is 0-5 and where B is COOH or a
pharmaceutically acceptable salt thereof, COOR8, or CONR9R10.
20. A compound of the formula
Figure imgf000187_0001
wherein X is S or O ; X2 is CH or N;
R4 is hydrogen, alkyl of 1 to 10 carbons, CN, or (CH2)CO2R8;
R5 is hydrogen, alkyl of 1 to 10 carbons, Si(R2)3, COR14, camphanoyl, CH2OCH3, 2-tetrahydropyranyl or 2-tetrahydrothiopyranyl, the substituted ethynyl group occupies either the 2 or 3 position of the
tetrahydronaphthalene nucleus, and
R8 is hydrogen, an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons.
21. A compound of Claim 20 where X is O.
22. A compound of Claim 21 where X2 is CH.
23. A compound of Claim 22 where R4 is H.
24. A compound of Claim 23 where R5 is
cyclohexyl.
25. A compound of Claim 24 where R8 is H or C2H5.
26. A compound of Claim 23 where R5 is H.
27. A compound of Claim 26 where R8 is H or C2H5.
28. A compound of Claim 21 where X2 is N.
29. A compound of Claim 28 where R4 is H, R5 is H and R8 is H or C2H5.
30. A compound of Claim 23 where R5 is CH2OCH3.
31. A compound of Claim 30 where R8 is H or C2H5.
32. A compound of Claim 23 where R5 is 2-tetrahydropyranyl.
33. A compound of Claim 32 where R8 is H or C2H5.
34. A compound of Claim 28 where R4 is H and R5 is 2-tetrahydropyranyl.
35. A compound of Claim 34 where R8 is H or C2H5.
36. A compound of Claim 22 where R4 is CN.
37. A compound of Claim 36 where R5 is
trimethylsilyl and R8 is H or C2H5.
38. A compound of Claim 23 where R5 is
trimethylsilyl and R8 is H or C2H5.
39. A compound of Claim 22 where R4 is CH2COOC2H5 and R5 is H.
40. A compound of Claim 39 where R8 is H, C2H5 or (CH2)2Si(CH3)3.
41. A compound of Claim 23 where R5 is 1-(S)-camphanoyl.
42. A compound of Claim 20 where X is S.
43. A compound of Claim 42 where X2 is CH.
44. A compound of Claim 43 where R4 is H.
45. A compound of Claim 44 where R5 is 2-tetrahydropyranyl.
46. A compound of Claim 45 where R8 is H or C2H5.
47. A compound of Claim 44 where R5 is CH3CO.
48. A compound of Claim 47 where R8 is H or C2H5.
49. A compound of Claim 44 where R5 is H.
50. A compound of Claim 49 where R8 is H or C2H5.
51. A compound of the formula
Figure imgf000189_0001
wherein R1 is hydrogen or alkyl of 1 to 10
carbons;
R2 and R3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the tetrahydronaphthalene nucleus; m is an integer having the value of 0 - 3;
o is an integer having the value 0 - 4;
Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl,
pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl,
oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R2 groups;
A is (CH2)n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6
carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
B is hydrogen, COOH or a pharmaceutically
acceptable salt thereof, COOR8, CONR9R10, -CH-.OH,
CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7 , CR7(OR12)2, CR7OR13O, or tri-lower alkylsilyl, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or
trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons;
X is O or S; R18 is alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, or the two R18 groups jointly form a ring having a total of 3 to 6 carbons, or
the two XR18 groups jointly symbolize an oxo (=O) or a thio (=S) function.
52. A compound of Claim 51 where Y is phenyl, pyridyl, thienyl or furyl.
53. A compound of Claim 51 where Y is phenyl.
54. A compound of Claim 53 where the phenyl ring is 1,4 (para) substituted.
55. A compound of Claim 51 where Y is pyridyl.
56. A compound of Claim 55 where the pyridyl ring is substituted in the 2 and 5 positions.
57. A compound of Claim 51 where Y is thienyl or furyl.
58. A compound of Claim 51 where R2 is hydrogen.
59. A compound of Claim 51 where R3 is hydrogen.
60. A compound of Claim 51 where the two XR18 groups jointly represent an oxo (=O) function.
61. A compound of Claim 51 where the two XR18 groups jointly represent a thio (=S) function.
62. A compound of Claim 51 where X is O and R18 is alkyl of 1 to 10 carbons or the two R18 groups jointly form a ring having a total of 3 to 6 carbons.
63. A compound of Claim 51 where X is S and R18 is alkyl of 1 to 10 carbons or the two R18 groups jointly form a ring having a total of 3 to 6 carbons.
64. A compound of the formula
Figure imgf000192_0001
wherein R1 is hydrogen or alkyl of 1 to 10
carbons;
R2 and R3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the tetrahydronaphthalene nucleus; m is an integer having the value of 0 - 3;
o is an integer having the value 0 - 4;
Y is phenyl or pyridyl said groups being
optionally substituted with one or two R2 groups;
A is (CH2)n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6
carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
B is hydrogen, COOH or a pharmaceutically
acceptable salt thereof, COOR8, CONR9R10, -CH2OH,
CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CH0R13O, -COR7, CR7(OR12)2, CR7OR13O, or tri-lower alkylsilyl, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or
(trimethylsilyl) alkyl where the alkyl group has l to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons;
X is O or S;
R18 is alkyl of 1 to 10 carbons, or the two R18 groups jointly form a ring having a total of 3 to 6 carbons, or
the two XR18 groups jointly symbolize an oxo (=O) or a thio (=S) function.
65. A compound of Claim 64 where X is O.
66. A compound of Claim 65 where A is (CH2)n where n is 0-5 and where B is COOH or a
pharmaceutically acceptable salt thereof, COOR8, or CONR9R10.
67. A compound of Claim 64 where X is S.
68. A compound of Claim 67 where A is (CH2)n where n is 0-5 and where B is COOH or a
pharmaceutically acceptable salt thereof, COOR8, or CONR9R10.
69. A compound of the formula
Figure imgf000194_0001
wherein X is O or S ;
X2 is CH or N ;
R8 is hydrogen, an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons;
R18 is alkyl of 1 to 10 carbons, or the two R18 groups jointly form a ring having a total of 3 to 6 carbons,
or the two XR18 groups jointly symbolize an oxo (=O) function, and the substituted ethynyl group occupies the 2 or 3 position of the
tetrahydronaphthalene nucleus.
70. A compound of Claim 69 where X is O and the two XR18 groups jointly symbolize an oxo (=O) function.
71. A compound of Claim 70 where X2 is CH.
72. A compound of Claim 71 where R8 is H, C2H5 or (CH2)2Si(CH3)3.
73. A compound of Claim 70 where X2 is N.
74. A compound of Claim 73 where R8 is H, C2H5 or (CH2)2Si(CH3)3.
75. A compound of Claim 69 where X is S and the two R18 groups jointly form a (CH2)3 bridge between the two S atoms.
76. A compound of Claim 75 where X2 is CH.
77. A compound of Claim 76 where R8 is H, C2H5 or (CH2)2Si(CH3)3.
78. A compound of Claim 75 where X2 is N.
79. A compound of the formula
Figure imgf000195_0001
wherein R1 is hydrogen or alkyl of 1 to 10
carbons;
R2 and R3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the tetrahydronaphthalene nucleus; m is an integer having the value of 0 - 3;
o is an integer having the value 0 - 4;
Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl,
pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl,
oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R2 groups;
A is (CH2)n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6
carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
B is hydrogen, COOH or a pharmaceutically
acceptable salt thereof, COOR8, CONR9R10, -CH2OH,
CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7 , CR7(OR12)2, CR7OR13O, or tri-lower alkylsilyl, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons, and
R19 is independently hydrogen, alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group
consisting of phenyl, C1 - C10-alkylphenyl, naphthyl, C1 - C10 _alkylnaphthyl, phenyl-C1 - C10alkyl, naphthyl-C1 - C10alkyl; CN, CHO, CH(OR12)2, CHOR13O,
(CH2)pCO2R8 (CH2)pCH2OH, (CH2)pCH2OR11,
(CH2)pCH2OCOR11, where p is an integer between 0 to 10, or the two R19 groups jointly represent 3 to 6
methylene groups which together with the alkylidene carbon complete a ring.
80. A compound of Claim 79 where Y is phenyl, pyridyl, thienyl or furyl.
81. A compound of Claim 79 where Y is phenyl.
82. A compound of Claim 81 where the phenyl ring is 1,4 (para) substituted.
83. A compound of Claim 79 where Y is pyridyl.
84. A compound of Claim 83 where the pyridyl ring is substituted in the 2 and 5 positions.
85. A compound of Claim 79 where Y is thienyl or furyl.
86. A compound of Claim 79 where R2 is hydrogen.
87. A compound of Claim 79 where R3 is hydrogen.
88. A compound of Claim 79 where R19 is hydrogen, alkyl of 1 to 10 carbons, cyano (CN), COOR8, or the two R19 groups jointly form a -(CH2)q radical where q is an integer having the values of 3 to 7.
89. A compound of the formula
Figure imgf000197_0001
wherein R1 is hydrogen or alkyl of 1 to 10
carbons;
R2 and R3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the tetrahydronaphthalene nucleus; m is an integer having the value of 0 - 3;
o is an integer having the value 0 - 4;
Y is phenyl or pyridyl, said groups being
optionally substituted with one or two R2 groups; A is (CH2)n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6
carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
B is hydrogen, COOH or a pharmaceutically
acceptable salt thereof, COOR8, CONR9R10, -CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, CR7OR13O, or tri-lower alkylsilyl, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl) alkyl where the alkyl group has l to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons, and
R19 is independently hydrogen, alkyl of 1 to 10 carbons, CN, CH2CO2R8 or the two R19 groups jointly represent 3 to 6 methylene groups which together with the alkylidene carbon complete a ring.
90. A compound of Claim 89 where A is (CH2)n where n is 0-5 and where B is COOH or a
pharmaceutically acceptable salt thereof, COOR8, or CONR9R10.
91. A compound of the formula
Figure imgf000199_0001
wherein X2 is CH or N;
R8 is hydrogen, an alkyl group of 1 to 10 carbons or (trimethylsilyl)alakyl where the alkyl group has 1 to
10 carbons;
R19' is H, cyano (CN) or lower alkyl, and
R19' ' is H, cyano (CN) or lower alkyl, or
the R19' and R19'' groups jointly form a -(CH2)5-group, and the substituted ethynyl group occupies the 2 or 3 position of the tetrahydronaphthalene nucleus.
92. A compound of Claim 91 where X2 is N.
93. A compound of Claim 91 where X2 is CH.
94. A compound of Claim 93 where the R19' and R19'' groups jointly form a -(CH2)5- group.
95. A compound of Claim 94 where R8 is H or C2H5.
96. A compound of Claim 93 where the R'19 is CO2C2H5 and R"19 is H.
97. A compound of Claim 96 where R8 is H or C2H5.
98. A compound of Claim 93 where the R19' is C2H5 and R19'' is C2H5.
99. A compound of Claim 98 where R8 is H or C2H5.
100. A compound of Claim 93 where one of the R19' and R19'' groups is cyano (CN) and the other is H.
101. A compound of Claim 100 where R8 is H or C2H5.
102 . A compound of the formula
Figure imgf000200_0001
wherein R1 is hydrogen or alkyl of 1 to 10
carbons;
R2 and R3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the tetrahydronaphthalene nucleus; m is an integer having the value of 0 - 3;
o is an integer having the value 0 - 4;
Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl,
pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl,
oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R2 groups;
A is (CH2)n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6
carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
B is hydrogen, COOH or a pharmaceutically
acceptable salt thereof, COOR8, CONR9R10, -CH2OH,
CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, CR7OR13O, or tri-lower alkylsilyl, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl) alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons;
the wavy line represents a single valence bond around which the configuration can be syn or anti, and
Z is OR1, R1, phenyl, benzyl, lower alkyl or lower alkoxy substituted phenyl, OSi(R2)3, OCOR14,
OC(R15)(R16)XR17, N(R14)2, NHCON(R14)2, NHCSN(R14)2, where X is O or S; R14 is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C1 - C10-alkylphenyl, naphthyl, C1 - C10-alkylnaphthyl, phenyl-C1 - C10alkyl, naphthyl-C1 - C10alkyl R15 and R16 are hydrogen or lower alkyl of 1 to 6 carbons, R17 is lower alkyl of 1 to 6
carbons, or R16 and R17 jointly form a ring having a total of 4 to 5 carbons and the X heteroatom.
103. A compound of Claim 102 where Y is phenyl, pyridyl, thienyl or furyl.
104. A compound of Claim 102 where Y is phenyl.
105. A compound of Claim 104 where the phenyl ring is 1,4 (para) substituted.
106. A compound of Claim 102 where Y is pyridyl.
107. A compound of Claim 106 where the pyridyl ring is substituted in the 2 and 5 positions.
108. A compound of Claim 102 where Y is thienyl or furyl.
109. A compound of Claim 102 where R2 is
hydrogen.
110. A compound of Claim 102 where R3 is
hydrogen.
111. A compound of Claim 102 where Z is OR1 or OC(R15) (R16)XR17.
112. A compound of Claim 111 where Z is OH, OCH3, OCH2CH3, 2-tetrahydropyranyloxy or OCH2OCH3.
113. A compound of the formula
Figure imgf000202_0001
wherein R1 is hydrogen or alkyl of 1 to 10
carbons;
R2 and R3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the tetrahydronaphthalene nucleus; m is an integer having the value of 0 - 3;
o is an integer having the value 0 - 4;
Y is phenyl or pyridyl, said groups being optionally substituted with one or two R2 groups;
A is (CH2)n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6
carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and l or 2 triple bonds;
B is hydrogen, COOH or a pharmaceutically
acceptable salt thereof, COOR8, CONR9R10, -CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, CR7OR13O, or tri-lower alkylsilyl, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of l to 10 carbons or (trimethylsilyl) alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R13L is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons;
the wavy line represents a single valence bond around which the configuration can be syn or anti, and
Z is OR1, OC(R15)(R16)XR17, where X is O or S; R15 and R16 are hydrogen or lower alkyl of l to 6 carbons, R17 is lower alkyl of 1 to 6 carbons, or R16 and R17 jointly form a ring having a total of 4 to 5 carbons and the X heteroatom.
114. A compound of Claim 113 where A is (CH2)n where n is 0-5 and where B is COOH or a
pharmaceutically acceptable salt thereof, COOR8, or CONR9R10.
115. A compound of Claim 114 where Z is OH, OCH3, OCH2CH3 or 2-tetrahydropyranyloxy.
116. A compound of the formula
Figure imgf000204_0001
wherein X2 is CH or N;
R8 is hydrogen, an alkyl group of 1 to 10 carbons or (trimethylsilyl) alkyl where the alkyl group has l to 10 carbons, the substituted ethynyl group occupies either the 2 or 3 position of the tetrahydronaphthalene nucleus, and
Z is OR1, OC(R15)(R16)XR17, where X is O or S; R1 is H or lower alkyl, R15 and R16 are hydrogen or lower alkyl, R17 is lower alkyl, or R16 and R17 jointly form a ring having a total of 4 to 5 carbons and the X heteroatom.
117. A compound of Claim 116 where X2 is CH.
118. A compound of Claim 117 where Z is OH.
119. A compound of Claim 118 where R8 is H or
C2H5.
120. A compound of Claim 117 where Z is OCH3.
121. A compound of Claim 120 where R8 is H or
C2H5.
122. A compound of Claim 117 where Z is OCH2CH3
123. A compound of Claim 122 where R8 is H or
C2H5
124. A compound of Claim 117 where Z is 2- tetrahydropyranyloxy.
125. A compound of Claim 124 where R8 is H or
C2H5.
126. A compound of Claim 116 where X2 is N.
127. A compound of Claim 126 where Z is OH.
128. A compound of Claim 126 where R8 is H or
C2H5.
129. A compound of the formula
Figure imgf000205_0001
wherein R1 is hydrogen or alkyl of 1 to 10
carbons;
R2 and R3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the tetrahydronaphthalene nucleus; m is an integer having the value of 0 - 3;
o is an integer having the value 0 - 4;
Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl,
pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl,
oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R2 groups;
A is (CH2)n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6
carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
B is hydrogen, COOH or a pharmaceutically
acceptable salt thereof, COOR8, CONR9R10, -CH2OH,
CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, CR7OR13O, or tri-lower alkylsilyl, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons, and
R14 is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bond, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C1 - C10-alkylphenyl, naphthyl, C1 - C10-alkylnaphthyl, phenyl-C1 - C10alkyl, naphthyl-C1 - C10alkyl, R14 is COR8, or the two R14 groups together with the N jointly form a 5 or 6 membered ring.
130. A compound of Claim 129 where Y is phenyl, pyridyl, thienyl or furyl.
131. A compound of Claim 129 where Y is phenyl.
132. A compound of Claim 131 where the phenyl ring is 1,4 (para) substituted.
133. A compound of Claim 129 where Y is pyridyl.
134. A compound of Claim 133 where the pyridyl ring is substituted in the 2 and 5 positions.
135. A compound of Claim 129 where Y is thienyl or furyl.
136. A compound of Claim 129 where R2 is
hydrogen.
137. A compound of Claim 129 where R3 is
hydrogen.
138. A compound of Claim 129 where R14 is
hydrogen or lower alkyl.
139. A compound of the formula
Figure imgf000207_0001
wherein R1 is hydrogen or alkyl of 1 to 10
carbons;
R2 and R3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the tetrahydronaphthalene nucleus; m is an integer having the value of 0 - 3;
o is an integer having the value 0 - 4;
Y is phenyl or pyridyl, said groups being
optionally substituted with one or two R2 groups;
A is (CH2)n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6
carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
B is hydrogen, COOH or a pharmaceutically
acceptable salt thereof, COOR8, CONR9R10, -CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7 , CR7(OR12)2, CR7OR13O, or tri-lower alkylsilyl, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has l to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons, and
R14 is hydrogen, alkyl of 1 to 10 carbons, or R14 is COR8.
140. A compound of Claim 139 where A is (CH2)n where n is 0-5 and where B is COOH or a
pharmaceutically acceptable salt thereof, COOR8, or CONR9R10.
141. A compound of Claim 140 where B is COOH or a pharmaceutically acceptable salt thereof, or COOR8 where R8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons.
142. A compound of the formula
Figure imgf000209_0001
wherein R8 is hydrogen, an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, and
R14 is H or lower alkyl.
143. A compound of Claim 142 where R14 is H and R8 is H or C2H5.
144. A compound of the formula
Figure imgf000209_0002
wherein R1 is hydrogen or alkyl of 1 to 10
carbons;
R2 and R3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the dihydronaphthalene nucleus; m is an integer having the value of 0 - 3;
o is an integer having the value 0 - 3;
Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl,
pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R2 groups;
A is (CH2)n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6
carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds ;
B is hydrogen, COOH or a pharmaceutically
acceptable salt thereof, COOR8, CONR9R10, -CH2OH,
CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7 , CR7(OR12)2, CR7OR13O, or tri-lower alkylsilyl, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of l to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons;
X is O, S, SO or SO2 and
R20 is Si(R2)3, R14, COR14, SO2R21, where R14 is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bond, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C1 - C10- alkylphenyl, naphthyl, C1 - C10-alkylnaphthyl, phenyl-C1 - C10alkyl, napthyl-C1 - C10alkyl, or R20 is
hydroxyalkyl, aminoalkyl or thioalkyl having 1 to 10 carbons; and R21 is alkyl of 1 to 10 carbons,
fluoroalkyl of 1 to 10 carbons, or carbocyclic aryl selected from the group consisting of phenyl, C1 - C10-alkylphenyl and phenyl-C1 - C10alkyl.
145. A compound of Claim 144 where Y is phenyl, pyridyl, thienyl or furyl.
146. A compound of Claim 144 where Y is phenyl.
147. A compound of Claim 146 where the phenyl ring is 1,4 (para) substituted.
148. A compound of Claim 144 where Y is pyridyl.
149. A compound of Claim 148 where the pyridyl ring is substituted in the 2 and 5 positions.
150. A compound of Claim 144 where Y is thienyl or furyl.
151. A compound of Claim 144 where R2 is
hydrogen.
152. A compound of Claim 144 where R3 is
hydrogen.
153. A compound of Claim 144 where R20 is R14, COR14, SO2R21 or Si(R2,)3.
154. A compound of Claim 153 where R20 is ethyl or CF3SO2.
155. A compound of Claim 144 where X is O.
156. A compound of Claim 144 where X is S.
157. A compound of Claim 144 where X is SO2.
158. A compound of the formula
Figure imgf000212_0001
wherein R1 is hydrogen or alkyl of 1 to 10
carbons;
R2 and R3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the dihydronaphthalene nucleus; m is an integer having the value of 0 - 3;
o is an integer having the value 0 - 3;
Y is phenyl or pyridyl, said groups being
optionally substituted with one or two R2 groups;
A is (CH2)n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6
carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
B is hydrogen, COOH or a pharmaceutically
acceptable salt thereof, COOR8, CONR9R10, -CH2OH,
CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, CR7OR13O, or tri-lower alkylsilyl, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has l to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons;
X is o, s, or SO2 and
R20 is Si(R2)3, R14, COR14, SO2R21, where R14 is hydrogen, alkyl of 1 to 10 carbons, carbocyclic aryl selected from the group consisting of phenyl, C1 - C10-alkylphenyl, , phenyl-C1 - C10alkyl, and R21 is alkyl of 1 to 10 carbons, fluoroalkyl of 1 to 10 carbons, or carbocyclic aryl selected from the group consisting of phenyl, C1 - C10-alkylphenyl and phenyl-C1 - C10alkyl.
159. A compound of Claim 158 where X is O.
160. A compound of Claim 159 where A is (CH2)n where n is 0-5 and where B is COOH or a
pharmaceutically acceptable salt thereof, COOR8, or CONR9R10.
161. A compound of Claim 158 where X is S.
162. A compound of Claim 161 where A is (CH2)n where n is 0-5 and where B is COOH or a
pharmaceutically acceptable salt thereof, COOR8, or CONR9R10.
163. A compound of Claim 158 where X is SO2.
164. A compound of Claim 163 where A is (CH2)n where n is 0-5 and where B is COOH or a
pharmaceutically acceptable salt thereof, COOR8, or CONR9R10.
165. A compound of the formula
Figure imgf000214_0001
wherein X is O or S or SO2;
R8 is hydrogen, an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, the substituted ethynyl group occupies the 2 or 3 position of the dihydronaphthalene nucleus, and
R20 is Si(CH3)3, R14, COR14, SO2CF3, where R14 is hydrogen, or alkyl of 1 to 10 carbons.
166. A compound of Claim 165 where X is O.
167. A compound of Claim 166 where R20 is CF3SO2.
168. A compound of Claim 167 where R8 is H or
C2H5.
169. A compound of Claim 166 where R20 is
Si(CH3)3.
170. A compound of Claim 169 where R8 is H or
C2H5.
171. A compound of Claim 166 where R20 is CH3CO.
172. A compound of Claim 171 where R8 is H or
C2H5.
173. A compound of Claim 165 where X is S.
174. A compound of Claim 173 where R20 is C2H5.
175. A compound of Claim 174 where R8 is H or
C2H5.
176. A compound of Claim 173 where R20 is phenyl
177. A compound of Claim 176 where R8 is H or
C2H5.
178. A compound of Claim 173 where R20 is t-butyl
179. A compound of Claim 178 where R8 is H or
C2H5.
180. A compound of Claim 173 where R20 is benzyl.
181. A compound of Claim 180 where R8 is H or
C2H5.
182. A compound of Claim 165 where X is SO2.
183. A compound of Claim 182 where R20 is C2H5.
184. A compound of Claim 183 where R8 is H or
C2H5.
185. A compound of Claim 182 where R20 is phenyl.
186. A compound of Claim 185 where R8 is H or
C2H5.
187. A compound of the formula
Figure imgf000215_0001
wherein R1 is hydrogen or alkyl of 1 to 10
carbons;
R2 and R3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the dihydronaphthalene nucleus; m is an integer having the value of 0 - 3;
o is an integer having the value 0 - 3;
Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl,
pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R2 groups;
A is (CH2)n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6
carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
B is hydrogen, COOH or a pharmaceutically
acceptable salt thereof, COOR8, CONR9R10, -CH2OH,
CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7 , CR7(OR12)2, CR7OR13O, or tri-lower alkylsilyl, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons, and
R22 is hydrogen, alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds,
carbocyclic aryl selected from the group consisting of phenyl, C1 - C10-alkylphenyl, naphthyl, C1 - C10-alkylnaphthyl, phenyl-C1 - C10alkyl, naphthyl-C1 - C10alkyl, C1 - C10-alkenylphenyl having 1 to 3 double bonds, C1 - C10-alkynylphenyl having 1 to 3 triple bonds, phenyl-C1 - C10alkenyl having 1 to 3 double bonds, phenyl-C1 - C10alkynyl having 1 to 3 triple bonds, hydroxy alkyl of 1 to 10 carbons, hydroxyalkynyl having 2 to 10 carbons and 1 to 3 triple bonds,
acyloxyalkyl of 1 to 10 carbons or acyloxyalkynyl of 2 to 10 carbons and 1 to 3 triple bonds where the acyl group is represented by COR14, CN, CON(R1)2,
(CH2)pCO2R8 where p is an integer between 0 to 10, or R22 is aminoalkyl or thioalkyl of 1 to 10 carbons, or a 5 or 6 membered heteroaryl group optionally substituted with a C1 to C10 alkyl group and having 1 to 3
heteroatoms, said heteroatoms being selected from a group consisting of O, S, and N, or R22 is represented by (CH2)pXR1 or by (CH2)pNR1R2; where X is O or S, the R14 group is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bond, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group
consisting of phenyl, C1 - C10-alkylphenyl, naphthyl, C1 - C10-alkynylphenyl, phenyl-C1 - C10alkyl, or naphthyl-C1 - C10alkyl.
188. A compound of Claim 187 where Y is phenyl, pyridyl, thienyl or furyl.
189. A compound of Claim 187 where Y is phenyl.
190. A compound of Claim 189 where the phenyl ring is 1,4 (para) substituted.
191. A compound of Claim 187 where Y is pyridyl.
192. A compound of Claim 191 where the pyridyl ring is substituted in the 2 and 5 positions.
193. A compound of Claim 187 where Y is thienyl or furyl.
194. A compound of Claim 187 where R2 is
hydrogen.
195. A compound of Claim 187 where R3 is
hydrogen.
196. A compound of Claim 187 where R22 is
hydrogen, alkyl of 1 - 10 carbons, alkynyl of 2 to 10 carbons having 1 triple bond, alkylphenyl having 1 to 10 carbons in the alkyl group, phenylalkyl having 1 to 10 carbons in the alkyl group, phenylalkynyl having 2 to 10 carbons in the alkynyl group, CH2CO2R8,
hydroxyalkyl having 1 to 10 carbons in the alkyl group or hydroxyalkynyl having 2 to 10 carbons in the alkynyl group.
197. A compound of Claim 187 where R22 is cyano (CN) or CONH2.
198. A compound of Claim 187 where R22 is
heteroaryl.
199. A compound of Claim 198 where R22 is a 5 or 6 membered heteroaryl group having l or 2 heteroatoms.
200. A compound of Claim 199 where R22 is 2-thiazolyl, 2-furyl, 2-thienyl or 2-pyridyl.
201. A compound of the formula
Figure imgf000218_0001
wherein R1 is hydrogen or alkyl of 1 to 10
carbons;
R2 and R3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the dihydronaphthalene nucleus; m is an integer having the value of 0 - 3;
o is an integer having the value 0 - 3;
Y is phenyl or pyridyl, said groups being
optionally substituted with one or two R2 groups;
A is (CH2)n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6
carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
B is hydrogen, COOH or a pharmaceutically
acceptable salt thereof, COOR8, CONR9R10, -CH2OH,
CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, CR7OR13O, or tri-lower alkylsilyl, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons, and
R22 is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C1 - C10-alkylphenyl, phenyl-C1 - C10alkyl, C1 - C10-alkenylphenyl having 1 to 3 double bonds, C1 C10-alkynylphenyl having 1 to 3 triple bonds, phenyl-C1
- C10alkenyl having 1 to 3 double bonds, phenyl-C1 - C10alkynyl having 1 to 3 triple bonds, hydroxy alkyl of 1 to 10 carbons, hydroxyalkynyl having 2 to 10 carbons and 1 to 3 triple bonds, acyloxyalkyl of 1 to 10 carbons or acyloxyalkynyl of 2 to 10 carbons and 1 to 3 triple bonds where the acyl group is represented by COR14, CN, CON(R1)2, (CH2)pCO2R8 where p is an integer between 0 to 10, or R22 is a 5 or 6 membered heteroaryl group having 1 to 2 heteroatoms, said heteroatoms being selected from a group consisting of O, S, and N; where the R14 group is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bond, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C1 - C10-alkylphenyl, or phenylC1 - C10alkyl.
202. A compound of Claim 201 where A is (CH2)n where n is 0-5 and where B is COOH or a
pharmaceutically acceptable salt thereof, COOR8, or CONR9R10.
203. A compound of Claim 202 where n is 0 and B is COOH or a pharmaceutically acceptable salt thereof.
204. A compound of the formula
Figure imgf000220_0001
wherein R8 is hydrogen, an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, and
R22 is hydrogen, alkyl of 1 to 10 carbons, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds,
carbocyclic aryl selected from the group consisting of phenyl, C1 - C10-alkylphenyl, phenyl-C1 - C10alkyl, C1 - C10-alkynylphenyl having 1 to 3 triple bonds,
phenyl-C1 - C10alkynyl having 1 to 3 triple bonds, hydroxy alkyl of 1 to 10 carbons, hydroxyalkynyl having 2 to 10 carbons and 1 to 3 triple bonds, CN, CONH2, (CH2)2CO2R8, or R22 is a 5 or 6 membered heteroaryl group having 1 to 2 heteroatoms, said heteroatoms being selected from a group consisting of O, S, and N, and the substituted ethynyl group occupies the 2 or 3 position of the dihydronaphthalene nucleus.
205. A compound of Claim 204 where R22 is 2-thiazolyl.
206. A compound of Claim 205 where R8 is H or
C2H5.
207. A compound of Claim 204 where R22 is 2-pyridyl.
208. A compound of Claim 207 where R8 is H or
C2H5.
209. A compound of Claim 204 where R22 is 2-furyl.
210. A compound of Claim 209 where R8 is H or
C2H5.
211. A compound of Claim 204 where R22 is 2-thienyl.
212. A compound of Claim 211 where R8 is H or
C2H5.
213. A compound of Claim 204 where R22 is H or lower alkyl of 1 to 10 carbons.
214. A compound of Claim 213 where R8 is H or
C2H5.
215. A compound of Claim 204 where R22 is phenyl,
216. A compound of Claim 215 where R8 is H or
C2H5.
217. A compound of Claim 204 where R22 is
CH2COOR8, CN or CONH2.
218. A compound of Claim 217 where R8 is H or
C2H5.
219. A compound of Claim 204 where R22 is C1 -
C10-alkylphenyl.
220. A compound of Claim 219 where R8 is H or
C2H5.
221. A compound of Claim 204 where R22 is
straight or brach-chained alkynyl having 2 to 10 carbons and 1 triple bond.
222. A compound of Claim 221 where R8 is H or
C2H5.
223. A compound of Claim 204 where R22 is 1-(3- hydroxy-3-methyl)butynyl.
224. A compound of Claim 223 where R8 is H or C2H5.
225. A compound of Claim 204 where R22 is
phenylethynyl.
226. A compound of Claim 225 where R8 is H or
C2H5.
PCT/US1995/016367 1994-12-29 1995-12-14 Acetylenes disubstituted with a 5 or 8 substituted tetrahydronaphthyl or dihydronaphthyl group and with an aryl or heteroaryl groups having retinoid-like biological activity WO1996020930A1 (en)

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AU45204/96A AU698527B2 (en) 1994-12-29 1995-12-14 Acetylenes disubstituted with a 5 or 8 substituted tetrahydronaphthyl or dihydronaphthyl group and with an aryl or heteroaryl groups having retinoid-like biological activity
EP95943828A EP0800517A1 (en) 1994-12-29 1995-12-14 Acetylenes disubstituted with a 5 or 8 substituted tetrahydronaphthyl or dihydronaphthyl group and with an aryl or heteroaryl groups having retinoid-like biological activity
JP52102396A JP2002504066A (en) 1994-12-29 1995-12-14 Acetylene having retinoid-like biological activity, disubstituted with a 5- or 8-substituted tetrahydronaphthyl or dihydronaphthyl group and an aryl or heteroaryl group

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US08/366,167 US5618943A (en) 1994-12-29 1994-12-29 Acetylenes disubstituted with a 5 OXO substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity
US08/366,168 1994-12-29
US08/366,167 1994-12-29
US08/366,193 1994-12-29
US08/366,183 1994-12-29
US08/366,172 1994-12-29
US08/366,182 US5489584A (en) 1994-12-29 1994-12-29 Acetylenes disubstituted with a 5-amino or substituted 5-amino substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity
US08/366,193 US5648514A (en) 1994-12-29 1994-12-29 Substituted acetylenes having retinoid-like biological activity
US08/366,168 US5514825A (en) 1994-12-29 1994-12-29 Acetylenes disubstituted with a 5 substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity
US08/366,172 US5543534A (en) 1994-12-29 1994-12-29 Acetylenes disubstituted with a 5 substituted tetrahydronaphthyl group and with an aryl or heteroaryl groups having retinoid-like biological activity
US08/366,169 1994-12-29
US08/366,169 US5599967A (en) 1994-12-29 1994-12-29 Acetylenes disubstituted with a 5 substituted tetrahydronaphthyl group and with an aryl of heteroaryl group having retinoid-like biological activity
US08/366,182 1994-12-29
US08/366,183 US5618931A (en) 1994-12-29 1994-12-29 Acetylenes disubstituted with a 5 substituted dihydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity

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JP2011031054A (en) * 1997-06-13 2011-02-17 Baxter Internatl Inc Method for treating biological tissue to mitigate calcification
WO2000068191A1 (en) * 1999-05-07 2000-11-16 Allergan Sales, Inc. Oxygen, sulfur and nitrogen substituted cyclohexene and cyclohexane derivatives having retinoid-like biological activity
US6465647B1 (en) 1999-05-07 2002-10-15 Allergan, Inc. Oxygen, sulfur and nitrogen substituted cyclohexene and cyclohexane derivatives having retinoid-like biological activity
WO2002018361A2 (en) * 2000-08-29 2002-03-07 Allergan, Inc. Compounds having activity as inhibitors of cytochrome p450rai
WO2002018361A3 (en) * 2000-08-29 2003-07-31 Allergan Inc Compounds having activity as inhibitors of cytochrome p450rai
JP2004507531A (en) * 2000-08-29 2004-03-11 アラーガン、インコーポレイテッド Compounds having activity as cytochrome P450 RAI inhibitors
AU2001286471B2 (en) * 2000-08-29 2006-09-07 Allergan, Inc. Compounds having activity as inhibitors of cytochrome P450RAI
JP2004509955A (en) * 2000-09-28 2004-04-02 アラーガン、インコーポレイテッド Methods for providing and using compounds (retinoids) having activity as cytochrome P450 RAI inhibitors
US8013001B2 (en) 2001-12-21 2011-09-06 Exelixis, Inc. Modulators of LXR
US7998986B2 (en) 2001-12-21 2011-08-16 Exelixis Patent Company Llc Modulators of LXR
WO2004045595A1 (en) * 2002-11-15 2004-06-03 Galderma Research & Development, S.N.C. USE OF AN RAR RECEPTOR ANTAGONIST FOR POTENTIATING THE ACTION OF TGFβ
FR2847167A1 (en) * 2002-11-15 2004-05-21 Galderma Res & Dev Method for treating disorders associated with TGF-beta signal deficiency, e.g. cicatrization disorders, ulcers, cancers or graft rejection, comprises administration of retinoic acid receptor-Gamma antagonists
US7659297B2 (en) 2003-10-08 2010-02-09 Bayer Schering Pharma, AG Tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents
US7662821B2 (en) 2003-10-08 2010-02-16 Bayer Schering Pharma Ag Tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents
US7638515B2 (en) 2003-10-08 2009-12-29 Bayer Schering Pharma Aktiengesellschaft Tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents
US8097627B2 (en) 2004-04-05 2012-01-17 Bayer Pharma AG Multiply-substituted tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents
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US7880042B2 (en) 2006-03-15 2011-02-01 Bayer Schering Pharma Ag Tetrahydronaphthalene derivatives, methods for the production thereof, and the use thereof as antiphlogistics

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