CA2129973A1 - Disubstituted acetylenes bearing heterobicyclic groups and heteroaromatic or phenyl groups having retinoid like activity - Google Patents

Abstract

Compounds of formula (I) where R1 and R2, independently are n-alkyl groups having 2 to 8 carbons, or cyclo or branch-chained alkyl groups of 3 to 8 carbons; R3 is hydrogen or lower alkyl; X is S, O or N-R4 where R4 is hydrogen or lower alkyl; Y
is phenyl or a heteroaryl group selected from a group consisting or pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, and pyrazinyl; A is (CH2)n where n is 0-5, lower branched chain alkyl having 3 to 6 carbons, cycloalkyl having 3 to 6 carbons, alkenyl having 2 to 6 carbons and 1 or 2 double bonds, alkynyl having 2 to 6 carbons and 1 or 2 triple bonds; B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR5, CONR6R7, -CH2OH, CH2OR8, CH2OCOR8, CHO, CH(OR9)2, CHOR10O, -COR11, CR11(OR9)2, or CR11OR10O, where R5 is an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R5 is phenyl or lower alkylphenyl, R6 and R7 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphenyl, R8 is alkyl of 1 to 10 carbons, phenyl or lower alkylphenyl, R9 is lower alkyl, R10 is divalent alkyl radical of 2-5 carbons and R11 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, have retinoic acid like activity.

Description

WO93/1~K8 PCT/US93/01116 DI8UBSTITUTED ACETYLENES BEA~ING HETEROBICYCLIC ~ROUPS
AND HETEROAROMATIC OR P~ENYL GROUP8 ~A~ING
-- ~ETINOID LIg~ ACTIVITY
BACKGROUND ~F T~E INVENTION
1. Cross-Reference to Related A~plication The present application ~s a continuation-in-part of application serial number 07/326,191, filed ~n March 20, 1989, expected to be issued as United States Patent' No. 5,08g,509 on February 18, 1992, which in turn was a continuation-in-part of application serial nu~ber 07/246,037, filed on September 15, '988, now abandoned, which itself was a continuation of application serial number 028,279, filed on March 20, 1987, now abandoned.

2. Field of the Invention The present invention is directed to novel compounds whieh have retinoic acid-like biological activity. More specifically, the pr~æent invention relates to compounds ha~ing an ethynyl-heteroaromatic or an ethynyl-phenyl portion and a second portion which is an alkyl-substituted thiochromanyl, chromanyl or tetrahydroquinolinyl group. The present invention also relates ~o pharmaceutical compositions ¢omprising these compounds and to methods o~ using the compounds and compositions.
3O Related Art United States Patent No. 4,326,055 discloses ethene derivatives which have a substituted phenyl ring and a substituted indane or tetrahydronaphtalene group.
The compounds are described as tumor inhibiting agents, and useful for treating dermatological conditions and rheumatic illnesses.
United States Patent No~ 4,723,028 discloses 1,2-diphenylethene (stilbene~ derivataves which have WO93~1~K8 PCT/US93/01116~
~1~9973 ; 2 retinoic acid-like activity.
United States Patent No. 4,740,519 discloses certain aromatic heterocycle derivatiYes which have retinoic acid like activity.
Published European Patent Application 0 130795 discloses ethene derivatives, where the ethene moiety is substituted by a substituted phenyl group and by a substitituted chroman, thiochroman or quinoline group.
The compounds are useful for inhibiting the degradation of cartilage in mammals.
European Patent Application 176034A (published April 2, 1986) discloses tetrahydronaphtalene compounds having an ethynylbenzoic group. United States Patent No. 4,739,098 discloses compounds wherein thre~
olefinic units from the acid-containing moiety of retinoic acid are replaced by an ethynylphenyl functionality. These compound ha~ xetinoic acid-like biological activity.
United States Patent No. 4,810,804 (issued on March 7, 1989) based on an application of the same inventor and assigned to the same assignee as the present application, discloses such disubstituted acetylene compounds wherein one of the subs~ituents of the acetylene (ethyne) qroup is a substituted phenyl group, and the second substituent is a 4,4-dimethyl substituted 6-chrcmanyl, 6-thiochromanyl or 6-tetrahydroquinolinyl group. The compounds disclosed and claimed in United States Patent No. 4,810,8Q4 have retinoic acid-like biological activity.
A published European patent application of the present app~icant (Publication No. 0284288, p~blished on September 28, 1988) describes compounds having retinoic acid like activity which are 4,4 dime~hyl WO 93/16068 PCI`/US93/01 1 16 212997'~

substituted chroman-6-yl, and 4,4 dimethyl-substituted thiochroman-6-yl acetylenes also substituted by a substituted heteroaryl group. This European application is based on the earliest of the "parent"
applications of the present continuation-in-part application.
United States Patent No. 4,980,369 describes compounds having retinoic acid like activity which are 2,2,4,4 tetraalkyl substituted chroman-6-yl, and 2,2,4,4 tetraalkyl substituted thiochroman-6-yl acetylenes also substituted by a substituted phenyl group.
5everal co pending applications and re~ently issued patents of the present in~entor~ which are assigned to the assignee of the present application, are directed to ~urther compounds having retinoic acid-like activity. Among these United States Patent No.
5,045,551 ~issued on September 3, 1991 and assigned to the same assignee as the present application) describes co~pounds ha~ing retinoic acid li~e activity which are 2,2,4,4 tetraalkyl substituted ohroman-6-yl, and 2,2,4,4 tetraalkyl substituted thiochroman-~-yl acetylenes also substituted by a substituted heteroaryl group.
Retinoic acid-like activity has been generally reco~niz~d in the art ~o be associated with useful biological activity. Specifically, compounds having retinoic acid-like activity are useful as regulators of cell proliferation and differentiation, and particularly as agents for treating dermatos~s, such as acne, ~arier's disease, psoriasis, icthyosis, eczema and atopic dermatitis, and for treating and pre~enting malignant hyperproliferative diseases such as WO93/16~ PCT/US93/01116.~

epithelial cancer, breast cancer, prostatic cancer, head and neck cancer and myeloid leukemias, for reversing and preventing atherosclerosis and restenosis resulting from neointimal hyperprolif~ration,~ for 5 treating and preventing other non-malignant hyperproliferative diseases such as endometrial hyperplasia, benign prostatic hypertrophy, proliferative ~itreal retinopathy and dysplasias, for treating autoimmune diseases and immunological 10 disorders (e.g. lupus erythematosus), for treating chronic inflammatory diseases such as pulmonary fibrosis, for treating and pre~enting diseases associated with lipid metabolism and transport such as dyslipidemias, for promoting wound healing, for lS treating dry eye syndro~e and for reversing and preventing the effects of sun damage to skin.
Summary of the Invention This invention covers compounds of Formul~ 1 ~Y--A ` B

Formula 1 wherein Rl and R2, independently are n-alkyl groups ha~ing 2 to 8 carbons~ or cyclo or branch-30 chained alkyl groups of 3 to 8 carbons;
R3 is hydrogen or lower alkyl;
~ is S, O or N-R~ where R~ is hydrogen or lower alkyl;

wos3Jl~Ks PCT/US93/01116 Y is phenyl or a heteroaryl group selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl;
A is (CH2)n where n is 0-5, lower branched chain 5 alkyl having 3 to 6 carbons, cycloalkyl having 3 to 6 carbons, alkenyl having 2 to 6 carbons and 1 or 2 double bonds, alkynyl having 2 to 6 carbons and 1 or 2 triple bonds;
B is hydrogen, COOH or a pharmaceutically 10 acceptable salt thereof, COOR5, CONR6R7, -CH20H, CH2OR8, CH2OCOR8, CHO, CH(ORg)2~ C~OR~oO ~ - CORll ~
CRl1(ORg)2, or CRllOR1oO~ where R5 is an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R5 is phenyl or lower alkylphenyl, R6 and 15 R7 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbor.s, or phenyl or lo~er alkylphenyl, R8 is alkyl of 1 to 10 carbons, phenyl or lower alkylphenyl, Rg is lower alkyl, ~10 is'divalent alkyl radical of 2 - 5 carbons 20 and Rl~ is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons.
In a second-aspect, this inYention relates to the use of the compounds of For~ula ~ as regulators of cell proli~eration and differentiation, and particul~rly as 25 agents for treating dermatoses, such as acne, Darier's disease, psoriasis, icthyosis, eczema and atopic dermatitis, and for treating and preventing malignant hyperproliferative diseases such as'epithelial cancer, ' breast cancer, prostatic cancer, head and neck cancer 30 and myeloid leukemias, for reversing and preventing atherosclerosis and restenosis resulting from neointimal hyperproliferation, f~r treating and preventing other non-~alignant hyperproliferative WO93~16068 PCT/US93/0111$~

2 129 9i73 ; 6 diseases such as endometrial hyperplasia, benign prostatic hypertrophy, proliferative ~itreal retinopaythy and dysplasias, for treating autoimmune diseases and immunological disorders Se.g. 1~pus erythematosus), for treating chronic inflammatory diseases such as pulmonary fibrosis, for treating and preventing diseases associated with lipid metabolism and transport such as dyslipidemias, for promoting wound healing, for treating dry eye syndrome and for lO reversing and preventing the effects of sun damage to skin.
This invention also relates to a pharmaceutical formulation comprising a compound of Formula 1 in admixture with a pharmaceutically acceptable excipient.
In another aspect, this invention relates to the process for making a compound of Formula 1 which process comprises reacting a compound of Formula 2 with a compound of ~ormula 3 in the presence of cuprous iodide and Pd(PQ3)2Cl2 ~Q is phenyl) or a similar 20 complex R1~R2 ' _ .

L--Y--A--B' For~la 2 Fo~mul~ 3 30 where A, Rl through R3, and Y are defined as above, ~
- is a halogen, preferably I; and B' is H, or a protected acid, alcohol, aldehyde or ketone, where B' can be identical with B as defined above, or B' is such a ~ NO93/1~K~ PCr/US93/01116 precursor of the group B which is converted readily - through a reaction or reactions well known by the practicing organic chemist into_the group B of the compounds of the present invention.
Alternati~ely, this invention relates to the process for making a compound of Formula 1 which process comprises reacting a a zinc salt of Formula with a compound of Formula 3 in the presence of Pd(PQ3)4 (Q is phenyl) or a similar complex. In 10 Formul~ ~, Rl through R3 and X are defined as in connection with Formul~ 1 above.

R1~ZnC

~ ormul~ ~
The present i m ention also relates to the process of comerting a compound of Formul~ 1 into another compound of the same general formula, or converting a 25 compound of For~ula 5 into a compound of Por~ul~ ~, : ~uch conversion being performed through a reaction or reactions well within the skill of the practicing organic chemist, and including reactions such as:
homologating an acid where A is ~CH2)n, where 30 n~ is 0-4 to g~ve an acid of Formula l; or co m erting an acid.of Formul~ 1 to a salt; or forming an acid addition salt;
- converting an acid of Formul~ 1 to an ester; or WO93/1~K8 PCT/US93/0111,~

2~.2997`3;~

converting an acid of Formul~ 1 to an amide; or reducing an acid of ~ormula 1 to an alcohol or aldehyde; or converting an alcohol of Formula 1 to an ether or 5 ester; or oxidizing an alcohol of Formula 1 to an aldehyde;
or con~erting an aldehyde of Formul~ 1 to an acetal;
or converting a ketone of Formul~ 1 to a ketal.
In Formula S all symbols are defined as above in connection with Formula 1 and For~ula 3, as app~icable.

R~ A--B' Form~la 5 General ~mbod~ments Defini~ions .The ter~ alkyl refer~ to and covers any and all 25 groups which are known as ~ormal alkyl, branch-chain alkyl and cycloalkyl. The term alkenyl refers to and covers normal alkenyl, bra~ch chain alkenyl and cycloalkenyl groups ha~ing one or more sites of unsaturation. Lower alkyl means the abo~e-defined 30 broad definition of alkyl groups having 1 to 6 carbons, and as applicable, 3 to ~ carbons ~or bran~h chained and cyclo-alkyl groups. Lower alkenyl is defined similarly ha~ing 2 to 6 carbons for normal alkenyl, and WO93/1~K8 PCT/US93/01116 3 to 6 carbons for branch chained and cycloalkenyl groups.
The term l'ester" as used here refers to and covers any compound falling within the definition of that term 5 as classically used in organic chemistry. Where B (of Formul~ l) is -COOH, this term covers the products deri~ed from treatment of this function with alcohols, preferably with aliphatic alcohols having 1-6 ca~bons.
Where the ester is derived from compounds where B is 10 -CH2OH, this term cov~rs compounds of the formula -CH200CR8 where R8 is ~ny sub;tituted or unsubstituted aliphatic, aromatic or aliphat:ic-aromatic group, preferably with l-6 carbons in the aliphatic portions.
Preferred esters are deri.ved from ~he saturated 15 aliphatic alcohols or acids of ten or fewer carbon atoms or the c:yclic or saturat.ed aliphatic cyclic alcohols and acids of 5 to lo carbon atoms.
Particularly preferred aliphatic esters are those derived from lower alkyl acids or alcohols. Also 20 preferred are the phenyl or lower alkylphenyl esters.
Amide has the meaning classically accorded that term in organic chemistry. In this ins~ance it includes the unsubstitut~d amides and all aliphatic and aromatic mono-and di-substituted amides. Preferred 25 amides are the mono- and di-substituted amides derived from the saturated aliphatic r~dicals of ten or fewer carbon atoms or the cyclic or saturated aliphatic-cyclic radicals of 5 to l0 carbon atoms. Particularly preferred amides are those derived from lower alkyl 30 amines. Also preferred are mono- and di-substitute~
amides derived from the phenyl or lower alkylphenyl amines. Unsubstituted amides are ~150 preferred.
A~etals and ketals include the radicals of the WO93/1~K~ PCT/US93/0111~

formula -CK where K is t-OR)2. Here, R is lower alkyl.
Also, K may be -OR1O- where R1 is lower alkyl of 2-5 carbon atoms, straight chain or branched. -A pharmaceutically acceptable salt may be prepared 5 for any compound of this invention having afunctionality capable of forming such salt, for example an acid or an amine functionality. A pharmaceutically acceptable salt may be any salt which retains the acti~ity of the parent compound and does not impart any 10 deleterious or untoward effect on the subject to which it is administered and in the context in which it is administered.
Such a salt may be derived from any organic or inorganic acid or base. The salt may be a mono or 15 polyvalent ion. Of particul~r interest where the acid function is concer~ed are the inorganic ions, sodium, potassium, caloium, and magnesium. Organic amine salts may be made with amines, p~rticularly ammonium salts such as mono-, di- and trialkyl amines or ethanol 20 amines. $alts may also be formed with caffeine, tromethamine and similar molecules. Where there is a nitrogen sufficiently basic as to be capable o~ forming - acid addi~ion salts, such may be formed with any inorganic or organic acids or alkylating agent such as 25 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 in~ention (those where A is alkenyl) contain at least one double bond and therefore may have trans and cis (E and Z) isomers. In addition, some of the compounds of the WO93/1~K8 PCT/US93/01116 - 212~973 present invention may contain one or more chiral centers and therefore exist in enantiomeric and diastereomeric 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 diastereomers and racemic mixtures of enantiomers (optical isomers) as well.
With respect to the groups ~l and ~2 f For~ula 1, .
the preferred compounds of the present invention are lO those where the Rl and R2 groups are identical with one another. Still more preferred are those compounds where Rl and R2 are normal alkyl having 2 to 6 carbons.
With respect to the R3 group in Formul~ 1, the compounds are preferred where Rl is hydrcgen or methyl.
With regard to the heterocyclic portion of the co~pounds of the invention which bears the Rl and R2 groups, the thiochroman and chroman rings ~X is S or O) are preferred. Between these two, still more preferred are the thiochroman derivatives (S is S).
With regard to the aromatic ring on the "other"
side of the ethyne moeity of the compounds of the present invention, compounds are preferred where the aromatic ring is phenyl, pyridyl or thienyl. In other words, for the preferred compounds in For~ula 1 the Y
25 substituent is selected from a divalent phenyl, pyridyl or thienyl radical, and among these the phenyl and pyridyl derivatives are still more preferred. With regard to the substitution pattern on the phenyl group (when Y is phenyl) the compounds are preferred where 30 the ethyne and A-B portions are 1,4 ( ara) to one another. The preferred substitution pattern on the pyridyl radical (when Y is pyridyl) is 2 and 5 in accordance with pyridine nomenclature (equivalent to 2 W093/l~KX PCT/US93/0111~

and 6 in accordance with nicotinic acid nomenclature.) With regard to the ~ subs'ituent on the phenyl or heteroaromati~ ring, compounds are preferred where A is (CH2)n, and still more preferred where n is zero.
With respect to the symbol B, the compounds of the invention are preferred where B is -COOH, or an alkali metal salt or organic amine salt thereof.
Alternatively, compounds are preferred where B is respresented by COOR5 (ester where R5 is lower alkyl) 10 CONR6R7 (amide) -CH~OH (alcohol), CH20CO~8, CH20R8 (R8 is lower alkyl; lower alkyl esters and ethers formed with a lower alkanol) or B is -CHO or CH(ORg)2~ CHOR~
(acetal derivatives), where R9 a~d Rlo are defined as in coJ~nection with Formula 1. The most preferred 15 compound~ of the in~ention are shown in Formul~ 6.

COORs-For~ulA 6 Compoun~ 1R1=~2=CH3cH2 Z=CH; ~5 =
ethyl;
Compou~ 2~ 2=CH3CH2- z=CH; ~ -30 ~;
- Compoun~ 3~1 R2=~3cH2- Z-N;
ethyl, Co~pou~ ~X1zR2=CH3cH2 z=N; ~5 WO93/l~K~ PCT/US93/01116 :.
H; .
Compou~ 5 Rl=~2=C~3(CH2)2 Z=CH; R5 =
ethyl;
Compound 6 Rl=~2ZCH3tCH2)2- . Z=CH; ~5 =
5 H;
Compound 7 ~1 R2 CH3(CH2)2 Z=N; R5 =
ethyl;
Co~poun~ 8 R~=R2=CH3(cH2)2 Z-N; ~5 H;
Compoun~ 9 Rl=~2=CH3(~H2)3 2=CH; R5 =
ethyl;
Compound 10 R1=R2=CH3(cH2)3 Z=CH; R5 =
H;
Compoun~ 11 Rl= ~ ZCH3(CH2)3 Z=N; R5 =
15 ethyl;

Compou~t 12 RlZR2'cH3(cH2)3- Z=N: R5 =
H;
The compounds of this ~nvention may be administered systemically or topically, depending on 20 such considerations as the condition to be treated, need for site-specific txeatment, quantity of drug to be administered, and similar considerations.
In the treatment of dermatoses, it will generally be preferred to administer the drug topically, tho~gh 25 in certain cases su~h as treatment of severe cystic acne, oral administration may also be used. Any co~mon topical formulation such as a solution, suspension, gel, ointment, or sal~e and:the like may be used.
Preparation of such topical formulations are well 30 described in the art of pharmaceutical formulations as exemplified, for example, Reming~on's Pharmaceutical Science, Edition 17, Mack Publishing Company, Easton, Pennsylvania. For topical application, these compounds WO93/1~$ PCT/US93/01116~

21299`73 `

could also be administered as a powder or spray, particularly in aerosol form.
If the drug i5 to be administered systemically, it may be confected as a powder, pill, tablet or the like, 5 or as a syrup or elixir 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 in 10 suppository form or as an extended release formulation for deposit under the skin or intermuscular injection.
Other medicaments can be added to such topical formulation for such secondary purposes as treating skin dryness, providing protection against light; other 15 medications for treating de.~atoses, preventing infection, reducing irritation, inflammation and the like.
Treatment of dermatoses or any other indications known or discovered to be susceptible to treatment by 20 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 e~fects reduction of the paxticular condition, or 25 retards its expansion. In certain instances, the drug potentially could be used in a prophylactic manner to prevent onset of a particular condition. A given therapeutic concentration will vary from condition to condition and in certain instances may vary with the 30 severity of the condition being treated and the patient'æ susceptibility to treatment. Accordingly, a given therapeutic concentration will be best determined at the time and place through routine experimentation.

WO93/l~K8 PCT/US93/01116 However, it is anticipated that in the treatment of, for example, acne, or other such dermatoses, that a formulation containing between 0.001 and 5 percent by weight, preferably about 0.01 to 1% will usually constitute a therapeutically effective concentration.
If administered systemically, an amount between 0. 01 and 100 mg per kg body weight per day, but preferably about 0.1 to 10 mg/kg, will effect a ther~peutic result in most instances.
The retionic acid like acti~ity of these compounds was confirmed through the classic measure of retionic acid activity involving the effects of retionic 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, ~, 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 causes for ODC acti~ity increase are unknown, it is known that 12-0-tetradecanoyl-phorbol-13-acetate (TPA) induces ODC
activity. Retinoic acid inhibits this induction of ODC
activity by TPA. The compounds of this invention also inhibit TPA i~duction of ODC as demonstrated by an assay essentially following the procedure set out in 30 Cancer Res., 35: 1662-1670, 1975.
By way of example of retinoic acid-iike activity it is noted that in the assay conducted essentially in accordance with the method of Verma & Boutwell, ibid, WO93/1~K8 PCT/US93/01116~
212g973 the following examples of the preferred compounds of the present invention (Compoun~3 3, ~ and ll) attained an 80% inhibition of TPA induced ODC activity at the following concent.rations (IC80):
5Compound IC80 conc (nmols) 3 0.3 7 2.5 ll 0.6 d Specific Embodiments The compounds of this invention c~n be made by a number of different synthetic chemical pathways~ To illustrate this inve~tion, there is here outlined a series of steps which have been proven to pro~ide the compounds of For~ula 1 when such synthe is is followed 15 in fact and in spir~t. The synthetic chemist will readily app~eciate that the conditions set ou~ here are specific embodiments which can be generalized to any and all of the compounds represented by Formul~ l.
Furthermore, the synthetic chemist will readily 20 appreciate that the herein described synthetic steps may be varied and or adjusted by those skilled in the art without departin~ from the scope and spirit of the ~;
invention.

3~ `

wo 93/16068 Pcr/uss3/ol 1 16 2129973 ~

HS~R3 1~ EtOJ--S~R3 Fonnula 7 Formula 8 R~zM~Br R~R2~Br P20s.H- ~Br Formula 9 Fonnula 10 Cul, Et3N R~x~C----C--Si(CH3h Formula 10 -- .
bis(lriphenyl) l , phosphine palladium(ll)~S~ ~--R3 chhride, (CH3)3Si-C=CH Formula 11 KOH ~C----CH Cul, Et3N
bis(triphenyl) S R3 ~ phosphine L~ palladium(ll) chloride I Fonnula 3 Formula~l (X ~ S) I

homologs and derivatives Reaction Scheme 1 WO93/1~K8 ` PCT/US93/0111~

The thiochroman derivatives of the present invention, that is compounds of Formula 1 where X is S, are prepared in accordance with Re~ction 8cheme 1. In accordance with this sequence of reactions, a 4-bromothiophenol derivative of Formul~ 7 is reacted withethyl acrylate to provide the ethyl 3-(4-bromophenylthio)propionate derivative of Formul~ 8. In this reaction scheme the symbol R3 has the same definition as in Formula 1 above. It follows from the foregoing that when R3 is H, then the starting material of the reaction sequence is 4-bromothiophenol: when R3 is methyl, for example, then the starting material of Por~ula 7 is 3-methyl-4-bromothiophenol. To introduce the Rl and R2 substituents into the compounds of the invention the ethyl 3-(4-bromophenylthio)propionate derivative of Fo~ula 8 is reacted with a Grignard reagent, such as ethyl-, n-Propyl-, and ~-butylmagnesium bromide. The Grignard reaction is preferably conducted in the presence of cerium trichloride (CeC13). In Reaction 8cheme 1 the Grignard reagent is denoted as "Rl 2u to signify that both the Rl and the a2 groups can be introduced in this manner, and that in the preferred embodi~ents these groups are identical wi~h one another. The product of the Grignard reaction is the tertiary alcohol of For~ula 9 which is thereafter cyclized (under Friedel Crafts like conditions, such as in the presence of phosphorous pentoxide and methanesulfonic acid) to provide the 6-bromo-4,4-dialkylthiochroman derivative of Formula 10.
-~ 30 The compound of Formula 10 is thereafter reacted with trimethylsilylacetylene in the presence of cuprous iodide (CuI) and a suitable catalyst, typically having the formula Pd(PQ3)2C12 (Q is phenyl). The reaction is WO ~3/1~ 2 1 2 9 9 73 PCT/US93/01116 typically conducted in the presence of bis(triphenylphosphine)palladium(II) chloride catalyst, an acid acceptor (such as triethylamine~ under an inert gas (argon) atmosphere by heating in a sealed tube.
5 The trimethylsilyl group is removed from the resulting (4,4-dialkylthiochroman-6-yl)-trimethylsilylacetylene derivative of Formula ll under ba~ic conditions to provide the (4,4-dialkylthiochroman-6-yl)-acetylene derivative of Formula 12.
In order to introduce the phenyl or heteroaryl substituent on the acetylen~ (ethyne~ portion of the compounds of Formul~ 12, the compound is coupled with the reagent L-Y-A-B' (Formula 3) where the symbols ~, Y, A and B~ ha~e the same meaning as defined in con-15 nection with Formula 3. In other words, the phenyl or h~teroaryl substituent is introduced into the 6-thiochromanylacetyle~e of Formula 12 by reacting the latter with a halogen substituted phenyl compound or heteroaromatic compound .(For~ula 3) in which the 20 aromatic nucleus tY) either has the desired substituent r~-B], or wherein the actual substituent A-B5 can be readily converted to the desired substituent by means of organic reactions well known in the art.
Coupling of the 4,4,-dialkyl-6-thiochromanyl 25 acetylene of Formul~ 12 with the reagent ~-Y~A-B' (For~ula 3) is affected directly in the presence of cuprous iodide, a suitable catalyst, typically of the formula Pd(PQ3)2Cl2 (Q i5 phenyl~ and an acid acceptor, such as triethylamine, by heating in a sealed tube 30 under an inert gas (argon3 atmosphere.
The resulting disubstituted acetylene compound (Formul~ lj ~=S) may be the ~arget com~ound made in accordance with the invention, or maybe readily W093/l~K~ PCT/US93tO111~ ~

converted into the target compound by such steps as salt formation, esterification, deesterification, hQmologation, amide formation and the like. These steps are further discussed below.
The disubstituted acetylene compound (Formula 1, ~=S) may also be obtained by first converting the 4,4-dialkyl-6-thiochromanyl acetylene derivative of Formul~
~2 into the corresponding metal salt, such as a zinc salt, and thereafter coupling the zinc salt with the 10 reagent L-Y-A-B' (Formul~ ~) in the presence of a catalyst having the formula Pd(PQ3)4 (Q is phenyl), or similar complex.
Derivatization of Compound 18 is indicated in React~on 8cheme 1 as conversion to "homologs and 15 derivativesn.
~ ore specifically with respect to either derivatization or deblocking of protected functionalities, or with respect to the pr~paration of compounds of the formula ~-Y-A-B' (Formul~ 3), (which 20 after coupling either directly yield the compounds of the invention, or are readily converted into them) the following is noted.
Where a protected phenyl or heteroaromatic compound ~s needed to couple with the compounds of 25 For~ula 2, such may be pxepared from their corresponding acids, alcohols, Xetones or aldehydes.
These starting materials, the protected acids, alcohols, aldehydes or ketones, are all available from chemical manufacturers or can be prepared by published 30 methods. 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, WO93/1~ 21 2 9 9 7 3 PCT/US93/0l116 , 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 5 means. Acetals and ketals are readily made by the method described in March, "Advanced Organi~
Chemistry," 2nd Edition, McGraw-Hill Book Company, p 810). Alcohols, aldehydes and ketones all may be protected by forming respectively, ethers and esters, 10 acetals or ketals ~y known methods such as those described in McOmie, Plenum Publishing Press, 1973 and Protectina Grou~s, Ed. Greene, John Wiley & Sons, 1981.
To increase the value of n before effecting a coupling reaction, where such compounds are not 15 available from a commercial source, the pheny or heteroaromatic derivatives where B is -COOH are subjected to homologation by successive treatment under Arndt-Eistert conditions or other homologation procedures. Alternatively, phenyl or heteroaromatic 20 derivatives where B is different from COOH, may also be homologated by appropriate procedures. The homologated acids can then be esterified by the general procedure outlined in the preceding paragraph.
An alternative means for making compounds of 25 Formul~ l where A is (CH2)n and ~ is 1 - S, is to subject the compounds of ~or~ula 1, where B is an acid or other function, to homologation, using the Arndt-Eistert method referred to above, or other homologation procedures.
The acids and salts derived from Form~l~ 1 are readily obtainable from the corresponding esters.
Basic saponification with an alkali metal base will provide the acid. For example, an ester of Formul~ 1 WO93/1~K8 PCT/US93/0~116 212997~ 22 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, potassium hydroxide. The solution is 5 stirred for an extended period of tLme, 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 10 esters or carboxylic acids. One way to prepare such compounds is to con~ert an acid to an acid chloride and then treat that compound with ammonium hydroxide or an appropriate amine. For example, the acid is treated with an alcoholic base solution such as ethanolic KOH
15 (in approximately a 10% molar excess) at room temperature for about 30 minutes. The solvent is removed and the re idue taken up in an organic solvent such as diethyl ether, treated with a dialkyl formamide and then a 10-fold excPss of oxalyl chloride. This is 20 all effected at a moderately reduced temperature between about -10 degrees and ~10 degrees C. The last mentioned solution is then stirred at th~ reduced temperature ~or 1-4 hours, preferably 2 hours. Solvent removal provides a residue which is taken up in an 25 inert inorganic 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 corr sponding acids to the acid chloride with thionyl chloride or other means (J. March, I'Advanced Organic Chemistry", 2nd Edition, McGraw-Hill Book Company), then reducing WO93/1~K8 PCT/US93/01116 the acid chloride with sodium borohydride (March, Ibid, pg. 1124), which gives the corresponding alcohols.
Alternat~vely, esters may be reduced with lithium aluminum hydride at reduced temperatures. ~Ikylating these alcohols with appropriate alky 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 dicyclohexlcarbodiimide and dimethlaminopyridine.
Aldehydes can be prepared from the corresponding primary alcohols using mild oxidizing agents such as pyridinium dichromate in methylene chloride ~Corey, E.
~., 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 where B is H can be prepared from the corresponding halogenated aromatic compound (preferably where the halogen is I) by hydrogenation.

WO 93/16068 RCr/US93/01116,~", 21299~3 HOJ~ + ~OEt - J ~~
Formula 13 Fonnula 14 Fl,,,M ~i~ R,~R2~ r ~R3 Formula 15 Fonnula 16 Cul, E~N R1~C--C--SltCH3)3 bis(triphenyi) ~, ~
phosphine palladium(ll) ~~ ~--R3 chloride, (CH ~)3Si-C--CH Formula 17 R1>~CgCH orrnu~ Formu~a 1 ~ Cbul( E.~3hN ~ h hi O R3 palladiumtll)ehlorid~
Fonnula 18 homologs and ~erivatives ~ctio~ 8~hemo 2 WO 93/16068 PCr/US93/01116 The chroman derivatives of the present invention (compounds of Formula 1 where X is O) can be prepared in a reaction sequence which is similar to the reaction ~equence used for preparing the thiochroman derivatives, with the major difference being that instead of a suitable thiophenol derivative the corresponding phenol derivative is used as a starting material. Thus, with reference to ~action ~cheme 2, the 4-bromophenol derivative of Formula 13 is reacted 10 with ethylacrylate to provide the ethyl 3-(4-bromophenyl)propionate derivative of Formula 1~. (The symbol R3 has the same definition as in Formula 1 above; when R3 is H, then the starting material of the reaction sequence is 4-bromophenol; when R3 is methyl 15 then the~ starting material of Formul~ 13 is 3-methyl-4-bromophenol.) To introduce the ~1 and R2 substituents into the compounds of the invention the ethyl 3-(4-bronophenyl)propionate derivative of Formul~ 1~ is reacted with a Grignard reagent, such as ethyl-, n-20 propyl-, and n-butylmagnesium bromide. As in the previo~s reaction scheme in this scheme also, the ~rignard reagent is denoted as "Rl 2" to signify that both the~`R~ and the R2 groups can be introduced in this manner, and that th-se groups are identical with one 25 another in the preferred embodiments. The product of the Grignard reaction is the tertiary alcohol of ~ormula 15 which is thereafter cyclized (under Friedel Crafts like conditions) to provide the 6-bromo-4,4-dialkylchroman derivative of Formula 16. The compound 30 of For~ula lC is thereafter reacted with trimethylsily-lacetylene in the presence of cuprous iodide (CoI) and a suitable catalyst, typically having the formula Pd(PQ3)2C12 (Q is phenyl). As the reaction of the WO93/1~ ; PCT/US93/01116 ~1299~3 corresponding thiochromans (Formul~ 10 ) this reaction also is typically conducted in the presence of bis(triphenylphosphine)palladium(II~ chloride catalyst, an acid acceptor (such as triethylamine) under an inert 5 gas (argon) atmosphere by heating in a sealed tube.
The trimethylsilyl group is removed from the resulting (4,4-dialkylchroman-6-yl)-trimethylsilylacetylene derivative of Formul~ 17 under basic conditions to provide the (4,4-dialkylchroman-6-yl)-acetylene 10 derivative of Formul~ l8. The compound of Formul~ 18 is therafter coupled with the reagent L-Y-A-B' (Formula 3). In analogy to the coupling of the corresponding thiochroman compounds of Formula 12 with the compounds of Formula 3, the coupling of the 4,4,-dialkyl-6-15 chromanyl acetyler.e of Formula l8 with the reagent ~-Y- :
A-B' (Formula 3) is also conducted in the presence of cuprous iodide, a suitable catalyst, typically of the formula PdtPQ3)2C12 (Q is phenyl) and an acid acceptor, such as triethylamine, by heating in a sealed tube 20 under an inert gas ~argon) atmosphere.
The resulting disubstituted acetylene compound (Formula l, Xzl may be the target compound made in accordance with the invention, or maybe readily co m erted into~the target compound by such steps as salt formation, esterification, deesterification, homologation, amide formation and the like.
An alternative method for preparing the compounds of Formula 1 where X=0, and specifically for preparing the intermediate of Formula 18 which is suitable for coupling with the reagent ~-Y-A-B' (Formula 3) is a modification of the procedure disclosed in United States Patent No. 4,810,804 and depicted in Reaction Scheme 2 of that patent. For this reason, the WO93/16~8 21~ 9 9 7 3 PCT/US93/01116 specification of United States Patent No. 4,810,804 is expressly incorporated herein by reference. The procedure as applied to compounds of Formul~ 1 where Rl and R2-would be methyl, is also disclosed in the parent 5 of the present continuation-in-part applicatlon serial number 07/326,191, filed on March 20, 1989, expected to be issued as United States Patent No. 5,089,509. The sequence of reactions according to this procedure is shown in React~on 8cheme 3 and is summarized below.
o (ao)2Pocl + R2~cH~cR1-cH2-cH2oH ~ R2~cH~Rlc-cH2cH2o~-~oQ)2 Fomlula 19 Fomlula 20 ~3~ Rl R2 R~ R2 Formub 21 ~ CH3COCI ~X~
O ~ Ra ~ ~ Ra Fomlula 22 Fornmb 29 R~ ~ _ .. ~ I
db~asphala lilhlumdlsoprop~anid~
fomlula 18 Reaction 8cheme 3 W093/1~K8 PCT/US93/01116 212997~ 28 Thus, diphenyl chlorophosphate indicated as (Q0)2POCl (commercially available e. q. from Aldrich, or prepared by means known in the art) and the alcohol of Formula l9 are reacted to form the phosphate of Formul~ 20. In the structure of the alcohol of Formul~
19 Rl is defined as in connection with Formul~ 1, and R2 is defined as an alkyl group one carbon shorter than the R2 group defined above in connection with Formul~
l. In other words, where as in the most preferred compounds of the invention R2 is respectively ethyl, B-propyl and n-butyl, the R2 group of the alcohol of Formula l9 is respectively methyl, ethyl, and g-propyl.
The unsaturated alcohol of Formul~ l9 can be prepared in accordance with procedures known in the art. A
preferred method for preparing the phosphate of Formula 20 is to dissolve the alcohol of Formula 19 in an excess of pyridine or the like under an inert atmosphere cooled to approximately -lO degrees to lO
degrees C. This solution is then added drop-wise, 20 under an inert atmosphere, to a solution of diphenyl chlorophosphate in about an equal amount of the - reaction solvent. About a 2-5% molar excess of diphenyl chlorophosphate relati~e to the alcohol of For~ul~ 9 is employed. Thereafter, the mixture is 25 heate~ until the formation of the phosphate ester of Formul~ 20 is substantially completed. The product is then recovered by conventional means. The diphenyl phoæphate ester~(For~ula 20) is then reacted with a phenol derivative of Formula 21 to effect formation of 30 the 4,4-dialkylchroman of Fo~mul~ 22. For the synthesis of the compounds of the invention where R3 is hydrogen, unsubstituted phenol is the reagent o Formul~ 21. In the event R3 is methyl, for example, WO93~1 ~ 8 PCT/US93/01l16 then the reagent of Formul~ 21 is 3-methylphenol.
Examplary conditions for the reaction of the phenol of Formul~ 21 and the phosphate of_Formula 20 are as follows. The phenol or substituted phenol is added to a flask already containing stannic chloride which has been cooled to between -lO degrees to 10 degrees C.
After thorough mixing of this combination at the reduced temperature, the phosphate ester ~Formula 20) is added at the reduced temperature. Both of these steps are carried out under an inert atmosphere such as argon or nitro~en. When the addition of the phosphate ester of Formul~ 20 is completed, the mixture is stirred at about ambient temperature for up to 24 hours. Then the reacti~n is quenched with a dilute solution of aqueous alkali metal base or the like. The product 4,4-dialkylchroman of Formul~ 22 is recovered by ex*raction and other conventional means.
The acetylenic tethynyl) function is introduced into the 4,4-disubstituted (and optionaly 7-substituted) chroman (Formul~ 22) by acetylation withacetyl chloride (to yield the compounds of Formul~ 23), and tbereafter the acetyl group is converted to the ethynyl group through treatment with lithi~m diisopropylamide, dialkyl chlorophosphate and another 25 treatment with lithium diisopropylamide. The gen~ralized conditions (and likely reaction mechanisms) for these latter transformation which yield the 4,4-dialkyl-6-chromanyl acetylene compounds of Fosmula 18 are as follows. The compound of the Formul~
30 22 is acetylated under Fridel Crafts conditions, or the like, preferably with acetyl chloride (AlCl3, CH2C12, reflux) to provide the 4,4-dialkyl-6-acetyl-chroman of Formula 23. Thé acetyl function of the compound of WO93/1~K* PCTJUS93/01116 ,~ f Formula 23 is converted into an acetylenic (ethynyl) function by means of lithium diisopropylamide, or a similar base, at reduced temperature. An intermediate darived from the compound of Formul~ 23 (presumably a lithium salt of the corresponding enol, not shown cn Reactlon ~cheme 3) is esterified by treatment with diethychlorophosphate (or the like) and is again reacted at reduced temperature (e.g. - 7~ degrees C) with lithium diisopropylamide, to form the triple bond (presumably by an elimination reaction) and to yield the 4,4-dialkyl-6-chromanyl acetylene derivative (Formula 18).
It is noted at this point that the presemt invention is not intended to be li~ited or bound by the i~ above-mentioned and other theories of reaction mechanisms. Brief description of theory of reaction mechanisms ~where applicable) are gi~en to further enable and facilitate the work of a skilled artisan in the field to modify and adjust the synthetic conditions 20 to fit particular specific intermediates and to make the several compounds of the invention, without departing from ~he scope and spirit of the in~ention.
The 4,4-dialky1-6-chromanyl acetylene ~btained in this manner is coupled with the reagent of Formula 3 as indicated in R~action 8che~Q 2. The generalized conditions of this coupling are described above.
Alternatively, the compounds of Formula 18 are first converted to the corresponding zinc salt, and are then utilized as such in the coupling reaction with the 30 reagent of Formula 3. In general terms, the formation of the zinc salts is conducted under conditions which exclude water and oxygen. A dry, ether-type solvent such as dialkyl ether or a cyclic ether such as a furan WO93/l~W~ PCT/US93/01116 or pyran, particularly a tetrahydrofuran, may be used as the solvent. A solution of the compound of Formula ~8 is first prepared under an inert atmosphere (argon or nitrogen) and then a strong base such as n-butyl 5 lithium is added (in about a 10% molar excess). This reaction is begun at a reduced temperature of between -10 degrees and ~10 degrees C, preferably about 0 degrees C. The reaction mixture is stirred for a short , period, between 30 minutes and 2 hours, and then 10 treated with about a 10% molar excess of fused zinc chloride dissolved in the reaction solvent. This mixture is stirred for an additional 1-3 hours at about the starting temperature, then th~ temperature is increased to about ambient temperature for 10-40 15 minutes.
The foregoing general description for the preparation of the ZnCl salts of ~ompounds symbolized by ~ormula 18, are also appl~cable, with such modifications which will be readily apparent to the 20 skilled artisan in the field, to the preparation of all ZnCl salts of the appropriate acetylene (ethyne) intermediates leading to the compounds of the present i mention.
A synthetic sequence which is suitable for 25 preparing the compounds of Formul~ 1 where X=NR~, and specifically for preparing a 4,4-dialkyl-6-tetrahydroquinolinyl acetylene intermediate which is suitable for coupling with the reagent ~-Y-A-B' (Formula 3) is a modification of the procedure 30 disclosed in United States Patent No. 4,810,804 and depicted in Reaction Scheme 3 of that patent. The procedure as applied to compounds of Formula 1 where Rl and ~2 would be methyl, is also disclosed in the parent WOg3/l~K~ PCT/US93/01~16 of the present continuation-in-part application serial number 07/326,191, filed on March 20, 1989, expected to be issued as United States Patent No. 5,089,509. The sequence of reactions according to this procedure, ~.
5 which itself follows a procedure of European..-Patent Application 0130795 (published Sept. 1, 19~5) is shown in Reactio~ 8cheme ~ and is summarized below.

o H,NJ~R, ~ H

Fomlub 24 Fomlub 25 Fomwb 26 R~ R2 R~Rz ~la3 X~ L
O~NJ~R~ ~ ~gor~ ~N~ ~R~

Fomwia 27 Fonnula 28 R~

Fonnub 29 .

WO 93~16068 PCr/US~3/01116 212~973 R~ P~2 lilhh~m dik;opropylanid~
Fomlu~ I _ dlan(ylchbn~p~losptlale lilh~m dDsopropylalrbd~ N
Fonnl~la 30 ~ L-Y A-~I
Fom~ub 3 Fomwb X.t~H

~act~cln 8cheme ~
Thus, with reference to Re~tio~ ~ch~e 4, the rea~ion sequence is hereinafter described with pr~ary emphasis to preferred embodiments where ~4 ~of 25 Fomlul~ l) is hydrogen. Thus, the aniline derivative o~ For~ul~ 24 is first acylated wit:h the acyl chloride of t~e FQr~U3~ 2S. In the eYent R3 is hydrogen, the starting material of Fo~ul~ 24 is unsubstituted anil.ine. qhe acyl chloride (:~?or~ul~ 25) carries 'che Rl 30 and R2 ~ubstituents of on its unsaturated carbon, in the ,B position. For the most preferr~d embodiment~ R
and R2 are respectfully ethyl, n-Propyl and n-butyl.
Such acid chlorides can be synthesized in accordance WO93/l~K~ PCT/US93/01~ 6 with procedures known in the art. The amide of Formul~
26 is then cyclized under Friedel-Crafts type reaction conditions (aluminum chloride) to give the 2-oxo-1,2,3,4-tetrahydroquinoline derivatives of F~rmula 27.
5 Lithium aluminum hydride or a~other acceptable reducing agent of similar type is then used to reduce the compounds of Formul~ 27, tpreferably in inert solvent such as diethyl ether). In order to introduce the acetyl (ethyne) group into the 6-position of the 4,4-10 dialkyl-tetrahydroquinoline derivative of Formul~ 28, the compound is N-acetylated using acetyl chloride (in a polar solvent such as pyridine) followed by acetylation under Friedel Crafts type conditions (aluminum chloride) to give an intermediate which is 15 thereafter subjected to base hydrolysis to remove the N-acetyl group and gi~e compounds of Fosmuls 29.
The 6-acetyl group of the compounds of Formuls 29 is thereafter converted into an ethynyl group in the manner described above or analo~ous transformation of 20 4,4-dialky1-6-acetyl chromans. The 4,4 dialkyl-6-ethynyl 1,2,3,4-tetrahydroquinoline (Fonmula 30) may be coupled directly or as the corresponding ZnCl ealt, with compounds of Fox~ul~ 3.
Alternatively c~pounds of ~or~ula ~ where X is 25 NR~ can also be prepared by starting fr~m the corresponding 4-~romo-aniline derivative, in analogy to the sequence outlined in Reaction ~che~e 4 up to the step of obtaining the 6-bromo analog of the compound of Formula 28. Thereafter, the acetylene (ethyne) group 30 is introduced into the mol~cule in analogy to the corresponding steps outlined in Rea~tion 8chem~ 1.
These ste~s will be self-evident to those skîlled in the art in light of the analogous reactions disclosed WO93/l~K~ 2 1 2 9 9 7 3 PCT/US93/01116 above.
The following examples of specific compounds of the invention, and specific examples of the synthetic steps in which the compounds and certain int~rmediates are made, are set out to illustrate the invention, not to limit its scope.
Specific Exam~les ~thvl 6-chloronicotinate rcompoun~ 20~
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 residue subjected to flash chromatography to give the title co~pound as a low-melting white ~olid. PMR (CDC13): ~ 1.44 t3H, t, J-6.2 Hz) 4.44 (2H, g, J-4.4 Hz), 7.44 ~lH, d, ~-8.1 Hz), 8.2~ (lH, dd, J-8.1 Hz, 3 Hz), 9.02 (lH, d, J-3 Hz).
29 The foregoing procedure may be used to esterify any of the other halo-substituted acids employed in the maXing of these compounds such as:
ethyl 2-(2-chloropyrid-5-yl)acetate;
-~- - ethyl 5-t2-chloropyrid-5-yl)pentanoate;
ethyl 2-(2-iodofur-5-yl)acetate;
ethyl 5-(2-iodofur-5-yl)pentanoate;
ethyl 2-(2-iodothien-5-yl)acetate;
ethyl 5-(2-iodothien-5-yl)pentanoate;
ethyl 2-(3-chloropyridazin-6-yl)acetate;
ethyl 5-(3-chloropyridazin-6-yl)pentanoate; and the corresponding chloro, or other halo, substituted ` pyrimidinyl or pyrazinyl analogues of such esters. The just mentioned esters (including ethyl-WO 93/16068 PCI`/US93/01116 chloronicotinatej and ethyl-6-iodomicotinate can serve as the reagents, for coupling with the correspoding ethynyl compounds or their zinc salts to provide the target compounds of the invention. -6-Iodo-nicotinic acid A mixture of 15.962 g ((0.106 mol) of sodium iodide in 51 g (30 ml, 40 mmol) of hydriodic acid were stirred for 5 minutes. To the mixture was added 17.184 g (0.109 mol) of 6-chloro-nicotinic acid and the resulting mixture refluxed at 100 - 130 CC for 40 hours. The dark brown mixture was then taken up in 300 ml of acetone and stirred to dissolve the excess NaI.
The product was collected by suction filtration, rinsed with 100 mL in lN NaHS03 and dried to give the title 15 compound as a yellow solid.
PMR (DMS0-d6): ~ 3.36 (lH, s), 7.89 ~lH, dd, J =
2.5, 8.2 Hz), 8.00 (lH, d, J = 7.5 Hz), 8.79 (lH, d, J --= 2.4 Hz).
Ethvl 6-Iodo-nicotinoate (Compoun~ 21) A mixture of 16.230 g (84.5 mmol) of 1-t3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 90 ml of methylene chloride was cannulated into a mixture of 17.80 g (71.2 mmol) of 6-iodo-nicotinic ~cid in 30 ml of methylene chloride. The resulting mixture 25 was stirred and 7.85 g (0.171 mmol) of ethanol, and then 0.826 g (6.8 mmol) of 4-dimethylaminopyridine was added and the resulting ~ixture refluxed at 55C fox 20 hours and then stirred at room temperature for 12 hours. Ether and water were added and the layers 30 separated. The aqueous layer was extracted with 2 X 40 ml of ether and the organic portions combined, washed with satu~ated NaCl, dried over Na2SO4, and concentrated yielding a white solid which was purified W093/l~K~ PCT/US93/01116 ~712~973 by flash chromatography (Sio2, 10% ethyl acetate in hexanes) to give the title compound as a white solid.
PMR (CDC13): ~ 1.41 (3H, t, J = 7.1 Hz), 4.41 (2H, q, J = 7.1 Hz), 7.83 (lH, d, J - 8.2 Hz), 7.89 ~lH, dd, 5 J = 2.4, 8.2 ~z), 8.93 (lH, d, J = 2.1 Hz).
Ethvl-4-iodobenzoate (Compound 22) To a suspension of lO 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 ' 10 reflux for 3 hours. Solvent was removed in vacuo and the residue was dissolved in loo ml ether. The ether solution was washed with saturated NaHC03 and saturated NaCl solutions and dried (MgS04). Solvent was then removed in vacuo and the residue kugelrohr distilled (lOO degrees C; O.55 mm) to give the title compound as a colorless oil, PMR (CDC13): ~ 1.42 (3H, t, J~7 Hz), 4,4 (2H, q, J~7 Hz), 7.8 (4H).
In the same manner, but substituting for 4-iodobenzoic acid the appropriate acid, the ~ollowing 20 examples of compounds can be prepared:
ethyl 4-iodophenylacetate;
ethyl 3-(4-iodophenyl)propionate;
ethyl 4-(4-iodophenyl)butanoate; and ethyl S-(4-iodophenyl)pentanoate.
25 ~thYl 3-(4-kromo~henYlthio-~oPionate (Compou~ 23) To a ~olution of ~0.4 g t55.2 mmol) of 4-bromothiophenol and 6.49 g (55.4 mmol of ethyl acrylate in S mL of dichloromethane was added 4.13 g (41 mmol) of triethylamine at 0C under argon. The resulting solUtion was warmed to room temperature and stirred for - 12 ho~rs. The solution was then treated with SO mL 10%
aqueous NaOH and the product extracted into 3 X lOO mL
ether.

WO93/1~K8 PCT/US93/01116 212997~ 38 The combined ether extracts were washed with saturated aqueous NaCl, dried (MgS04), filtered and the solvent removed under reduced pressure. The residue was purified by flash chromatography (sio2~ 10% ethyl 5 acetate in hexanes) to give the title compound as a white solid.
PMR (CDC13): ~ 1.26 (3H, t, J = 7.1 Hz), 2.61 (2H, t, J = 7.4 HZ), 3.15 (2H, t, J = 7.5 Hz), 4.15 (2H, q, J = 7.2 Hz), 7.24 (2H, dd, J = 6.4, 8.5 Hz), 7.43 (2H, 10 dd, J = 6.4, 8.5 Hz).
~-Eth~1-5-(4-bromo~henYlthio)-3-~entanol (compo~n~ 2~) To a stirred suspension of 20 g (81 mmol) of cerium trichloride in 50 mL of tetrahydrofuran was added 19~9 g of ethylmagnesium bromide (3S mmol~ lM in 15 THF). The resulting mixture was stirred for 1 hour and then cooled to 0C. A solution of 4.71 g (17.36 mmol) of ethyl 3-t4-bromophenylthio)propionate (Compoun~ 23) in 25 mL of tetrahydrofuran was then cannulated into the cool mixture and the resulting suspension stirred 20 at room temperature for 16 hours. The reaction ~ixture was then cooled to 0C and treated with 200 mL of water and extracted with 5 X 50 mL of ether.
The ether extracts were combined and washed successiYely with 2 X 20 mL of saturated aqueous NaCl 25 and dried (Na2S04). The solvent was removed in-vacuo and the residue purified by flash chromatography (SiO2, 10% ethyl acetate in hexanes) to give the title compound as an orange oil.
PMR (CDC13): ~ 0.86 (6H, t, J = 7.6 Hz), 1.49 (4H, 30 q, J = 7.4 Hz), 1.74 (2H! m ), 2.05 (lH, s), 2.96 (2H, m), 7.21 (2H, dd, J - 2.0, 6.5 Hz), 7.41 (2H, dd, J -2.0, 6.5 Hz).

6-Bromo-4.4-diethvlthiochroman (Compoun~ 25) WO93/1~K8 PCT/US93/01116 A mixture of l.lB g (8.3 mmol) o_ phosphorus pentoxide in lO mL of methanesulfonic acid wc~ heated for 45 minutes at 75C. The solution was allowed to cool slightly and 2.58 g (8.5 mmol) of 3-ethyl-5-(4-bromophenylthio)-3-pentanol (compoun~ 24~ was added.
The resulting mLxture was stirred at room temperature for 2 hours. The mixture was then cooled to 0C and treated with 50 ~ of water and extracted with 3 X 50 mL of ether.
The ether extracts were combined and washed with saturated aqueous NaCl and then dried (Na2S04). The solvent was removed in-vacuo and the residual oil purified by flash chromatography (SiO2, lO% ethyl acetate in hexanes) to give the title compound as an 15 orange oil.
PMR (CDC13): ~ 0.78 ~6H, t, J = 7.5 Hz), 1.~6 (4H, ~), 1.94 (2H, m), 2.98 (2H, m), 6.96 (lH, d, J = 8.4 ~z), 7.12 (lH, dd, J ~ 2.3, 8.6 Hz), 7.30 (lH, d, J =
2.2 Hz).
(4~4-Diethvlthiochroman-6-~l)ttrimethvlsilyl)acetylene (Compound 26) A mixture of 1.96 g (6.90 mmol) of 6-bromo-4,4-diéthylthiochroman (Compoun~ 25), O.ll g (O.S9 mmol) of copper (I) iodide and 4.36 g (4.31 ~mol) of 2~ triethylamine was degassed with argon for 15 minutes at -78C. To the s~spension was added 6.95 g (71 mmol) of (trimethylsilyl)acetylene then 0.41 g (58 mmol) of bis(triphenylphosphine)palladium (II) chloride. The solution was degassed with argon for an additional 5 30 minutes and the resulting mixture was allowed to warm to 0C. The tube was sealed and the mixture heated to 55C for 15 hours~
The mixture was allowed to cool to room WO93~1~K8 PCT/US93/o~ 6 2129973` 40 temperature and was filtered through celite and silica gel using 200 mJ of hexane. The solvent was removed in-v~cuo and the residual oil purified by flash chromatography (Sio2, 100% hexane) to give the title compound as an orange oil.
PMR (CDC13): ~ O.Oo (9H, s), 0.79 (6H, t, J = 7.7 Hz), 1.69 (4H, m), 1.95 (2H, m), 3.00 (2H, m), 6.96 ~lH, ~, H = 8.4 Hz), 7.13 (lH, dd, J = 2.2, 8.3 Hz), 7.30 (lH, d, J = 2.2 Hz).
(4.4-Diethvlthiochroman-6-yllacetYlene (Compound 27) A solution of 2.21 g (39 mmol) of potassium hydroxide in 2.0 mL of water and 20. 0 mL of ethanol was added to 1.4g g t4.93 mmol~ of (4,4-diethylthiochroman-6-yl)(trimethylsilyl)acetylene (Compou~ 26) and the 15 resulting mixture stirred at room temperature for 5 hours during which time it became homogeneous~ The solvent was removed in-vacuo and the residue was acidified with 5% aqueous ~2S04. The product was extracted with 2 X 50 mL of ether.
The combined ether extracts were washed successively with 10% aqueous NaHC03 and saturated aqueous NaCl. The solvent was removed in-vacuo and the xesidue purified ~y Kugelrohr distillation (135C, 0.75 mm) to give the title compound as an orange oil.
PNR (CDC13): ~ 0.79 (6H, t, J = 7.6 Hz), 1.68 (4H, m), 1.96 (2H, m), 3.02 t3H, o~erlapping m, s), 7.04 (lH, d, J z 8.1 Hz), 7.14 (lH, dd, J - 7.1, 8.2 Hz), 7.32 (lH, s).
E~hY1 2- r 2-(4.4-dieth~lthiochroman-6-vl~-ethyn-1-vll-5-30 nicotinate (Compound 3) A mixture of 0.632 g (2.75 mmol) of (4,4-diethylthiochroman-6-yl)acetylene (Compou~d 27), 64 mg (0.33 mmcl) of copper (I) iodide, and S.08 g ~50.3 WO93/1~K~ PCT/US93/01116 mmol) of triethylamine w~re degassed with argon for 15 minutes. To the suspension was added 0.83 g (3.00 mmol) of ethyl 6-iodo-nicotinate (Compound 21) and then O.15 g (O.22 mmol) of Bis(triphenylphosphine-3palladium (II) chloride. The suspension was degassed with argon for an additional 5 minutes, the tube was sealed and the mixture stirred at 55C for 16 hours.
The mixture was cooled to room temperature and filtered through celite and silica gel using 200 mL of hexane and 20 mL of ethyl acetate. The solvents were removed in-vacuo and the residual oil was pur~fied by flash chromatography tsio2, 5% ethyl acetate in hexanes) to give the title compound as a yellow oil.
PMR (CDCl3): ~ 0.81 (6~, t, J - 7.3 Hz), 1-43 (3H, -t, J - 6.8 Hz), 1.64 (2H, m), 1.79 (2H, m), 1.98 (2H, t, J ~ 6.1 Hz), 3.04 (2H, t, J = 6.3 Hz), A.32 (2H, q, J = 7.1 Hz), 7.10 (lH, dd, J = 1.6 Hz), 7.46 tlH, d, J
= 1.6 Hz), 7.58 (lH, d, J = 8.2 Hz), 8.27 tlH, dd, J =
2.2, 8.2 Hz), 9.l9 tlH, d, J = 2.2 Hz).
Ethvl 4- r 2-(4.4-diethylthiochroman-6-yl)-ethYn-l-Yl~benzoate (Compoun~ l) A mixture of 0.338 g (1.47 mmol) of (4,4-diethylthiochroman-6-yl)acetylene, 24 mg ~0.13 mmol) of copper (I) iodide, and 2.54 g (25 mmol) of triethylamine were degassed with argon for lS minutes.
To the suspension was added O.S7 g (2.07 mmol) of ethyl 4-iodobenzoate (Compound 22) and then 0.12 g (0.17 mmol) of bis(triphenylphosphine)palladium (II) chloride. The suspension was degassed with argon for an additional 5 minutes, the tu~e was sealed and the mixture stirred at 55C for 16 hours.
The mixtuxe was cooled to room temperature and filtered through celite and silica gel using 200 mL of WO93/1~K8 PCT/US93/01116 hexane and 20 mL of ethyl acetate. The sol~ents were removed in-vacuo and residual oil purified by flash chromatography (SiO2, 5% ethyl acetate in hexanes) to ~ive the title compound as a yellow oil. .
PMR (CDC13): ~ 0.82 (6H, t, J = 7.4 Hz), 1.41 (3H, t, J = 7.1 Hz), 1.65 (2H, m), 1.79 (2H, m). 1.98 (2H, t, J = 6.1 Hz~, 3.03 (2H, t, J = 6.2 Hz), 4.38 (2H, q, J = 7.1 Hz), 7.08 (lH, d, J = 1.6, 8.2 Hz), 7.20 (lH, dd, J = 1.67, 8.2 Hz~, 7.37 (lH, s), 7.57 (lH, d, J =

8.4 Hz), 8.01 (lH, d, J = 8.4 Hz).
4-Pro~yl-6-(4-bromoPhen~lthio)-4-hexanol (Compou~ 28) To a stirred suspension of 14 g (57 mmol) of cerium trichloride in 40 mL of tetrahydrofuran was added 6.18 g of ethylmagnesium bromide (60 mmol, 2M in THF). The resulting mixture was stirred for 1 hour and cooled to 0C. A solution of 4.91 g (17.0 mmol) of ethyl 3-(4-bromophenylthio)propionate ~Compoun~ 23) in .- 20 mL of tetrahydrofuran was then cannulated into the cool mixture and the resulting mixture stirred at room 20 temperature for 16 hours. The reaction mixture was then cooled to 0C and treated with 200 mL of water and extracted with S X S0 mL of ether.
The ether extracts were combined and wa~hed .
successively with 2 X 20 mL of saturated aqueous NaCl 25 and dried (Na2S04). The ~olvent was removed in-vacuo and the residue purified by flash chromatography ~sio2;
10% ethyl acetate in hexanes) to give the title compound as a greenish oil.
PMR ~CDC13): ~ 0.92 (6H, t, J = 7.0 Hz), 1.29 (SH, 30 m), 1.43 (4H, m) 1.75 (2H, m~, 2.95 t2H, s), 7.20 (2H, - dd, J = 2.0, 6.5 Hz), 7.40 (2H, dd, J = 2.1, 6.7 Hz).
6-Bromo-4.4-di~roD~lthiochrQman (Compoun~ 29) A mixture of 1.13 g (7.92 mmol) of phosphorus WOg3/l~K8 PCT/US93/01116 43 21299~3 :

pentoxide in lO mL of methanesulfonic acid was heated for 45 minutes at 75C. The solution was allowed to cool slightly and 3.~5 g (9.~5 mmol) of 4-propyl-6-(4-bromophenylthio)-4-hexanol (Compoun~ ~8) was added.
5 The reaction was stirred a~ room temperature for 2 hours. The mixture was then cooled to 0C, treated with 50 mL of water and extracted with 3 X 50 mL of ether.
The ether extracts were combined and washed with 10 saturated aqueous NaCl and then dried (Na2S04)~ The solvent was re~oved in-vacuo and the residual oil purified by flash chromatography (SiO2, lO~ ethyl acetate in hexanes) to give the title compound as an orange oil.
i5 PMR (CDC13): ~ 0.8~ ~6H, t, J = 7.5 Hz), 1.20 ~4H, m), l.59 (4H, m), 1.97 ~2~, m), 2.99 (2H, m), 6.96 tlH, d, J = 8.3 Hz), 7.13 (lHl dd, J = 2.1, 8.4 Hz), 7.30 " (lH, s).
(4.4-DiDro~lthiochroman-6-vll (trimethylsilylLacetvlerle (compou~ 30) A mixture-of ~.04 g t6.54 mmol) of 6-bromo-4,4-dipropylthiochroman (Compound 29), 0.12 g(0.64 mmol) of copper (I) iodide and 5.4 g (54 ~mol~ o~ triethylamine was degassed using argon for lS minutes at -78C. To the suspension was added l.95 g (l9.8 mmol) of (trimethylsilyl)acetylene then 0.41 g (58 mmol) of bis(triphenylphosphine)palladium (II) chloride. The solution was degassed with argon for an additional 5 minutes and the resulting mixture was allowed to warm to 0C. The tube was sealed and the mixture heated to ~5C for 15 hours.
The mixture was allowed to cool to room temperature and was filtered through celite and silica WO93/1~K8 PCT/US93/011~

gel using 200 mL of hexane. The solvent was removed in-vacuo and the residual oil purified by flash chromatography (sio2~ lO0~ hexane) to give the title compound as an orange oil.
PMR (CDCl3): ~ 0.23 (9H, s), 0.86 (6H, t, J 8 7.4 Hz), 1.17 (5H, m), 1.58 (4H, m), 1.95 t2H, m), 2.98 (2H, m), 6.96 (lH, d, H = 8.1 Hz), 7.09 (lH, dd, J =
1.7, 8.1 Hz), 7.26 (lH, d, J = 1.7 Hz3.
(4,4-DipropYlthiochroman-6-~l)acetYlene ~CompounC 31) A solution of l.82 g (32.4 mmol) of potassium hydroxide in l.8 mL of water and lO.0 mL of ethanol was added to 1.22 g (3.70 mmol) of (4,4-dipropylthiochroman-6-yl)(trimethylsilyl)acetylene (Co~poun~ 30~ and the resulting mixture stirred at room 1~ temperature for 5 hours during which time it became homogeneous. The solvent was removed in-vacuo and the residue was acidified with 5% aq H2S04 and the product was extracted with 2 X 50 mL of ether.
The combined ether extracts were washed successively with 10% aqueous NaHC03 and saturated aqueous NaCl. The solvent was removed in-~acuo and the residue purified by Xugelrohr distillation (135C, 0.75 mm) to gi~e the title compound as a yellow oil.
PMR (CDC13): ~ 0.88 (6H, t, J - 7.3 Hz), 1.20 (4H, m), 1.59 (4H, m), 1.98 (2H, m), 3.01 (3H, oYerlapping m, 8), 7.02 (lH, d, J = 8.1 Hz), 7.13 (l~, dd, J z 1.8, 8.1 Hz), 7.32 (lH, d, J = 1.7 Hz~.
Eth~l ~I2-~4 4-di~ro~lthiochroman-6-vl~-ethYn-l-Yll-5-nicotinate (Compoun~ 7) A mixture of 0.760 g (2.95 mmol) of (4,4-dipropylthiochroman-6-yl)acetylene, (Compoun~ 31), 61 mg (0.32 mmol~ of copper (I) iodide, and 3.6 g (3 mmol) WO93/l~K~ PCT/US93/01116 . .

~5 of triethylamine were degassed with argon for 15 minutes. To the suspension was added 0.89 g (3.22 mmol) of ethyl-6-iodo-nicotinate (Compoun~ 21) and then 0.30 g (0.43 mmol) of bis(triphenylphosphine~palladium (II) chloride. The suspension was degassed with argon for an additional 5 minutes, the tube was sealed and the mixture stirred at 5SC for 16 hours and at room temperature for six days.
The mixture was then filtered through celite and 10 silica gel using 200 mL of hexane and 20 mL of ethyl acetate. The solvents were removed in-vacuo and residual oil purified by flash chromatography (SiO2, 5%
ethyl acetate in hexanes) to give the title compound as an orange oil.
PMR (CDC13): ~ 0.89 ~6H, t, J = 7.3 Hz), 1.23 (4H~
m), 1.43 (3H, t, J = 7.1 ~z), 1.62 (4H, m), 2.00 (2H, m), 3.03 (2H, m), 4.42 (2H, g, J = 7.1 Hz), 7.09 (lH, d, J - 8.1 Hz), 7.25 (lH, dd, J = 1.7, 8.5 Hz), 7.46 (lH, d, J = 1.7 Hz), 7.57 (lH, dd, J = 0.8, 8.2 Hz), 20 8.27 (lH, dd, J = 2.2, 8.2 Hz), 9.19 (lH, d, J = 2.1 Hz).
EthYl 4-t2-14.4-di~ropYlthiochroman-6-Yl)-ethvn-l-yllbenzoate (Co~pou~ S) - A mixture of 0.338 g (1.47 mmol) of 4,4-25 dipropylthiochroman-6-yl)acetylene (Co~poun~ 31), 24 mg, (0.13 mmol) of copper (I) iodide, and 2.54 g (25 mmol of triethylamine were degassed with argon for 15 minutes. To the suspension was added 0.57 g (2.07 mmol) of ethyl 4-iodobenzoate (Compoun~ 22) and then 30 0.12 g (O.17 mmol) of bis(triphenylphosphine)palladium (II) chloride. The suspension was degassed with argon for an additional 5 minutes, the tube was sealed and the mixture stirred at 55C for 16 hours.

W093/1~K8 PCT/US93/01116 f~

The mixture was cooled to room temperature and filtered through celite and silica gel using 200 mL of hexane and 20 mL of ethyl acetate. The solvents were removed in-vacuo and residual oil purified by flash chromatography (Sio2, 5% ethyl acetate in hexanes) to give the title compound as a yellow oil.
PMR (CDC13): ~ 0.89 (6H, t, J = 7.3 Hz), 1.22 (4H, m), 1.40 (3H, t, J - 7.2 Hz), 1.55 (2H, m), 1.68 (2H, m), 1.98 (2H, m), 3.01 (2H, m), 4.37 (2H, q, J = 7.1 Hz), 7.06 (lH, d, J = 8.2 Hz), 7.18 (lH, dd, J = 1.7, 8.1 Hz), 7.36 (lH, d, J = 1.7 Hz), 7.58 (2H, d, J = 8.7 Hz), 8.01 (2H, d, J = 8.1 Hz).
5-Butyl-7-(4-bromoDhenylthio)-5-heptanol ~Compoun~
32) 15- To a stirred suspension of 9.5 g (39 mmol) of cerium trichloride in 30 mL of tetrahydrofuran was added 5.9 g of butylmagnesium bromide (50 mmol, 2M in THF). The resulting mixture was stirred for 1 hour at room temperature and then cooled to 0C. A solution of 4.29 g (14.8 mmol) of ethyl 3-(4-~romophenylthio)propionate (Compou~ 23) in 15 mL of tetrahydrofuran was then cannulated into the cool mixture and the resulting suspension ~tirred at room temperature for 12 hour~. The reaction mixture was then recooled to 0C and treated with 200 mL of water a~d extracted with 5 X 50 ~L of ether.
The ether extracts were combined and washed successively with 2 X 20 mL of saturated aqueous NaCl and dried (Na2S04). The solvent was removed in-vacuo and the residue purified by flash chromatography (Sio2, 10% ethyl acetate in hexanes) to give the title compound as an orange oil.
PMR (CDC13): ~ 0.91 (6H, t, J = 7.2 Hz), 1.26 (8H, ~129973 m), 1.43 (4H, m), 1.75 (2H, m), 2.97 (2H, m), 7.20 (2H, d, J = 1.9 Hz~, 7.41 (2H, d, J - 1.9 Hz).
6-Bromo-4, 4-dibutylthiochroman (Compoun~ 33 ~
A mixture of 0. 7 g (~.1 mmol) of phos~horus 5 pentoxide in 8 mL of methanlesulfonic acid was heated for 45 minutes at 75C. Th,e solution was allowed to cool slightly and 3.59 g (10.0 mmol) of 5-butyl-7-(4-bromophenylthio)-5-heptanol (Compoun~ 32) was added.
The resulting mixture was stirred at room temperature for 2 hours. The mixture was then cooled to 0C and treated with 50 mL of water and extracted with 3 X 40 mL of ether.
The ether extracts were combined and washed with saturated aqueous NaCl and ~hen dried (Na2S04). The 15 solvent was remo~ed in-vacuo and the r~sidual oil purified by flash chromatography (SiO~, 5% ethyl acetate in hexanes) to give the title compound as an orange oil.
PMR (CDC13): ~ 0.88 (6H, t, J = 7.3 Hz), 1.22 (8H, 20 m), 1.66 t4H, ~), 1.97 (2H, m), 2.98 (2H, m~, 6.96 (lH, d, J z 8.7 Hz), 7.13 (1~, d~l~ J = 2.0, 8.3 Hz), 7.31 (lH, d, J = 2.1 Hz).

!4 ~4-Dibutvlthiochroman-6-y~L~t~imethylsilyl)acetvlç~e 25 ~compou~l~ 3~
A mixture of 1.68 g (5~.38 mmol) of 6-bromo-4,4-dibutylthiochroman (Co~pound 33), 0.28 g (1.5 mmol) of copper (I~ iodide and 2.5 g (25 m~ol) of triethylamine.
was degassed with argon for ~5 minutes at 78C. To 30 the suspension was addea 1.18 g (71 ~mol) of (trimethylsilyl) acetylene and 0.24 g (0~35 mmol) of bis(triphenylphosphine)palladium (II) chloride. The solution was degassed with argon for an additional 5 W093/1~K8 PCT/US93/01116 minutes and the resulting mixture was allowed to warm to 0C. The tube was sealed and the mixture was heated to 55C for 22 hours.
The mixture was allowed to cool to room.
5 temperature and was filtered through celite and silica gel using 200 mL of hexane. The ~olvent was remo~ed in-vacuo and the residual oil purified by flash chromatography (SiO2, 100% hexane) to give the title compound as an orange oil.
PMR (CDCl3): ~ 0.25 (9H, s), 0.88 (6H, t, J = 7.3 Hz), 1.25 (8H, m), 1.65 (4H, m), 1.98 (2H, m), 3.00 (2H, m), 7.05 (lH, d, H = 8.1 Hz), 7.11 (lH, dd J =
1.7, 8.8 Bz), 7.29 (lH, d, J = 1.7 Hz).
- (4~4-DibutYlthiochroman-6-yl)acety-lene (Compound 35) i5 A solution of 1.41 g (25 mmol) of potassiu~
hydroxide in 1.4 mL of water and 10.0 mL of ethanol was ~dded to 1.44 g (4.00 mmol) of (4,4-dibutylthiochroman-6-yl)(trimethylsilyl)acetylene (Compoun~ 34) and the resulting mixture stirred at room temperature for 16 20 hours during which time it became homogeneous. The solvent was removed in-vacuo and the residue was acidified with 5% aqueous H2S04. The product was extracted with 2 X 50 mL of ether.
m e combined ether extracts were washed successively with 10% aqueous NaHC03 and saturated aqueous ~aCl. The solvent was removed in-vacuo and the residue purified by Kugelrohr distillation (165C, 3mm) to give the title compound as an orange oil.
PMR (CDC13): ~ 0.88 (6H, t, J = 7.3 Hz), 1.22 (8H,-m), 1.66 (4H, m), 1.97 (2H, m), 3.00 t3H, overlappingm, s), 7.02 (lH, d.,J = 8.1 Hz), 7.13 (lH, dd, J = 1.8, 8.1 H2), 7.32 (lH, d, J = 1.7 Hz).
Eth~l 2- r 2-l4,4-dibutvlthiochroman-6-vl)-ethYn-1-vll-~-WO93/1~K~ PCT/US93/01116 . , ~
21~9973 nicotinate ~Compound ll) A mixture of 0.49 g (1.72 mmol) of (4,4-dibutylthiochroman-6-yl)acetylene (Compound 35), 52 mg (0.27 mmol) of copper (I) iodide, 2.20 g (22 mmol) of triethylamine and 0.49 g (1.75 mmol) of ethyl 6-iodo-nicotinate (Compou~ 21) was degassed with argon for lO
minutes. To the suspension was added 3.lO g (O.lS
mmol) of bis(triphenylphosphine)palladium (II) chloride. The suspension was degassed with argon for an additional 5 minutes, the tube was sealed, and the mixture stirred at 55C for 8 hours and at room temperature for 24 hours.
The mixture was cooled to room temperature and filtered through celite and silica gel using 200 mL of hexane. The solvents were removed in-vacuo and the residual oil purified by flash chromatography (SiO2, 5%
ethyl acetate in hexanes) to give the title compound as an ox~nge oil.
PMR (CDC13): ~ 0.88 (6H, t, J = 7.2 Hz), 1.25 (8H, m), 1.43 (3H, t, J = 7.1 Hz), 1.64 (4H, m), 2.00 (2H, m), 3.03 (2H, m), 4.42 (2H, q, J = 7.1 Hz), 7.09 (lH, d, J - 8.2 Hz), 7.26 (IH, dd, J = 1.7, 7.8 Hz), 7.47 (lH~ d~rJ - 1.7 Hz), 7~.58 (lH, d, J ~ 8.3 Hz), 8.27 ~lH, dd, J --2.2, 8.3 Hz), 9.20 (lH, d, J G 3.3 Hz) Eth~l 4- r 2-~4.4-dibutylthiochroman-6-Yl~-ethYn-l-yl~benzoate (Compound 9) A mixture of 0.234 g (0.82 mmol) of (4,4-dibutylthiochroman-6-yl)acetylene (Compound 35), 2l mg ~O.11 mmol) of copper (I) iodide, and 1.45 g (14 mmol) - 30 of triethylamine were degassed with argon for 15 min.
To the suspension was added 0.49 g (1.8 mmol) of ethyl 4-iodobenzoate (Compoun~ 21) and then 0.065 g (0.09 mmol) o~ bis(triphenyliphosphine)palladium (II) WO93/l~K~ PCT/US93/0111~6 chloride. The suspension was degassed with argon for an additional 5 minutes, the tube was sealed and the mixture stirred at 55C for 20 hours.
The mixture was cooled to room temperature and filtered through celite and silica gel using 200 mL of hexane and 20 mL of ethyl acetate. The solvents were removed in-vacuo and the residual oil purified by flash chromatography (Sio2l 5~ ethyl acetate in hexanes) to give the title compound as a yellow oil.
PMR (CDC13): ~ 0.89 (GH, t, J = 7.3 Hz), 1.24 (8H, m), 1.41 (3H, t, J = 7.2 Hz), 1.60 (2H, m), 1.72 (2H, m), 2.00 (2H, m~, 3.0Z (2H, m), 4.38 ~2H, q, J = 7.2 ~z), 7.07 (lH, d, J = 8.1 Hz), 7.19 (lH, dd, J = 1.7, 8.1 Hz), 7.36 (lH, d, J = 1.7 Hz), 7.58 (1~, d, J = 8~4 Hz), 8.02 (lH, d, J = 8.4 Hz).
~2-r4.4 dieth~lthiochroman~6~ ethYn-1-vll-5-nicotinic acid (Compoun~ ~) A solution of 1.1 g (20.5 mmol3 of potassium hydroxide in 1.0 mL of water and 10.0 mL of ethanol was added to 0.456 g (1.20 mmol) of ethyl 2-t2-(4,4-diethylthiochroman-6-yl)-ethyn-1-yl]-S-nicotinate (Compou~d 3) and the resulting mixture was stirred at room temperature for 16 hours during which time it became homogeneous. The solvent was removed in-vacuo and the residue was acidified with 5% aqueous H2S04.
The product was extracted with 2 X 65 mL of 15% ether in methylene chloride.
~ he combined ether extracts were washed ~uccessively with 10% aqueous NaHC03, saturated aqueous Nacl, and dried over Na2SO4. The solvent was removed in-vacuo yielding a yellow solid which was recrystallized using EtO~ to give the title compound as a yellow solid.

WO93/1~K~ PCT/US93/01116 2129~73 PMR tDMSO): ~ 0.70 (6H, t, J ~ 7.5 Hz), 1.54 (2H, m), 1.73 (2H, m), 1.86 (2H, m), 3.01 (2H, m), 7.11 (lH, d, J = 8.1 Hz), 7.26 (lH, dd, J = 1.7, 8.3 Hz), 7.44 (lH, d, J - l.S Hz), 7.73 (lH, d, J = 8.2 Hz.~, 8.25 (lH, dd, J = 2.2, 8.1 Hz), 9.04 (lH, d, J - 1.3 Hz).
4- r 2-t4.4-di~ropylthiochroman-6-yl~-ethYn-1-vllbenzoic acid (Compoun~ 6) A solution of 1.15 g (20.5 mmol) of potassium hydroxide in 1.0 mL of water and 10.0 mL of ethanol was added to 0.381 g (0.94 mmol) of ethyl 4 t2-(4,4-dipropylthiochroman-~-yl)-ethyn-l-yl]benzoate (Compound S) and the resulting mixture stirred at room te~perature for 15 hours during which time it became homogeneous. The solvent was removed in-vacuo and the residue was acidified with S% aqueous H2SO4. The product was extracted with 2 -X 6~ mL of 15% ether in methylene chloride.
The combined ether extracts were washed successively with 10% aqueous NaHCO3, saturated aqueous NaCl, and dried over Na2S04. The solvent was removed in-~acuo yielding a yellow solid which was recrystallized using EtOH to give the title compound as a yellow solid.
PMR (DMSO): ~ 0.82 (6H, t, J = 7.~ Hz), 1.13 (5H, m), 1.51 (2H, m), 1.67 (2H, m), 1.92 (2H, m), 3.01 (2H, m3, 7.08 (1~, d, J = ~.1 Hz), 7.20 (lH, dd, J - 1.7, 8.1 Hz), 7.40 (lH, d, J = 1.66 Hz), 7.53 (lH, d, J =
8.3 Hz), 7.91 (lH, d, J = 8.3 Hz).
2-~2-(4.4-dipropylthiochroman-6-~lL~ethyn-l-vll-5-nicotinic acid (Compoun~ 8) A solution of 1.08 g (19.3 mmol) of potassiumhydroxide in 1.0 mL of water and 10.0 mL o~ ethanol was added to 0.470 g (1.15 mmol) of e~hyl 2-~2-(4,4-WO93/16~8 PCT/US93/01116 ffn~, 21299~3 dipropylthiochroman-6-yl)-ethyn-l-yl~-5-nicotinoate ~Compound 7) and the resulting mixture stirred at room temperature for 15 hours during which time it became homogeneous. The solvent was removed in-vacuo and the residue was acidified with 5% aqueous H2S04~ The product was extracted with 2 X 65 mL of 15% ether in methylene chloride.
The combined ether extracts were washed successively with 10% aqueous NaHC03, saturated aqueous NaCl, and dried over Na2SO4. The solvent was removed in-vacuo yielding a yellow solid which was recrystallized using EtOH to gi~e the title compound as a yellow solid.
PMR (DNSO): ~ 0.85 (6H, t, J = 7.3 ~z), 1.14 (4H, m), 1-52 (2H, m), 1.70 (2H, m), 1.93 (2H, m), 3.03 (2H, m), 3.32 (1~, s), 7.13 (lH, d, J = 8.1 Hz), 7.27 (lH, dd, J = 1.6, 8.1 Hz), 7~47 (lH, d, J = 1.5 Hz), 7.75 (IH, d, J = 8.3 Hz), 8.27 (lH, dd, J = 2.2, 8.2 Hz), 9.20 (lH, d, J = 2.1 Hz).
20 2 - r 2-(4~4-dibutYlthiochroman-6-yl)-ethvn-1-yll-5-nicotinic acid (Compoun~ 12) A solution of 1. 05 g ( 18.8 mmol) of potassium hydroxide in 1.0 mL of water and 10.0 mL of ethanol was added to 0.341 g ~0.78 mmol) of ethyl 2-t2-~4,4-dibutylthiochroman-6-yl)-ethyn-l-yl~-s-nicotinoate (Compound 11) and the resulting mixture stirred at room temperature f or 15 hours during which time it became homogeneous. The solvent was removed in-vacuo and the residue was acidified with 5% aqueous H2S04. The product was extracted with 2 X 65 mL of 15% ether in methylene chloride.
The combined ether extracts were washed successively with 10% aqueous NaHC03, saturated aqueous WO 93/1606f~ PCI'/VS93/01116 Z.~.99~f'~3 NaCl, and dried o~er Na2SO4. The solvent was removed in-vacuo yielding a yellow solid which was recrystallized using EtOH to give the title compound as a yellow solid. .-PMR (DMSO): ~ 0.83 (6H, t, J = 7.3 Hz), 1.09 (4H, m), 1.23 (4H, m), 1.54 (2H, m), 1.72 (2H, m), 1.92 (2H, m~, 3.02 (2H, m), 3.32 (lH, m), 7.12 (lH, d, J - 8.1 Hz), 7.27 (lH, dd, J = 1.7, 8.2 Hz), 7.47 (lH, d, J -1.7 Hz), 7.74 (lH, dd, J = 0.8, 8.3 Hz), 8.26 (lH, dd, 10 J = 2.2, 8.2 Hz), 9.04 (lH, dd, J - 0.8, 2.2 Hz).
Using as an example the method for the preparation of Co~poun~ 1, but substituti~g the appropriately substituted ethynylthiochroman (Formula 12 in Re~ctio~
~cheme 1) and the appropriate halo substituted phenyl 15 ester tFormul~ 3, prepared for example as specifically described for Compou~ 22) the following further examplary compounds of the invention can be prepared:
ethyl 4-~(4,4-diethyl-7-methylthiochroman-6-yl)-ethynyl]benzoate;
ethyl 4-~(4,4,7 tri-ethylthiochroman-6-yl)-ethynyl]benzoate;
ethyl 4-tt4,4-diethyl-7-propylthiochroman 6-yl)-ethynyl~benzoate;
ethyl 4-t(4,4-diethyl-7-hexylthiochroman-6-yl)-25 ethynyl~benzoate;
ethyl 2-t4-[(4,4-diethylthiochroman-6-yl)ethynyl)~
phenyl3acetate;
ethyl 2-tt4 (4,4-diethyl-7-methylthiochroman-6-yl)ethynyl)-phenyl3acetate;
ethyl 2-t4-t4,4,7-triethylthiochroman-6-yl)-ethynyl)phenyl~acetate;
ethyl 2-~4-(4,4-diethyl-7-hexylthiochroman-6-yl)ethynyl)phenyl]a~etate;

WO93/1~K8 PCT/US93/0ll16 2 12 9 g73 54 ethyl 3-~4-(4,4-diethylthiochroman-2 yl)-ethynyl)phenyl3propionat~; ~
ethyl 3-[4-(4,4-diethyl-7-methylthiochroman-6-yl)-ethynyl)phenyl]propionate;
ethyl 3-~4-(4,4-triethylthiochroman-6-yl)-5 ethynyl)phenyl]propionate;
ethyl 3-~4-(4,4-diethyl-7-hexylthiochroman-6-yl)-ethynyl)phenyl]propionate;
ethyl 5-[4-(4,4-diethylthiochroman-6-yl)ethynyl)-phenyl~pentanoate;
ethyl 5-[4-(4,4-diethyl-7-methylthiochroman-6-yl)-ethynyl)phenyl]pentanoate;
ethyl 5-[4-(4,4,7-triethylthiochroman-6-yl)-ethynyl)phenyl]pentanoate, and the corresponding free carboxylic acid derivatives.
Using the following examplary inter~ediates of Formul~ 18 in Rea¢tion ~cheme 2 or 3, 4,4,7-triethyl-6-ethynyl-chroman;
4,4-diethyl-6-ethynyl-7-propylchroman;
4,4-diethyl-6-ethynyl-7-butylchroman;
4,4-diethyl-6-ethynyl-7-pentylchroman;
4,4-diethyl-6-ethynyl-7-hexylchroman;
the following examplary compo~nds of the invention can be prepared:
ethyl 4-[(4,4,7-triethylchroman-6-yl)-25 ethynyl]benzoate;
ethyl 4-[(4,4-diethyl-7-propylchroman-6-yl)-ethynyl]benzoate;
ethyl 4-~(4,4-diethyl 7-hexylchroman-6-yl)- -ethynyl]benzoate;
ethyl [2-(4-t4,4-diethylchroman-6-yl)ethynyl)-phenyl]acetate;
ethyl t2-(4-(4,4-diethyl-7-methylchroman-6-WO93/1~K8 PCT/US93/01116 yl)ethynyl)-phenyl]acetate;
ethyl ~2-(4-(4,4,7-triethylchroman-6-yl)-ethynyl)phenyl]acetate;
ethyl ~2-t4-(4,4-diethyl 7-hexylchroman-6-yl)-ethynyl)phenyl]acetate;
ethy~ 3-[4~(4,4-diethylchroman-2-yl~-- ethynyl)phenyl]propionate;
ethyl 3-~4-~4,4-diethyl-7-methylchroman-6-yl)-ethynyl)-phenyl]propionate;
1~ ethyl 3-[4-(4,4,7-triethylchroman-6-yl~-ethynyl)phenyl]propionate;
ethyl 3-[4-(4,4-diethyl-7hexylchroman-6-yl)-ethynyl)phenylp~opionate;
ethyl 5-[4-(4,4-diethylchroman-6-yl)ethynyl)-phenyl]pentanoate;
ethyl 5-t4-(4,4-diethyl-7-methylchroman-6-yl)-ethynyl)phenyl]pentanoate; -ethyl 5-~4-(4,4,7-triethylchroman-6-yl)~
ethynyl)phenyl]pentanoate, and the corresponding fee carboxylic acid derivatives.
The positional isomers of the above-noted examples - (and of analogous compounds~ can also be prepared in accordance wYth the foregoing procedures or by apparent - modifications of such procedures.
Still further, substitu~ing the appropriate 6-ethynylthiochroman or-6-ethynylchroman of ~or~ula 12 and 18, respectively, and reacting them with the appropriate halogenated heteroaromatic compound as per ~s~ction ~ch~me~ 1 an~ 2, the following further examplary compounds of ~he invention can be prepared.
- ethyl 6-t(4,4-diethyl-7-methylthio~hroman-6-yl)-ethynyl]nicotinate;
ethyl 6-t~4,4,7-triethylthiochroman-6-yl3-W093/t6068 PCT/US93/011~16 56 .

ethynyl~nicotinate;
ethyl 6-[(4,4-diethyl-7-propylthiochroman-6-yl)-ethynyl]nicotinate;
ethyl 6-t(4,4-diethyl-7-hexylthiochroman-6-yl)-5 ethynyl]nicotinate;ethyl ~(4,4-diethylthiochroman-6-yl)ethynyl) pyrid-5-yl]acetate;
ethyl [((4,4-diethyl-7~methylthiochroman 6-yl)ethynyl)-pyrid-5-yl]acetate;
ethyl [((4,4,7-triethylthiochroman-6-yl)-ethynyl)pyrid-5-yl~acetate;
ethyl ~((4,4-diethyl-7-hexylthiochroman-6-yl) ethynyl)pyrid-5-yl3acetate;
ethyl 3-~((4,4-diethylthiochroman-2-yl)-15 ethynyl)pyrid-5-yl~propionate;
ethyl 3-[ ~ (4,4-diet~yl-7-methylthiochroman-6-yl~-ethynyl)pyrid-5-yl]propion~te;
ethyl 3-t((4,4,7-triethylthiochroman-6-yl)-ethynyl)pyrid-5-yl]propionate;
ethyl 3-~(4,4-diethyl-7-hexylthiochroman 6-yl)-ethynyl)pyrid-5-yl~propionate;
ethyl 5-~(.(4 r 4-diethylthiochrom~n-6-yl)et.hynyl)-pyrid-5-yl]pentanoate: - -ethyl 5-t((4,4-diethyl-7-methylthiochroman-6-yl)-ethynyl~pyrid-5-yl~pentanoate;
ethyl 5-r ~(4,4,7-triethylthiochroman-6-yl)-ethynyl)pyrid-5-yl]pentanoate;
ethyl ~5-((4,4-die*hylthiochroman-6yl~ethynyl)-fur-2-yl]acetate;
ethyl ~5-(~4,4-diethyl-7-methylthiochroman-6-yl)ethynyl)-fur-2-yl]acetate;
ethyl ~5-((4,4,7-triethylthiochroman-6-yl)-ethynyl)fur-2-yl~acetate;

~'~93/1~K8 PCT/US93/01116 2 1 .~

ethyl t5-((4,4-diethyl-7-hexylthiochroman-6-yl)-ethynyl)fur-2-yl]acetate;
ethyl 5-[((4,4-diethylthiochroman-6-yl)ethynyl)-fur-2-yl~pentanoate;
ethyl 5-~5((4,4-diethyl-7-methylthiochroman-6-yl)-ethynyl)fur-2-yl~pentanoate;
ethyl 5-[5-((4,4l7-triethylthiochroman-6-yl)-ethynyl)fur-2-yl]pentanoate;
ethyl 5-~5-((4,4-dietyl-7-hexylthiochroman-6-yl)-10 ethynyl)fur-2-yl]pentanoate;
ethyl t5-((4,4-diethylthiochroman-6-yl)ethynyl)-thien-2-yl3acetate;
ethyl [5-((4,~-diethyl-7-methylthiochroman-6-yl~ethynyl)-thien-2-yl]acetate;
ethyl t5-((4,4,7-triethylthiochroman-6-yl~-ethynyl)thien-2-yl]~cetate;
- ethyl t5-((4,4-diethyl-7-hexylthiochroman-6-yl)-ethyn~l)thien-2-yl]acetate;
ethyl 5-t5-4~4-diethylthiochroman 6-yl~-ethynyl)-20 thien-2-yl~pentanoate;
ethyl 5-t5-((4~4-diethyl-7-methylthiochroman-6 yl)-ethynyl)thien-2-yl]pentanoat@;
ethyl 5~ r s- ( ( 4,4,7-triethylthiochroman-6-yl)-ethynyl)thien-2-yl~pentanoate;
ethyl 5-t5-((4,4-diethyl-7-hexylthiochroman-6-yl~-ethynyl)thien-2 yl]pentanoate;
ethyl ~6-((4,4-diethylthiochr4man-6-yl~ethynyl)-pyridazin-3-yl]acetate;
ethyl t6((4,4-diethyl-7-methylthiochroman-6-30 yl)ethynyl)-pyridazin-3-yl3acetate;
ethyl t6-((4,4,7-triethylthiochroman-6~yl)-ethynyl)pyridazin-3-yl~acetate;
ethyl ~6-t(4,4-diethyl-7-hexylthiochroman-6-yl) WO93/1~K8 PCT/US93/01~6 2129~73 . 58 ethynyl)pyridazin-3-yl]acetate;
ethyl-5-[6((4,~-diethylthiochroman-6-yl)~thynyl)-pyridazin-3-yl]pentanoate;
ethyl 5-[6-((4,4-diethyl-7-methylthiochroman-6-yl)-ethynyl)pyridazin-3-yl]pentanoate;
ethyl 5-~6-((4,4,7-triethylthiochroman-6-yl)-ethynyl)pyridazin-3-yl]pentanoate;
ethyl 5-~6-((4,4-diethyl-7-hexylthiochroman-6-yl)-ethynyl)pyridazin-3-yl]pentanoate;
ethyl ~S-((4,4-diethylthiochroman-6-yl)ethynyl)-pyrimidin-2-yl]acetate;
ethyl ~5-((4,4-diethyl-7-methylthiochroman-6-yl)ethynyl)-pyrimidin-2-yl~acetate;
ethyl t5-((4,4,7-triethylthiochroman-6-yl)-is ethynyl)pyrimidin-2-yl]acetate;
ethyl t5-((4,4-diethyl-7-hexylthiochroman-6-yl)-ethynyl)pyri~idin-2-yl~acetate;
et~yl 5-tS-(4,4-diethylthiochroman-6-yl)ethynyl)-pyrimidin-2-yl]pentanoate;
ethyl 5-t5-((4,4-diethyl-7-methylthiochroman-6-yl)-ethynyl)pyrimidin-2-yl]pentanoate;
ethyl 5-t5-((2,2,4,4,7-triethylthiochroman-6-yl)-ethynyl)pyrimidin-2-yl~pentanoate;
ethyl S-t5-((4,4-diethyl-7-hexylthiochroman-6-yl)-ethynyl)pyrimidin-2-yl]pentanoate;
ethyl [5-((4,4-diethylthicchroman-6-yl)ethynyl)-pyr~zin-2-yl]acetate;
ethyl ~5-((4,4-diethyl-7-methylthiochroman~6-yl)ethynyl)-pyrazin-2-yl]acetate;
ethyl 15-((2,2,7-triethylthiochroman-6-yl)-ethynyl)pyrazin-2-yl]acetate;
ethyl t5-((4,4-diethyl-7-hexylthiochroman-6-yl)-ethynyl)pyrazin-2-yl]acetate;

WQ 93/1 ~ 8 PCT/US93/01l16 2129~73 ethyl 5-~5-((4,4-diethyl~hiochroman-6-yl)ethynyl)-pyrazin-2-yl]pentanoate;
ethyl 5-[5-((4,4-diethyl-7-methylthiochroman-6-yl)-ethynyl)pyrazin-2-yl]pentanoate;
ethyl 5-[S-((4,4,7-triethylthiochroman-6-yl)-ethynyl)pyrazin-2-yl]pentanoate;
ethyl 5-t5-((4,4-diethyl-7-hexylthiochroman-6-yl)-ethynyl)pyrazin-2-yl]pentanoate;
ethyl 6-t4,4-diethylchroman-6-yl)-ethynyl~nicotinate;
ethyl 6-t(4,4-diethyl-7-hexylchroman-6-yl)-ethynyl]nicotinate;
ethyl [2-((4,4-diethylchroman-6-yl)ethynyl)-pyrid-5-yl]acet2te;
ethyl t2-((4,4-diethyl-7-methylchroman-6- :
yl)ethynyl)-pyrid-5-yl]acetate;
ethyl t2-t(4,4,7-triethylchroman-6-yl)-ethynyl)pyrid-5-yl~acetate;
ethyl t2-((4,4-diethyl-7-hexylchroman-6-yl)-Z0 ethynyl)pyrid-5-yl]acetate;
ethyl 3-t2-((4,4-diethylchroman-2-yl)-ethynyl)pyrid-5-yl~propionate;
ethyl 3-t2-((4,4-diethyl-7-methylchroman-6-yl)-ethynyl)-pyrid-5-yl~propionate;
ethyl 3-t2((4,4,7-triethylchroman-6-yl)-ethynyl)pyrid-5-yl]propionate;
ethyl 3-t2((4,4-diethyl-7-hexylchroman-6-yl)-ethynyl)pyrid-5-yl]propionate:
ethyl 5-t2-t(4,4-diethylchroman-6-yl)ethynyl)-pyrid-5-yl]pentanoate;
ethyl 5-~2-((4,4-diethyl-7-methylchroman-6-yl)-ethynyl)pyrid-5-yl~pentanoate;
ethyl 5-t2-((4,4,7-triethylchroman-6-yl)-wo 93/16068 Pcr/usg3/ol~

2129!)73 60 ethynyl)pyrid-5-yl]pentanoate;
ethyl 5-[2-(~4,4-diethylchroman-6-yl)ethynyl)-fur-2-yl]acetate;
ethyl [5-((4,4-diethyl-7-methylchroman-6-yl)ethynyl)-fur-2-yl]acetate;
ethyl t5-((4,4,7-triethylchroman-6-yl)-ethynyl)fur-2-yl]acetate;
ethyl ~5-((4,4-diethyl-7-hexylchroman-6-yl3-ethynyl-fur-2-yl]acetate;
ethyl 5-[5-((4,4-diethylchroman 6~yl)ethynyl)-fur-2-yl]pentanoate;
ethyl 5-~5-((4,4,7-pentamethylchroman-6~yl)-ethynyl)fur-2-yl~pentanoate;
ethyl 5-~5 ((4,4,7-triethylchroman-6-yl)-ethynyl~fur-2-yl]pentanoate;
ethyl 5-~5-((4,4-diethyl-7-hexylchroman 6-yl)-ethynyl)fur-2-yl]pentanoate;
ethyl 5-~5-((4,4-diethylchroman-6-yl~ethynyl)-20 thien-2-yl]acetate;
ethyl t-(~4,4-diethyl-7-methylchroman-6-yl)ethy-- nyl)-thien-2-yl~acetate;
ethyl t5-((4,4,7triethylchroman6-yl~-ethynyl)thien-2-yl] aGetate;
ethyl [5-~(4,4-diethyl-7-hexylchroman-6-yl)-ethynyl)thien-2-yl]acetate;
ethyl 5-t5((4,4-diethylchroman-6 yl)ethynyl)-thien-2-yl]pentanoate;
ethyl 5-~5-((4,4-diethyl-7-methylchroman-6-yl)-ethynyl)-thien-2-yl]pentanoate;
ethyl 5-~5~ ,4,7-triethylchroman-6-yl)-ethynyl~thien-2-yl~pentanoate;

WO93/1~K~ PCT/US93/011J6 ethyl 5-t5-((4,4-diethyl-7-hexylchroman-6-yl)-ethynyl)thien-2-yl]pentanoate;
ethyl [6-((4,4-diethylchroman-6-yl)ethynyl)-pyridazin-3-yl]acetate;
ethyl ~6-((4,4-diethyl-7-methylchroman-6;
yl)ethynyl)-pyridazin-3-yl]acetate;
ethyl [6-t~4,4,7-triethylchroman-6-yl)-ethynyl)pyridazin-3-yl3acetate;
ethyl [6-((4,4-diethyl-7-hexylchroman-6-yl)-10 ethynyl)pyridazin-3-yl]acetate ethyl 5- r 6-(~4,4-diethylchroman-6-yl)ethynyl)-pyridazin-3-yl]pentanoate;
ethyl 5-C6-((4,4-diethyl-7-methylchroman-6-yl)-ethynyl)-pyridazin-3-yl]pentanoate;
ethyl 5-16-((4,4,7 triethylchroman-6-yl)-ethynyl)pyridazin-3 oyl ~pentanoate;
ethyl 5-16-((4,4-diethyl-7-hexylchroman-6-yl)-ethynyl)pyradazin-3-yl]pentanoate;
ethyl t5-((4,4-diethylchroman-6-yl)ethynyl)-20 pyrlmidin-2-yl3acetate;
ethyl ~5-((4,4-diethyl-7 methylchroman 6-yl)ethynyl)-pyrimidin-2-yl]acetate;
e~hyl ~5-((4,4,7-triethylchroman-6-yl)-ethynyl)pyrimidin-2-yl]acetate;
ethyl [5-((4,4-diethyl-7-hexylchroman-6-yl)-ethynyl)pyrimidin-~-yl]acetate;
ethyl 5-~5-((4,4-diethylchroman=6-yl)ethynyl)-pyrimidin-2-yl]pentanoate;
ethyl 5-t5-((4,4-diethyl-7-methylchroman-6-yl)-30 ethynyl)-pyrimidino2-yl3pentanoate;
ethyl 5-~4-(( 4, 4, 7 -triethylchroman-6-yl)- -ethynyl)pyrimidin-2-yl3pentanoate;
ethyl 5-[5-( (4,4-diethyl-7-h~xylchroman-S-yl)~

WO93/16068 PCT/US93/011~6 ethynyl3pyrimidin-2-yl~pentanoate;
ethyl ~5-((4,4-diethylchroman-6-yl)ethynyl)-pyrazin-2-yl]acetate;
ethyl [5-((4,4-diethyl-7-methylchroman-6-5 yl)ethynyl)-pyrazin-2-yl]acetate;
ethyl ~5-((4,4,7-triethylchroman-6-yl)-ethynyl)pyrazin-2-yl]acetate;
ethyl [5-((4,4-diethyl-7-hexylchroman-6-yl)-ethynyl~pyrazin-2-yl]acetate;
ethyl ~5-[5-((4,4-diethylchroman-6-yl)ethynyl3-pyrazin-2-yl3pentanoate; b ethyl 5-~5-((4,4-diethyl-7-methylchroman-6-yl)-ethynyl)-pyrazin-2-yl~pentanoate;
ethyl 5-~5-((4,4,7-triethylchroman-6-yl)-ethynyl)pyrazin-2-yl]pentanoate;
ethyl S-t5-((4,4-diethyl-7-hexylchroman-6-yl)- :
ethynyl)pyrazin-2--yl~pentanoate, and the corre~ponding free carboxylic acids.

Claims (33)

WHAT IS CLAIMED IS:

1. A compound of the formula wherein R1 and R2, independently are n-alkyl groups having 2 to 8 carbons, or cyclo or branch-chained alkyl groups of 3 to 8 carbons;
R3 is hydrogen or lower alkyl;
X is S, O or N-R4 where R4 is hydrogen or lower alkyl;
Y is phenyl or a heteroaryl group selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, and pyrazinyl, A is (CH2)n where n is 0-5, lower branched chain alkyl having 3 to 6 carbons, cycloalkyl having 3 to 6 carbons, alkenyl having 2 to 6 carbons and 1 or 2 double bonds, alkynyl having 2 to 6 carbons and 1 or 2 triple bonds;
B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR5, CONR6R7, -CH2OH, CH2OR8, CH2OCOR8, CHO, CH(OR9)2, CHOR10O, -COR11, CR11(OR9)2, or CR11OR10O, where R5 is an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R5 is phenyl or lower alkylphenyl, R6 and independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphenyl, R8 is alkyl of 1 to 10 carbons, phenyl or lower alkylphenyl, R9 is lower alkyl, R10 is divalent alkyl radical of 2 - 5 carbons and R11 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons.

2. A compound in accordance with Claim 1 where X
is S.

3. A compound in accordance with Claim 1 where X
is O.

4. A compound in accordance with Claim 1 where X
is NH.

5. A compound in accordance with Claim 1 where the R1 and R2 groups are identical with one another.

6. A compound in accordance with Claim 1 where the R1 and R2 groups are both n-alkyl.

7. A compound in accordance with Claim 1 where Y
is phenyl.

8. A compound in accordance with Claim 1 where Y
is selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

9. A compound in accordance with Claim 8 where Y
is selected from a group consisting of pyridyl and thienyl.

10. A compound of the formula where R1 and R2, independently are n-alkyl groups having 2 to 8 carbons;

R3 is hydrogen or lower alkyl;
X is S or O;
A is (CH2)n where n is 0-5, and B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR5, CONR6R7, -CH2OH, CH2OR8, CH2OCOR8, CHO, CH(OR9)2, CHOR10O, -COR11, CR11(OR9)2, or CR11OR10O, where R5 is an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R5 is phenyl or lower alkylphenyl, R6 and R7 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphenyl, R8 is alkyl of 1 to 10 carbons, phenyl or lower alkylphenyl, R9 is lower alkyl, R10 is divalent alkyl radical of 2 - 5 carbons and R11 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons.

11. A compound in accordance with Claim 10 where X is S.

12. A compound in accordance with Claim 11 where A is (CH2)n and where n is 0.

13. A compound in accordance with Claim 12 where B is COOH, COOR5, CONR6R7 or a pharmaceutically acceptable salt thereof.

14. A compound in accordance with Claim 10 where X is O.

15. A compound in accordance with Claim 14 where A is (CH2)n and where n is 0.

16. A compound in accordance with Claim 15 where B is COOH, COOR5, CONR6R7 or a pharmaceutically acceptable salt thereof.

17. A compound of the formula where R1 and R2, independently are n-alkyl groups having 2 to 8 carbons;
R3 is hydrogen or lower alkyl;
X is S or O;
A is (CH2)n where n is 0-5, and B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR5, CONR6R7, -CH2OH, CH2OR8, CH2OCOR8, CHO, CH(OR9)2, CHOR10O, -COR11, CR11(OR9)2, or CR11OR10O, where R5 is an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R5 is phenyl or lower alkylphenyl, R6 and R7 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphenyl, R8 is alkyl of 1 to 10 carbons, phenyl or lower alkylphenyl, R9 is lower alkyl, R10 is divalent alkyl radical of 2 - 5 carbons and R11 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons.

18. A compound in accordance with Claim 17 where X is S.

19. A compound in accordance with Claim 18 where A is (CH2)n and where n is 0.

20. A compound in accordance with Claim 19 where B is COOH, COOR5, CONR6R7 or a pharmaceutically acceptable salt thereof.

21. A compound in accordance with Claim 17 where X is O.

22. A compound in accordance with Claim 21 where A is (CH2)n and where n is 0.

23. A compound in accordance with Claim 22 where B is COOH, COOR5, CONR6R7 or a pharmaceutically acceptable salt thereof.

24. A compound of the formula where where R1 and R2 are identical and are selected from the group consisting of ethyl, n-propyl and n-butyl;
Z is N or CH, and R5 is ethyl or hydrogen.

25. A compound of claim 24 where R1 and R2 are ethyl.

26. A compound of Claim 25 where Z is CH.

27. A compound of Claim 25 where Z is N.

28. A compund of claim 24 where R1 and R2 are n-propyl.

29. A compound of Claim 28 where Z is CH.

30. A compound of Claim 28 where Z is N.

31. A compound of claim 24 where R1 and R2 are n-butyl.

32. A compound of Claim 31 where Z is CH.

33. A compound of Claim 31 where Z is N.