ARYL- AND HETEROARYLCYCLOHEXENYL SUBSTITUTED ALKENES HAVING RETINOID AGONIST, ANTAGONIST OR INVERSE AGONIST TYPE BIOLOGICAL ACTIVITY

Abstract: Compounds of formula (1) wherein the symbols have the meaning defined in the specification, have retinoid-like, retinoid antagonist or retinoid inverse agonist-like biological activity.

Description: ι ARYL- AND HETEROARYLCYCLOHEXENYL 2 SUBSTITUTED ALKENES HAVING RETINOID AGONIST, 3 ANTAGONIST OR INVERSE AGONIST TYPE BIOLOGICAL ACTIVITY 4 BACKGROUND OF THE INVENTION 5 1. Field of the Invention 6 The present invention relates to novel compounds having 7 retinoid-like, retinoid antagonist and/or retinoid inverse-agonist-like 8 biological activity. More specifically, the present invention relates to 9 aryl and heteroarylcyclohexenyl substituted alkene derivatives which ιo have retinoid-like, retinoid antagonist or retinoid inverse agonist-like ιι biological activity. 12 2. Background Art 13 Compounds which have retinoid-like activity are well 14 known in the art, and are described in numerous United States and is other patents and in scientific publications. It is generally known and 16 accepted in the art that retinoid-like activity is useful for treating 17 animals of the mammalian species, including humans, for curing or 18 alleviating the symptoms and conditions of numerous diseases and 19 conditions. In other words, it is generally accepted in the art that 20 pharmaceutical compositions having a retinoid-like compound or 21 compounds as the active ingredient are useful as regulators of cell 22 proliferation and differentiation, and particularly as agents for treating 23 skin-related diseases, including, actinic keratoses, arsenic keratoses, 24 inflammatory and non-inflammatory acne, psoriasis, ichthyoses and 25 other keratinization and hyperproliferative disorders of the skin, 26 eczema, atopic dermatitis, Darriers disease, lichen planus, prevention 27 and reversal of glucocorticoid damage (steroid atrophy), as a topical 28 anti-microbial, as skin anti-pigmentation agents and to treat and reverse ι the effects of age and photo damage to the skin. Retinoid compounds 2 are also useful for the prevention and treatment of cancerous and 3 precancerous conditions, including, premalignant and malignant 4 hyperproliferative diseases such as cancers of the breast, skin, prostate, 5 cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral 6 cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, 7 leukoplakias and papillomas of the mucous membranes and in the β treatment of Kaposi's sarcoma. In addition, retinoid compounds can be 9 used as agents to treat diseases of the eye, including, without limitation, ιo proliferative vitreoretinopathy (PVR), retinal detachment, dry eye and ιι other corneopathies, as well as in the treatment and prevention of 12 various cardiovascular diseases, including, without limitation, diseases 13 associated with lipid metabolism such as dyslipidemias, prevention of 14 post-angioplasty restenosis and as an agent to increase the level of is circulating tissue plasminogen activator (TPA). Other uses for retinoid 16 compounds include the prevention and treatment of conditions and 17 diseases associated with human papilloma virus (HPV), including warts is and genital warts, various inflammatory diseases such as pulmonary 19 fibrosis, ileitis, colitis and Krohn's disease, neurodegenerative diseases 20 such as Alzheimer's disease, Parkinson's disease and stroke, improper 21 pituitary function, including insufficient production of growth hormone, 22 modulation of apoptosis, including both the induction of apoptosis and 23 inhibition of T-Cell activated apoptosis, restoration of hair growth, 24 including combination therapies with the present compounds and other 25 agents such as MinoxidiP, diseases associated with the immune system, 26 including use of the present compounds as immunosuppressants and 27 immunostimulants, modulation of organ transplant rejection and 28 facilitation of wound healing, including modulation of chelosis. ι Several United States Patents assigned to the same assignee as 2 the present application and patents and publications cited therein 3 describe or relate to cyclohexane, cyclohexene or disubstituted alkene 4 derivatives having retinoid like biological activity. Examples of such 5 patents are: 4,992,468; 5,068,252; 5,324,840; 5,326,898; 5,344,959; e 5,391,753; 5,399,586; 5,426,118; 5,434,173; 5,451,605; 5,455,265; 7 5,475,022; and 5,475,113. Still further, several co-pending applications 8 and recently issued patents which are assigned to the assignee of the 9 present application, are directed to further compounds having ιo retinoid-like activity. ιι Although pharmaceutical compositions containing retinoids have 12 well established utility (as is demonstrated by the foregoing citation of 13 patents and publications from the voluminous literature devoted to this 14 subject) retinoids also cause a number of undesired side effects at is therapeutic dose levels, including headache, teratogenesis, 16 mucocutaneous toxicity, musculoskeletal toxicity, dyslipidemias, skin 17 irritation, headache and hepatotoxicity. These side effects limit the is acceptability and utility of retinoids for treating disease. 19 It is now general knowledge in the art that two main types of 20 retinoid receptors exist in mammals (and other organisms). The two 21 main types or families of receptors are respectively designated the 22 RARs and RXRs. Within each type there are subtypes; in the RAR 23 family the subtypes are designated RAR α , RAR β and RAR γ , in RXR 24 the subtypes are: RXR α , RXB β and RXR γ . It has also been established 25 in the art that the distribution of the two main retinoid receptor types, 26 and of the several sub-types is not uniform in the various tissues and 27 organs of mammalian organisms. Moreover, it is generally accepted in 28 the art that many unwanted side effects of retinoids are mediated by ι one or more of the RAR receptor subtypes. Accordingly, among 2 compounds having agonist-like activity at retinoid receptors, specificity 3 or selectivity for one of the main types or families, and even specificity 4 or selectivity for one or more subtypes within a family of receptors, is 5 considered a desirable pharmacological property. Some compounds 6 bind to one or more RAR receptor subtypes, but do not trigger the 7 response which is triggered by agonists of the same receptors. A β compound that binds to a biological receptor but does not trigger an 9 agonist-like response is usually termed an antagonist. Accordingly, the ιo "effect" of compounds on retinoid receptors may fall in the range of ιι having no effect at all, (inactive compound, neither agonist nor 12 antagonist), the compound may elicit an agonist-like response on all 13 receptor subtypes (pan-agonist), or a compound may be a partial agonist 14 and/or partial antagonist of certain receptor subtypes if the compound is binds to but does not activate certain receptor subtype or subtypes but 16 elicits an agonist-like response in other receptor subtype or subtypes. 17 A pan-antagonist is a compound that binds to all known retinoid is receptors but does not elicit an agonist-like response in any of the 19 receptors. 20 Recently a two-state model for certain receptors, including the 21 above-mentioned retinoid receptors, have emerged. In this model, an 22 equilibrium is postulated to exist between inactive receptors and 23 spontaneously active receptors which are capable of coupling with a G 24 protein in the absence of a ligand (agonist). In this model, so-called 25 "inverse agonists" shift the equilibrium toward inactive receptors, thus 26 bringing about an overall inhibitory effect. Neutral antagonists do not 27 effect the receptor equilibrium but are capable of competing for the 28 receptors with both agonists (ligands) and with inverse agonists. ι It has been recently discovered and described in pending 2 applications assigned to the same assignee as the present application 3 that the above mentioned retinoid antagonist and/or inverse agonist- 4 like activity of a compound is also a useful property, in that such 5 antagonist or inverse agonist-like compounds can be utilized to block 6 certain undesired side effects of retinoids, to serve as antidotes to 7 retinoid overdose or poisoning, and may lend themselves to other β pharmaceutical applications as well. More particularly, regarding the 9 published scientific and patent literature in this field, published PCT ιo application WO 94/14777 describes certain heterocyclic carboxylic acid ιι derivatives which bind to RAR retinoid receptors and are said in the 12 application to be useful for treatment of certain diseases or conditions, 13 such as acne, psoriasis, rheumatoid arthritis and viral infections. A 14 similar disclosure is made in the article by Yoshimura et al. J Med. is Chem. 1995, 38, 3163-3173. Kaneko et al. Med. Chem Res. (1991) 16 1:220-225; Apfel et al. Proc. Natl. Acad. Sci. USA Vol 89 pp 7129-7133 17 August 1992 Cell Biology; Eckhardt et al. Toxicology Letters, 70 (1994) 18 299-308; Keidel et al. Molecular and Cellular Biology, Vol 14, No. 1, 19 Jan. 1994, p 287-298; and Eyrolles et al. J. Med. Chem. 1994, 37, 20 1508-1517 describe compounds which have antagonist like activity at one 21 or more of the RAR retinoid subtypes. 22 SUMMARY OF THE INVENTION 23 The present invention relates to compounds of Formula 1 8 Formula 1 ι wherein one of the dashed lines respectively designated and β 2 represents a bond and the other represents absence of a bond, the 3 dashed line designated γ represents absence of a bond when β 4 represents a bond, and wherein the dashed line designated γ represents 5 absence of a bond or a bond when represents a bond; 6 the cyclohexene ring is unsubstituted or substituted with 1 to 7 7 R t groups where R t is independently selected from the group consisting β of alkyl of 1 to 6 carbons, F, Cl, Br and I; 9 R 3 is H, alkyl of 1 to 6 carbons, F, Cl, Br or I; ιo R 4 is phenyl, naphthyl, or heteroaryl where the heteroaryl group is ιι 5-membered or 6-membered and has 1 to 3 heteroatoms selected from 12 the group consisting of O, S and N, and where the R 4 group is 13 unsubstituted or substituted with 1 to 5 R 5 groups where R s is 14 independently selected from the group consisting of F, Cl, Br, I, N0 2 , is N(R 8 ) 2 , N(R 8 )COR 8 , NR 8 CON(R 8 ) 2 , OH, OCOR 8 , OR 8 , CN, COOH, 16 COOR 8 an alkyl group having 1 to 10 carbons, fluoro substituted alkyl 17 group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons is and 1 to 3 double bonds, alkynyl group having 1 to 10 carbons and 1 to 19 3 triple bonds, or a (trialkyl)silyl group where the alkyl groups 20 independently have 1 to 6 carbons; 21 Z is -CR^N, 22 where n' is an integer having the value 0 - 5, 23 -CO-NR r , 24 -CS-NR , 25 -COO-, 26 -CSO-; 27 -CO-CR^CR ! -; 28 Y is phenyl or naphthyl, or heteroaryl selected from a group ι consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, 2 thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl, naphthyl or 3 heteroaryl groups being unsubstituted or substituted with one or two R 2 4 groups, where R 2 is independently selected from the group consisting of 5 lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 , fluoro substituted alkyl 6 of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, and alkylthio of 1 7 to 6 carbons; alternatively when Z is -(CR 1 =CR 1 ) n ,- and n' is 2, 3, 4 or 5 8 then Y may represent a direct valence bond between said (CR 2 =CR 2 ) n , 9 group and B; ιo A is (CH 2 ) q where q is 0-5, lower branched chain alkyl having 3-6 ιι carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 12 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds, 13 and 14 B is hydrogen, COOH or a pharmaceutically acceptable salt is thereof, COOR 8 , CONR,R 10 , -CH 2 OH, CH 2 OR u , CH 2 OCOR n , CHO, 16 CH(OR 12 ) 2 , CHOR 13 0, -COR 7 , CR 7 (OR u ) 2 , CR 7 OR 13 0, or Si(C 1 6 alkyl) 3 , 17 where R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 18 carbons, R 8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl) alkyl 19 where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 20 10 carbons, or R 8 is phenyl or lower alkylphenyl, R, and R 10 21 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a 22 cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R u is 23 lower alkyl, phenyl or lower alkylphenyl, R n is lower alkyl, and R 13 is 24 divalent alkyl radical of 2-5 carbons. 25 In a second aspect, this invention relates to the use of the 26 compounds of Formula 1 for the treatment of skin-related diseases, 27 including, without limitation, actinic keratoses, arsenic keratoses, 28 inflammatory and non-inflammatory acne, psoriasis, ichthyoses and ι other keratinization and hyperproliferative disorders of the skin, 2 eczema, atopic dermatitis, Darriers disease, lichen planus, prevention 3 and reversal of glucocorticoid damage (steroid atrophy), as a topical 4 anti-microbial, as skin anti-pigmentation agents and to treat and reverse 5 the effects of age and photo damage to the skin. The compounds are 6 also useful for the prevention and treatment of cancerous and 7 precancerous conditions, including, premalignant and malignant 8 hyperproliferative diseases such as cancers of the breast, skin, prostate, 9 cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral ιo cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, ιι leukoplakias and papillomas of the mucous membranes and in the 12 treatment of Kaposi's sarcoma. In addition, the present compounds can 13 be used as agents to treat diseases of the eye, including, without 14 limitation, proliferative vitreoretinopathy (PVR), retinal detachment, dry is eye and other corneopathies, as well as in the treatment and prevention 16 of various cardiovascular diseases, including, without limitation, diseases 17 associated with lipid metabolism such as dyslipidemias, prevention of 18 post-angioplasty restenosis and as an agent to increase the level of 19 circulating tissue plasminogen activator (TPA). Other uses for the 20 compounds of the present invention include the prevention and 21 treatment of conditions and diseases associated with Human papilloma 22 virus (HPV), including warts and genital warts, various inflammatory 23 diseases such as pulmonary fibrosis, ileitis, colitis and Krohn's disease, 24 neurodegenerative diseases such as Alzheimer's disease, Parkinson's 25 disease and stroke, improper pituitary function, including insufficient 26 production of growth hormone, modulation of apoptosis, including both 27 the induction of apoptosis and inhibition of T-Cell activated apoptosis, 28 restoration of hair growth, including combination therapies with the ι present compounds and other agents such as Minoxidil R , diseases 2 associated with the immune system, including use of the present 3 compounds as immunosuppressants and immunostimulants, modulation 4 of organ transplant rejection and facilitation of wound healing, including 5 modulation of chelosis. 6 Alternatively, those compounds of the invention which act as 7 antagonists or inverse agonists of one or more retinoid receptor β subtypes are useful to prevent certain undesired side effects of retinoids 9 which are administered for the treatment or prevention of certain ιo diseases or conditions. For this purpose the retinoid antagonist and/or ιι inverse agonist compounds of the invention may be co-administered 12 with retinoids. The retinoid antagonist and inverse agonist compounds 13 of the present invention are also useful in the treatment of acute or 14 chronic toxicity resulting from overdose or poisoning by retinoid drugs is or Vitamin A. 16 This invention also relates to a pharmaceutical formulation 17 comprising a compound of Formula 1 in admixture with a is pharmaceutically acceptable excipient, said formulation being adapted 19 for administration to a mammal , including a human being, to treat or 20 alleviate the conditions which were described above as treatable by 21 retinoids, to be co-administered with retinoids to eliminate or reduce 22 side effects of retinoids, or to treat retinoid or Vitamin A overdose or 23 poisoning. 24 BIOLOGICAL ACTIVITY, MODES OF ADMINISTRATION 25 Assays of Retinoid-like or Retinoid Antagonist and Inverse Aαonist- 26 like Biological Activity 27 A classic measure of retinoic acid activity involves measuring the 28 effects of retinoic acid on ornithine decarboxylase. The original work ι on the correlation between retinoic acid and decrease in cell 2 proliferation was done by Verma & Boutwell, Cancer Research, 1977, 37, 3 2196-2201. That reference discloses that ornithine decarboxylase 4 (ODC) activity increased precedent to polyamine biosynthesis. It has 5 been established elsewhere that increases in polyamine synthesis can be 6 correlated or associated with cellular proliferation. Thus, if ODC 7 activity could be inhibited, cell hyperproliferation could be modulated. β Although all cases for ODC activity increases are unknown, it is known 9 that 12-0-tetradecanoylphorbol-13-acetate (TPA) induces ODC activity. ιo Retinoic acid inhibits this induction of ODC activity by TPA. An assay ιι essentially following the procedure set out in Cancer Research: 12 1662-1670,1975 may be used to demonstrate inhibition of TPA induction 13 of ODC by compounds of this invention. "I o" is that concentration of 14 the test compound which causes 60% inhibition in the ODC assay. By is analogy, "IC 80 ", for example, is that concentration of the test compound 16 which causes 80% inhibition in the ODC assay. 17 Other assays described below, measure the ability of the 18 compounds of the present invention to bind to, and/or activate various 19 retinoid receptor subtypes. When in these assays a compound binds to 20 a given receptor subtype and activates the transcription of a reporter 21 gene through that subtype, then the compound is considered an agonist 22 of that receptor subtype. Conversely, a compound is considered an 23 antagonist of a given receptor subtype if in the below described 24 co-tranfection assays the compound does not cause significant 25 transcriptional activation of the receptor regulated reporter gene, but 26 nevertheless binds to the receptor with a K,, value of less than 27 approximately 1 micromolar. In the below described assays the ability 28 of the compounds to bind to RAR α , RAR β , RAR γ , RXR a , RXR β and ι RXR r receptors, and the ability or inability of the compounds to 2 activate transcription of a reporter gene through these receptor subtypes 3 can be tested. 4 Specifically, a chimeric receptor transactivation assay which tests 5 for agonist-like activity in the RAR ff , RAR β , RAR γ , RXR α receptor 6 subtypes, and which is based on work published by Feigner P. L. and 7 Holm M. (1989) Focus, 112 is described in detail in United States e Patent No. 5,455,265 the specification of which is hereby expressly 9 incorporated by reference. 10 A holoreceptor transactivation assay and a ligand binding assay ιι which measure the antagonist/agonist like activity of the compounds of 12 the invention, or their ability to bind to the several retinoid receptor 13 subtypes, respectively, are described in published PCT Application No. 14 WO W093/11755 (particularly on pages 30 - 33 and 37 - 41) published is on June 24, 1993, the specification of which is also incorporated herein 16 by reference. A description of the holoreceptor transactivation assay is 17 also provided below. is HOLORECEPTOR TRANSACTIVATION ASSAY 19 CV1 cells (5,000 cells/well) were transfected with an RAR 20 reporter plasmid MTV-TREp-LUC (50 ng) along with one of the RAR 21 expression vectors (10 ng) in an automated 96-well format by the 22 calcium phosphate procedure of Hevman et al. Cell 68, 397 - 406, 23 (1992). For RXR α and RXR γ transactivation assays, an RXR-responsive 24 reporter plasmid CRBPII-tk-LUC (50 ng) along with the appropriate 25 RXR expression vectors (10 ng) was used substantially as described by 26 Hevman et al. above, and Allegretto et al. J. Biol. Chem. 268, 26625 - 27 26633. For RXR β transactivation assays, an RXR-responsive reporter 28 plasmid CPRE-tk-LUC (50 mg) along with RXR β expression vector (10 ι mg) was used as described in above. These reporters contain DRI 2 elements from human CRBPII and certain DRI elements from 3 promoter, respectively, (see Mangelsdorf et al. The Retinoids: Biology, 4 Chemistry and Medicine, pp 319 - 349, Raven Press Ltd., New York and 5 Hevman et al., cited above) (1, 8). A β-galactosidase (50 ng) expression 6 vector was used as an internal control in the transfections to normalize 7 for variations in transfection efficiency. The cells were transfected in 8 triplicate for 6 hours, followed by incubation with retinoids for 36 hours, 9 and the extracts were assayed for luciferase and β-galactosidase ιo activities. The detailed experimental procedure for holoreceptor ιι transactivations has been described in Hevman et al. and Allegretto et 12 al ^ cited above. The results obtained in this assay are expressed in 13 EC 50 numbers, as they are also in the chimeric receptor transactivation 14 assay. The Hevman et al. Cell 68, 397 - 406, Allegretto et al. J. Biol. is Chem. 268, 26625 - 26633, and Mangelsdorf et al. The Retinoids: 16 Biology, Chemistry and Medicine, pp 319 - 349, Raven Press Ltd., New 17 York, are expressly incorporated herein by reference. The results of is ligand binding assay are expressed in K^ numbers. (See Cheng et al. 19 Biochemical Pharmacology Vol. 22 pp 3099-3108, expressly incorporated 20 herein by reference.) 21 Table 1 shows the results of the ligand binding assay for certain 22 exemplary compounds of the invention for the receptor subtypes in the 23 RAR group. TABLE 1 Ligand Binding Assay Compound K,, (nanomolar, nM) No. RARα RARβ RARγ 13 148 6 21 14 454 24 98 15 136 4 36 16 875 13 333 24 134 48 33 Inverse agonists are ligands that are capable of inhibiting the basal receptor activity of unliganded receptors. Recently, retinoic acid receptors (RARs) have been shown to be responsive to retinoid inverse agonists in regulating basal gene transcriptional activity. Moreover, the biological effects associated with retinoid inverse agonists are distinct from those of retinoid agonists or antagonists. For example, RAR inverse agonists, but not RAR neutral antagonists, cause a dose- dependent inhibition of the protein MRP-8 in cultured human keratinocytes differentiated with serum. MRP-8 is a specific marker of cell differentiation, which is also highly expressed in psoriatic epidermis, but is not detectable in normal human skin. Thus, retinoid inverse agonists may offer a unique way of treating diseases such as psoriasis. The activity of retinoid inverse agonists can be tested by the procedure of Klein et al. J. Biol. Chem. 271, 22692 - 22696 (1996) which is expressly incorporated herein by reference. In this assay, retinoid inverse agonists are able to repress the basal activity of a RARγ -VP-16 chimeric receptor where the constituitively active domain of the herpes simplex virus (HSV) VP-16 is fused to the N-terminus of RARγ. CV-1 cells are cotransfected with RARγ -VP-16, an ER-RXRα chimeric receptor and an ERE-tk-Luc ι chimeric reporter gene to produce a basal level of luciferase activity, as 2 shown by Nagpal et al. EMBO J. 12, 2349 -2360 (1993) expressly 3 incorporated herein by reference. Retinoid inverse agonists are able to 4 inhibit the basal luciferase activity in these cells in a dose dependent 5 manner and IC 50 s measured. In this assay, Compound 10 had an IC 50 of e 1.0 nM. 7 Modes of Administration β The compounds of this invention may be administered 9 systemically or topically, depending on such considerations as the ιo condition to be treated, need for site-specific treatment, quantity of ιι drug to be administered, and numerous other considerations. 12 In the treatment of dermatoses, it will generally be preferred to 13 administer the drug topically, though in certain cases such as treatment 14 of severe cystic acne or psoriasis, oral administration may also be used. is Any common topical formulation such as a solution, suspension, gel, 16 ointment, or salve and the like may be used. Preparation of such 17 topical formulations are well described in the art of pharmaceutical is formulations as exemplified, for example, by Remington's 19 Pharmaceutical Science, Edition 17, Mack Publishing Company, Easton, 20 Pennsylvania. For topical application, these compounds could also be 21 administered as a powder or spray, particularly in aerosol form. If the 22 drug is to be administered systemically, it may be confected as a 23 powder, pill, tablet or the like or as a syrup or elixir suitable for oral 24 administration. For intravenous or intraperitoneal administration, the 25 compound will be prepared as a solution or suspension capable of being 26 administered by injection. In certain cases, it may be useful to 27 formulate these compounds by injection. In certain cases, it may be 28 useful to formulate these compounds in suppository form or as extended ι release formulation for deposit under the skin or intramuscular 2 injection. 3 Other medicaments can be added to such topical formulation for such secondary purposes as treating skin dryness; providing protection 5 against light; other medications for treating dermatoses; medicaments e for preventing infection, reducing irritation, inflammation and the like. 7 Treatment of dermatoses or any other indications known or β discovered to be susceptible to treatment by retinoic acid-like 9 compounds will be effected by administration of the therapeutically ιo effective dose of one or more compounds of the instant invention. A ιι therapeutic concentration will be that concentration which effects 12 reduction of the particular condition, or retards its expansion. In 13 certain instances, the compound potentially may be used in prophylactic 14 manner to prevent onset of a particular condition. 15 A useful therapeutic or prophylactic concentration will vary from 16 condition to condition and in certain instances may vary with the 17 severity of the condition being treated and the patient's susceptibility to 18 treatment. Accordingly, no single concentration will be uniformly 19 useful, but will require modification depending on the particularities of 20 the disease being treated. Such concentrations can be arrived at 21 through routine experimentation. However, it is anticipated that in the 22 treatment of, for example, acne, or similar dermatoses, that a 23 formulation containing between 0.01 and 1.0 milligrams per milliliter of 24 formulation will constitute a therapeutically effective concentration for 25 total application. If administered systemically, an amount between 0.01 26 and 5 mg per kg per day of body weight would be expected to effect a 27 therapeutic result in the treatment of many diseases for which these 28 compounds are useful. ι The partial or pan retinoid antagonist and/or retinoid inverse 2 agonist compounds of the invention, when used to take advantage of 3 their antagonist and/or inverse agonist property, can be co-administered 4 to mammals, including humans, with retinoid agonists and, by means of 5 pharmacological selectivity or site-specific delivery, preferentially 6 prevent the undesired effects of certain retinoid agonists. The 7 antagonist and/or inverse agonist compounds of the invention can also 8 be used to treat Vitamin A overdose, acute or chronic, resulting either 9 from the excessive intake of vitamin A supplements or from the ιo ingestion of liver of certain fish and animals that contain high levels of ιι Vitamin A. Still further, the antagonist and/or inverse agonist 12 compounds of the invention can also be used to treat acute or chronic 13 toxicity caused by retinoid drugs. It has been known in the art that the 14 toxicities observed with hypervitaminosis A syndrome (headache, skin is peeling, bone toxicity, dyslipidemias) are similar or identical with 16 toxicities observed with other retinoids, suggesting a common biological 17 cause, that is RAR activation. Because the antagonist or inverse agonist 18 compounds of the present invention block or diminish RAR activation, 19 they are suitable for treating the foregoing toxicities. 20 Generally speaking, for therapeutic applications in mammals, the 21 antagonist and/or inverse agonist compounds of the invention can be 22 admistered enterally or topically as an antidote to vitamin A, or 23 antidote to retinoid toxicity resulting from overdose or prolonged 24 exposure, after intake of the causative factor (vitamin A, vitamin A 25 precursor, or other retinoid) has been discontinued. Alternatively, the 26 antagonist and/or inverse agonist compounds of the invention are 27 co-administered with retinoid drugs, in situations where the retinoid 28 provides a therapeutic benefit, and where the co-administered ι antagonist and/or inverse agonist compound alleviates or eliminates one 2 or more undesired side effects of the retinoid. For this type of 3 application the antagonist and/or inverse agonist compound may be 4 administered in a site-specific manner, for example as a topically 5 applied cream or lotion while the co-administered retinoid may be given 6 enterally. For therapeutic applications the antagonist compounds of 7 the invention, like the retinoid agonists compounds, are incorporated 8 into pharmaceutical compositions, such as tablets, pills, capsules, 9 solutions, suspensions, creams, ointments, gels, salves, lotions and the ιo like, using such pharmaceutically acceptable excipients and vehicles ιι which per se are well known in the art. For topical application, the 12 antagonist and/or inverse agonist compounds of the invention could also 13 be administered as a powder or spray, particularly in aerosol form. If 14 the drug is to be administered systemically, it may be confected as a is powder, pill, tablet or the like or as a syrup or elixir suitable for oral 16 administration. For intravenous or intraperitoneal administration, the 17 compound will be prepared as a solution or suspension capable of being 18 administered by injection. In certain cases, it may be useful to 19 formulate these compounds by injection. In certain cases, it may be 20 useful to formulate these compounds in suppository form or as extended 21 release formulation for deposit under the skin or intramuscular 22 injection. 23 The antagonist and/or inverse agonist compounds also, like the 24 retinoid agonists of the invention, will be administered in a 25 therapeutically effective dose. A therapeutic concentration will be that 26 concentration which effects reduction of the particular condition, or 27 retards its expansion. When co-administering the compounds of the 28 invention to block retinoid-induced toxicity or side effects, the ι antagonist and/or inverse agonist compounds of the invention are used 2 in a prophylactic manner to prevent onset of a particular condition, such 3 as skin irritation. 4 A useful therapeutic or prophylactic concentration will vary from 5 condition to condition and in certain instances may vary with the 6 severity of the condition being treated and the patient's susceptibility to 7 treatment. Accordingly, no single concentration will be uniformly β useful, but will require modification depending on the particularities of 9 the chronic or acute retinoid toxicity or related condition being treated. ιo Such concentrations can be arrived at through routine experimentation. ιι However, it is anticipated that a formulation containing between 0.01 12 and 1.0 milligrams of the active compound per mililiter of formulation 13 will constitute a therapeutically effective concentration for total 14 application. If administered systemically, an amount between 0.01 and 5 is mg per kg per day of body weight would be expected to effect a 16 therapeutic result. 17 GENERAL EMBODIMENTS AND SYNTHETIC METHODOLOGY 18 Definitions 19 The term alkyl refers to and covers any and all groups which are 20 known as normal alkyl, branched-chain alkyl and cycloalkyl. The term 21 alkenyl refers to and covers normal alkenyl, branch chain alkenyl and 22 cycloalkenyl groups having one or more sites of unsaturation. Similarly, 23 the term alkynyl refers to and covers normal alkynyl, and branch chain 24 alkynyl groups having one or more triple bonds. 25 Lower alkyl means the above-defined broad definition of alkyl 26 groups having 1 to 6 carbons in case of normal lower alkyl, and as 27 applicable 3 to 6 carbons for lower branch chained and cycloalkyl 28 groups. Lower alkenyl is defined similarly having 2 to 6 carbons for ι normal lower alkenyl groups, and 3 to 6 carbons for branch chained and 2 cyclo- lower alkenyl groups. Lower alkynyl is also defined similarly, 3 having 2 to 6 carbons for normal lower alkynyl groups, and 4 to 6 4 carbons for branch chained lower alkynyl groups. 5 The term "ester" as used here refers to and covers any compound 6 falling within the definition of that term as classically used in organic 7 chemistry. It includes organic and inorganic esters. Where B of β Formula 1 is -COOH, this term covers the products derived from 9 treatment of this function with alcohols or thiols preferably with ιo aliphatic alcohols having 1-6 carbons. Where the ester is derived from ιι compounds where B is -CH 2 OH, this term covers compounds derived 12 from organic acids capable of forming esters including phosphorous 13 based and sulfur based acids, or compounds of the formula 14 -CH 2 OCOR u where R u is any substituted or unsubstituted aliphatic, is aromatic, heteroaromatic or aliphatic aromatic group, preferably with 16 1-6 carbons in the aliphatic portions. 17 Unless stated otherwise in this application, preferred esters are is derived from the saturated aliphatic alcohols or acids of ten or fewer 19 carbon atoms or the cyclic or saturated aliphatic cyclic alcohols and 20 acids of 5 to 10 carbon atoms. Particularly preferred aliphatic esters are 21 those derived from lower alkyl acids and alcohols. Also preferred are 22 the phenyl or lower alkyl phenyl esters. 23 Amides has the meaning classically accorded that term in organic 24 chemistry. In this instance it includes the unsubstituted amides and all 25 aliphatic and aromatic mono- and di- substituted amides. Unless stated 26 otherwise in this application, preferred amides are the mono- and 27 di-substituted amides derived from the saturated aliphatic radicals of ten 28 or fewer carbon atoms or the cyclic or saturated aliphatic-cyclic radicals ι of 5 to 10 carbon atoms. Particularly preferred amides are those 2 derived from substituted and unsubstituted lower alkyl amines. Also 3 preferred are mono- and disubstituted amides derived from the 4 substituted and unsubstituted phenyl or lower alkylphenyl amines. 5 Unsubstituted amides are also preferred. e Acetals and ketals include the radicals of the formula-CK where 7 K is (-OR) 2 . Here, R is lower alkyl. Also, K may be -OR 7 0- where R 7 β is lower alkyl of 2-5 carbon atoms, straight chain or branched. 9 A pharmaceutically acceptable salt may be prepared for any ιo compounds in this invention having a functionality capable of forming a ιι salt, for example an acid functionality. A pharmaceutically acceptable 12 salt is any salt which retains the activity of the parent compound and 13 does not impart any deleterious or untoward effect on the subject to 14 which it is administered and in the context in which it is administered. is Pharmaceutically acceptable salts may be derived from organic or 16 inorganic bases. The salt may be a mono or polyvalent ion. Of 17 particular interest are the inorganic ions, sodium, potassium, calcium, 18 and magnesium. Organic salts may be made with amines, particularly 19 ammonium salts such as mono-, di- and trialkyl amines or ethanol 20 amines. Salts may also be formed with caffeine, tromethamine and 21 similar molecules. Where there is a nitrogen sufficiently basic as to be 22 capable of forming acid addition salts, such may be formed with any 23 inorganic or organic acids or alkylating agent such as methyl iodide. 24 Preferred salts are those formed with inorganic acids such as 25 hydrochloric acid, sulfuric acid or phosphoric acid. Any of a number of 26 simple organic acids such as mono-, di- or tri- acid may also be used. 27 Some of the compounds of the present invention may have trans 28 and cis (E and Z) isomers. In addition, the compounds of the present invention may contain one or more chiral centers and therefore may exist in enantiomeric and diastereomeric forms. 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. In the present application when no specific mention is made of the configuration (cis, trans, or R or S) of a compound (or of an asymmetric carbon) then a mixture of such isomers, or either one of the isomers is intended. In a similar vein, when in the chemical structural formulas of this application a straight line representing a valence bond is drawn to an asymmetric carbon, then isomers of both R and S configuration, as well as their mixtures are intended. The numbering system used in the naming of the compounds of the present invention, as well as of the intermediate compounds utilized in the synthetic routes leading to the compounds of the invention, is illustrated below for two exemplary compounds of the invention. Compound 13 Compound 14 Generally speaking, compounds of the invention where Z is an ethyne function are obtained in a sequence of reactions which involve first the synthesis of a 2-(2-iodoethenyl)-2-cyclohexen-l-one derivative that is coupled with an ethynyl aryl or heteroaryl compound of the ι formula HC≡C-Y(R 2 )-A-B, where the symbols are defined as in 2 connection with Formula 1. The endocyclic double bond of the 3 cyclohexenone moiety is thereafter saturated, and the ketone function of 4 the resulting cyclohexanone moiety is converted to a vinyl 5 (trifluoromethanesulfonyl)oxy (triflate) derivative. The vinyl triflate 6 derivative is thereafter reacted with a halogen substituted aryl or 7 heteroaryl group of the formula Xχ-R 4 (X x is a halogen) which is s lithiated with a strong base such as r-butyllithium, and then treated with 9 ZnBr 2 and tetrakis(triphenylphosphine)palladium catalyst to introduce ιo the R 4 substituent into the molecule. ιι Compounds of the invention where Z is other than an ethyne 12 function (as defined in connection with Formula 1) are, generally 13 speaking, obtained by first synthesizing an intermediate 2-(2- 14 (trimethylsilyl)ethenyl)-2-cyclohexen-l-one derivative, the endocyclic is double bond of which is saturated in the next reaction to provide a 16 cyclohexanone derivative. The cyclohexanone derivative is then 17 converted into an aryl- or heteroaryl-(2-(trimethylsilyl)ethenyl)- 18 cyclohexene derivative through the corresponding vinyl triflate which is 19 coupled with an aryl or heteroaryl zinc compound of the formula R 4 - 20 ZnBr, in the presence of tetrakis(triphenylphosphine)palladium catalyst. 21 The trimethylsilyl group of the aryl or heteroaryl-(2- 22 (trimethylsilyl)ethenyl)cyclohexene intermediate is thereafter converted 23 into an iodo group and the latter is functionalized or converted in a 24 series of reactions into the polyene, carboxylic acid ester, carboxylic acid 25 amide and other functional groups which are represented by the symbol 26 Z in Formula 1. Details of the above-outlined generalized synthetic 27 schemes are provided below in connection with the description of the 28 specific embodiments and specific examples. ι The synthetic methodology employed for the synthesis of the 2 compounds of the present invention may also include transformations of 3 the group designated -A-B in Formula 1. Generally speaking, these 4 transformations involve reactions well within the skill of the practicing 5 organic chemist. In this regard the following well known and published 6 general principles and synthetic methodology are briefly described. 7 Carboxylic acids are typically esterified by refluxing the acid in a 8 solution of the appropriate alcohol in the presence of an acid catalyst 9 such as hydrogen chloride or thionyl chloride. Alternatively, the ιo carboxylic acid can be condensed with the appropriate alcohol in the ιι presence of dicyclohexylcarbodiimide (DCC) and 4- 12 (dimethylamino)pyridine (DMAP). The ester is recovered and purified 13 by conventional means. Acetals and ketals are readily made by the 14 method described in March, "Advanced Organic Chemistry," 2nd is Edition, McGraw-Hill Book Company, p 810). Alcohols, aldehydes and 16 ketones all may be protected by forming respectively, ethers and esters, 17 acetals or ketals by known methods such as those described in McOmie, 18 Plenum Publishing Press, 1973 and Protecting Groups, Ed. Greene, 19 John Wiley & Sons, 1981. 20 To increase the value of q in the compounds of the invention (or 21 in precursors thereof which include the -Y(R 2 )-A-B moiety where such 22 compounds are not available from a commercial source) aromatic or 23 heteroaromatic carboxylic acids are subjected to homologation by 24 successive treatment under Arndt-Eistert conditions or other 25 homologation procedures. Alternatively, derivatives which are not 26 carboxylic acids may also be homologated by appropriate procedures. 27 The homologated acids can then be esterified by the general procedure 28 outlined in the preceding paragraph. Compounds of the invention as ι set forth in Formula 1 (or precursors thereof) where A is an alkenyl 2 group having one or more double bonds can be made for example, by 3 synthetic schemes well known to the practicing organic chemist; for 4 example by Wittig and like reactions, or by introduction of a double 5 bond by elimination of halogen from an alpha-halo-arylalkyl-carboxylic e acid, ester or like carboxaldehyde. Compounds of the invention or 7 precursors thereof, where the A group has a triple (acetylenic) bond, β can be made by reaction of a corresponding aromatic methyl ketone 9 with strong base, such as lithium diisopropylamide, reaction with diethyl ιo chlorophosphate and subsequent addition of lithium diisopropylamide. ιι The acids and salts derived from compounds of the invention are 12 readily obtainable from the corresponding esters. Basic saponification 13 with an alkali metal base will provide the acid. For example, an ester of 14 the invention may be dissolved in a polar solvent such as an alkanol, is preferably under an inert atmosphere at room temperature, with about 16 a three molar excess of base, for example, lithium hydroxide or 17 potassium hydroxide. The solution is stirred for an extended period of is time, between 15 and 20 hours, cooled, acidified and the hydrolysate 19 recovered by conventional means. 20 The amide may be formed by any appropriate amidation means 21 known in the art from the corresponding esters or carboxylic acids. One 22 way to prepare such compounds is to convert an acid to an acid chloride 23 and then treat that compound with ammonium hydroxide or an 24 appropriate amine. For example, the ester is treated with an alcoholic 25 base solution such as ethanolic KOH (in approximately a 10% molar 26 excess) at room temperature for about 30 minutes. The solvent is 27 removed and the residue taken up in an organic solvent such as diethyl 28 ether, treated with a dialkyl formamide and then a 10-fold excess of ι oxalyl chloride. This is all effected at a moderately reduced 2 temperature between about -10 degrees and +10 degrees C. The last 3 mentioned solution is then stirred at the reduced temperature for 1-4 4 hours, preferably 2 hours. Solvent removal provides a residue which is 5 taken up in an inert organic solvent such as benzene, cooled to about 0 6 degrees C and treated with concentrated ammonium hydroxide. The 7 resulting mixture is stirred at a reduced temperature for 1 - 4 hours. β The product is recovered by conventional means. 9 Alcohols are made by converting the corresponding acids to the ιo acid chloride with thionyl chloride or other means (J. March, "Advanced ιι Organic Chemistry", 2nd Edition, McGraw-Hill Book Company), then 12 reducing the acid chloride with sodium borohydride (March, Ibid, pg. 13 1124), which gives the corresponding alcohols. Alternatively, esters may 14 be reduced with lithium aluminum hydride at reduced temperatures. is Alkylating these alcohols with appropriate alkyl halides under 16 Williamson reaction conditions (March, Ibid, pg. 357) gives the 17 corresponding ethers. These alcohols can be converted to esters by is reacting them with appropriate acids in the presence of acid catalysts or 19 dicyclohexylcarbodiimide and dimethylaminopyridine. 20 Aldehydes can be prepared from the corresponding primary 21 alcohols using mild oxidizing agents such as pyridinium dichromate in 22 methylene chloride (Corey, E. J., Schmidt, G., Tet. Lett.. 399, 1979), or 23 dimethyl sulfoxide/oxalyl chloride in methylene chloride (Omura, K, 24 Swern, D., Tetrahedron. 1978. 34. 1651). 25 Ketones can be prepared from an appropriate aldehyde by 26 treating the aldehyde with an alkyl Grignard reagent or similar reagent 27 followed by oxidation. 28 Acetals or ketals can be prepared from the corresponding ι aldehyde or ketone by the method described in March, Ibid, p 810. 2 Compounds of the invention, or precursors thereof, where B is 3 H can be prepared from the corresponding halogenated aromatic or 4 heteroaromatic compounds, preferably where the halogen is I. 5 SPECIFIC EMBODIMENTS 6 With reference to the symbol Y in Formula 1, the preferred 7 compounds of the invention are those where Y is phenyl, naphthyl, β pyridyl, thienyl or furyl. Even more preferred are compounds where Y 9 is phenyl. As far as substititutions on the Y (phenyl) and Y (pyridyl) ιo groups are concerned, compounds are preferred where the phenyl group ιι is 1,4 (para) substituted and where the pyridine ring is 2,5 substituted. 12 (Substitution in the 2,5 positions in the "pyridine" nomenclature 13 corresponds to substitution in the 6-position in the "nicotinic acid" 14 nomenclature.) In the presently preferred compounds of the invention is there is no R 2 substituent on the Y group. 16 The A-B group of the preferred compounds is (CH 2 ) q COOH or 17 (CH 2 ) q -COOR 8 , where R 8 is defined as above. Even more preferably q is is zero and R 8 is lower alkyl. 19 In the presently preferred compounds of the invention Z is an 20 ethynyl ( -C≡C-) group. However, compounds are also preferred in 21 accordance with the invention where Z is -(CR^CR j ),,,-, -CO-NR,-, 22 -COO-, and -COS-. 23 In the preferred compounds of the invention R 3 is H or lower 24 alkyl, even more preferably H. Furthermore, in the preferred 25 compounds of the invention the cycohexene ring is substituted with one 26 or two, preferably with two R t groups, and the two R x groups are 27 preferably both methyl. Even more preferably, the two R x groups 28 geminally occupy the position adjacent to the ethene -(R 3 )C=C(R 3 )- moiety in the cylohexene ring. Referring now to the R 4 substituent in the compounds of Formula 1, compounds are preferred where this substituent is phenyl, R 5 - substituted phenyl, pyridyl, Rj-substituted pyridyl, thienyl, R 5 -substituted thienyl, furyl, R 5 -substituted furyl, thiazolyl or R 5 -substituted thiazolyl. Even more preferred are compounds where the R 4 substituent is phenyl, or 4-alkylphenyl, and particularly 4-methylphenyl, 4-ethylphenyl and A-t- butylphenyl. In the heteroaryl "series", compounds are further preferred where the R 4 group is 3-pyridyl, 6-methyl-3-pyridyl, 2-thienyl and 5- methyl-2-thienyl, 2-furyl and 5-methyl-2-furyl. The most preferred compounds of the invention are listed below in Table 2 with reference to Formula 2 or Formula 2a. Formula 2 Formula 2a TABLE 2 The compounds of this invention can be made by the general procedures outlined above under the title "GENERAL EMBODIMENTS AND SYNTHETIC METHODOLOGY". The following chemical pathways represent the presently preferred synthetic routes to certain classes of the compounds of the invention and to certain specific exemplary compounds. However, the synthetic chemist will readily appreciate that the conditions set out here for these specific embodiments can be generalized to any and all of the compounds represented by Formula 1. Formula 3 Formula 4 Formula 5 Formula 6 Formula 8 Formula 10 Formula 11 Reaction Scheme 1 1 2 3 4 5 6 10 Formula 10 Formula 11 11 R 4 -X,, t-BuU; R 4 -X 1 t t-BuLi; 12 ZnBr 2 , Pd(PPh 3 ) 4 ZnBr 2 , Pd(PPh 3 ) 4 13 17 Formula 12 Formula 13 18 19 20 21 Homologs and Homologs and Derivatives Derivatives 22 Reaction Scheme 1 (continued) 23 24 25 26 27 28 Referring now to Reaction Scheme 1 a synthetic process is described whereby compounds of the invention are obtained in which, with reference to Formula 1, the Z group is an ethynyl (-C≡C-) function. The starting material of this scheme is a 2-cyclohexenone derivative of Formula 3. The cyclohexenone derivative of Formula 3 may already have one or more of the optional R x substituents. In the presently preferred componds of the invention there are two geminally positioned methyl substituents in the cyclohexene ring. For this reason the starting material for the synthesis of the majority of the presently preferred compounds is 3-methyl-2-cyclohexen-l-one, which is available from Aldrich Chemical Company. In accordance with the scheme, a compound of Formula 3 is reacted with iodine in the presence of azidotrimethylsilane, to provide the 2-iodo-2-cyclohexene-l-one derivative of Formula 4. The 2-iodo-2-cyclohexene-l-one derivative of Formula 4 is then reacted with 2-(tributylstanyl)ethenyltrimethylsilane in an ether type solvent, such as tetrahydrofuran, in the presence of bis(triphenylphosphine)palladium (II) chloride catalyst to give the 2-(2-(trimethylsilyl)ethenyl)-2-cyclohexen-l-one derivative of Formula 5. The reagent 2-(tributylstanyl)ethenyltrimethylsilane can be obtained by heating 2,2'-azobisisobutyronitrile, (trimethylsilyl) acetylene and tributyltin hydride. The 2-(2-(trimethylsilyl)ethenyl)-2-cyclohexen-l-one compound of Formula 5 is then subjected to treatment with iodine in an inert solvent or mixture of inert solvents, such as methylene chloride and tetrahydrofuran, to replace the trimethylsilyl group with an iodo group, and yield the 2-(2-iodoethenyl)-2-cyclohexen-l-one derivative of Formula 6. Referring still to Reaction Scheme 1, the 2-(2-iodoethenyl)-2- ι cyclohexen-1-one derivative of Formula 6 is reacted with an ethyne 2 compound of the formula HC≡C-Y(R 2 )-A-B (Formula 7), where the 3 symbols Y, R 2 , A and B are defined as in connection with Formula 1. 4 Generally speaking, the reagents of Formula 7 can be obtained by 5 reacting halogenated aryl or heteroaryl compounds of the formula e X 1 -Y(R 2 )-A-B (X x is halogen) with (trimethylsilyl)acetylene in the 7 presence triethylamine, copper (I) iodide and s bis(triphenylphosphine)palladium (II) chloride catalyst, followed by 9 treatment with base (for example K 2 C0 3 ) or tetrabutylamonium fluoride ιo to remove the trimethylsilyl group. Examples for the reagent X X -Y(R 2 )- ιι A-B are ethyl 4-iodobenzoate, ethyl 6-bromo-2-naphthoate, ethyl 6- 12 iodonicotinate, ethyl 2-iodofuran-5-carboxylate, and ethyl 2- 13 iodothiophen-5-carboxylate. Examples for the reagent of Formula 7 are 14 ethyl 4-ethynylbenzoate, ethyl 6-ethynyl-2-naphthoate, ethyl 6- 15 ethynylnicotinate, ethyl 2-ethynylfuran-5-carboxylate, and ethyl 2- 16 ethynylthiophen-5-carboxylate. 17 The coupling reaction between the 2-(2-iodoethenyl)-2- 18 cyclohexen-1-one derivative of Formula 6 and the ethynyl derivative of 19 Formula 7 is also conducted in the presence triethylamine, copper (I) 20 iodide and bis(triphenylphosphine)palladium (II) chloride catalyst. 21 These reactions are analogous to the reactions described in several 22 United States Letters Patent, such as United States Patent Nos. 23 5,348,972 and 5,346,915, assigned to the assignee of the present 24 application, where introduction of an ethynyl group into a heteroaryl 25 nucleus and subsequent coupling with a halogenated aryl or heteroaryl 26 function are described. The specifications of United States Patent 27 Nos. 5,348,972 and 5,346,915 are specifically incorporated herein by 28 reference. The product of the coupling reaction shown in Reaction Scheme 1 is a 1-aryl- or l-heteroaryl-4-(2-cyclohexen-l-on-2-yl)but-l-yn- 2 3-ene derivative of Formula 8. In the next reaction shown in Reaction 3 Scheme 1 the endocyclic double bond of the 1-aryl or 1-heteroaryl 4-(2- 4 cyclohexen-l-on-2-yl)but-l-yn-3-ene derivative of Formula 8 is saturated, 5 preferably by addition of another R x (preferably methyl) substituent. 6 The additional R 2 substituent is added in a "cuprate addition" reaction, 7 utilizing (R 1 ) 2 CuLi reagent in the presence of trimethylsilyl chloride. In β the preparation of the presently preferred compounds of the invention 9 where geminal dimethyl groups occupy the 3-position of the cyclohexene ιo nucleus, the "cuprate addition" reaction introduces the second methyl ιι substituent into the 3-position of the cyclohexene ring. Precise 12 conditions of this example of the "cuprate addition" reaction, utilizing 13 methyllithium, copper (I) bromide in dimethyl sulfide and 14 hexamethylphosphoramide, are described in the description of the is Specific Examples. The product of the "cuprate addition" reaction (or 16 of other reaction that saturates the endocyclic double bond of the 17 cyclohexene ring) is a 1-aryl- or l-heteroaryl-4-(2-cyclohexan-l-on-2-yl)- 18 but-l-yn-3-ene derivative of Formula 9. 19 Continuing with the description of the exemplary reaction 20 sequence depicted in Reaction Scheme 1, the 1-aryl or 1-heteroaryl 4-(2- 21 cyclohexan-l-on-2-yl)but-l-yn-3-ene derivative of Formula 9 is converted 22 to the corresponding vinyl (trifluoromethanesulfonyl)oxy ("triflate") 23 derivatives of Formula 10 and Formula 11, by treatment with 24 trifluoromethanesulfonic anhydride (abbreviated Tf 2 0) in the presence 25 of 2,6-di-tert-butyl-4-methylpyridine. The (trifluoromethanesulfonyl)oxy 26 ("triflate") derivatives of Formula 10 and 11 are isomers with respect to 27 the position of the double bond in the cyclohexene ring, and can be 28 isolated by conventional techniques, such as high pressure liquid ι chromatography (HPLC). Each of the (trifluoromethanesulfonyl)oxy 2 ("triflate") derivatives of Formula 10 and 11 are subsequently reacted 3 with a halogen substituted aryl or heteroaryl group of the formula X x -R 4 4 (X ! is a halogen), which is lithiated with a strong base such as t- 5 butyllithium, and treated with ZnBr 2 and 6 tetrakis(triphenylphosphine)palladium catalyst. In the latter reactions 7 the (trifluoromethanesulfonyl)oxy group is replaced with the R 4 group β that is defined in connection with Formula 1. The resulting aryl or 9 heteroaryl cyclohexenyl-but-l-yn-3-ene derivatives of Formula 12 and 13 ιo are within the scope of the invention, and can be converted to further ιι compounds still within the scope of the invention by reactions generally 12 discussed above, such as esterification, saponification, amide formation, 13 homologation and the like. These reactions are symbolically indicated 14 in Reaction Scheme 1 as conversion to Homologs and Derivatives. Formula 5 Formula 14 Formula 15 Formula 16 (+ isomer) (+ isomer) Formula 17 Formula 18 (+ isomer) (+ isomer) Formula 19 Formula 20 (+ isomer) (+ isomer) Homologs and Derivatives Formula 21 (+ isomer) Reaction Scheme 2 ι Referring now to Reaction Scheme 2 an example of a synthetic 2 route to compounds of the invention is disclosed where in accordance 3 with Formula 1 Z is -(CR 1 =CR 1 ) n ,- and n' is an integer having the 4 value of 3. The starting material in this scheme is the 5 2-(2-(trimethylsilyl)ethenyl)-2-cyclohexen-l-one derivative of Formula 5. 6 In the first reaction shown in Reaction Scheme 2 the endocyclic double 7 bond of the ketone of Formula 5 is saturated, preferably by addition β of another R x (preferably methyl) substituent. This reaction is 9 analogous to the reaction described in connection with Reaction Scheme ιo 1 where the endocyclic double bond of the 1-aryl or 1-heteroaryl 4-(2- ιι cyclohexen-l-on-2-yl)but-l-yn-3-ene derivative of Formula 8 is saturated, 12 preferably by addition of another R x (most preferably methyl) 13 substituent. As in Scheme 1, in this reaction sequence also, the 14 additional R x substituent is preferably added in a "cuprate addition" is reaction, utilizing (R^CuLi reagent in the presence of trimethylsilyl 16 chloride. The result of the "saturation" (alkyl group addition) reaction 17 is a 2-[2-(trimethylsilyl)ethenyl]-cyclohexanone derivative of Formula 14. 18 The compound of Formula 14 is treated with an appropriate reagent 19 combination, such as trifluoromethanesulfonic anhydride (Tf 2 0) in the 20 presence of 2,6-di-te/τ-butyl-4-methylpyridine to provide the 21 (trifluoromethanesulfonyl)oxy ("triflate") derivative of Formula 15 and 22 an isomer in which the endocyclic double bond is not conjugated with 23 the double bond of the (trimethylsilyl)vinyl side chain. The isomers of 24 Formula 15 can be separated at this stage of the synthetic route, or at a 25 later stage. When carried through the reaction sequence shown in this 26 scheme, the minor isomer gives rise to compounds within the scope of 27 the invention where the double bond is in the non-conjugated position 28 (designated in Formula 1) relative to the "vinyl" side chain. However ι for the sake of ease of demonstration the latter isomer is indicated only 2 as an "isomer" and is not fully illustrated in this and in the following 3 reaction schemes. 4 Returning now to the description of the reactions illustrated in 5 Scheme 2, the (trifluoromethanesulfonyl)oxy ("triflate") derivative of 6 Formula 15 and isomer are reacted with a halogen substituted aryl or 7 heteroaryl group of the formula Xi-R 4 (X ! is a halogen), which is 8 lithiated with a strong base such as t-butyllithium, and treated with 9 ZnBr 2 and tetrakis(triphenylphosphine)palladium catalyst. This ιo reaction is analogous to the reaction described in connection with ιι Reaction Scheme 1 for the "replacement" of the 12 (trifluoromethanesulfonyl)oxy group with an aryl or heteroaryl group 13 designated R 4 . The resulting aryl or heteroaryl [2- 14 (trimethylsilyl)ethenyl]-cyclohexene derivative of Formula 16 and is isomer are treated with iodine in an inert solvent to yield aryl or 16 heteroaryl (2-iodoethenyl)cyclohexene derivatives of Formula 17. The 17 aryl or heteroaryl (2-iodoethenyl)cyclohexene compounds of Formula 17 is are reacted with (l-ethoxyvinyl)tributyltin in the presence of 19 bis(triphenylphosphine)palladium(II) chloride to introduce the acetyl 20 group adjacent to the vinyl group and to yield the enone compounds of 21 Formula 18 (and their positional isomers, as discussed above). The 22 latter reaction is known in the art as a Stille coupling. (1- 23 Ethoxyvinyl)tributyltin is available from Aldrich Chemical Co.) The 24 enone compounds of Formula 18 (and isomers) are then reacted in a 25 Homer Emmons reaction, in the presence of strong base such as lithium 26 diisopropylamide (LDA), with diethyl cyanomethylphosphonate. The 27 latter reagent is commercially available. The product of the Homer 28 Emmons reaction is an aryl or heteroaryl cyclohexene derivative of ι Formula 19 having a l-cyano-2-methylbutadiene side chain. Those 2 skilled in the art will readily understand that instead of a Homer 3 Emmons reaction the compounds of Formula 19 can also be obtained 4 as a result of an analogous Wittig reaction. 5 Referring still to Reaction Scheme 2, the cyano function of the 6 compounds of Formula 19 (and isomers) is reduced with a mild 7 reducing agent, such as diisobutylaluminum hydride (Dibal-H) to s provide the aldehyde compounds of Formula 20. Another Homer 9 Emmons reaction performed on the aldehydes of Formula 20 with the ιo reagent diethyl(£)-3-carboethoxy-2-methyl-l-allylphosphonate ιι (Compound A) provides compounds of Formula 21 which are within 12 the scope of the present invention. It will be readily apparent to those 13 skilled in the art that the herein described exemplary synthetic process 14 can be readily adapted or modified by utilizing analogous phosphonate is or phosponium salt reagents in Homer Emmons or Wittig reactions, 16 respectively, to obtain additional compounds within the scope of 17 Formula 1 in which Z is -(CR 1 =CR 1 ) n ,- , and n' is 3 - 5. The is compounds of Formula 21 can be converted into further compounds 19 within the scope of the invention by reactions such as saponification, 20 amide formation, reduction to the aldehyde or alcohol stage, and the 21 like. This is indicated in the reaction scheme by conversion to 22 "homologs and derivatives". 23 A class of preferared compounds in accordance with Formula 21 24 are 1-aryl or l-heteroaryl-3,3-dimethylcyclohexene derivatives. These 25 are obtained in accordance with the reaction sequence described in 26 Reaction Scheme 2, starting with 27 2-(2-(trimethylsilyl)ethenyl)-3-methyl-2-cyclohexen-l-one (Compound 28 3) which is obtained as described in Reaction Scheme 1 from the commercially available 3-methyl-2-cyclohexen-l-one (Compound 1). The reagent diethyl(is)-3-carboethoxy-2-methyl-l-allylphosphonate (Compound A) is obtained in a sequence of reactions starting from the commercially available ethyl (Z)-3-formyl-2-butenoate (Compound B). In this preparation the aldehyde function of Compound B is reduced with sodium borohydride, and the resulting primary alcohol is reacted with phosphorous tribromide. The resulting ethyl (Z)-3-bromo-2- butenoate (Compound C) is reacted with triethyl phosphonate to give Compound A. Formula 23 Formula 18 (+ isomer) (+ isomer) Homologs and Derivatives Reaction Scheme 3 ι Reaction Scheme 3 discloses a synthetic route for the preparation 2 of compounds of the invention where, with reference to Formula 1, Z is 3 -(CR^CRx),,,- and n' is 1. In accordance with this scheme, the enone 4 compounds of Formula 18 (and positional isomers, as discussed above) 5 are reacted in a Homer Emmons reaction, in the presence of strong 6 base (lithium diisopropylamide, LDA) with a phosphonate reagent of 7 the formula (EtO) 2 POCH 2 -Y(R 2 )A-B' (Formula 22) where the symbols β Y, R 2 , A are defined as in connection with Formula 1, and B' is either 9 the B group of Formula 1 or a suitably protected derivative thereof. ιo Examples for the phosphonate reagent of Formula 22 are ethyl [4- ιι (diethoxyphosphinyl)methyl]benzoate, ethyl [6- 12 (diethoxyphosphinyl)methyl]pyridine-3-carboxylate, ethyl [5- 13 (diethoxyphosphinyl)methylfuran-2-carboxylate and ethyl [5- 14 (diethoxyphosphinyl)methylthiophen-2-carboxylate. These reagents can is be obtained in accordance with or in analogy to the process described in 16 United States Patent No. 5,455,265 for the synthesis of ethyl [4- 17 (diethoxyphosphinyl)methyl]benzoate and ethyl [5- 18 (diethoxyphosphinyl)methylfuran-2-carboxylate. The specification of 19 United States Patent No. 5,455,265 is incorporated herein by reference. 20 Instead of a Homer Emmons reaction that utilizes a phosphonate 21 reagent, a Wittig reaction that utilizes a triphenylphosphonium salt 22 (bromide or chloride) of the formula Br " + Ph 3 PCH 2 -Y(R 2 )A-B' can also 23 be used to obtain the butadiene derivatives of Formula 23. The 24 compounds of Formula 23 are within the scope of the invention and can 25 be converted into still further compounds within the scope of the 26 invention by reactions such as esterification, saponification, 27 homologation and the like, as described above. 28 Formula 17 Formula 24 (+ isomer) (+ isomer) Homologs and Derivatives Formula 26 (+ isomer) Reaction Scheme 4 Reaction Scheme 4 discloses a presently preferred synthetic route to compounds of the invention where, with reference to Formula 1, Z is -CONH- (amides), -COO- (esters) -COS- (thioesters) and -CSNH- (thioamides). In accordance with this scheme the aryl or heteroaryl (2- iodoethenyl)cyclohexene derivatives of Formula 17 (and isomers with respect to the position of the endocyclic double bond) are first reacted with strong base (n-butyl lithium or t-butyl lithium) and carbon dioxide to "capture" the carbon dioxide and to provide aryl or heteroaryl 3- (cyclohexenyl)propenoic acid compounds of Formula 24. The carboxylic acids of Formula 24 can be converted into amides within the ι scope of the invention by reaction with reagents of the formula H 2 N- 2 Y(R 2 )-A-B, into esters within the scope of the invention by reaction 3 with reagents of the formula HO-Y(R 2 )-A-B, and into thioesters within 4 the scope of the invention by reaction with reagents of the formula HS- 5 Y(R 2 )-A-B, where the symbols are defined as in connection with 6 Formula 1. The above mentioned amine, alcohol and thiol reagents are 7 collectively illustrated in Reaction Scheme 4 as HX 2 Y(R 2 )A-B (Formula 8 25) where X 2 is NH, O or S. Examples for the reagents of formula 9 H 2 N-Y(R 2 )-A-B are ethyl 4-aminobenzoate and ethyl 6-aminonicotinate, ιo for the reagents of the formula HO-Y(R 2 )-A-B ethyl 4-hydroxybenzoate ιι and ethyl 6-hydroxynicotinate, and for the reagents of the formula HS- 12 Y(R 2 )-A-B ethyl 4-mercaptobenzoate and ethyl 6-mercaptonicotinate. 13 The reactions between the carboxylic acids of Formula 24 and the 14 reagents of the formulas H 2 N-Y(R 2 )-A-B, HO-Y(R 2 )-A-B and HS-Y(R 2 )- 15 A-B can be performed in several ways in which amides, esters and 16 thioesters are normally prepared. For example, the carboxylic acids of 17 Formula 24 can be activated to form an acid chloride or an activated is ester which is thereafter reacted with the amines, alcohols or thiols of 19 the above formulas. More advantageously, however, the formation of 20 the amides, esters or thioesters of the Formula 26 is performed by 21 condensation of the carboxylic acids of Formula 24 with the amines, 22 alcohols or thiols in a suitable aprotic solvent, such as pyridine, in the 23 presence of a condensing agent such as dicyclohexylcarbodiimide (DCC) 24 or more preferably l-(3-dimethylaminopropyl)-3- 25 ethylcarbodiimidehydrochloride (EDC1). Amide derivatives within the 26 scope of Formula 26 can be converted to thioamides (not specifically 2 shown in Scheme 4) within the scope of Formula 1 by reaction with 28 [2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4-disulfide] (Lawesson's reagent). Amide derivatives within the scope of Formula 26 where the symbol B represents an ester function (such as COOEt) can be readily saponified by treatment with aqueous base, for example LiOH, to yield the corresponding amide derivatives where B represents a free carboxylic acid or its salt. Similar saponification of the compounds within the scope of Formula 26 where Z represents an ester or thioester function is problematic, however, because of the lability of the internal ester and thioester functions. The free acids of these derivatives (where B is COOH or a salt thereof) can be obtained by first preparing and thereafter subjecting to hydrogenation the corresponding benzyl esters (B represents COOCH 2 C 6 H 5 ). The compounds of Formula 26 can be converted to further derivatives within the scope of the invention, as indicated in Reaction Scheme 4. TFA Formula 16 (+ isomer) (+ isomer) Homologs and Derivatives Formula 29 (+ isomer) Reaction Scheme 5 ι Reaction Scheme 5 discloses a preferred method for the synthesis 2 of compounds of the invention where, with reference to Formula 1, Z is 3 -(CR 1 =CR 1 ) n .- and n' is 0. In accordance with this scheme an aryl or 4 heteroaryl (2-trimethylsilyl)ethenylcyclohexene compound of Formula 16 5 (and its isomer with respect to the position of the endocyclic double 6 bond) is treated with acid (preferably trifluoroacetic acid) to remove the 7 trimethylsilyl group. The resulting aryl or heteroaryl β ethenylcyclohexene of Formula 27 (and its positional isomer) is reacted 9 with the reagent X r Y(R 2 )-A-B (Formula 28) where X x is halogen. The ιo reaction is conducted in the presence of palladium acetate (Pd(OAc) 2 ) ιι and tri-(o-tolyl)phosphine (P(o-tol) 3 ). Examples for the reagent X r 12 Y(R 2 )-A-B are ethyl 4-iodobenzoate, ethyl 6-bromo-2-naphthoate, ethyl 13 6-iodonicotinate, ethyl 2-iodofuran-5-carboxylate, and ethyl 2- 14 iodothiophen-5-carboxylate. The product of the coupling reaction is the is disubstituted vinyl compound of Formula 29, which is within the scope 16 of the invention, and can be converted to further compounds of the 17 invention, as is indicated in Reaction Scheme 5. Compound 17 Compound 18 Compound 19 Compound 20 Compound 21 Compound 22 Compound 23 Reaction Scheme 6 ι Compounds of the invention where, with reference to Formula 1, 2 the dashed lines designated and γ both represent a bond (there are 3 two double bonds in the 6-membered ring), can be prepared in 4 accordance with the synthetic route that is illustrated in Reaction 5 Scheme 6 for the preferred examplary compounds 22 - 25. The steps of 6 this examplary synthetic route are described in detail in the Specific 7 Examples section of this application, in connection with Compounds 17 β - 25. 9 SPECIFIC EXAMPLES ιo 2-Iodo-3-methyl-2-cyclohexen-l-one (Compound 2) ιι Freshly distilled azidotrimethylsilane (2.65 mL, 20 mmol) was 12 added to a stirred solution of 3-methyl-2-cyclohexen-l-one (Compound 13 1, 1.13 mL, 10 mmol) and dichloromethane (15 mL) at 0 °C under 14 argon. The solution was stirred for 2 hours at 0 °C before adding a is solution of iodine (5.08 g, 20 mmol) in 15 mL of pyridine and 15 mL of 16 dichloromethane. The resulting solution was stirred for 4 hours at room 17 temperature, diluted with ethyl acetate, and was washed successively is with 20 % aqueous Na 2 S 2 0 3 , 10 % aqueous HC1, water, and brine. The 19 solvents were dried (MgS0 4 ) and concentrated under reduced pressure. 20 The residue was purified by flash chromatography on silica gel (7:1, 21 hexanes: ethyl acetate) to give the title compound as a yellow oil. 22 PNMR (300 MHz, CDC1 3 ) δ 1.96 (m, 2 H), 2.23 (s, 3 H), 2.53 (t, 2 H, J 23 = 6.1 Hz), 2.57 (t, 2 H, J = 6.7 Hz). 24 2-(Tributylstanyl)ethenyltrimethylsilane 25 2,2'-Azobisisobutyronitrile (50 mg, 0.30 mmol) was added to a 26 solution of (trimethylsilyl)acetylene (3.17 mL, 22.4 mmol) and tributyltin 27 hydride (4.0 mL, 14.95 mmol) in a resealable glass tube. The tube was 28 sealed and the mixture was heated to 60 °C for 18 hours. Excess ι acetylene was removed in vacuo and the residue was purified by silica 2 gel chromatography (hexanes) to give the title compound as a clear, 3 colorless oil. PNMR (300 MHz, CDC1 3 ) 8 0.06 (s, 9 H), 0.89 (m, 15 H), 4 1.30 (m, 6H), 1.47 (m, 6 H), 6.60 (d, 1 H, J = 22.6 Hz), 7.0 (d, 1 H, J = s 22.6 Hz). e 2-(2-(Trimethylsilyl)ethenyl)-3-methyl-2-cyclohexen-l-one (Compound 3) 7 2-Iodo-3-methyl-2-cyclohexen-l-one (Compound 2, 0.75 g, 3.2 8 mmol) and 2-(tributylstanyl)ethenyltrimetylsilane (1.61 g, 4.13 mmol) 9 were dissolved in 25 mL of tetrahydrofuran (THF) and the resulting ιo solution was purged with dry argon for 10 minutes. ιι Bis(triphenylphosphine)palladium (II) chloride (160 mg, 0.224 mmol) 12 was added and the solution was refluxed for 24 hours under argon. The 13 solution was cooled to room temperature and ethyl acetate and aqueous 14 ammonium chloride solution were added. The layers were separated is and the aqueous layer was extracted 3 x with ethyl acetate. The 16 combined organic extracts were washed with water, and brine, and dried 17 (MgS0 4 ). After filtration, the solvent was removed in vacuo and the is residue purified by silica gel chromatography (9:1, hexanes:ethyl acetate) 19 to give the title compound as a yellow oil. 20 PNMR (300 MHz, CDC1 3 ) 8 0.11 (s, 9 H), 1.94 (m, 2 H), 2.04 (s, 3 H), 21 2.41 (t, 4 H, J = 7.0 Hz), 6.11 (d, 1 H, J = 19.6 Hz), 6.64 (d, 1 H, J = 22 19.6 Hz). 23 2-(2-Iodoethenyl)-3-methyl-2-cyclohexen-l-one (Compound 4) 24 Iodine (750 mg, 2.96 mmol) was dissolved in 10 mL of THF and 25 the solution was added to a solution of 26 2-(2-(trimethylsilyl)ethenyl)-3-methyl-2-cyclohexen-l-one (Compound 3, 27 560 mg, 2.70 mmol) and dichloromethane (50 mL) at room 28 temperature. The solution was stirred overnight, and then treated with ι 10 % aqueous Na 2 S 2 0 3 to remove the excess iodine. The layers were 2 separated and the aqueous layer was extracted 3 x with ethyl acetate. 3 The combined organic extracts were washed with brine, dried (MgS0 4 ), 4 and filtered, and the solvent was removed under reduced pressure. The 5 residue was purified by flash chromatography on silica gel (9:1, 6 hexane :ethyl acetate) to give the product as a brown oil. 7 PNMR (300 MHz, CDC1 3 ) δ 1.94 (m, 2 H), 2.01 (s, 3 H), 2.37 (m, 4 H), s 6.99 (d, 1 H, J = 14.4 Hz), 7.19 (d, 1 H, J = 14.4 Hz). 9 Ethyl 4-Ethynylbenzoate ιo A solution of ethyl 4-iodobenzoate (6.9 g, 25 mmol), ιι (trimethylsilyl) acetylene (7.1 mL, 50 mmol) and triethylamine (200 mL) 12 was purged with argon for 10 minutes, and then treated with 13 bis(triphenylphosphine)palladium (II) chloride (175 mg, 0.25 mmol) and 14 copper (I) iodide (48 mg, 0.25 mmol). The suspension was stirred at is room temperature for 3 hours and concentrated under the vacuum of a 16 water aspirator. The residue was dissolved in hexane and washed with 17 10 % aqueous HC1. The layers were separated and the aqueous layer 18 was extracted 2 x with hexane. The combined organic fractions were 19 washed with water, and brine. The separated organic layer was treated 20 directly with 1 M solution of tetrabutylammonium fluoride and THF (35 21 mL, 35 mmol). After 30 minutes, the solution was washed with water (2 22 x), and brine, dried (MgS0 4 ) and filtered through silica gel. The 23 solvents were removed under reduced pressure and the residue was 24 purified by silica gel chromatography (98:2, hexane:ethyl acetate) to give 25 the title compound as a yellow oil. 26 PNMR (300 MHz, CDC1 3 ) δ 1.39 (t, 3 H, J = 7.1 Hz), 3.24 (s, 1 H), 27 4.38 (q, 2 H, J = 7.1 Hz), 7.54 (d, 2 H, J = 8.3 Hz), 7.99 (d, 2 H, J = 28 8.3 Hz). ι Ethyl 4-(4-(3-Methyl-2-cyclohexen-l-on-2-yπbut-3-en-l-yn-l-yl)benzoate 2 (Compound 5). 3 A solution of 2-(2-iodoethenyl)-3-methyl-2-cyclohexen-l-one 4 (Compound 4, 1.74 g, 6.64 mmol), ethyl 4-ethynylbenzoate (1.73 g, 9.96 5 mmol) and triethylamine (80 mL) was purged with argon for 10 e minutes, and then treated with bis(triphenylphosphine)palladium (II) 7 chloride (23 mg, 0.03 mmol) and copper (I) iodide (6.3 mg, 0.03 mmol). β The solution was stirred 40 °C for 3 hours, and concentrated under the 9 vacuum of a water aspirator. The residue was dissolved in ethyl acetate ιo and washed with saturated aqueous NH 4 C1. The layers were separated ιι and the aqueous layer was extracted 2 x with ethyl acetate. The 12 combined organic fractions were washed with water, and brine, and 13 dried (MgS0 4 ). The solvents were removed under reduced pressure, 14 and the residue was purified by silica gel chromatography (88:12, is hexane:ethyl acetate) to give the title compound as a yellow crystaline 16 solid. 17 PNMR (300 MHz, CDC1 3 ) δ 1.39 (t, 3 H, J = 7.1 Hz), 1.97 (m, 2 H), 18 2.11 (s, 3 H), 2.45 (m, 4 H), 4.37 (q, 2 H, J = 7.1 Hz), 6.58 (d, 1 H, J = 19 16.4 Hz), 6.85 (d, 1 H, J = 16.4 Hz), 7.49 (d, 2 H, J = 8.5 Hz), 7.98 (d, 20 2 H, J = 8.5 Hz). 21 Ethyl (±VfEV4-(;4-r3.3-dimethylcvclohexan-l-on-2-vnbut-3-en-l- 22 yn-l-yl)benzoate (Compound 6) 23 A 1.3 M solution of methyllithium (2.2 mL, 2.85 mmol) was 24 added to a stirring suspension of copper (I) bromide-dimethyl sulfide 25 (293 mg, 1.43 mmol) and 6 mL of THF at -78 °C. The solution was 26 warmed to -40 °C over 30 minutes and then recooled to -78 °C. Freshly 27 distilled hexamethylphosphoramide (0.37 mL, 2.14 mmol) was added, 28 and the solution was stirred at -78 °C for 30 min. A solution of ethyl ι 4-(4-(3-methyl-2-cyclohexen-l-on-2-yl)but-3-ene-l-yn-l-yl)benzoate 2 (Compound 5, 220 mg, 0.713 mmol), chlorotrimethylsilane (0.271 mL, 3 2.14 mmol) and 1.5 mL of THF was added. The solution was stirred at 4 -78 °C for 1 hour, and warmed slowly to -30 °C. The reaction was then 5 quenched by the addition of saturated aqueous NH 4 C1 and ethyl acetate. 6 The layers were separated and the aqueous layer extracted 3 x with 7 ethyl acetate. The combined organic layers were washed with 10 % 8 aqueous HC1 until all of the enol ether was hydrolyzed. The layers 9 were separated and the organic layer was washed with water, and brine, ιo and dried (MgS0 4 ). The solvents were removed under reduced ιι pressure, and the residue was purified by silica gel chromatography 12 (10:1, hexane:ethyl acetate) to give the title compound as a yellow oil. is PNMR (300 MHz, CDC1 3 ) δ 0.88 (s, 3H), 1.02 (s, 3 H), 1.38 (t, 3 H, J 14 = 7.1 Hz), 1.66 (m, 2 H), 1.91 (m, 2 H), 2.37 (m, 2 H), 2.88 (d, 1 H, J is = 9.8 Hz), 4.36 (q, 2 H, J = 7.1 Hz), 5.68 (d, 1 H, J = 15.9 Hz), 6.39 16 (dd, 1 H, J = 9.8, 15.9 Hz), 7.47 (d, 2 H, J = 8.4 Hz), 7.98 (d, 2 H, J = 17 8.4 Hz). is Ethyl 19 (E)-4-(4-(l-(Trifluromethanesulfonyl)oxy-3,3-dimethylcvclohexen-2-yl)bu 20 t-3-en-l-yn-l-vπbenzoate (Compound 7) and Ethyl 21 ±V E)-4-f4-(2- Trifluromethanesulfonyl)oxy-4.4-dimethylcvclohexen-3-v 22 l)but-3-en- 1-yn- 1 -yl)benzoate (Compound 8) 23 Trifluoromethanesulfonic anhydride (0.135 mL, 0.80 mmol) was 24 added to a solution of ethyl (±)-(E)-4-(4-(3,3-dimethylcyclohexan- 25 l-on-2-yl)but-3-en-l-yn-l-yl)benzoate (93 mg, 0.30 mmol) and 26 2,6-di-tert-butyl-4-methylpyridine (165 mg, 0.80 mmol) in 27 dichloromethane (4.5 mL). The flask was sealed with a plastic cap and 28 the mixture was stirred for 3 days at room temperature. The solution ι was diluted with diethyl ether and washed with saturated NH 4 C1, 5 % 2 aqueous NaHC0 3 , and brine, and dried (MgS0 4 ). The solvents were 3 removed under reduced pressure, and the residue was purified by silica 4 gel chromatography (10:1, hexane:ethyl acetate) to give the title 5 compounds as a 1:1 mixture of isomers. The compounds were e separated by HPLC using a Whatman Partisil-10 1 X 50 cm column 7 (95:5, hexane:ethyl acetate) to provide ethyl s (E)-4-(4-(l-(trifluromethanesulfonyl)oxy-3,3-dimethylcyclohexen-2-yl)but- 9 3-en-l-yn-l-yl)benzoate: PNMR (300 MHz, CDC1 3 ) δ 1.16 (s, 6 H), 1.39 ιo (t, 3 H, J = 7.1 Hz), 1.53 (m, 2 H), 1.79 (m, 2 H), 2.44 (m, 2 H), 4.37 ιι (q, 2 H, J = 7.1 Hz), 6.08 (d, 1 H, J = 16.5 Hz), 6.52 (d, 1 H, J = 16.5 12 Hz), 7.50 (d, 2 H, J = 8.4 Hz), 7.99 (dd, 2 H, J = 2.0, 8.4 Hz), and 13 ethyl (±)-(E)-4-(4-(2-(trifluromethanesulfonyl)oxy-4,4- 14 dimethylcyclohexen-3-yl)but-3-en-l-yn-l-yl)benzoate: PNMR (300 MHz, is CDC1 3 ) δ 0.95 (s, 3H), 1.04 (s, 3 H), 1.25-1.58 (m, 4 H), 1.39 (t, 3 H, J 16 = 7.2 Hz), 2.23 (m, 2 H), 2.76 (d, 1 H, J = 11.3 Hz), 4.37 (q, 2 H, J = 17 7.2 Hz), 5.82 (d, 1 H, J = 14.5 Hz), 5.86 (t, 1 H, J = 4.5 Hz), 6.08 (dd, 18 1 H, J = 11.3, 14.5 Hz), 7.48 (d, 2 H, J = 8.3 Hz), 7.98 (d, 2 H, J = 8.3 19 Hz). 20 Ethyl rEV4-r4-( i-(;4-MethylphenylV3.3-dimethylcvclohexen-2-vnbut-3-en- 21 l-yn-l-yl)benzoate (Compound 9) 22 General Procedure A 23 To a solution of 4-iodotoluene (100 mg, 0.46 mmol) and 1 mL of 24 THF at -78 °C under argon was added 1.7 M solution of 25 terf-butyllithium and pentane (0.54 mL, 0.92 mmol). The solution was 26 stirred at -78 °C for 20 minutes and then treated with a solution of 27 ZnBr 2 (155 mg, 0.688 mmol) and 2 mL of THF. The solution was 28 warmed to room temperature and stirred for 1 hour. To this solution ι was then added a mixture of ethyl (E)-4-(4-(l-(trifluromethane- 2 sulfonyl)oxy-3,3-dimethylcyclohexen-2-yl)but-3-en- 1-yn- l-yl)benzoate 3 (Compound 7, 43 mg, 0.092 mmol), 4 tetrakis(triphenylphosphine)palladium (20 mg, 0.02 mmol) and 2 mL of 5 THF, and the resulting mixture was stirred at room temperature for 30 6 minutes and at 50 °C for 10 minutes. Then the reaction mixture was cooled to room temperature and quenched by adding saturated aqueous s NH 4 C1, and the products were extracted 3 x with diethyl ether. The 9 combined organic layers were washed with brine, dried (MgS0 4 ), and ιo the solvents were removed under reduced pressure. The residue was ιι purified by silica gel chromatography (20:1, hexane:ethyl acetate) to give 12 the title compound containing a slight impurity, which was removed by is HPLC using a Whatman Partisil-10 1 X 50 cm column (2.5 % ethyl 14 acetate in hexane): is PNMR (300 MHz, CDC1 3 ) δ 1.23 (s, 6 H), 1.34 (t, 3 H, J = 7.1 Hz), 16 1.60 (m, 2 H), 1.73 (m, 2 H), 2.29 (s, 3 H), 2.35 (t, 2 H, J = 6.5 Hz), 17 4.32 (q, 2 H, J = 7.1 Hz), 5.58 (d, 1 H, J = 16.8 Hz), 6.65 (d, 1 H, J = 18 16.8 Hz), 7.03 (d, 2 H, J = 8.1 Hz), 7.13 (d, 2 H, J = 8.1 Hz), 7.43 (d, 2 19 H, J = 8.4 Hz), 7.93 (d, 2 H, J = 8.4 Hz). 20 Ethyl ( ± )-(E 4-(4-(;2-(;4-MethylphenylV4.4-dimethylcvclohexen-3-vnbut- 21 3-en- 1-yn- 1 -yl)benzoate (Compound 10) 22 Following General Procedure A, ethyl 23 (±)-(E)-4-(4-(2-(trifluromethanesulfonyl)oxy-4,4-dimethylcyclohexen-3-yl 24 )but-3-en-l-yn-l-yl)benzoate (Compound 8, 46 mg, 0.098 mmol) was 25 converted into the title compound: 26 PNMR (300 MHz, CDC1 3 ) δ 1.01 (s, 3H), 1.03 (s, 3 H), 1.38 (t, 3 H, J 27 = 7.1 Hz), 1.58 (m, 2 H), 2.24 (m, 2 H), 2.32 (s, 3 H), 2.96 (d, 1 H, J = 28 8.3 Hz), 4.37 (q, 2 H, J = 7.1 Hz), 5.59 (d, 1 H, J = 15.9 Hz), 6.05 (t, 1 ι H, J = 3.7 Hz), 6.26 (dd, 1 H, J = 8.3, 15.9 Hz), 7.09 (d, 2 H, J = 8.1 2 Hz), 7.22 (d, 2 H, J = 8.1 Hz), 7.41 (d, 2 H, J = 8.4 Hz), 7.95 (d, 2 H, J 3 = 8.4 Hz). 4 Ethyl (E)-4-(4- -r4-ethylphenyl)-3.3-dimethylcvclohexen-2-vnbut-3-en-l- 5 yn-l-yl)benzoate (Compound 11) 6 Following General Procedure A, ethyl 7 (E)-4-(4-(l-(trifluromethanesulfonyl)oxy-3,3-dimethylcyclohexen-2-yl)but- 8 3-en-l-yn-l-yl)benzoate (Compound 7, 35 mg, 0.077 mmol) was 9 converted into the title compound: ιo PNMR (300 MHz, CDC1 3 ) δ 1.23 (s, 6 H), 1.25 (t, 3 H, J = 7.6 Hz), ιι 1.38 (t, 3 H, J = 7.1 Hz), 1.60 (m, 2 H), 1.71 (m, 2 H), 2.35 (t, 2 H, J = 12 6.5 Hz), 2.65 (q, 2 H, J = 7.6 Hz), 4.35 (q, 2 H, J = 7.1 Hz), 5.54 (d, 1 13 H, J = 16.7 Hz), 6.62 (d, 1 H, J = 16.7 Hz), 7.04 (d, 2 H, J = 8.1 Hz), 14 7.15 (d, 2 H, J = 8.1 Hz), 7.39 (d, 2 H, J = 8.4 Hz), 7.93 (d, 2 H, J = is 8.4 Hz). 16 Ethyl (;EV4-(;4-( i-(4-tert-butylphenvn-3.3-dimethylcvclohexen-2-vnbut-3- 17 en- 1 -vn- l-yl)benzoate (Compound 12) 18 Following General Procedure A, ethyl 19 (E)-4-(4-(l-(trifluromethanesulfonyl)oxy-3,3-dimethylcyclohexen-2-yl)but- 20 3-en-l-yn-l-yl)benzoate (Compound 7, 45 mg, 0.098 mmol) was 21 converted into the title compound: 22 PNMR (300 MHz, CDC1 3 ) δ 1.24 (s, 6 H), 1.33 (s, 9 H), 1.37 (t, 3 H, J 23 = 7.2 Hz), 1.60 (m, 2 H), 1.72 (m, 2 H), 2.37 (t, 2 H, J = 6.5 Hz), 4.35 24 (q, 2 H, J = 7.2 Hz), 5.56 (d, 1 H, J = 16.6 Hz), 6.63 (d, 1 H, J = 16.6 25 Hz), 7.03 (d, 2 H, J = 8.1 Hz), 7.31 (d, 2 H, J = 8.1 Hz), 7.38 (d, 2 H, J 26 = 8.4 Hz), 7.93 (d, 2 H, J = 8.4 Hz). 27 (EV4-r4- -r4-Methylphenvn-3.3-dimethylcvclohexen-2-vnbut-3-en-l- 28 yn-l-yl)benzoic Acid (Compound 13) ι General Procedure B 2 To a solution of ethyl (E)-4-(4-(l-(4-methylphenyl)-3,3- 3 dimethylcyclohexen-2-yl)but-3-en-l-yn-l-yl)benzoate (Compound 9, 24.5 4 mg, 0.062 mmol) and 2 mL of ethanol was added 1 M solution of 5 aqueous NaOH (1 mL, 1 mmol). The solution was stirred at 50 °C for 6 1 hour, cooled to room temperature and washed once with hexane/ether 7 (5:1). The aqueous layer was separated, acidified with 1 M aqueous β HC1, and the product was extracted with ethyl acetate. The combined 9 organic layers were washed with brine, dried (MgS0 4 ), and the solvents ιo were removed under reduced pressure. The residue was purified by ιι silica gel chromatography (1:1, hexane:ethyl acetate)to give the title 12 compound as a yellow solid: PNMR (300 MHz, CDC1 3 ) δ 1.16 (s, 6 H), 13 1.53 (m, 2 H), 1.65 (m, 2 H), 2.27 (s, 3 H), 2.27 (t, 2 H, J = 5.6 Hz), 14 5.46 (d, 1 H, J = 16.6 Hz), 6.56 (d, 1 H, J = 16.6 Hz), 6.95 (d, 2 H, J = is 8.1 Hz), 7.05 (d, 2 H, J = 8.1 Hz), 7.35 (d, 2 H, J = 8.4 Hz), 7.92 (d, 2 16 H, J = 8.4 Hz). 17 f±V(EV4- 4-(2- 4-MethylphenylV4.4-dimethylcvclohexen-3-vπbut-3-en- 18 l-yn-l-yl)benzoic acid (Compound 14) 19 Following General Procedure B, ethyl 20 ( ± )-(E)-4-(4-(2-(4-methylphenyl)-4,4-dimethylcyclohexen-3-yl)but-3-en- 21 l-yn-l-yl)benzoate (Compound 10, 22 mg, 0.055 mmol) was converted 22 into the title compound and purified by recrystalization from 23 acetonitrile: 24 PNMR (300 MHz, acetone-d6) δ 1.00 (s, 3H), 1.05 (s, 3 H), 1.29 (m, 2 25 H), 1.60 (m, 2 H), 2.08 (s, 3 H), 3.14 (d, 1 H, J = 8.9 Hz), 5.67 (d, 1 H, 26 J = 15.9 Hz), 6.05 (t, 1 H, J = 3.8 Hz), 6.22 (dd, 1 H, J = 8.9, 15.9 27 Hz), 7.09 (d, 2 H, J = 8.2 Hz), 7.27 (d, 2 H, J = 8.2 Hz), 7.47 (d, 2 H, J 28 = 8.3 Hz), 7.96 (d, 2 H, J = 8.3 Hz). ι (EV4-r4- -(;4-Ethylρhenvn-3.3-dimethylcvclohexen-2-vnbut-3-en-l- 2 vn-l-yl)benzoic acid (Compound 15) 3 Following General Procedure B, ethyl (E)-4-(4-(l-(4-ethylphenyl)-3,3- 4 dimethylcyclohexen-2-yl)but-3-en-l-yn-l-yl)benzoate (Compound 11, 13 5 mg, 0.034 mmol) was converted into the title compound and purified by e recrystalization from acetonitrile. 7 PNMR (300 MHz, DMSO-d6) δ 1.17 (t, 3 H, J = 7.7 Hz), 1.19 (s, 6 H), s 1.56 (m, 2 H), 1.67 (m, 2 H), 2.31 (br t, 2 H), 2.58 (q, 2 H, J = 7.7 Hz), 9 5.59 (d, 1 H, J = 16.7 Hz), 6.57 (d, 1 H, J = 16.7 Hz), 7.04 (d, 2 H, J = ιo 8.0 Hz), 7.16 (d, 2 H, J = 8.0 Hz), 7.44 (d, 2 H, J = 8.3 Hz), 7.85 (d, 2 ιι H, J = 8.3 Hz). 12 tEV4-r4- -(4-tert-butylphenylV3.3-dimethylcvclohexen-2-vnbut-3-en-l- 13 yn-l-yl)benzoic acid (Compound 16) 14 Following General Procedure B, ethyl is (E)-4-(4-(l-(4-tert-butylphenyl)-3,3-dimethylcyclohexen-2-yl)but-3-en-l- 16 yn-l-yl)benzoate (Compound 12, 35 mg, 0.085 mmol) was converted into 17 the title compound and purified by recrystalization from acetonitrile: 18 PNMR (300 MHz, DMSO-d6) δ 1.21 (s, 6 H), 1.27 (s, 9 H), 1.56 (m, 2 19 H), 1.67 (m, 2 H), 2.31 (br t, 2 H), 5.63 (d, 1 H, J = 16.6 Hz), 6.57 (d, 1 20 H, J = 16.6 Hz), 7.05 (d, 2 H, J = 8.2 Hz), 7.35 (d, 2 H, J = 8.2 Hz), 21 7.43 (d, 2 H, J = 8.1 Hz), 7.85 (d, 2 H, J = 8.1 Hz). 22 2-Iodo-4.4-dimethyl-2-cyclohexen-l-one (Compound 17) 23 Freshly distilled azidotrimethylsilane (4.61 mL, 34.7 mmol) was 24 added to a stirred solution of 4,4-dimethyl-2-cyclohexen-l-one (available 25 from Aldrich Chemical Co., 3.04 mL, 23.2 mmol) and dichloromethane 26 (35 mL) at 0°C under argon. The solution was stirred for 2 hours at 0°C 27 before adding a solution of iodine (11.8 g, 46.3 mmol) in 35 mL of 28 pyridine and 35 mL of dichloromethane. The resulting solution was ι stirred for 20 hours at room temperature, diluted with ethyl acetate, and 2 was washed with 20 % aqueous Na 2 S 2 0 3 , and 10 % aqueous HC1, and 3 water, and brine. The solvents were dried over MgS0 4 , filtered, and 4 concentrated under reduced pressure. The residue was purified by flash 5 chromatography on silica gel (7:1, hexanes:ethyl acetate) to give the title 6 compound as a yellow oil. 7 PNMR (300 MHz, CDC1 3 ) δ 1.17 (s, 6 H), 1.91 (dd, 2 H, / = 6.4, 7.4 Hz), β 2.66 (dd, 2 H, / = 6.4, 7.4 Hz), 7.44 (s, 1H). 9 jgV2- 2-(Trimethylsilv ethenylV4,4-dimethyl-2-cvclohexen-l-one ιo (Compound 18) ιι 2-Iodo-4,4-dimethyl-2-cyclohexen-l-one (Compound 17, 1.0 g, 4.0 12 mmol) and (£)-(2-(tributylstanyl)ethenyl)trimethylsilane (2.18 g, 5.6 13 mmol) were dissolved in 25 mL of THF and the solution purged with 14 dry argon for 10 minutes. Bis(triphenylphosphine)palladium (II) is chloride (140 mg, 0.20 mmol) was added and the solution was refluxed 16 for 4 hours under argon. The solution was cooled to room temperature 17 and hexane and aqueous ammonium chloride were added. The layers is were separated and the aqueous layer was extracted 3 x with hexane. 19 The combined organic extracts were washed with water, and brine, and 20 dried (MgS0 4 ). After filtration, the solvent was removed in-vacuo and 21 the residue purified by silica gel chromatography (9:1, hexanes:ethyl 22 acetate) to give the title compound as a yellow oil. 23 PNMR (300 MHz, CDC1 3 ) δ 0.095 (s, 9 H), 1.18 (s, 6 H), 1.83 (t, 2 H, / 24 = 6.7 Hz), 2.49 (t, 2 H, J = 6.7 Hz), 6.33 (d, 1 H, / = 19.3 Hz), 6.75 (d, 25 1 H, / = 19.3 Hz), 6.73 (s, 1 H). 26 fEV2-( -iodoethenylV4.4-dimethyl-2-cvclohexen-l-one (Compound 19) 27 Iodine (657 mg, 2.59 mmol) was dissolved in 5 mL of THF and 28 the solution was added to a solution of 2-(2-(trimethylsilyl)ethenyl)-4,4- ι dimethyl-2-cyclohexen-l-one (Compound 18, 575 mg, 2.59 mmol) and 2 dichloromethane (15 mL) at room temperature. The solution was stirred 3 for 6 hours, and then treated with 10 % aqueous Na 2 S 2 0 3 to remove the 4 excess iodine. The layers were separated and the aqueous layer was 5 extracted 3 x with ethyl acetate. The combined organic extracts were 6 washed with brine, dried (MgS0 4 ), and filtered, and the solvent was 7 removed under reduced pressure. The residue was purified by flash 8 chromatography on silica gel (9:1, hexane:ethyl acetate) to give the 9 product as a brown oil. ιo PNMR (300 MHz, CDC1 3 ) δ 1.18 (s, 6 H), 1.84 (t, 2 H, / = 6.8 Hz), ιι 2.49 (t, 2 H, / = 6.8 Hz), 5.62 (d, 1 H, / = 14.3 Hz), 6.50 (d, 1 H, / = 12 14.3 Hz), 6.68 (s, 1 H). 13 Ethyl (E)-4-f4-(4.4-Dimethyl-2-cvclohexen-l-on-2-vπbut-3-ene-l-vn-l- 14 yl)benzoate (Compound 20) is A solution of (E)-2-(2-iodoethenyl)-3-methyl-2-cyclohexen-l-one 16 (Compound 19, 0.22 g, 0.797 mmol), ethyl 4-ethynylbenzoate (0.167 g, 17 0.956 mmol) and triethylamine (9.5 mL) was purged with argon for 10 is minutes, and then treated with bis(triphenylphosphine)palladium (II) 19 chloride (28 mg, 0.04 mmol) and copper (I) iodide (8 mg, 0.04 mmol). 20 The solution was stirred 40 °C for 3 hours, and concentrated under a 21 water aspirator vacuum. The residue was dissolved in ethyl acetate and 22 washed with saturated aqueous NH 4 C1. The layers were separated and 23 the aqueous layer was extracted 2 x with ethyl acetate. The combined 24 organic fractions were washed with water, and brine, and dried 25 (MgS0 4 ). The solvents were removed under reduced pressure, and the 26 residue was purified by silica gel chromatography (88:12, hexane:ethyl 27 acetate) to give the title compound as a yellow crystaline solid. 28 PNMR (300 MHz, CDC1 3 ) δ 1.21 (s, 6H), 1.39 (t, 3 H, = 7.2 Hz), 1.87 ι (dd, 2 H, / = 6.7, 6.8 Hz), 2.53 (dd, 2 H, / = 6.7, 6.8 Hz), 4.37 (q, 2 H, 2 / = 7.2 Hz), 6.54 (d, 1 H, / = 16.2 Hz), 6.71 (s, 1 H), 6.75 (d, 1 H, / = 3 16.2 Hz), 7.48 (d, 2 H, / = 8.4 Hz), 7.98 (d, 2 H, / = 8.4 Hz). 4 Ethyl ^V4-(4- 2- trifuoromethanesulfonyl)oxy-5.5-dimethyl-1.3- 5 cvclohexadien-3-yl)but-3-ene-l-yn-l-yl)benzoate (Compound 21) 6 A solution of ethyl (£)-4-(4-(4,4-dimethyl-2-cyclohexen-l-on-2- yl)but-3-ene-l-yn-l-yl)benzoate (Compound 20, 0.050 g, 0.156 mmol) β and 1 mL of THF were added to a solution of sodium 9 bis(trimethylsilyl)amide at -78 °C under argon. The resulting blood red ιo solution was stirred at - 78 °C for 15 min and treated with a solution of ιι 2-[Λ/,N-bis(trifuoromethylsulfonyl)amino]-5-chloropyridine (0.077 g, 12 0.203 mmol) over a period of 3 minutes. The red color faded as the 13 solution was stirred for an additional 1.5 hours at -78 °C. The reaction 14 was quenched at - 78 °C by the addition of saturated aqueous NH 4 C1 is and ethyl acetate. The layers were separated and the aqueous layer was 16 extracted 3 x with ethyl acetate. The organic fractions were combined 17 and washed with 10 % aqueous Hcl, and water , and brine, dried is (MgS0 4 ), and the solvents removed in-vacuo. The residue was purified 19 by silica gel chromatography (5 % ethyl acetate:hexane) to give the title 20 compound as an off-white solid. 21 PNMR (300 MHz, CDC1 3 ) δ 1.11 (s, 6H), 1.40 (t, 3 H, / = 7.1 Hz), 2.28 22 (d, 2 H, / = 4.9 Hz), 4.38 (q, 2 H, / = 7.1 Hz), 5.81 (t, 1 H, = 4.9 23 Hz), 5.94 (s, 1 H), 6.11 (d, 1 H, / = 16.3 Hz), 6.59 (d, 1 H, / = 16.3 24 Hz), 7.49 (d, 2 H, / = 8.6 Hz), 7.99 (d, 2 H, = 8.6 Hz). 25 Ethyl E)-4-(4-(2-(4-methylphenyl)-5.5-dimethyl-1.3-cyclohexadien-3- 26 yl)but-3-ene-l-yn-l-yl)benzoate (Compound 22) 27 Following General Procedure A, ethyl (£)-4-(4-(2- 28 (trifuoromethanesulfonyl)oxy-5,5-dimethyl-l,3-cyclohexadien-3-yl)but-3- ι ene-l-yn-l-yl)benzoate (Compound 21, 46 mg, 0.098 mmol) was 2 converted into the title compound. 3 PNMR (300 MHz, acetone-d 6 ) δ 1.10 (s, 6H), 1.34 (t, 3 H, / = 7.1 Hz), 4 2.20 (d, 2 H, / = 4.9 Hz), 2.32 (s, 3 H), 4.32 (q, 2 H, / = 7.1 Hz), 5.54 5 (d, 1 H, / = 162 Hz), 5.87 (t, 1 H, = 4.9 Hz), 6.13 (s, 1 H), 6.54 (d, 1 e H, / = 16.2 Hz), 7.10 (d, 2 H, / = 6.4 Hz), 7.17 (d, 2 H, / = 6.4 Hz), 7 7.45 (d, 2 H, = 8.5 Hz), 7.94 (d, 2 H, / = 8.5 Hz). s Ethyl rEV4-(4-(2-(;4-fe/ -butylphenylV5. 5-dimethyl-1.3-cvclohexadien-3- 9 yl)but-3-ene- 1 -yn- l-yl)benzoate (Compound 23) ιo Following General Procedure A, ethyl (E)-4-(4-(2- ιι (trifuoromethanesulfonyl)oxy-5,5-dimethyl-l,3-cyclohexadien-3-yl)but-3- 12 ene-l-yn-l-yl)benzoate (Compound 21, 46 mg, 0.098 mmol) was 13 converted into the title compound. 14 PNMR (300 MHz CDC1 3 ) δ 1.09 (s, 6H), 1.34 (s, 9 H), 1.38 (t, 3 H, = is 7.1 Hz), 2.20 (d, 2 H, / = 4.8 Hz), 4.35 (q, 2 H, / = 7.1 Hz), 5.55 (d, 1 16 H, / = 16.1 Hz), 5.88 (t, 1 H, / = 4.8 Hz), 6.00 (s, 1 H), 6.57 (d, 1 H, / 17 = 16.1 Hz), 7.15 (d, 2 H, / = 6.6 Hz), 7.34 (d, 2 H, / = 6.6 Hz), 7.41 is (d, 2 H, / = 8.4 Hz), 7.94 (d, 2 H, J = 8.4 Hz). 19 rEV4-(4-(2-( 4-MethylphenylV5.5-dimethyl-1.3-cvclohexadien-3-vnbut-3- 20 ene-l-yn-l-yl)benzoic Acid (Compound 24) 21 Following General Procedure B, ethyl (E)-4-(4-(2-(4- 22 methylphenyl)-5, 5-dimethyl-l,3-cyclohexadien-3-yl)but-3-ene-l-yn-l- 23 yl)benzoate (Compound 22, 20 mg, 0.050 mmol) was converted into the 24 title compound. 25 PNMR (300 MHz, CD 3 OD) δ 0.99 (s, 6H), 2.09 (d, 2 H, / = 4.7 Hz), 26 2.23 (s, 3 H), 5.33 (d, 1 H, / = 16.3 Hz), 5.73 (t, 1 H, / = 4.7 Hz), 6.93 27 (s, 1 H), 6.36 (d, 1 H, / = 16.3 Hz), 6.94 (d, 2 H, / = 8.1 Hz), 7.03 (d, 2 28 H, / = 8.1 Hz), 7.29 (d, 2 H, / = 8.4 Hz), 7.82 (d, 2 H, = 8.4 Hz). fE -f4-f2-(4-fert-ButyrphenylV5. 5-dimethyl-1.3-cvclohexadien-3-vnbut- 3-ene-l-yn-l-yl)benzoic Acid (Compound 25) Following General Procedure B, ethyl (E)-4-(4-(2-(4-fert- butylphenyl)-5,5-dimethyl-l,3-cyclohexadien-3-yl)but-3-ene-l-yn-l- yl)benzoate (Compound 23, 10.8 mg, 0.025 mmol) was converted into the title compound. PNMR (300 MHz, CDC1 3 ) δ 1.10 (s, 6H), 1.34 (s, 9 H), 2.20 (d, 2 H, / = 4.7 Hz), 5.47 (d, 1 H, / = 16.2 Hz), 5.88 (t, 1 H, / = 4.7 Hz), 6.01 (s, 1 H), 6.58 (d, 1 H, / = 16.2 Hz), 7.16 (d, 2 H, / = 8.4 Hz), 7.35 (d, 2 H, J = 8.4 Hz), 7.44 (d, 2 H, / = 8.4 Hz), 7.99 (d, 2 H, / = 8.4 Hz).

Claims: WHAT IS CLAIMED IS: 1. A compound of the formula wherein one of the dashed lines respectively designated a and β o represents a bond and the other represents absence of a bond, the dashed line designated γ represents absence of a bond when β represents a bond, and wherein the dashed line designated γ represents absence of a bond or a bond when a represents a bond; the cyclohexene ring is unsubstituted or substituted with 1 to 7 s R x groups where R x is independently selected from the group consisting of alkyl of 1 to 6 carbons, F, Cl, Br and I; R 3 is H, alkyl of 1 to 6 carbons, F, Cl, Br or I; R 4 is phenyl, naphthyl, or heteroaryl where the heteroaryl group is 5-membered or 6-membered and has 1 to 3 heteroatoms selected from o the group consisting of O, S and N, and where the R 4 group is unsubstituted or substituted with 1 to 5 R 5 groups where R 5 is independently selected from the group consisting of F, Cl, Br, I, N0 2 , N(R 8 ) 2 , N(R 8 )COR 8 , NR 8 CON(R 8 ) 2 , OH, OCOR 8 , OR 8 , CN, COOH, COOR 8 , an alkyl group having 1 to 10 carbons, fluoro substituted alkyl 5 group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a (trialkyl)silyl or (trialkyl)silyloxy group where the alkyl groups independently have 1 to 6 carbons; Z is -CR^N, -(CR 1 =CR 1 ) n> - where n' is an integer having the value 0 - 5, -CO-NR r , -CS-NR , s -COO-, -C≡C-, -CSO-, -CO-CR^CR ! -; Y is phenyl or naphthyl, or heteroaryl selected from a group o consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl, naphthyl or heteroaryl groups being unsubstituted or substituted with one or two R 2 groups, where R 2 is independently selected from the group consisting of lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 , fluoro substituted alkyl s of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, and alkylthio of 1 to 6 carbons; alternatively when Z is -(CR^CR ,,,- and n' is 2, 3, 4 or 5 then Y may represent a direct valence bond between said (CR 2 =CR 2 ) n , group and B; A is (CH 2 ) q where q is 0-5, lower branched chain alkyl having 3-6 o 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, COOR 8 , CONR^, -CH 2 OH, CH 2 OR n , CH 2 OCOR u , CHO, 5 CH(OR 12 ) 2 , CHOR^O, -COR,, CR 7 (OR 12 ) 2 , O^OR^O, or S^C^alkyl);,, where R, is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R 8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl, R, 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 n is lower alkyl, phenyl or lower alkylphenyl, R is lower alkyl, and R 13 is divalent alkyl radical of 2-5 carbons. 2. A compound of Claim 1 where the Z group is selected from the group consisting of -C≡C-, -CH=CH-, -CONH-, -COO-, -COS-, -CSNH-, -(CR^CRJ,,,- where n' is 3, and -(CR^CR ,,,- where n' is 0. 3. A compound of Claim 1 where R 4 is phenyl, R 5 -substituted phenyl, pyridyl, R 5 -substituted pyridyl, thienyl, R 5 -substituted thienyl, furyl or R 5 -substituted furyl. 4. A compound of Claim 1 wherein Z is -C≡C-, and Y is phenyl or naphthyl, or heteroaryl selected from a group consisting of pyridyl, thienyl, and furyl, said phenyl, naphthyl or heteroaryl groups being unsubstituted or substituted with one or two R 2 groups. 5. A compound of Claim 4 where the dashed line designated γ represents absence of a bond. 6. A compound of Claim 4 where the dashed line designated γ represents a bond. 7. A compound of Claim 4 where R 4 is phenyl or R 5 -substituted phenyl. 8. A compound of Claim 4 where Y is phenyl. 9. A compound of the formula wherein one of the dashed lines respectively designated and β represents a bond and the other represents absence of a bond, thus forming a single double bond in the six-membered ring; R 5 is H or an alkyl group having 1 to 6 carbons; R 8 is H, or an alkyl group of 1 to 6 carbons, or a pharmaceutically acceptable salt thereof. 10. A compound of Claim 9 where the line designated represents a bond. 11. A compound of Claim 10 where R 5 is methyl. 12. A compound of Claim 9 where the line designated β represents a bond. 13. A compound of Claim 12 where R 5 is methyl, ethyl or tertiary-butyl. 14. A compound of Claim 13 where R 8 is H, methyl or ethyl, or a pharmaceutically acceptable salt thereof. 15. A compound of the formula where R 5 is H or an alkyl group having 1 to 6 carbons; R 8 is H, or an alkyl group of 1 to 6 carbons, or a pharmaceutically acceptable salt thereof. 16. A compound of Claim 15 where R 5 is methyl, or tertiary-butyl. 17. A compound of Claim 16 where R 8 is H, methyl or ethyl, or a pharmaceutically acceptable salt thereof.

Inventors: BEARD RICHARD L, CHANDRARATNA ROSHANTHA A, JOHNSON ALAN T, TENG MIN, VULIGONDA VIDYASAGAR, BEARD, RICHARD, L., CHANDRARATNA, ROSHANTHA, A., JOHNSON, ALAN, T., TENG, MIN, VULIGONDA, VIDYASAGAR
Applicants: VISION PHARM LP, VISION PHARMACEUTICALS L.P.
Application year: 1998
Main classification: C07C63
IPC codes: A61K31, A61P3, A61P9, A61P17, A61P25, A61P37, C07C63, C07C69, C07C309