CA2240401A1 - ((3"-thioxacyclohex-1"-enyl))-but-3'-ene-1'-ynyl)aryl and heteroaryl carboxylic acids and esters having retinoid-like biological activity - Google Patents

Abstract

Compounds of formula (1) where R1, R2, R3 and R4 independently are H or lower alkyl of 1 to 10 carbons; R5 is lower alkyl of 1 to 10 carbons, fluoro, chloro, bromo, iodo, nitro or fluoroalkyl having 1 to 10 carbons; m is an integer having the value of 1-4; n is an integer having the value of 0-4; Y is phenyl or a heteroaryl group selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl and oxazolyl, said Y group being optionally substituted with one or more R5 group; A is (CH2)p, where p is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds, and B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, -CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, or CR7OR13O, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons have retinoid-like biological activity.

Description

CA 0224040l l998-06-l2 (~3"-THIOXACYCLOHEX-l"-ENYL))-BUT-3'-ENE-l'-YNYL)ARYL AND HETEROARYL
3 CARBOXYLIC ACIDS AND ESTERS HA~IING RETINOID-LIKE BIOLOGICAL ACTIVITY

5BACKGROUND OF T~E l~v~-~-ION
1. Field of the Invention ~The present invention is directed to novel Bcompounds which have retinoid-like ~iological g activity. More specifically, the present invention relates to [(3~-thioxacyclohexyl~-enyl)]-but-3~-ene ~ ynyl3aryl and [(3"-thioxacyclohex-1"-enyl)]-but-12 3'-ene-1'-ynyllheteroaryl car~oxylic acid and ester 13 derivatives. The acid or ester function, may also 14 be converted to an alcohol, aldehyde or ketone, or 15 derivatives thereof, or may be reduced to -CH3.
16 2. Related Art 17 Compounds which have retinoid like activity are 18 well known in the art, and are described in numerous 13 United States and foreign patents and in scientific publications. It is generally known and accepted in 21 the art that retinoid like activity is useful for 22 treating animals of the m~mmAlian species, including 23 humans, for curing or alleviating the symptoms and 24 conditions of numerous diseases and conditions. In other words, it is generally accepted in the art 26 that pharmaceutical compositions having a 27 retinoid-like compound or compounds as the active 28 ingredient are useful as regulators of cell 29 proliferation and differentiation, and particularly ~ as a~ents for treating skin-related diseases, 31 including, actinic keratoses, arsenic keratoses, 32 inflammatory and non-inflammatory acne, psoriasis, 33 ichthyoses and other keratinization and hyperproliferati~e disorders of the skin, eczema, CA 0224040l l998-06-l2 1 atopic dermatitis, Darriers disease, lichen planus, 2 prevention and reversal of glucocorticoid damage 3 ( steroid atrophy), as a topical anti-microbial, as 4 skin anti-pigmentation agents and to treat and s reverse the effects of age and photo damage to the 6 skin. Retinoid compound~ are also useful for the 7 prevention and treatment of cancerous and 8 prec~lncerous conditions, including, premalignant and g malignant hyperproliferative disea~es such as cancers of the breast, skin, prostate, cervix, 11 uterus, colon, bladder, esophagus, stomach, lung, 12 larynx, oral cavity, blood and lymphatic system, 13 metaplasias, dysplasias, neoplasias, leukoplakias 14 and papillomas of the mucous membranes and in the treatment of Kaposi's sarcoma. In addition, 16 retinoid compounds can be used as agents to treat 17 diseases of the eye, including, without limitation, 18 proliferative vitreoretinopathy (PVR), retinal 19 detachment, dry eye and other corneopathies, as well as in the treatment and prevention of various 21 cardiovascular diseases, including, without ~ limitation, diseases associated with lipid 23 metabolism such as dyslipidemias, prevention of 24 post-angioplasty restenosis and as an agent to increase the level of circulating tissue plasminogen 26 acti~rator (TPA). Other uses for retinoid compounds 27 include the prevention and treatment of conditions 28 and diseases associated with human papilloma virus 29 (HPV), including warts and genital warts, various inflammatory diseases such as pulmonary fibrosis, 31 ileitis, colitis and Krohn~s disease, 32 neurodegenerative diseases such as Alzheimer~s 33 disease, ParkinSOn's disease and stroke, improper W O 97~4348 PCTrUS96/20459 1 pituitary function, including insufficient 2 production of growth hormone, modulation of 3 apoptosis, including both the induction of apoptosis 4 and inhibition of T-Cell activated apoptosis, restoration of hair growth, including combination 6 therapies with the present compounds and other 7 agents such as MinoxidilR, diseases associated with ~ the immune system, including use of the present 9 compounds as i ~ unosuppressants and immunostimulants, modulation of organ transplant 11 rejection and facilitation of wound healing, 12 including modulation of chelosis.
13 United States Patent No. 4,810,804 di~closes 14 such disubstituted acetylene compounds wherein one 15 of the substituents of the acetylene group is a 16 substituted phenyl group, and the second substituent 17 iS substituted or unsubstituted 6-chromanyl, 18 6-thiochromanyl or 6-tetrahydroquinolinyl group.
19 The compounds disclosed and claimed in United States 20 Patent No. 4,810,804 have retinoid acid-like 21 biological activity.
~ A published European patent application of the 23 present applicant (Publication No. 0284288, 24 published on September 28, 1988) describes compounds 25 ha~ring retinoic acid-like activity which are 26 4,4-disubsituted 6-chromanyl, 4,4-disubsituted 27 6-thiochromanyl and 4,4-disubsituted 28 6-tetrahydroquinolinyl acetylenes also substituted 29 by a substituted heterosryl group.
United States Patent Nos. 5,013,744, 5,023,341, 31 5, 053,523, and 5,08g,509 describe ethyne compounds 32 substituted with a heteroaromatic or monocyclic aromatic substituent and also with a second CA 0224040l l998-06-l2 W O 97~4348 PCTrUS96/20459 I monocyclic aromatic or heteroaromatic substituent.
2 United States Patent No. 5,399,561 describes ethyne 3 compounds which have a phenyl or a heteroaryl 4 substituent and also a 2-oxochromanyl, 5 2-oxothiochromanyl or 2-oxo-1,2,3,4-tetrahydro-6 quinolinyl substituent.

7 United States ~atent Nos. 4,992,468, 5,068,252, a 5,175,185, 5,202,471, 5,264,456, 5,324,840, 9 5,326,898, 5,349,10S, 5,391,753, 5,414,007 and 10 5,434,173 (assigned to the ~ame assignee as the 11 present application) and patents and publications 12 cited therein, describe or relate to compounds which 13 have retinoid-like biological activity and a 14 structure wherein a phenyl and a heteroaryl or a 15 phenyl and a second phenyl group is linlced with an 16 olephinic or acetylenic linkage.
17 Published European Application 0 272 921 18 (published on June 29, 1988 describes 19 [(cyclohex~ enyl)-but-3'-ene-1'-ynyl]heteroaryl 20 c~rboxylic acids. Substantially the same disclosure 21 iS found in United States Patent No. 4,927,947.
22 United States Patent No. 4,739,098 describes 23 l( cyclohex-1"-enyl)-but-3'-ene-1'-ynyl]benzoic 24 acids, and United Statea Patent No. 5,426,118 2~ describes [4-(l~2-epoxycyclohaxanyl)but-3-en 26 ynyl)aromatic and heteroaromatic acids.
27 The compounds described in these patents have 28 retinoid-like biological activity. Numerous further 29 United States patents and applications for patent ~ assigned to the same assignee as the present 31 invention, are directed to compounds having ~ retinoid-like biological activity.

CA 0224040l l998-06-l2 wo s7n4348 PCT/US96/20459 SUMMARY OF INVENTI ON
2 The present invention relates to compounds of 3 Formula 1 A ~

~ ~ ~ Y~Rs):

Formula 11 where Rl, R2, R3, and R4 independently are H or 12 lower alkyl of 1 to 10 carbons;
~3 R5 is lower alkyl of 1 to 10 carbons, fluoro, 14 chloro, bromo, iodo, nitro, or fluoroalkyl having to 10 carbons;
16 m is an integer having the value of 1 - 4;
17 n is an integer having the value of O - 4;
1~ Y is phenyl or a heteroaryl group selected from 19 a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl and 21 oxazolyl, said Y group being optionally su~stituted 22 with one or more R5 group;
A is (CH2jp where p is 0-5, lower branched chain 24 alkyl having 3-6 carbons, cycloalkyl having 3-6 2~ carbons, alkenyl having 2-6 carbons and 1 or 2 26 double ~onds, alkynyl having 2-6 carbons and 1 or 2 27 triple bonds, and 28 B is hydrogen, COOH or a pharmaceutically 29 acceptable salt thereof, COOR8, CONRgRlo, -CH20H, CH20Rl" CH20CORl" CHO, CH(ORl2) 2~ CHORl~,O, -COR"
31 CE~7~ORl2)2, or CR70R~30, where R7 is an alkyl, 32 cycloalkyl or alkenyl group containing 1 to ~
33 carbons, R8 is an alkyl group of 1 to 10 car~ons, or CA 0224040l l998-06-l2 1 a cycloalkyl group of 5 to 10 carbons, or R8 is 2 phenyl or lower alkylphenyl, Rg and Rlo independently 3 are hydrogen, an alkyl group of 1 to 10 carbons, or 4 a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R,l is lower alkyl, phenyl or 6 lower alkylphenyl, Rl2 is lower alkyl, and Rl3 is 7 divalent alkyl radical of 2-5 carbons.

8 In a second aspect, this invention relates to g the use of the compounds of ~ormula 1 for the treatment of skin-related diseases, including, 11 without limitation, actinic keratoses, arsenic 12 keratoses, inflammatory and non-inflammatory acne, 13 psoriasis, ichthyoses and other keratinization and 14 hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, 16 prevention and reversal of glucocorticoid damage 17 ~ steroid atrophy), as a topical anti-microbial, as skin anti-pigmentation a~ents and to treat and 1~ reverse the effects of age and photo damage to the s}cin. The compounds are also useful for the 21 prevention and treatment of cancerous and ~ precancerous conditions, including, premalignant and 23 malignant hyperproliferative diseases such as 24 cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, 26 larynx, oral cavity, blood and lymphatic system, 27 metsplasias, dysplasias, neoplasias, leukoplakias 2B and papillomas of the mucous membranes and in the 29 treatment of Kaposi's sarcoma. In addition, the ~ present compounds can be used as agents to treat 31 diseases of the eye, including, without limitation, ~ proliferative vitreoretinopathy (PVR), retinal 33 detachment, dry eye and other corneopathies, as well CA 0224040l l998-06-l2 WO 97/24348 PCrlUS96/20459 1 as in the treatment and prevention of various 2 eardiovascular diseases, ineluding, without 3 limitation, diseases assoeiated with lipid 4 metal~olism sueh as dyslipidemias, prevention of post-angioplasty re~tenosis and as an agent to 6 increase the level of cireulating tissue plasminogen 7 aetivator (TPA). Other uses for the compounds of 8 the present invention inelude the prevention and ~ treatment of eonditions and diseases assoeiated with human papilloma virus (HPV), ineluding warts and ~1 genital warts, various inflammatory diseases such as 12 pulmonary fibrosis, ileitis, eolitis and Krohn's 13 disease, neurodegenerative diseases sueh as 4 Alzheimer/s disease, Parkinson's disease and stroke, 5 improper pituitary funetion, ineluding insuf f ieient 16 produetion of growth hormone, modulation of 17 apoptosis, ineluding both the induetion of apoptosis 18 and inhibition of T-Cell aetivated apoptosis, 19 restoration of hair growth, ineluding eombination 20 ther~pies with the present eompounds and other 21 agents such as MinoxidilR, diseases associated with 22 the im~ntlne system, ineluding use of the present 23 compounds as imTnnnosuppressants and 24 ;~mnnostimulants~ modulation of organ transplant 25 rejeetion and faeilitation of wound healing, 26 ineluding modulation of ehelosis.
27 This invention also relates to a pharmaeeutieal 28 formulation comprising a eompound of Formula 1 in 2~ admixture with a pharmaeeutieally aeeeptable 30 excipient.
31 In another aspeet, this in~rention relates to 32 proeess for making A eompound of Formula 1 whieh proeess eo~prises:

W O 97~4348 PCT~US96/204~9 2 ~"~ X--'~(FS)n--A--11 4 (R2)m ~ Jl, R~

7 Formula 2 Form~la 3 B

R~ Zn Xr (R2)m 16Formula 4 17 reacting a compound of Formula 2 with a compound 18 of Formula 3 in the presence of cuprous iodide and 19 Pd(PQ3~2Cl2 (Q is phenyl) or a similar complex, 20 giving the corresponding compound of Formula 1; or 21 to the process of making a compound of Formula 22 which consists of reacting a zinc salt of Formula 4 23 with a compound of Formula 3 in the presence of 24 Pd(PQ3)4 (Q is phenyl) or a similar complex. In 25 Formulas 2, 3 and 4 the symbols Rl, R2, R3, R4, R5, Y, 26 A, m and n have the same definition as in connection 27 with Formula 1, X is a halogen, preferably I, B is 28 H, or a protected acid, alcohol, aldehyde, or 29 ketone, and x'~ is a monovalent anion such as 30 chloride, bromide or iodide.
31 Still further the present invention relates to 32 the processes of homologating a compound of Fon~ula 33 1 where A is (CH2) L and n is 0-4 to give an acid of W O 97/24348 PCT~US96nO459 1 Fonmula l; or 2 converting an acid of Fon~ula 1 to a salt; or 3 forming an acid addition salt;
4 converting an acid of Formula 1 to an ester; or s converting an acit of Formula 1 to an amide; or 6 reducing an acid of ~ormula 1 to an alcohol or 7 aldehyde; or 8 converting an alcohol of Formula 1 to an ether o or ester; or oxidizing an alcohol of Formula 1 to an aldehyde; or 2 converting an aldehyde of Formula 1 to an 3 acetal; or 4 converting a ketone of Formula 1 to a ketal.
DE~AT~-~n l~.,BC'PTPTION OF T}IE INVENTION
6 General Embodiments 7 Definitions 8 The term alkyl refers to and covers any and all 19 groups which are known as normal alkyl, 20 ~ranched-chain alkyl and cycloalkyl. The term 21 alkenyl re~ers to and covers normal alkenyl, branch ~ chain alkenyl and cycloalkenyl groups having one or 23 more sites of unsaturation. Unless stated otherwise 24 in these specifications lower alkyl means the above-defined broad definition of alkyl groups 26 having 1 to 6 carbons, and as applicable, 3 to 6 27 carbons for branch chained and cyclo-alkyl groups.
28 Lower alkenyl is defined similarly having 2 to 6 29 carbons for normal alkenyl, and 3 to 6 carbons for branch chained and cyclo~lkenyl groups.
31 The term ~ester" as u~ed here refers to and 32 covers any compound falling within the definition of 33 that term as classically used in organic chemistry.

1 It includes organic and inorganic esters. Where B
2 ( of Formula 1) is -COOH, this term covers the 3 products derived from treatment of this function 4 with alcohols or thioalcohols preferably with s aliphatic alcohols having 1-6 carbons. Where the 6 ester is derived from compounds where B is -CH20H, 7 this term covers compounds derived from or~anic 8 acids capable of forming esters including g phosphorous based and sulfur based acids, or o compounds of the formula -CH20COR1l where R11 is ~1 defined ~s above.
12 The term "amides" has the meaning classically 13 accorded that term in organic chemistry. In this 14 instance it includes the unsubstituted amides and all aliphatic and aromatic mono- and di- substituted 16 amides.
17 A pharmaceutically acceptable salt may be 13 prepared for any compounds in this invention having 19 a functionality capable of forming such salt, for example an acid functionality. A pharmaceutically 21 acceptable salt is any salt which retains the ~ actlvity of the parent compound and does not impart 23 any deleterious or untoward effect on the subject to :24 which it is administered and in the context in which it is administered.
26 PharmaceutiCally acceptable salts may be derived 27 from or~anic or inorganic bases. The salt may be a 2a mono or polyvalent ion. Of particular interest are 29 the inorganic ions, sodium, potassium, calcium, and ~ magnesium. Organic salts may ~e made with amines, 31 particu}arly ammonium salts such as mono-, di- and ~ trialkyl amines or e~h~nol amines. Salts may also 33 be formed with caffeine, trome~hAmine and similar CA 0224040l l998-06-l2 1 molecules. Where there is a nitrogen sufficiently 2 basic as to be capable of forming acid addition 3 salts, such may be formed with any inorganic or 4 organic acids or alkylating agent such as methyl iodide. Preferred ~alts are those formed with 6 inorganic acids such a~ hydrochloric acid, sulfuric 7 acid or phosphoric acid. Any of a number of simple 8 organic acids such as mono-, di- or tri- acid may ~ also be used.
The compounds of the present invention contain 11 at least two double bonds, and therefore have trans 12 and cis (E and Z) isomers. However, presently it t3 was found that only the trans isomers of the 14 exocyclia double bond have aignificant retinoid-like biologic~l acti~ity. In addition, the compounds of 16 the pre~ent invention may contain one or more chiral 17 centers and therefore exist in enantiomeric and 18 diastereomeric forms. The scope of the present invention is intended to cover trans i~omers, 20 mixtures of cis and tr~ns isomers, mixtures of 21 diastereomers and r~cemic mixtures of enantiomers 22 (optical isomers) as well.
23 With reference now to Fo-~ula 1, the preferred 24 compound~ of this invention are those where Y is 25 phenyl, pyridyl, thienyl or furyl, with the phenyl 26 and pyridyl derivatives being particularly 27 preferred. When Y i~ phenyl, compounds are 28 preferred where the ethynyl group and the A-B group 2~ are attached to the 1 and 4 positions respectively of a benzene ring (i.e., where the phenyl moiety of 31 the compound is l~ar~ substituted). When the Y group 32 is pyridyl, thienyl or furyl, compounds are 33 preferred where the ethynyl group ~nd the A-B group CA 0224040l l998-06-l2 wo g7124348 rcr/uss61204~s 1 are attached to the 2 and 5 positions respectively 2 of a pyridine ring ~the 6 and 3 positions of the 3 nicotinic acid nomenclature being equivalent to the 4 2J5 designation in the pyridine nomenclature) or to the 5 and 2 positions respectively of a thiophene or 6 furan group, respectively. Compounds where Y is 7 phenyl, and where the phenyl group is para 8 substituted and compounds where Y is pyridyl and g the pyridyl group is 2,5-substituted in the above-described manner, are particularly preferred.
11 With regard to the A-B side chain (substituent) 12 on the phenyl or heteroaryl group Y, compounds are 13 preferred where A is (CH2)p and p is 0. With regard 14 to group B, compounds are preferred where B is -COOH, an alkali metal salt or organic amine salt, 16 or a lower alkyl ester therof.
In the preferred compounds of the invention Rl 8 and R~ are ~ or lower alkyl of 1 to 6 carbons, most 19 prefera~ly these groups are methyl. The R2, R~ and 20 Rs groups are preferably H or lower alkyl of 1 to 6 21 carbons, most preferably ~. The most preferred 22 compounds of the invention are shown in Table 1 with 23 reference to Formula 5.

26 ~3~CO2R~-28 X~ ~'~x2 29 ~ 11 S/\

33 Formula S

w o g7n4348 PCT~US96120459 , Table l 2 Compou~d No. X2 ~;
3 l CH Et 3 N Et 7 Modes of ~dmi~istration 8 The compounds of this invention may be g a~mi n i stered systemicA~ly or topical}y, depending on .o such considerations as the condition to be treated, 11 need for site-qpecific treatment, ~uantity of drug 12 to be administered, and numerous other 13 considerations.
14 In the treatment of dermatoses, it will 15 ~enerally be preferred to a~mi n ister the drug 16 topically, though in certain cases such as treatment 17 of severe cystic acne or psoriasis, oral 18 administration may also be used. Any common topical l9 formulation such as a solution, suspension, gel, ointment, or salve and the like may be used.
21 Preparation of such topical formulations are well ~ described in the art of pharmaceutical formulations 2:1 as exemplified, for example, R~mington~s 24 Pharmaceutical Science, Edition 17, Mack Publishing 2S C~ompany, Easton, Pennsylvania. For topical 26 application, the~e compounds could al80 be 27 administered as a powder or spray, pArticularly in 28 aerosol form. If the drug is to be a~m;nistered systemically, it may be confected as a powder, pill, tablet or the like or as a ~yrup or elixir suitable 31 for oral a~lm;~istration. For intravenous or 32 intraperitoneal a~ministration, the compound will be prepared as a solution or suspension capable of CA 0224040l l998-06-l2 W O 97/24348 PCTrUS96120459 1 being administered by injection. In certain cases, 2 it may be useful to formulate the~e compounds by 3 injection. In certain cases, it may be useful to 4 formulate these compound~ in suppository form or as s extended release formulation for deposit under the 6 skin or intramuscular injection.
7 Other medicaments can be added to such topical 8 formulation for ~uch secondary purposes as treating g skin dryness; providing protection against light;
other medications for treating dermatoses;
11 medicaments for preventing infection, reducing 12 irritation, inflamm~tion and the like.
~3 Treatment of dermatoses or any other indications 14 known or di~covered to be susceptible to treatment by retinoic acid-like compounds will be effected by 16 a~llninistration of the therapeutically effective dose 17 of one or more compounds of the instant invention.
18 A therapeutic concentration will be that tg concentration which effects reduction of the 20 particular condition, or retards it expansion. In 21 certain instances, the compound potentially may be 22 used in prophylactic manner to prevent onset of a 23 particular condition.
24 A useful therapeutic or prophylactic 25 concentration will vary from condition to condition 26 and in certain instances may vary with the severity 27 of the condition being treated and the patient~s 28 susceptibility to treatment. Accordingly, no single concentration will be uniformly useful, but will ~ re~uire modification depending on the 31 particularities of the disease being treated. Such 32 concentrations can be arrived at through routine 33 experimentation. However, it is anticipAted that in CA 0224040l l998-06-l2 W O 97/24348 PCT~US96/2045g 1 the treatment of, for example, acne, or similar 2 dermatoses, that a formulation containing between 3 0.01 and 1.0 milligrams per mililiter of formulation 4 will constitute a therapsutically effective concentration for topic~l application. If 6 administered systemically, an amount between 0.01 7 and 5 mg per kg per day o~ bo~y weight would be 8 expected to effect a therapeutic result in the 9 treatment of many disease for which these compounds are useful.
11 Assay of Retinoid-like Biological Activity 12 The retinoid-like activity of these compounds is 13 confirmed through the classic measure of retinoic 14 acid activity involving the effects of retinoic acid ~5 on ornithine decarboxylase. The original work on 16 the correlation between retinoic acid and decrease 17 in cell proliferation was done by Verma & Boutwell, 18 Cancer R~search, 1977, 37,2196-2201. That reference 19 discloses that ornithine decarboxylase (ODC) activity increased precedent to polyamine 21 biosynthesis. It has been established elsewhere that incre~ses in polyamine synthesis can be 23 correlated or associated with cellular 24 proliferation. Thus, if ODC activity could be 2~; ;nhihited, cell hyperproliferation could ~e 2& modulated. Although all causes for ODC activity 77 increa~es are unknown, it i8 known that 2R 12-0-tetradecanoylphorbol-13-acetate (TPA~ induces 2~ ODC acti~ity. Retinoic acid i n~li hits this induction of ODC activity by TPA. An ~say essentially 31 following the procedure set out in Cancer Res:
32 1662-1670,1975 may be used to demon~trate i~hibition ~ of TPA induction of ODC by compounds of this CA 0224040l l998-06-l2 1 invention. The results of this assay for certain 2 exemplary compounds of the invention are shown in 3 Table 1 below, wherein either the IC80 or IC60 value 4 for each exemplary compound is indicated in namolar concentration units. (As is known in the art, the 6 IC60 value is that concentration of the compound (in 7 nanomols) which results in 60 % inhibition.) 8 Table 1 Compound # IC60 g IC90 0 1 3.8 ----11 2 1.4 ----13 4 -- 33.6 SPECIFIC EMBODI~ENTS
Synthetic Processes for Preparinq Compounds of 17 the Invention 18 The compounds of this invention can be made by a 19 number of different synthetic chemical pathways. To illustrate this invention, there is here outlined a 21 series of steps which have been proven to provide 22 the compounds of ~ormula 1 when such synthesis is 23 followed in fact and in spirit. The synthetic 24 chemist will readily appreciate that the conditions set out here are specific embodiments which can be 26 generalized to any and all of the compounds 27 represented by Formula 1. Furthermore, the 28 synthetic chemist will r-adily appreciate that the 29 herein described synthet$c steps may be varied and ~ or adjusted by those skilled in the art without 31 departing from the scope and spirit of the 32 invention.

~ [~ m ~ L ~

¢ ~ U' ~Ci L

.~ m ~' 0~

c Reaction Scheme 1 S~Jt~S 111 ~JTE SHEET (RULE 26) CA 0224040l l998-06-l2 1 Referring now to Reaction Scheme 1 a 2 ( 3'-thioxacyclohexyl-enyl)-but-1-ene-3-one 3 derivative of Formula 6 which has the desired ~1~ R2r 4 R3 and R,~ substituents is reacted with with strong ~ base, such as lithium diisopropyl amide, and diethyl 6 chlorophosphate, to introduce the triple bond into 7 the Dnlolecule and yield the (3'-thioxacyclohexyl-8 enyl)-but-1-ene-3-yne derivati~re of For~ula 2. The ~ starting ~aterial, compound of Formula 6, can be obtained in accordance with the state of the art.
11 An example for a compound of Formula 6, which is 12 used to prepare the herein described preferred 13 ex~mrles of the compounds of the invention is 14 1-( 2~,4',4'-trimethyl-1'-thiacyclohex-2'-ene-3'-yl)-15 but-1-ene-3-one (Compound ~). Compound 5 is 16 available in accordance with chemical literature, as 17 described in Tetrahedron 1966, 22 pp259-264. Thus, 18 in accordance with the first step shown in Reaction 19 Scheme 1, Compound 5 is converted into 20 1-( 2~4~4~-trimethy~ thiacyclohex-2~-ene-3~-yl) 21 but-1-ene-3-yne (Compound 6).
22 In order to introduce a phenyl or heteroaryl 23 substitutent on the acetylene (ethyne) portion of a 24 co~pound of Formula 2, the latter compound is 25 coupled with the reagent X-Y(R5)n-A-B (Formula 3). In 26 other words, the phenyl or heteroaryl substitutent 27 i~ introduced into the (3'-thioxacyclohexyl-enyl)~-28 but-1-ene-3-yne derivative of Formula 2 by reacting 2~ the latter with a halogen substituted phenyl or ~ heteroaromatic compound of ~ormula 3 in which the 31 phenyl or heteroaromatic nucleus (Y~ either has the 32 desired substituent (A-B) or wherein the actual subsituent A-B can be readily converted to the CA 0224040l l998-06-l2 W O 97~24348 PCTAUS96/20459 1 desired substituent by means of organic reactions 2 well known in the art.
3 Coupling of the (3'-thioxscyclohexyl-enyl)]-4 but-1-ene-3-yne derivative of Formula 2 with the s reagent X-Y(R5)n-A-B (Formula 3) i8 affected directly 6 in the presence of cuprous iodide, a suita}~le 7 catalyst, typically of the formula Pd(PQ3)Cl2 (Q is 8 phenyl) and an acid acceptor, such as triethylamine, 9 in an inert ga5 ( argon) atmosphere. Alternatively, a metal salt, such a~ the zinc salt of For~ula 4 derived from the ethynyl compound of Formula 2 is 12 reacted with the reagent of Formula 3 in the 13 presence of a palladium complex catalyst having the 14 formula Pd(PQ3)4 (Q is phenyl) or similar complex.
Generally speaking, coupling between an 1~ ethynylbenzene compound or its zinc salt and a 17 halogen substituted aryl or heteroaryl compound, 1~ such as the reagent of Formula 3, is described in United States Patent No. 5,264,456, the 20 specification of which i8 expressly incorporated 2t herein by reference. Coupling between ~ 2',6~,6~-trimethylcyclohex-1'-enyl)but-1-ene-3-yn 23 e and ethyl 6-chlorinicotinate is described in 24 United States Patent No. 4,927,947, and coupling 2~ between l-(2~r6~t6~-trimethylcyclohex-l~-enyl)but-26 1-ene-3-yne and ethyl 4-iodobenzoate is described in 27 United States Patent No. 4,739,098. The 28 specification of United States Patent No. 4,927,947 29 and 4,739,098 are expressly incorporated herein by ~ reference.
31 The disubstituted acetylene compounds of Formula 32 1 which result from the coupling reaction shown in 33 Reaction Scheme 1 may be the target compounds made W 097~4348 PCTAUS96~04~9 1 in accordance with the invention, or may be readily 2 converted into the target compounds by such steps as 3 salt formation, esterification, deesterification, 4 homologation, amide formation and the like. These steps are further discussed below, and are indicated 6 in Reaction Sche ~ 1 as conversion into homologs and 7 derivatives.
8 Carboxylic acids are typically esterified by ~ refluxing the acid in a solution of the appropriate alcoho~ in the presence of an acid catalyst such as 11 hydrogen chloride or thionyl chloride.
12 Alternatively, the carboxylic acid can be condensed 13 with the appropriate alcohol in the presence of 14 dicyclohexylcarbodiimide and dimethylaminopyridine.
15 The ester is recovered and purified by conventional 16 means. Acetals and ketals are readily made by the 17 method described in March, "Advanced Organic 18 Chemistry," 2nd Edition, McGraw-Hill Book Company, p 19 810). Alcohols, aldehydes and ketones all may be 20 protected by forming respectively, ethers and 21 esters, acetals or ketals by known methods such as 22 those described in ~ScOmie, Plenum Publishing Press, 23 1973 and Protectinq Groups, Ed. Greene, John Wiley &
24 Sons, 1981.
A means for making compounds where A is (CH2)~
26 (n i8 1 - 5) iS to subjeat the compounds of Formula 27 1, where B is an acid or other function, to 2a homologation, using the wel} known Arndt-Eistert 29 method of homologation, or other known homologation 30 procedures.
31 Compounds of ForDlula 1, where A is an alkenyl ~ group having one or more double bonds can be made 33 for ex~mple, by having the requisite number of CA 0224040l l998-06-l2 W O 97~4348 PCTAJS96/20459 1 double bonds incorporated into the reagent of 2 Formula 3 which is reacted with the ethyne compound 3 or its metal salt, as shown in Reaction Sch ~ e 1.
4 Generally speaking, such compounds where A is an s unQaturated carbon chain can be obtained by 6 synthetic schemes well ~cnown to the practicing 7 organic chemist; for example by Wittig and like 8 reactions, or by introduction of a double bond by g elimination of halogen from an alpha-halo-carboxylic acid, ester or like carboxaldehyde. Compounds of 11 Formula 1 where the A group has a triple 12 ~ acetylenic) bond can be made by using the 13 corresponding aryl or heteroaryl aldehyde 14 intermediate. Such intermediate can be obtained by reactions well known in the art, for example, by 16 reaction of a corresponding methy~ ketone with 17 strong base, such as lithium diisopropyl amide.
The acids and salts derived from compounds of 19 Fonm~la 1 are readily obtainable from the corresponding esters. Basic saponification with an 21 alkali metal base will provide the acid. For ~ eY~mple, an ester of Formula 1 may be dissolved in a 23 polar solvent such as an alkanol, preferably under 24 an inert atmosphere at room temperature, with about a three molar excess of }ase, for example, potassium 26 hydroxide, sodium hydroxide or lithium hydroxide.
27 The solution is stirred for an extended period of 28 time, between 15 and 20 hours, cooled, acidified and 29 the hydrolysate recovered by conventional means.
The synthesis of carboxylic acids from the esters 31 which are obtained in the coupling step between a 32 reagent of Formula 2 and of Fo~ula 3 (where B
~ represents for P~mrle COOC2HS) is a step that leads CA 0224040l l998-06-l2 W O 97/24348 PCTAUSg6~04S9 1 to several preferred eompounds of the pre~ent 2 invention.
3 The amide may be formed by any appropriate 4 amidation means known in the art from the 5 eorresponding esters or earboxylie aeids. One way 6 to prepare sueh eompounds i~ to eonvert an aeid to 7 an aeid ehloride and then treat that eompound with s ammonium hydroxide or ~n appropriate amine.
9 Aleohols are made by eonverting the eorresponding aeids to the aeid ehloride with thionyl ehlor~de or 11 other means (J. Mareh, "Advaneed Organic Chemistry~', 12 2nd Edition, MeGraw-~ill Book Company), then 13 reducing the aeid ehloride with sodium borohydride ~4 (Nareh, Ibid, pg. 1124), which gives the eorresponding aleohols. Alternatively, esters may 16 be redueed with lithium aluminum hydride at reduced 17 temperatures. Alkylating the~e alcohols with 18 appropriate alky halides under Williamson reaction 19 conditions (March, Ibid, pg. 357) gi~es the 20 eorresponding ethers. These aleohols ean be 21 converted to esters by reaeting them with 22 appropriate acids in the presenee of acid catalysts 23 or dieyclohexylcarbodiimide and 24 dimethlaminopyridine.
Aldehydes ean be prepared from the eorresponding 26 primary aleohols using mild oxidizing agents sueh as 27 pyridinium diehromate in methylene ehloride (Corey, 28 E. J., Sehmidt, G., Tet. Lett., 399, 1979), or 29 dimethyl sulfoxide/oxalyl ehloride in methylene 30 ehloride (Omura, K., Swern, D., Tetrahedron, 1978, 31 34, 1651).
32 Ketone~ e~n be prepared from an ~ppropriate 33 aldehyde by treating the aldehyde with an alkyl CA 0224040l l998-06-l2 W O 97/24348 rCT~USg6/2045g 1 Grignard reagent or similar reagent followed by 2 oxidation.
3 Acetals or ketals can be prepared from the 4 corresponding aldehyde or ketone by the method 5 described in March, Ibid, p 810.
6 Compounds of Fon~ula 1 where B is H can be pre-7 pared from the corresponding halogenated aromatic 8 compounds, preferably where the halogen is I.
9 The reagent of Formula 3 is generally speaking available in accordance with the chemical 11 literature, or when necessary can be o~tained, 12 within the skill of the practicing organic chemist, 13 in accordance with the reaction steps outlined 14 above. Preferred methods for the syntheses of ls certain reagents of Formula 3 (where A-B represents 16 -COOR8) which are used for the preparation of the 17 preferred examples of the present invention, are 18 also described below.
19 8PeCifiC Examples Ethyl 4-iodobenzoate 21 To a suspension of 10 g (40.32 mmol) of 22 4-iodobenzoic acid in 100 ml absolute ethanol was 23 added 2 ml thionyl chloride and the mixture was then 24 heated at reflux for 3 hours. Solvent was removed in vacuo and the residue was dissolved in 100 ml 26 ether. The ether solution was w~shed with saturated 27 NaHCO3 and saturated NaCl solutions ~nd dried 28 (MgSO4). Solvent was then removed in vacuo and the 29 residue kugelrohr distilled (100 degrees C; 0.5~ mm) to give the title compound ~ a colorless oil, PMR
31 (CDCl3): 1.42 (3H, t, J-7 Hz), 4,4 (2H, q, J-7 Hz), 32 7.8 (4H).

CA 0224040l l998-06-l2 W O 97~4348 PCT~US96/20459 1 6-Iodonicotinic acid 2 To 27.97 g (186.6 mmol) of sodium iodide cooled 3 to -78~C W8S added 121.77 g (71.6 ml, 952.0 mmol) of 4 hydriodic acid (in 57 wt 96 aqueous solution). The reaction mixture was allowed to warm slightly with 6 stirring for 5 minUteQ, and then 30.00 g (190.4 7 mmol) of 6-chloronicotinic acid was added. The 8 resulting mixture w~s allowed to warm to room 9 temperature with stirring and then heated at 120-125~C in an oil bath for 42 hours. A dark brown 11 layer formed above the yellow solid material. The 12 reaction mixture was allowed to cool to room 13 temperature and then poured into acetone (chilled to 14 0~C). The resultant yellow solid was collected by filtration, washed with 200 ml of lN NaE~SO3 solution, 16 and dried in vacuum (3 mm Hg) to give the title 17 compound as a pale yellow solid.
18 PMR (D~5SO-d6): d 7.90 (lH, dd, J = 8.1, 2 Hz), 7.99 19 (lH, d, J = 8.1 ~z), 8.80 (lH, d, J ~ 2 Hz).
Ethyl 6-iodonicotinoate 21 To a suspension of 23.38 g (94.2 mmol) of ~ 6-iodonicotinic acid in 100 ml of dichloromethane 23 was added a solution of 19.86 g (103.6 mmol) of 24 1-( 3-dimethylaminopropyl)-3-ethylcarbodiimide 25 hydrochloride in 250 ml of dich}oromethane. To this 26 suspension was added 12.40 g (15.8 ml, 269.3 mmol) 27 of ethanol (95%) and 1.15 g (9.4 mmol) of 28 4-dimethylaminopyridine. The resulting solution was 28 then heated at 50~C in an oil bath for 24.5 hours, 30 concentrated in vacuo, partitioned between 200 ml of 31 water and 250 ml of ethyl ether, and the layers were separated. The a~ueous pha~e was washed with 2 x 150 ml-portions of ethyl ether. All organic CA 0224040l l998-06-l2 1 phases were combined, washed once with 75 ml of 2 brine solution, dried over MgSO4, filtered and 3 concentrated in vacuo to yield a yellow solid 4 residue. Purification by flash chromatography ( silica, 10% ethyl acetate in hexane) yielded the 6 title compound as a white solid.
PMR (CDCl3): d 1.41 (3H, t, J = 7.1 Hz), 4.41 (2H, 8 q, J = 7.1 Hz), 7.85 (lH, d, J = 8.2 Hz), 7.91 (lH, dd, J = 8.2, 2.1 Hz), 8.94 (lH, d, J = 2.1 Hz).
o 1-(2~, 4~,4'-Trimethyl-l'-thiacyclohex-2'-ene-3~-11 yl)-but-l(E)-ene-3-yne (Compound 6) 12 To a solution of lithium diisopropyl amide (LDA) 13 prepared at 0~C by mixing diisopropylamine (0.06 ml) 14 and BuLi (1.7 M in hexane, 0.26 ml) in 3 ml of THF
15 was added dropwise 1-(2',4~,4'-trimethyl~
16 thiacyclohex-2~-ene-3'-yl)-but-1-ene-3-one (Compound 17 5, 4-thia-ionone, 84 mg, 0.4 mmol) at -78~C.
18 ( Compound 5 is available in accordance with 1~ Tetrahedron 1966, 22 pp259-264, incorporated herein 20 by reference.) The re~ction mixture was stirred 21 for l hour when diethyl chlorophosphate (0.06 ml) ~ was added at -78~C. The reaction mixture was 23 gradually warmed to room temperature and then 24 transferred through cannulation into a solution of LDA at -7~~C, prepared as above. The reaction 26 mixture was slowly warmed to room temperature and 27 left overnight. Water was added to the reaction 28 mixture and the mixture was extracted into ethyl 29 acetate. The org~nic layer was washed with 10% of ~ RCl, NaHCO3, brine and dried over MgSO4. The solvent 31 was evaporated and the residue was purified by ~ column chromatography (ethyl acetate/heYAne 1/10) to 33 give the title compound as a yellow oil (50 mg).

CA 0224040l l998-06-l2 1 lH NMR ~ (CDCl3) 6.66 (d, J = 16.5 Hz, lH), 5.43 (dd, 2 J = 16.3, 2.3 Hz, lH), 2.g6 (d, J = 2.3 Hz, lH), 3 2.83 (m, 2H), 1.95 (s, 3H), 1.85 (m, 2H), 1.09 (s, 4 6H).
Ethyl 4-[4'-(2",6",6",-Trimethyl-3"-thioxacyclohex-6 1~-enyl)-but-3'(E)-ene-l'- ynyl1benzoate (Compound 1) 8 A solution of }-(2',4~,4~-trimethyl-1~-thia-~ cyclohex-2'-ene-3'-yl)-but-1-ene-3-yne (Compound 6, 232 mg, 1.21 mmol), CuI (45.9 mg) and ethyl 4-l1 iodobenzo~te (334 mg, 1.21 mmol) in 10 ml of 12 triethylamine (TEA) was purged with N2 for 1 minute 13 before Pd(Ph3P)2Cl2 (255 mg) was added to the 14 solution. The resulting yellow slurry was stirred at room temperature for 2 days. The reaction was 16 filtered and the solution W~!18 concentrated to give a 17 brown residue. The residue was purified by column 18 chromatogrsphy (ethyl acetate/hexane 1/50) to give 19 the title compound as a yellow oil (248 mg, 60%).
20 lH NNR ~ (CDCl3) 7.99 (d, J = 8.5 Hz, 2H), 7.49 (d, J
21 = 8.5 Hz, 2H), 6.72 (d, J = 15.6 Hz, lH), 5.68 ~d, J
~ = 15.6 Hz, lH), 4.37 (q, J = 7.1 Hz, 2H), 2.85 (m, 23 2H), 2.00 (s, 3H), 1.86 (m~ 2H), 1.40 (t, J = 7.2 24 Hz, 3H), 1.12 (s, 6H).
25 4-~4~-(2~6~6~-Trimethyl-3~-thioxacyclohex~ -enyl) 26 -but-3'(E)-ene-1'-ynyllbenzoic Acid (Compound 2) 27 To a solution of ethyl 4-14'-(2~,6",6~ trim-28 ethyl-3~-thioxacyclohex-1"-enyl)-but-3~-ene~
29 ynyl~benzoate (compound 1, 130 mg) in 3 ml of EtOH
30 was added lml of lN NaOH. The reaction mixture was 31 stirred at room temperature for 12 hours. The 32 solvent was removed and ethyl acetate was added to 33 the residue. The resulting solution was washed with CA 0224040l l998-06-l2 wO 97/2434~ PCT/USg6/204S9 1 10% of HCl until the aqueous layer became neutral.
2 The organic layer was separated, washed with brine 3 and dried over MgS04. After concentration, the 4 residue was purified by column chromAtography (ethyl acetate/hexane 1/1) to give the title compound as a 6 yellow crystals (95 mg).
~ 1H NMR ~ (CDCl3) 8.03 (d, J = 8.3 Hz, 2H), 7.52 (d, J
8 = 8.3 Hz, 2H), 6.74 (d, J = 15.9 Hz, lH), 5.69 (d, J
9 = 15.9 Hz, lH), 2.86 (m, 2H), 2.01 (8, 3H), 1.86 (m, o 2H), 1.14 (s, 6~).
11 Ethyl 6- r 4r-(2",6",6",-Trimethyl-3~-thioxacyclohex-12 1~-enyl)-but-3'(E)-ene-1'- ynyllnicotinate (Compound 13 3) 14 Using the same procedure as for the synthes.s of ethyl 4-l4~-~2",6~,6",-trimethyl-3~-thioxacyclohex-16 1"-enyl)-but-3'-ene-1'-ynyl]benzoate (Compound 1) but using 50 mg of 1-(2~, 4',4~-trimethyl~
1~ thiacyclohex-2'-ene-3'-yl)-but-1-ene-3-yne (Compound 19 5), 72 mg of ethyl 6-iodo nicotinate, 55 mg of 20 Pd(Ph3P)2Cl2 and 9.9 mg of CuI in 2 ml of TEA, the 21 title compound was obtained as a yellow oil (59 mg, 67%). lH NMR ~ (CDCl3) 9.08 (d, J = 2.1 ~z, lH), 23 8.27 (dd, J = 8.2, 2.2 Hz, lH), 7.60 (d, J = 9.28 24 Hz, lH), 6.90 (d, J = 16.5 Hz, lH), 5.80 (d, J =
25 16.4 Hz, lH), 4.37 (q, J = 7.1 Hz, 2H), 2.88 (m, 26 2H), 1.98 (s, 3H), 1.87 (m, 2H), 1.37 (t, J = 7.1 27 Hz, 3H), 1.15 (s, 6H).
2a 6- r 4~-(2~6~6~-Trimethyl-3~-thioxac~Tclohex~ -en 29 )-but-3 ' ( E ) -ene- 1 ' -ynyl~ nicotinic Acid ( Compound 4) ~ Using the ~ame procedure as for the synthesis of 31 4-[4~-(2~6~6~-trimethyl-3~-thioxacyclohex-ln-enyl) -but-3'-ene-1'-ynyl]benzoic acid (Compound 2) but using ethyl 6-~4'-(2",6~,6~,-trimethyl-3"-thio-W O 97~24348 PCT~US9612045g 1 xacyclohex-1"-enyl)-but-3'-ene-1'-ynyllnicotinate 2 (Compouud 3, 15 mg), the title compound was obtained 3 as a yellow solid (12 mg, 80~).
4 lH NMR ~ (CDCl3) 9.29 (s, lH), 8.34 (d, J = 8.3 Hz, 6 lH), 7.53 (d, J = 8.2 Hz, lH), 6.91 (d, J = 16.1 ~z, 6 lH), 5.74 (d, J = 16.1 Hz, lH), 2.86 (m, 2H), 2.01 7 (S, 3H), 1.86 (m~ 2H), 1.14 (s, 6H).

Claims (22)

WHAT IS CLAIMED IS:

1. A compound of the formula where Rl, R2, R3, and R4 independently are H
or lower alkyl of 1 to 10 carbons;
R5 is lower alkyl of 1 to 10 carbons, fluoro, chloro, bromo, iodo, nitro, or fluoroalkyl having 1 to 10 carbons;
m is an integer having the value of 1 - 4;
n is an integer having the value of O - 4;
Y is phenyl or a heteroaryl group selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl and oxazolyl, said Y group being optionally substituted with one or more R5 group;
A is (CH2)p where p is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds, and B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, -CH20H, CH2ORll, CH2OCOR11, CHO, CH(ORl2)2, CHORl3O, -COR7, CR7(ORl2)2, or CR7OR13O, where R, is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons.

2. A compound in accordance with Claim 1 where Y is selected from a group consisting of phenyl, pyridyl, thienyl and furyl.

3. A compound in accordance with Claim 2 where Y is phenyl.

4. A compound in accordance with Claim 3 where the phenyl group is 1,4 substituted by the ethynyl and A-B groups.

5. A compound in accordance with Claim 4 where A is (CH2)p, p is 0 and and B is COOH, COOR2 or CONR9R10.

6. A compound in accordance with Claim 2 where Y is pyridyl.

7. A compound in accordance with Claim 6 where the pyridyl group is 2,5 substituted by the ethynyl and A-B groups.

8. A compound in accordance with Claim 7 where A is (CH2)~, n is 0 and and B is COOH, COOR~ or CONR9R10.

9. A compound of the formula where Rl, R2, R3, and R4 independently are H or lower alkyl of 1 to 10 carbons;
m is an integer having the value of 1 - 4, and R8 is H, an alkyl group of 1 to 10 carbons or a pharmaceutically acceptable cation.

10. A compound in accordance with Claim 9 where R4 is H or CH3.

11. A compound in accordance with Claim 9 where R3 is H or CH3.

12. A compound in accordance with Claim 9 where Rl is H or CH3.

13. A compound in accordance with Claim 9 where Rl is CH3, m is 0, R3 is CH3, and R4 is H.

14. A compound in accordance with Claim 13 where R8 is H, or a pharmaceutically acceptable cation.

15. A compound in accordance with Claim 13 where R8 is CH3CH2.

16. A compound of the formula where R1, R2, R3, and R4 independently are H or lower alkyl of 1 to 10 carbons;
m is an integer having the value of 1 - 4, and R8 is H, an alkyl group of 1 to 10 carbons or a pharmaceutically acceptable cation.

17. A compound in accordance with Claim 16 where R4 is H or CH3.

18. A compound in accordance with Claim 16 where R3 is H or CH3.

19. A compound in accordance with Claim 16 where Rl is H or CH3.

20. A compound in accordance with Claim 16 where Rl is CH3, m is 0, R3 is CH3, and R4, is H.

21. A compound in accordance with Claim 20 where R8 is H or a pharmaceutically acceptable cation.

22. A compound in accordance with Claim 20 where R8 is CH3CH2.