((3"-THIOXACYCLOHEX-1"-ENYL))-BUT-3'-ENE-1'-YNYL)ARYL AND HETEROARYL CARBOXYLIC ACIDS AND ESTERS HAVING RETINOID-LIKE BIOLOGICAL ACTIVITY

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: ((3"-THIOXACYCL0HEX-l"-ENYL))-BUT-3'-ENE-l'-YNYL)ARYL AND HETEROARYL 3 CARBOXYLIC ACIDS AND ESTERS HAVING RETINOID-LIKE BIOLOGICAL ACTIVITY 4 5 BACKGROUND OF THE INVENTION e 1. Field of the Invention 7 The present invention is directed to novel β compounds which have retinoid-li e biological g activity. More specifically, the present invention ιo relates to [ (3"-thioxacyclohexyl"-enyl) ]-but-3'-ene- ιι l'-ynyl]aryl and [ (3"-thioxacyclohex-l"-enyl) ]-but- 12 3'-ene-l'-ynyl]heteroaryl carboxylic acid and ester 13 derivatives. The acid or ester function, may also 14 be converted to an alcohol, aldehyde or ketone, or is derivatives thereof, or may be reduced to -CH 3 . 16 2. Related Art 17 Compounds which have retinoid like activity are is well known in the art, and are described in numerous 19 United States and foreign patents and in scientific 0 publications. It is generally known and accepted in 1 the art that retinoid like activity is useful for 2 treating animals of the mammalian species, including 3 humans, for curing or alleviating the symptoms and 4 conditions of numerous diseases and conditions. In 5 other words, it is generally accepted in the art 6 that pharmaceutical compositions having a 7 retinoid-like compound or compounds as the active 8 ingredient are useful as regulators of cell 9 proliferation and differentiation, and particularly 0 as agents for treating skin-related diseases, 1 including, actinic keratoses, arsenic keratoses, 2 inflammatory and non-inflammatory acne, psoriasis, 3 ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Oarriers disease, lichen planus, prevention and reversal of glucocorticoid damage (steroid atrophy), as a topical anti-microbial, as skin anti-pigmentation agents and to treat and reverse the effects of age and photo damage to the skin. Retinoid compounds are also useful for the prevention and treatment of cancerous and precancerous conditions, including, premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of Kaposi's sarcoma. In addition, retinoid compounds can be used as agents to treat diseases of the eye, including, without limitation, proliferative vitreoretinopathy (PVR), retinal detachment, dry eye and other corneopathies, as well as in the treatment and prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of post-angioplasty restenosis and as an agent to increase the level of circulating tissue plasminogen activator (TPA) . Other uses for retinoid compounds include the prevention and treatment of conditions and diseases associated with human papilloma virus (HPV), including warts and genital warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn's disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and stroke, improper ι 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, 5 restoration of hair growth, including combination 6 therapies with the present compounds and other agents such as Minoxidil R , diseases associated with s the immune system, including use of the present 9 compounds as immunosuppressants and o immunostimulants, modulation of organ transplant i rejection and facilitation of wound healing, 2 including modulation of chelosis. 3 United States Patent No. 4,810,804 discloses such disubstituted acetylene compounds wherein one s of the substituents of the acetylene group is a 6 substituted phenyl group, and the second substituent 7 is substituted or unsubstituted 6-chromanyl, 8 6-thiochromanyl or 6-tetrahydroquinolinyl group. 9 The compounds disclosed and claimed in United States 0 Patent No. 4,810,804 have retinoid acid-like 1 biological activity. 2 A published European patent application of the 3 present applicant (Publication No. 0284288, 4 published on September 28, 1988) describes compounds 5 having retinoic acid-like activity which are 6 4,4-disubsituted 6-chromanyl, 4,4-disubsituted 7 6-thiochromanyl and 4,4-disubsituted β 6-tetrahydroquinolinyl acetylenes also substituted 9 by a substituted heteroaryl group. o United States Patent Nos. 5,013,744, 5,023,341, 5,053,523, and 5,089,509 describe ethyne compounds 2 substituted with a heteroaromatic or monocyclic 3 aromatic substituent and also with a second 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-l,2,3,4-tetrahydro- 6 quinolinyl substituent. 7 United States Patent Nos. 4,992,468, 5,068,252, β 5,175,185, 5,202,471, 5,264,456, 5,324,840, 9 5,326,898, 5,349,105, 5,391,753, 5,414,007 and ιo 5,434,173 (assigned to the same assignee as the ii present application) and patents and publications 12 cited therein, describe or relate to compounds which 13 have retinoid-like biological activity and a 4 structure wherein a phenyl and a heteroaryl or a is phenyl and a second phenyl group is linked with an i6 olephinic or acetylenic linkage. 17 Published European Application 0 272 921 is (published on June 29, 1988 describes 19 [ (cyclohex-l"-enyl)-but-3'-ene-l'-ynyl]heteroaryl 20 carboxylic 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 [ (cyclohex-l"-enyl)-but-3'-ene-1'-ynyl]benzoic 24 acids, and United States Patent No. 5,426,118 25 describes [4-(l,2-epoxycyclohaxanyl)but-3-en-l- 26 ynyl)aromatic and heteroaromatic acids. 27 The compounds described in these patents have 2β retinoid-like biological activity. Numerous further 29 United States patents and applications for patent so assigned to the same assignee as the present 31 invention, are directed to compounds having 32 retinoid-like biological activity. 1 SUMMARY OP INVENTION 2 The present invention relates to compounds of 3 Formula 1 . - 8 9 o Formula 1 i where R lf R 2 , R 3 , and R 4 independently are H or 2 lower alkyl of 1 to 10 carbons; s R 5 is lower alkyl of 1 to 10 carbons, fluoro, 4 chloro, bromo, iodo, nitro, or fluoroalkyl having 1 s to 10 carbons; 6 m is an integer having the value of 1 - 4; 7 n is an integer having the value of 0 - 4; 8 Y is phenyl or a heteroaryl group selected from 9 a group consisting of pyridyl, thienyl, furyl, 0 pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl and 1 oxazolyl, said Y group being optionally substituted 2 with one or more R 5 group; 3 A is (CH- j )., where p is 0-5, lower branched chain 4 alkyl having 3-6 carbons, cycloalkyl having 3-6 5 carbons, alkenyl having 2-6 carbons and 1 or 2 6 double bonds, alkynyl having 2-6 carbons and 1 or 2 7 triple bonds, and β B is hydrogen, COOH or a pharmaceutically 9 acceptable salt thereof, COOR β , CONR 9 R 10 , -CH 2 0H, o CH-OR^, CH 2 OCOR 1JL , CHO, CH(OR 12 ) 2 , CH0R 13 0 , -COR,, 1 CR 7 (OR 12 ) 2/ or CR,OR 13 0, where R 7 is an alkyl, 2 cycloalkyl or alkenyl group containing 1 to 5 3 carbons, R 8 is an alkyl group of 1 to 10 carbons, or ι a cycloalkyl group of 5 to 10 carbons, or R β is 2 phenyl or lower alkylphenyl, R 9 and R 10 independently 3 are hydrogen, an alkyl group of 1 to 10 carbons, or 4 a cycloalkyl group of 5-10 carbons, or phenyl or 5 lower alkylphenyl, R X1 is lower alkyl, phenyl or 6 lower alkylphenyl, R 12 is lower alkyl, and R 13 is 7 divalent alkyl radical of 2-5 carbons. β In a second aspect, this invention relates to 9 the use of the compounds of Formula 1 for the o treatment of skin-related diseases, including, i without limitation, actinic keratoses, arsenic 2 keratoses, inflammatory and non-inflammatory acne, 3 psoriasis, ichthyoses and other keratinization and 4 hyperproliferative disorders of the skin, eczema, s atopic dermatitis, Darriers disease, lichen planus, 6 prevention and reversal of glucocorticoid damage 7 (steroid atrophy), as a topical anti-microbial, as s skin anti-pigmentation agents and to treat and 9 reverse the effects of age and photo damage to the 0 skin. The compounds are also useful for the 1 prevention and treatment of cancerous and precancerous conditions, including, premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, 5 uterus, colon, bladder, esophagus, stomach, lung, 6 larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the 9 treatment of Kaposi's sarcoma. In addition, the present compounds can be used as agents to treat 1 diseases of the eye, including, without limitation, proliferative vitreoretinopathy (PVR), retinal detachment, dry eye and other corneopathies, as well 1 as in the treatment and prevention of various 2 cardiovascular diseases, including, without 3 limitation, diseases associated with lipid 4 metabolism such as dyslipidemias, prevention of 5 post-angioplasty restenosis and as an agent to 6 increase the level of circulating tissue plasminogen 7 activator (TPA). Other uses for the compounds of β the present invention include the prevention and treatment of conditions and diseases associated with 10 human papilloma virus (HPV), including warts and 1 genital warts, various inflammatory diseases such as 12 pulmonary fibrosis, ileitis, colitis and Krohn's 13 disease, neurodegenerative diseases such as i Alzheimer's disease, Parkinson's disease and stroke, is improper pituitary function, including insufficient 16 production of growth hormone, modulation of 17 apoptosis, including both the induction of apoptosis is and inhibition of T-Cell activated apoptosis, 19 restoration of hair growth, including combination 0 therapies with the present compounds and other 2 agents such as Minoxidil R , diseases associated with 2 the immune system, including use of the present 3 compounds as immunosuppressants and 4 immunostimulants, modulation of organ transplant 5 rejection and facilitation of wound healing, 6 including modulation of chelosis. 7 This invention also relates to a pharmaceutical 8 formulation comprising a compound of Formula 1 in 9 admixture with a pharmaceutically acceptable 0 excipient. 1 In another aspect, this invention relates to 2 process for making a compound of Formula 1 which 3 process comprises: Formula 2 Formula 3 Formula 4 reacting a compound of Formula 2 with a compound of Formula 3 in the presence of cuprous iodide and Pd(PQ 3 )2Cl 2 (Q is phenyl) or a similar complex, giving the corresponding compound of Formula 1; or to the process of making a compound of Formula 1 which consists of reacting a zinc salt of Formula 4 with a compound of Formula 3 in the presence of Pd(PQ 3 ) 4 (Q is phenyl) or a similar complex. In Formulas 2, 3 and 4 the symbols R lf R 2 , R 3 , R 4 , R 5 , Y, A, and n have the same definition as in connection with Formula 1, X is a halogen, preferably I, B is H, or a protected acid, alcohol, aldehyde, or ketone, and X'" is a monovalent anion such as chloride, bromide or iodide. Still further the present invention relates to the processes of homologating a compound of Formula 1 where A is (CH 2 ) n and n is 0-4 to give an acid of ι Formula 1; or 2 converting an acid of Formula 1 to a salt; or 3 forming an acid addition salt; converting an acid of Formula 1 to an ester; or 5 converting an acid of Formula 1 to an amide; or β reducing an acid of Formula 1 to an alcohol or 7 aldehyde; or a converting an alcohol of Formula 1 to an ether 9 or ester; or ιo oxidizing an alcohol of Formula 1 to an π aldehyde; or i2 converting an aldehyde of Formula 1 to an 13 acetal; or i converting a ketone of Formula 1 to a ketal. is DETAILED DESCRIPTION OF THE INVENTION 6 General Embodiments 17 Definitions s The term alkyl refers to and covers any and all i9 groups which are known as normal alkyl, 0 branched-chain alkyl and cycloalkyl. The term 21 alkenyl refers to and covers normal alkenyl, branch 22 chain alkenyl and cycloalkenyl groups having one or 23 more sites of unsaturation. Unless stated otherwise 2 in these specifications lower alkyl means the 5 above-defined broad definition of alkyl groups 6 having 1 to 6 carbons, and as applicable, 3 to 6 7 carbons for branch chained and cyclo-alkyl groups. β Lower alkenyl is defined similarly having 2 to 6 carbons for normal alkenyl, and 3 to 6 carbons for o branch chained and cycloalkenyl groups. i The term "ester" as used here refers to and 2 covers any compound falling within the definition of 3 that term as classically used in organic chemistry. ι 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 with alcohols or thioalcohols preferably with 5 aliphatic alcohols having 1-6 carbons. Where the 6 ester is derived from compounds where B is -CH 2 OH, this term covers compounds derived from organic β acids capable of forming esters including 9 phosphorous based and sulfur based acids, or ιo compounds of the formula -Cϊ^OCOR^ where R lx is 11 defined as 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 is all aliphatic and aromatic mono- and di- substituted 16 amides. 17 A pharmaceutically acceptable salt may be ιβ prepared for any compounds in this invention having 19 a functionality capable of forming such salt, for 20 example an acid functionality. A pharmaceutically 21 acceptable salt is any salt which retains the 22 activity of the parent compound and does not impart 23 any deleterious or untoward effect on the subject to 2 which it is administered and in the context in which 25 it is administered. 26 Pharmaceutically acceptable salts may be derived 27 from organic or inorganic bases. The salt may be a 2β mono or polyvalent ion. Of particular interest are 29 the inorganic ions, sodium, potassium, calcium, and 30 magnesium. Organic salts may be made with amines, 31 particularly ammonium salts such as mono-, di- and 32 trialkyl amines or ethanol amines. Salts may also 33 be formed with caffeine, tromethamine and similar 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 5 iodide. Preferred salts are those formed with β inorganic acids such as hydrochloric acid, sulfuric 7 acid or phosphoric acid. Any of a number of simple β organic acids such as mono-, di- or tri- acid may 9 also be used. ιo The compounds of the present invention contain ii at least two double bonds, and therefore have trans 12 and cis (E and Z) isomers. However, presently it i3 was found that only the trans isomers of the 14 exocyclic double bond have significant retinoid-like is biological activity. In addition, the compounds of 16 the present invention may contain one or more chiral 17 centers and therefore exist in enantiomeric and is diastereomeric forms. The scope of the present 19 invention is intended to cover trans isomers, 0 mixtures of cis and trans isomers, mixtures of 1 diastereomers and racemic mixtures of enantiomers 2 (optical isomers) as well. 3 With reference now to Formula 1, the preferred 4 compounds of this invention are those where Y is 5 phenyl, pyridyl, thienyl or furyl, with the phenyl 6 and pyridyl derivatives being particularly 7 preferred. When Y is phenyl, compounds are 8 preferred where the ethynyl group and the A-B group 9 are attached to the 1 and 4 positions respectively o of a benzene ring (i.e., where the phenyl moiety of 1 the compound is para substituted) . When the Y group 2 is pyridyl, thienyl or furyl, compounds are 3 preferred where the ethynyl group and the A-B group are attached to the 2 and 5 positions respectively of a pyridine ring (the 6 and 3 positions of the nicotinic acid nomenclature being equivalent to the 2/5 designation in the pyridine nomenclature) or to the 5 and 2 positions respectively of a thiophene or furan group, respectively. Compounds where Y is phenyl, and where the phenyl group is para substituted and compounds where Y is pyridyl and the pyridyl group is 2,5-substituted in the above-described manner, are particularly preferred. With regard to the A-B side chain (substituent) on the phenyl or heteroaryl group Y, compounds are preferred where A is (CH 2 ) p and p is 0. With regard to group B, compounds are preferred where B is -C00H, an alkali metal salt or organic amine salt, or a lower alkyl ester therof. In the preferred compounds of the invention R x and R 3 are H or lower alkyl of 1 to 6 carbons, most preferably these groups are methyl. The R 2 , R 4 and R 5 groups are preferably H or lower alkyl of 1 to 6 carbons, most preferably H. The most preferred compounds of the invention are shown in Table 1 with reference to Formula 5. Formula 5 • Table 1 2 Compound No. X 2 «J 3 1 CH Et 4 2 CH H 5 3 N Et 6 4 N H 7 Modes of Administration β The compounds of this invention may be 9 administered systemically or topically, depending on ιo such considerations as the condition to be treated, ii need for site-specific treatment, quantity of drug 12 to be administered, and numerous other 13 considerations. 14 In the treatment of dermatoses, it will is generally be preferred to administer the drug 16 topically, though in certain cases such as treatment 17 of severe cystic acne or psoriasis, oral iβ administration may also be used. Any common topical 19 formulation such as a solution, suspension, gel, 0 ointment, or salve and the like may be used. 1 Preparation of such topical formulations are well 2 described in the art of pharmaceutical formulations 3 as exemplified, for example. Remington's 4 Pharmaceutical Science, Edition 17, Mack Publishing 5 Company, Easton, Pennsylvania. For topical β application, these compounds could also be 7 administered as a powder or spray, particularly in 8 aerosol form. If the drug is to be administered 9 systemically, it may be confected as a powder, pill, 0 tablet or the like or as a syrup or elixir suitable 1 for oral administration. For intravenous or 2 intraperitoneal administration, the compound will be 3 prepared as a solution or suspension capable of ι being administered by injection. In certain cases, 2 it may be useful to formulate these compounds by 3 injection. In certain cases, it may be useful to 4 formulate these compounds in suppository form or as ε extended release formulation for deposit under the 6 skin or intramuscular injection. 7 Other medicaments can be added to such topical β formulation for such secondary purposes as treating 9 skin dryness; providing protection against light; ιo other medications for treating dermatoses; ii medicaments for preventing infection, reducing 12 irritation, inflammation and the like. 13 Treatment of dermatoses or any other indications 14 known or discovered to be susceptible to treatment is by retinoic acid-like compounds will be effected by 16 administration of the therapeutically effective dose 17 of one or more compounds of the instant invention. ιβ A therapeutic concentration will be that i9 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 β susceptibility to treatment. Accordingly, no single 9 concentration will be uniformly useful, but will 0 require 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 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 therapeutically effective 5 concentration for topical application. If 6 administered systemically, an amount between 0.01 7 and 5 mg per kg per day of body weight would be 8 expected to effect a therapeutic result in the treatment of many disease for which these compounds o are useful. 1 Assay of Retinoid-like Biological Activity 2 The retinoid-like activity of these compounds is 3 confirmed through the classic measure of retinoic acid activity involving the effects of retinoic acid s on ornithine decarboxylase. The original work on 6 the correlation between retinoic acid and decrease in cell proliferation was done by Verma & Boutwell, s Cancer Research, 1977, 37,2196-2201. That reference 9 discloses that ornithine decarboxylase (ODC) 0 activity increased precedent to polyamine 1 biosynthesis. It has been established elsewhere that increases in polyamine synthesis can be 3 correlated or associated with cellular proliferation. Thus, if ODC activity could be 5 inhibited, cell hyperproliferation could be modulated. Although all causes for ODC activity increases are unknown, it is known that 12-0-tetradecanoylphorbol-13-acetate (TPA) induces 9 ODC activity. Retinoic acid inhibits this induction of ODC activity by TPA. An assay essentially following the procedure set out in Cancer Res: 1662-1670,1975 may be used to demonstrate inhibition of TPA induction of ODC by compounds of this ι invention. The results of this assay for certain 2 exemplary compounds of the invention are shown in 3 Table 1 below, wherein either the IC 80 or IC 60 value 4 for each exemplary compound is indicated in namolar 5 concentration units. (As is known in the art, the e IC 60 value is that concentration of the compound (in 7 nanomols) which results in 60 % inhibition.) β Table 1 Compound # IC 60 9 10 11 12 13 14 15 SPECIFIC EMBODIMENTS 6 Synthetic Processes for Preparing Compounds of 17 the Invention is The compounds of this invention can be made by a i9 number of different synthetic chemical pathways. To 20 illustrate this invention, there is here outlined a 21 series of steps which have been proven to provide 22 the compounds of Formula 1 when such synthesis is 3 followed in fact and in spirit. The synthetic 2 chemist will readily appreciate that the conditions 25 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 2β synthetic chemist will readily appreciate that the 29 herein described synthetic steps may be varied and 30 or adjusted by those skilled in the art without si departing from the scope and spirit of the 32 invention. 33 Reaction Scheme 1 ι Referring now to Reaction Scheme 1 a 2 (3'-thioxacyclohexyl-enyl)-but-l-ene-3-one 3 derivative of Formula 6 which has the desired R x , R 2 , 4 R 3 and R 4 substituents is reacted with with strong 5 base, such as lithium diisopropyl amide, and diethyl β chlorophosphate, to introduce the triple bond into 7 the molecule and yield the (3'-thioxacyclohexyl- s enyl)-but-l-ene-3-yne derivative of Formula 2. The starting material, compound of Formula 6, can be ιo 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 examples of the compounds of the invention is 14 1-(2' ,4' ,4'-trimethyl-1'-thiacyclohex-2'-ene-3'-yl)- s but-1-ene-3-one (Compound 5). Compound 5 is 16 available in accordance with chemical literature, as i7 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 l-(2' ,4' ,4'-trimethyl-1'-thiacyclohex-2'-ene-3'-yl)- 21 but-l-ene-3-yne (Compound 6). 22 In order to introduce a phenyl or heteroaryl 23 substitutent on the acetylene (ethyne) portion of a 24 compound of Formula 2, the latter compound is 25 coupled with the reagent X- (R 5 ) B -A-B (Formula 3). In 26 other words, the phenyl or heteroaryl substitutent 27 is introduced into the (3'-thioxacyclohexyl-enyl) ]- 2β but-l-ene-3-yne derivative of Formula 2 by reacting 29 the latter with a halogen substituted phenyl or so heteroaromatic compound of Formula 3 in which the 31 phenyl or heteroaromatic nucleus (Y) either has the 32 desired substituent (A-B) or wherein the actual 33 subsituent A-B can be readily converted to the 1 desired substituent by means of organic reactions 2 well known in the art. 3 Coupling of the (3'-thioxacyclohexyl-enyl) ]- 4 but-1-ene-3-yne derivative of Formula 2 with the 5 reagent X- (R 5 ) n -A-B (Formula 3) is affected directly e in the presence of cuprous iodide, a suitable 7 catalyst, typically of the formula Pd(PQ 3 )Cl 2 (Q is β phenyl) and an acid acceptor, such as triethylamine, 9 in an inert gas (argon) atmosphere. Alternatively, o a metal salt, such as the zinc salt of Formula 4 i derived from the ethynyl compound of Formula 2 is 2 reacted with the reagent of Formula 3 in the s presence of a palladium complex catalyst having the 4 formula Pd(PQ 3 ) 4 (Q is phenyl) or similar complex. s Generally speaking, coupling between an 6 ethynylbenzene compound or its zinc salt and a 7 halogen substituted aryl or heteroaryl compound, s such as the reagent of Formula 3, is described in 9 United States Patent No. 5,264,456, the specification of which is expressly incorporated 1 herein by reference. Coupling between l-(2' ,6' ,6'-trimethylcyclohex-l'-enyl)but-l-ene-3-yn 3 e and ethyl 6-chlorinicotinate is described in 4 United States Patent No. 4,927,947, and coupling between l-(2',6' ,6'-trimethylcyclohex-1'-enyl)but- l-ene-3-yne and ethyl 4-iodobenzoate is described in United States Patent No. 4,739,098. The specification of United States Patent No. 4,927,947 and 4,739,098 are expressly incorporated herein by reference. The disubstituted acetylene compounds of Formula 1 which result from the coupling reaction shown in Reaction Scheme 1 may be the target compounds made ι 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 5 steps are further discussed below, and are indicated e in Reaction Scheme 1 as conversion into homologs and 7 derivatives. β Carboxylic acids are typically esterified by 9 refluxing the acid in a solution of the appropriate ιo alcohol in the presence of an acid catalyst such as ii 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. is The ester is recovered and purified by conventional 16 means. Acetals and ketals are readily made by the i7 method described in March, "Advanced Organic is 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 McOmie, Plenum Publishing Press, 23 1973 and Protecting Groups, Ed. Greene, John Wiley & 4 Sons, 1981. 5 A means for making compounds where A is (CH 2 ) a 26 (n is 1 - 5) is to subject the compounds of Formula 7 1, where B is an acid or other function, to β homologation, using the well known Arndt-Eistert 29 method of homologation, or other known homologation 30 procedures. 31 Compounds of Formula 1, where A is an alkenyl 32 group having one or more double bonds can be made 3 for example, by having the requisite number of ι double bonds incorporated into the reagent of 2 Formula 3 which is reacted with the ethyne compound or its metal salt, as shown in Reaction Scheme 1. 4 Generally speaking, such compounds where A is an 5 unsaturated carbon chain can be obtained by 6 synthetic schemes well known to the practicing organic chemist; for example by Wittig and like β reactions, or by introduction of a double bond by β elimination of halogen from an alpha-halo-carboxylic ιo acid, ester or like carboxaldehyde. Compounds of ii 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 is reactions well known in the art, for example, by i6 reaction of a corresponding methyl ketone with 17 strong base, such as lithium diisopropyl amide, is The acids and salts derived from compounds of 19 Formula 1 are readily obtainable from the 0 corresponding esters . Basic saponification with an 1 alkali metal base will provide the acid. For 2 example, an ester of Formula 1 may be dissolved in a 3 polar solvent such as an alkanol, preferably under an inert atmosphere at room temperature, with about 5 a three molar excess of base, for example, potassium 6 hydroxide, sodium hydroxide or lithium hydroxide. 7 The solution is stirred for an extended period of 8 time, between 15 and 20 hours, cooled, acidified and 9 the hydrolysate recovered by conventional means, o The synthesis of carboxylic acids from the esters 1 which are obtained in the coupling step between a 2 reagent of Formula 2 and of Formula 3 (where B 3 represents for example C00C 2 H 5 ) is a step that leads ι to several preferred compounds of the present 2 invention. 3 The amide may be formed by any appropriate 4 amidation means known in the art from the 5 corresponding esters or carboxylic acids. One way β to prepare such compounds is to convert an acid to 7 an acid chloride and then treat that compound with β ammonium hydroxide or an appropriate amine. g Alcohols are made by converting the corresponding o acids to the acid chloride with thionyl chloride or i other means (J. March, "Advanced Organic Chemistry", 2 2nd Edition, McGraw-Hill Book Company), then 3 reducing the acid chloride with sodium borohydride 4 (March, Ibid, pg. 1124), which gives the s corresponding alcohols. Alternatively, esters may 6 be reduced with lithium aluminum hydride at reduced 7 temperatures. Alkylating these alcohols with s appropriate alky halides under Williamson reaction 9 conditions (March, Ibid, pg. 357) gives the 0 corresponding ethers. These alcohols can be 1 converted to esters by reacting them with 2 appropriate acids in the presence of acid catalysts 3 or dicyclohexylcarbodiimide and dimethlaminopyridine. 5 Aldehydes can be prepared from the corresponding 6 primary alcohols using mild oxidizing agents such as 7 pyridinium dichromate in methylene chloride (Corey, β E. J., Schmidt, G., Tet. Lett.. 399, 19791. or 9 dimethyl sulfoxide/oxalyl chloride in methylene 0 chloride (Omura, K., Swern, D., Tetrahedron, 1978, 1 34.r 1651). 2 Ketones can be prepared from an appropriate 3 aldehyde by treating the aldehyde with an alkyl ι 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. e Compounds of Formula 1 where B is H can be pre- 7 pared from the corresponding halogenated aromatic β compounds, preferably where the halogen is I. g The reagent of Formula 3 is generally speaking ιo available in accordance with the chemical ii literature, or when necessary can be obtained, 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 is certain reagents of Formula 3 (where A-B represents i6 -C00R β ) which are used for the preparation of the 17 preferred examples of the present invention, are 18 also described below. 19 Specific Examples 20 Ethyl 4-iodobenzoate 21 To a suspension of 10 g (40.32 mmol) of 2 4-iodobenzoic acid in 100 ml absolute ethanol was 3 added 2 ml thionyl chloride and the mixture was then 4 heated at reflux for 3 hours. Solvent was removed 5 in vacuo and the residue was dissolved in 100 ml 6 ether. The ether solution was washed with saturated 7 NaHC0 3 and saturated NaCl solutions and dried β (MgS0 4 ). Solvent was then removed in vacuo and the 9 residue kugelrohr distilled (100 degrees C; 0.55 mm) 0 to give the title compound as a colorless oil, PMR 1 (CDC1 3 ): 1.42 (3H, t, J-7 Hz), 4,4 (2H, q, J-7 Hz), 2 7.8 (4H). 3 ι 6-Iodonicotinic acid 2 To 27.97 g (186.6 mmol) of sodium iodide cooled 3 to -78°C was added 121.77 g (71.6 ml, 952.0 mmol) of 4 hydriodic acid (in 57 wt % aqueous solution). The s reaction mixture was allowed to warm slightly with e stirring for 5 minutes, and then 30.00 g (190.4 7 mmol) of 6-chloronicotinic acid was added. The s resulting mixture was allowed to warm to room 9 temperature with stirring and then heated at o 120-125°C in an oil bath for 42 hours. A dark brown i layer formed above the yellow solid material. The 2 reaction mixture was allowed to cool to room 3 temperature and then poured into acetone (chilled to 4 0°C) . The resultant yellow solid was collected by s filtration, washed with 200 ml of IN NaHS0 3 solution, 6 and dried in vacuum (3 mm Hg) to give the title 7 compound as a pale yellow solid. 8 PMR (DMS0-d 6 ): d 7.90 (IH, dd, J = 8.1, 2 Hz), 7.99 9 (IH, d, J = 8.1 Hz), 8.80 (IH, d, J = 2 Hz). 0 Ethyl 6-iodonicotinoate 1 To a suspension of 23.38 g (94.2 mmol) of 2 6-iodonicotinic acid in 100 ml of dichloromethane 3 was added a solution of 19.86 g (103.6 mmol) of 4 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 5 hydrochloride in 250 ml of dichloromethane. To this 6 suspension was added 12.40 g (15.8 ml, 269.3 mmol) 7 of ethanol (95%) and 1.15 g (9.4 mmol) of β 4-dimethylaminopyridine. The resulting solution was 9 then heated at 50°C in an oil bath for 24.5 hours, 0 concentrated in vacuo, partitioned between 200 ml of i water and 250 ml of ethyl ether, and the layers 2 were separated. The aqueous phase was washed with 2 3 x 150 ml-portions of ethyl ether. All organic ι phases were combined, washed once with 75 ml of 2 brine solution, dried over MgS0 4 , filtered and 3 concentrated in vacuo to yield a yellow solid 4 residue. Purification by flash chromatography 5 (silica, 10% ethyl acetate in hexane) yielded the 6 title compound as a white solid. 7 PMR (CDC1 3 ): d 1.41 (3H, t, J = 7.1 Hz), 4.41 (2H, β q, J = 7.1 Hz), 7.85 (IH, d, J = 8.2 Hz), 7.91 (IH, 9 dd, J = 8.2, 2.1 Hz), 8.94 (IH, d, J = 2.1 Hz). ιo 1-(2' , 4' .4'-Trimethyl-1'-thiacyclohex-2'-ene-3'- ii y1)-but-1 (E )-ene-3-yne (Compound 6) 12 To a solution of lithium diisopropyl amide (LDA) is 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 is was added dropwise l-(2' ,4' ,4'-trimethyl-1'- i6 thiacyclohex-2'-ene-3'-yl)-but-l-ene-3-one (Compound 17 5, 4-thia-ionone, 84 mg, 0.4 mmol) at -78°C. is (Compound 5 is available in accordance with 19 Tetrahedron 1966, 2J. pp259-264, incorporated herein 0 by reference. ) The reaction mixture was stirred 1 for 1 hour when diethyl chlorophosphate (0.06 ml) 2 was added at -78 β C. The reaction mixture was 3 gradually warmed to room temperature and then 4 transferred through cannulation into a solution of 5 LDA at -78 β C, prepared as above. The reaction 6 mixture was slowly warmed to room temperature and 7 left overnight. Water was added to the reaction 8 mixture and the mixture was extracted into ethyl 9 acetate. The organic layer was washed with 10% of o HCl, NaHC0 3 , brine and dried over MgS0 4 . The solvent 1 was evaporated and the residue was purified by 2 column chromatography (ethyl acetate/hexane 1/10) to 3 give the title compound as a yellow oil (50 mg) . 1 X H NMR 6 (CDC1 3 ) 6.66 (d, J = 16.5 Hz, IH), 5.43 (dd, 2 J = 16.3, 2.3 Hz, IH), 2.96 (d, J = 2.3 Hz, IH), 3 2.83 (m, 2H), 1.95 (s, 3H), 1.85 (m, 2H), 1.09 (s, 6H). 5 Ethyl 4-f4'- ( 2" ,6".6" .-Trimethyl-3"-thioxacyclohex- 6 l"-enyl)-but-3' (El-ene-1'- ynyl benzoate (Compound f 1) β A solution of l-(2' ,4' ,4'-trimethyl-1'-thia- 9 cyclohex-2'-ene-3'-yl)-but-l-ene-3-yne (Compound 6, 10 232 mg, 1.21 mmol), Cul (45.9 mg) and ethyl 4- 11 iodobenzoate (334 mg, 1.21 mmol) in 10 ml of 12 triethylamine (TEA) was purged with N 2 for 1 minute 13 before Pd(Ph 3 P) 2 Cl 2 (255 mg) was added to the 14 solution. The resulting yellow slurry was stirred 15 at room temperature for 2 days. The reaction was ιe filtered and the solution was concentrated to give a 17 brown residue. The residue was purified by column is chromatography (ethyl acetate/hexane 1/50) to give 19 the title compound as a yellow oil (248 mg, 60%). 20 l H NMR δ (CDC1 3 ) 7.99 (d, J = 8.5 Hz, 2H), 7.49 (d, J 21 = 8.5 Hz, 2H), 6.72 (d, J = 15.6 Hz, IH), 5.68 (d, J 22 = 15.6 Hz, IH), 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-r4'- (2".6".6"-Trimethyl-3"-thioxacyclohex-1"-eny1 ) 26 -but-3' (Eϊ-ene-l'-ynyl1 enzoic Acid (Compound 2) 27 To a solution of ethyl 4-[4'-(2",6",6",-trim- 2β ethyl-3"-thioxacyclohex-l"-enyl)-but-3'-ene-1'- 29 ynyl]benzoate (Compound 1, 130 mg) in 3 ml of EtOH 30 was added 1ml of IN 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 ι 10% of HCl until the aqueous layer became neutral. 2 The organic layer was separated, washed with brine 3 and dried over MgS0 4 . After concentration, the 4 residue was purified by column chromatography (ethyl 5 acetate/hexane 1/1) to give the title compound as a 6 yellow crystals (95 mg) . 7 J H NMR δ (CDC1 3 ) 8.03 (d, J = 8.3 Hz, 2H), 7.52 (d, J 8 = 8.3 Hz, 2H), 6.74 (d, J = 15.9 Hz, IH), 5.69 (d, J 9 = 15.9 Hz, IH), 2.86 (m, 2H), 2.01 (s, 3H), 1.86 (m, ιo 2H), 1.14 (s, 6H). ii Ethyl 6-f4'- ( 2".6".6" .-Trimethyl-3"-thioxacvclohex- 12 1"-eny11-but-3' (E)-ene-l'- ynyl]nicotinate (Compound 13 3) 4 Using the same procedure as for the synthesis of is ethyl 4-[4'-(2",6",6",-trimethyl-3"-thioxacyclohex- 16 l"-enyl)-but-3'-ene-1'-ynyl]benzoate (Compound 1) 17 but using 50 mg of l-(2', 4' ,4'-trimethyl-1'- ιβ thiacyclohex-2'-ene-3'-yl)-but-l-ene-3-yne (Compound 19 5), 72 mg of ethyl 6-iodo nicotinate, 55 mg of 20 Pd(Ph 3 P) 2 Cl 2 and 9.9 mg of Cul in 2 ml of TEA, the 21 title compound was obtained as a yellow oil (59 mg, 2 67%). *H NMR δ (CDC1 3 ) 9.08 (d, J = 2.1 Hz, IH), 3 8.27 (dd, J = 8.2, 2.2 Hz, IH), 7.60 (d, J = 9.28 4 Hz, IH), 6.90 (d, J = 16.5 Hz, IH) , 5.80 (d, J = 5 16.4 Hz, IH), 4.37 (q, J = 7.1 Hz, 2H), 2.88 (m, 6 2H), 1.98 (s, 3H), 1.87 (m, 2H), 1.37 (t, J = 7.1 7 Hz, 3H), 1.15 (S, 6H). β 6-f4'- ( 2" .6".6" .-Trimethyl-3"-thioxacyclohex-1"-enyl 9 )-but-3WE)-ene-1'-ynyl]nicotinic Acid (Compound 4) 0 Using the same procedure as for the synthesis of 1 4-[4'-(2",6",6"-trimethyl-3"-thioxacyclohex-1"-enyl) 2 -but-3'-ene-1'-ynyl]benzoic acid (Compound 2) but 3 using ethyl 6-[4'-(2",6",6",-trimethyl-3"-thio- ι xacyclohex-1"-enyl)-but-3'-ene-1'-ynyl]nicotinate 2 (Compound 3, 15 mg), the title compound was obtained 3 as a yellow solid (12 mg, 80%). l H NMR δ (CDC1 3 ) 9.29 (s, IH), 8.34 (d, J = 8.3 Hz, s IH), 7.53 (d, J = 8.2 Hz, IH) , 6.91 (d, J - 16.1 Hz, β IH), 5.74 (d, J = 16.1 Hz, IH), 2.86 (m, 2H), 2.01 7 (s, 3H), 1.86 (m, 2H), 1.14 (s, 6H) .

Claims: WHAT IS CLAIMED IS 1. A compound of the formula where R lf R 2 , R 3 , and R 4 independently are H or lower alkyl of 1 to 10 carbons; R s 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 R 5 group; A is (CH 2 ) 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, C00R 8 , CONR 9 R 10 , -CH 2 0H, CH j OR^, CH j OCOR^, CHO, CH(0R 12 ) 2 , CH0R 13 0, -C0R 7 , CR 7 (0R 12 ) 2 , or CR-0R 13 0, where R, is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R„ is an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl, R 9 and R 10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R u is lower alkyl, phenyl or lower alkylphenyl, R 12 is lower alkyl, and R 13 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 (CH 2 ) p , p is 0 and and B is COOH, COOR B or CONR 9 R 10 . 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 (CH 2 ) n , n is 0 and and B is COOH, COOR 8 or CONR 9 R 10 9. A compound of the formula ι where R x , R 2 , R 3 , and R 4 independently are H or 2 lower alkyl of 1 to 10 carbons; 3 m is an integer having the value of 1 - 4, and 4 R* is H, an alkyl group of 1 to 10 carbons or a 5 pharmaceutically acceptable cation. 6 10. A compound in accordance with Claim 9 where 7 R 4 is H or CH 3 . β 11. A compound in accordance with Claim 9 where 9 R 3 is H or CH 3 . o 12. A compound in accordance with Claim 9 where 1 R x is H or CH 3 . 2 13. A compound in accordance with Claim 9 where 3 R x is CH 3 , m is 0, R 3 is CH 3/ and R 4 is H.. 4 14. A compound in accordance with Claim 13 s where R * is H, or a pharmaceutically acceptable 6 cation. 7 15. A compound in accordance with Claim 13 s where R 8* is CHJ,CH,2. 9 16. A compound of the formula 9 where R l f R 2 , R 3 , and R 4 independently are H or o lower alkyl of 1 to 10 carbons; i m is an integer having the value of 1 - 4, and R^ is H, an alkyl group of 1 to 10 carbons or a pharmaceutically acceptable cation. 17. A compound in accordance with Claim 16 where R 4 is H or CH 3 . 18. A compound in accordance with Claim 16 where R 3 is H or CH 3 . 19. A compound in accordance with Claim 16 where R x is H or CH 3 . 20. A compound in accordance with Claim 16 where R x is CH 3 , m is 0, R 3 is CH 3 , and R 4 is H. 21. A compound in accordance with Claim 20 where R* is H or a pharmaceutically acceptable cation. 22. A compound in accordance with Claim 20 where RI 8 is CH 3 CH 2

Inventors: CHANDRARATNA ROSHANTHA A, TENG MIN, CHANDRARATNA, ROSHANTHA, A., TENG, MIN
Applicants: ALLERGAN INC, ALLERGAN
Application year: 1996
Main classification: C07D335
IPC codes: A61K31, A61P1, A61P3, A61P9, A61P17, A61P25, A61P27, A61P35, A61P43, C07D335, C07D409