MXPA01003363A - 2, 4-pentadienoic acid derivatives having selective activity for retinoid x (rxr) receptors - Google Patents

Abstract

Compounds of Formula (1), Formula (2) or Formula (3) where X is O, S, or (CR1R1)n where n is 0, 1, or 2;Y is a bivalent radical having Formula (4) or Formula (5) where o is an integer from 1 to 4 or Y is a bivalent aryl or 5 or 6 membered heteroaryl radical having 1 to 3 heteroatoms selected from N, S and O, said aryl or heteroaryl groups being unsubstituted, or substituted with 1 to 3 C1-6 alkyl or with 1 to 3 C1-6 fluoroalkyl groups;and the remaining symbols have the meaning described in the specification, have RXR selective retinoid agonist-like activity.

Description

DERIVATIVES OF ACID 2, -PENTADIENOICO THAT HAVE SELECTIVE ACTIVITY BY RETINOID RECEPTORS X (RXR) BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to novel compounds having biological activity similar to that of a retinoid. More specifically, the present invention relates to derivatives of 2,4-pentadienoic acid having selective activity by retinoid X (RXR) receptors. 2. Prior art Compounds having activity similar to that of a retinoid are well known in the art, and are described in numerous US patents and others and in scientific publications. It is generally known and accepted in the art that activity similar to that of a retinoid is useful for treating animals of mammalian species, including humans to cure or alleviate the symptoms and conditions of numerous diseases and conditions. In other words, it is generally accepted in the art that pharmaceutical compositions having a similar compound or retinoid-like compounds as the active ingredient are useful as proliferation regulators and ref: 128153 cell differentiation, and particularly as agents for treat skin-related diseases, including actinic keratosis, arsenic keratosis, inflammatory and noninflammatory acne, psoriasis, ichthyosis and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage (steroid atrophy), as a topical antimicrobial, as antipigmentation agents of the skin and to treat and reverse the effects of age and photodamage to the skin. Retinoid compounds are also useful for the prevention and treatment of cancerous and precancerous conditions, including premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx , oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leucoplasias and papillomas of mucous membranes and in the treatment of Kaposi's sarcoma. In addition, retinoid compounds can be used as agents to treat diseases of the eyes, including, without limitation, proliferative vitreoretinopathy (PVR), retinal detachment, dry eyes and other corneopathies, as well as in the treatment and prevention of various cardiovascular diseases. , including, without limitation, diseases associated with lipid metabolism, such as dyslipidemias, prevention of postangioplasty restenosis and as an agent to increase the level of circulating tissue plasminogen activator (TPA). Other uses for retinoid compounds include the prevention and treatment of conditions and diseases associated with human papillomavirus (HPV), including warts and genital warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn's disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and stroke, inappropriate pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis and the inhibition of apoptosis activated by T cells, restoration of hair growth, including therapies combined with the compounds of the present and other agents such as Minoxidil®, diseases associated with the immune system, including the use of the present compounds as immunosuppressants and immunostimulants, the modulation of transplant rejection of organs and the facilitation of wound healing, including the modulation of chemosis. Although pharmaceutical compositions comprising retinoids have a well established utility, retinoids also cause a number of undesirable side effects at therapeutic dose levels, including headache, teratogenesis, ucocutaneous toxicity, musculoskeletal toxicity, dislipedy, skin irritation, headache and hepatotoxicity. These side effects limit the acceptability and usefulness of retinoids for the treatment of diseases. It is now generally known in the art that there are two main types of retinoid receptors in mammals (and other organisms). The two main types or families of recipients were designated respectively as RAR and RXR. Within each type there are subtypes; in the RAR family the subtypes are designated as RARa, RARß and RAR ?, in the RXR the subtypes are: RXRa, RXRß and RXR ?. It has also been established in the art that the distribution of the two major types of retinoid receptors, and of the different subtypes, is not uniform in the different tissues and organs of mammalian organisms. However, it is generally accepted in the art that many undesirable side effects of retinoids are mediated by one or more of the RAR receptor subtypes. Accordingly, between compounds that have activity similar to that of an agonist at the retinoid receptors, specificity or selectivity for one of the major types or families, and still specificity or selectivity for one or more subtypes within a family of receptors. , is considered a desirable pharmacological property. Some compounds bind to one or more subtypes of RAR receptors, but do not trigger the response, which is triggered by agonists of the same receptors. A compound that binds to a biological receptor but does not trigger a response similar to that of an agonist is usually called an antagonist. Consequently, the "effect" of the compounds on the retinoid receptors can fall in the range of not completely affecting (inactive compound, neither agonist nor antagonist) or the compound can produce a response similar to that of an agonist over all subtypes of receptors (panagonist). As another alternative, a compound may be a partial agonist and / or a partial antagonist of certain receptor subtypes if the compound binds to, but does not activate, a certain subtype or receptor subtypes but produces a response similar to that of an agonist in another subtype. or subtypes of receptors. A panagonist is a compound that binds to all known retinoid receptors but does not produce a response similar to that of an agonist at any of the receptors. Recently a two-state model has emerged for certain receptors, including the retinoid receptors mentioned above. In this model, it is postulated that there is a balance between inactive receptors and spontaneously active receptors, which are capable of coupling with a G protein in the absence of a ligand (agonist). In this model, the so-called "inverse agonists" shift the balance towards the inactive receptors, thus producing a total inhibitory effect. Neutral antagonists do not affect receptor equilibrium but are able to compete for receptors with both agonists (ligands) and with inverse agonists. The published PCT application WO 97/09297, assigned to the same beneficiary of the present application, describes several compounds having biological activity of the retinoid antagonist and retinoid inverse agonist type, and describes that activity similar to that of the retinoid antagonist and / or inverse retinoid agonist described above of a compound is also a useful property, since such antagonist-like or inverse agonist-like compounds can be used to block certain undesirable side effects of retinoids, to serve as antidotes for overdoses of or poisoning with retinoid, and may be endowed by themselves for other pharmaceutical applications as well. Numerous compounds having activity similar to that of a selective agonist for the retinoid RXR receptors are described in published PCT applications WO 93/21146, WO 95/04036 and WO 97/12853. In these PCT publications, the specific compounds of particular interest as background for the present invention are, in WO 93/21146: 4- [1- (3, 5, 5, 8, 8-pentamethyl-5,6, 7, 8- tetrahydro-2-naphthyl) epoxy] benzoic acid, 4- [1- (3,5,5,8,8-pentyl-5,6,7,8-tetrahydro-2-naphthyl) cyclopropyl] benzoic, 2- [1- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl) cyclopropyl] pyridine-5-carboxylic acid and 2- [1- (3 , 5, 5, 8, 8-pentamet? L-5, 6, 7, 8-tetrahydro-2-naphthyl) cyclopropyl] pyridine-5-carboxylic acid methyl ester (Compounds 47, 48, 62 and Me-62 in the pages 15 and 17 of WO 93/21146); In reference WO 95/04036: (2E, 4E) -3-methyl-5- [1- (3, 5, 8, 8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl) cyclopropyl acid J penta-2,4-dienoic acid (Compound 104 on page 23 of WO 95/04036). In reference WO 97/12853: tetramethyl-3-propyloxy-5,6,7,8-tetrahydronaphthalen-2-yl) cyclo? Ropan-1-yl] -3-methyl hexadienoic acid (Compound 152); (2E, 4E) -6- [2- (5, 5, 8, d-tetramethyl-3-heptyloxy-5,6,7,8-tetrahydronaphthalen-2-yl) cyclopropan-1-yl] -3- acid methyl hexadienoic (Compound 153); (2E, 4E) -6- [2- (5,5,8,8-tetramethyl-3-benzyloxy-5,6,7,8-tetrahydronaphthalen-2-yl) cyclopropan-i-yl] -3- acid methyl hexadienoic (Compound 154); (2E, 4E) -7- [(5, 5, 8, 8-tetramethyl-3-propyloxy-5,, 7, 8-tetrahydronaphthalen-2-yl) cyclopropan-1-yl] -3-methyl heptadienoic acid ( Compound 155); acid (2E, 4E -7- [(5, 5, 8, 8-tetramethyl-3-heptyloxy-5, 6, 7, 8-tetrahydronaphthalen-2-yl) cyclopropan-1-yl] -3-methyl heptadienoic acid ( Compound 156): (2E, 4E) -7- [(5, 5, 8, 8-tetramethyl-3-benzyloxy-5, 6, 7, 8-tetrahydronaphthalen-2-yl) cyclopropan-1-yl] acid - 3-methyl heptadiene (Compound 157): (2E, 4E) -5- [2- (5, 5, 8, 8-tetramethyl-3-propyloxy-5,6,7,8-tetrahydronaphthalen-2-acid) il) cyclopent-1-en-l-yl] -3-methyl pentadienoic acid (Compound 158), cis (2E, 4E) -5- [2- (5, 5, 8, 8-tetramethyl-3-propyloxy) acid 5,6,7,8-tetrahydro-2-naphthyl) cyclopentan-1-yl] -3-methyl pentadienoic acid (Compound 159) The following compounds of the prior art are also of interest for the present invention: Acid (2E, 4E) -6- [1- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) cyclopropan-1-yl] -3-methyl hexadienoic acid (Compound 101); (2E, 4E) -6- [(3, 5, 5, 8, 8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) cyclopropan-1-yl] -3-methyl hexadienoic acid (Compound 102 acci do (2E, 4E) -6- [(5, 5, 8, 8-tetramethyl-3-methoxy-5, 6, 7, 8-tetrahydronaphthalen-2-yl) cyclopropan-1-yl] -3- methyl hexadienoic (Compound 103); (2E, 4E) -6- [(5,5,8,8-Tetramethyl-3-ethoxy-5,6,7,8-tetrahydro-naphthalen-2-yl) -cyclopropan-1-yl] -3- acid methyl hexadienoic (Compound 104); (2E, 4E) -6 - [(3,5-di-t-butyl phenyl) cyclopropan-1-yl] -3-methyl hexadienoic acid (Compound 105); (2E, 4E) -6 - [(3,4-diethylphenyl) cyclopropan-1-yl] -3-methyl hexadienoic acid (Compound 106); (2E, 4E) -6- [1- (6-t-Butyl-1, l-dimethyl-indan-4-yl) -cyclopropyl] -3-methyl hexadienoic acid (Compound 107); and (2E, 4E) -6- [(5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydronaphthalen-2-yl) cyclopentane-1-yl] -3-methyl hexa-dienoic acid ( Compound 108). The publication WO 96/39374 published in December 12, 1996 (corresponding to U.S. Patent Nos. 5,663,367 and 5,675,033) discloses 2,4-pentadienoic acid derivatives having selective activity by retinoid RXR receptors. The compounds of this reference include a cyclic portion (tetrahydronaphthyl, chromanyl or thiochromanyl) condensed, and a cycloalkyl (cyclopropyl mainly) or phenyl or heteroaryl moiety binding the pentadienoic acid portion to the condensed cyclic portion. U.S. Patent No. 5,648,514 describes phenylethynyl or heteroarylethynyl dihydronaphthalene derivatives wherein the 5 or 8 position (depending on the numbering system) of the dihydronaphthalene nucleus is substituted with an alicyclic, aryl or heteroaryl group. U.S. Patent No. 5,723,666 (formula 6 in Column 9) discloses additional dihydronaphthalene derivatives where the 5 or 8 position (depending on the numbering system) of the dihydronaphthalene nucleus is substituted with an alicyclic, aryl or heteroaryl group. The compounds of this reference have biological activity similar to that of a retinoid or similar to that of a retinoid antagonist.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to compounds of Formula 1, Formula 2 or Formula 3 Formula 1 Formula 2 Formula 3 where X is 0, S, or (CR? R?) N where n is 0, 1 or 2; And it's a bivalent radical that has Formula 4 or Formula 5 where o is a number from 1 to 4 Formula 4 Formula 5 or Y is a bivalent aryl or a 5- or 6-membered heteroaryl radical having 1 to 3 heteroatoms selected from N, S and 0, the aryl or heteroaryl groups are unsubstituted, or substituted with 1 to 3 alkyl of C? -6 or with 1 to 3 fluoroalkyl groups of C? -6, -Xi is 0, S or NH; Ri is independently H, lower alkyl of 1 to 6 carbons, or lower fluoroalkyl of 1 to 6 carbons; R2 is independently H, lower alkyl of 1 to 6 carbons, ORi, 1-adamantyl or lower fluoroalkyl of 1 to 6 carbons, or the two R2 groups together represent an oxo group (= 0); R3 is hydrogen, lower alkyl of 1 to 6 carbons, ORi, lower alkyl substituted with fluorine of 1 to 6 carbons or halogen, N02, NH2, NHCOalkyl of (C? -C6), or NHCOalkenyl of (C? -C6); A is hydrogen, COOH or a pharmaceutically acceptable salt thereof, C00R8, CONR9R10, -CH20H, CH20Rn, CH20C0Rn, CHO, CH (OR? 2) 2, CH (0R? 30), -C0R7, CR7 (OR? 2 ) 2, CR7 (OR? 30), or Si (C? -6 alkyl) 3, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl) alkyl wherein the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or cycloalkyl group of 5-10 carbons, or phenyl, hydroxyphenyl or lower alkylphenyl, Rp is lower alkyl, phenyl or lower alkylphenyl, R? 2 is lower alkyl, and R? 3 is a divalent alkyl radical of 2-5 carbons, and R? is alkyl of 1 to 10 carbons, alkyl substituted with fluorine of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 tr iples, carbocyclic aryl selected from the group consisting of phenyl, Ci-Cι alkylphenyl, naphthyl, C?-C? alkylnaphthyl, phenyl-Ci-Cι alkyl, naphthyl Ci-Cι alkyl, Ci-Cio alkenylphenyl having 1 to 3 double bonds, C alqu-C? alkynylphenyl or having from 1 to 3 triple bonds, Ci-Cι phenyl-alkenyl having from 1 to 3 double bonds, phenyl-C 1 -C 3 alkynyl having from 1 to 3 triple bonds, hydroxyalkyl of 1 to 10 carbons, hydroxyalkenyl having 2 to 10 carbons and 1 to 3 double bonds, hydroxyalkynyl having 2 to 10 carbons and 1 to 3 triple bonds, acyloxyalkyl of 1 to 10 carbons, acyloxyalkenyl having 2 to 10 carbons and 1 to 3 double bonds, or acyloxyalkynyl of 2 to 10 carbons and of 1 to 3 triple bonds wherein the acyl group is represented by COR8, or Ri4 is a 5- or 6-membered heteroaryl group has from 1 to 3 heteroatoms, the heteroatoms being selected from a group consisting of 0, S, and N, the heter group being oaryl unsubstituted or substituted with a C 1 to C 1 0 alkyl group, with a C 1 to C 1 fluoroalkyl group, or with halogen, and with the dashed line in Formula 4 represents a bond or the absence of a bond. In a second aspect, this invention relates to the use of the compounds of Formula 1, Formula 2, and Formula 3 for the treatment of skin-related diseases, including, without limitation, actinic keratosis, arsenic keratosis, inflammatory acne, and inflammatory, psoriasis, ichthyosis and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage (steroid atrophy), as a topical antimicrobial, as antipigmentation agents of the skin and to treat and reverse the effects of age and photodamage to the skin. The compounds are also useful for the prevention and treatment of metabolic diseases such as type II diabetes and diabetes mellitus and for the prevention and treatment of cancerous and precancerous conditions, including premalignant and malignant hyperproliferative diseases such as breast cancers, skin prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasms, leucoplasias and papillomas of mucous membranes and in the treatment of Kaposi's sarcoma. In addition, the compounds of the present invention can be used as agents for treating diseases of the eyes, including, without limitation, proliferative vitreoretinopathy (PVR), retinal detachment, dry eyes and other corneopathies, as well as in the treatment and prevention of various diseases. cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism, such as dyslipidemias, prevention of postangioplasty restenosis and as an agent to increase the level of circulating tissue plasminogen activator (TPA). Other uses for the compounds of the present invention include the prevention and treatment of conditions and diseases associated with human papillomavirus (HPV), including warts and genital warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and stroke, inappropriate pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis and the inhibition of apoptosis activated by T cells, restoration of hair growth, including therapies combined with the compounds of the present and other agents such as Minoxidil®, diseases associated with the immune system, including the use of the compounds of the present as immunosuppressants and immunostimulants, the modulation of the rejection of transpl before organs and the facilitation of wound healing, including the modulation of chemosis. Alternatively, those compounds of the invention which act as antagonists or inverse agonists of one or more of the retinoid receptor subtypes are useful for preventing certain undesirable side effects of retinoids, which are administered for the treatment or prevention of certain diseases or conditions. For this purpose the antagonist and / or inverse retinoid agonist compounds of the invention can be coadministered with retinoids. The antagonist and inverse retinoid agonist compounds of the present invention are useful in the treatment of acute or chronic toxicity resulting from an overdose or poisoning by retinoid drugs or Vitamin A. This invention also relates to a pharmaceutical formulation comprising a compound of Formulas 1, 2 or 3 in admixture with a pharmaceutically acceptable excipient, the formulation being adapted to be administered to a mammal, including a human, to treat or alleviate the conditions that were previously described as treatable by retinoids, to be coadministered with retinoids to eliminate or reduce the side effects of retinoids, or to treat overdose or poisoning with retinoid or Vitamin A.

BIOLOGICAL ACTIVITY, METHODS OF ADMINISTRATION Retinoid or Retinoid-like Antagonist Tests and Biological Activity Similar to a Reverse Antagonist A classic measure of retinoic acid activity involves measuring the effects on retinoic acid and ornithine decarboxylase. The original work on the correlation on retinoic acid and the decrease in cell proliferation was carried out by Verma & Boutwell, Cancer Research, 1977, 37, 2196-2201. This reference describes that the activity of ornithine decarboxylase (ODC) increases as a precedent to polyamine biosynthesis. It has been established elsewhere that increases in polyamine synthesis may be correlated or associated with cell proliferation. Thus, if the activity of ODC could be inhibited, cell hyperproliferation could be modulated. Although all cases for ODC activity increases are unknown, 12-0-tetradecanoylphorbol-13-acetate (TPA) is known to induce ODC activity. Retinoic acid inhibits this induction of ODC activity by TPA. An assay that essentially follows the procedure of the method set forth in Cancer Research: 1662-1670,1975 can be used to demonstrate the inhibition of TPA induction of ODC by the compounds of this invention. The "IC60" is that concentration of the test compound that produces the 60% inhibition of the ODC test. By analogy, the "IC80" for example, is that concentration of the test compound that produces the 80% inhibition in the ODC test. Other assays described below, measure the ability of the compounds of the present invention to bind to and / or activate various subtypes of retinoid receptors. When in those assays a compound binds to a given receptor subtype and activates the transcription of a reporter gene through that subtype, then the compound is considered an agonist of that receptor subtype. In contrast, a compound is considered an antagonist of a given receptor subtype if in the cotransfection assays described below the compound does not produce significant transcriptional activation of the receptor regulated by the reporter gene, but nevertheless binds to the receptor with a Kd value at least about 1 micromolar. In the assays described below, the ability of the compounds to bind to the RARa, RARβ, RAR ?, RxRa, RxRβ and RxR? Receptors can be tested. and the ability or inability of the compounds to activate the transcription of a reporter gene through those receptor subtypes. It is expected that these assays demonstrate that the compounds of the present invention are selective agonists primarily of the RXR receptors, preferably over the RAR receptors. However, some of the compounds of the invention may behave as retinoid antagonists or partial antagonists and / or inverse agonists. Due to the complex distribution of the different retinoid receptors in various organs of the body of a mammal, partial agonists and partial antagonists and compounds having the characteristics of both may be endowed by themselves to be particularly useful in therapeutic applications and they can avoid the serious side effects of conventional retinoid drugs. In regard to specific assays for demonstrating the activities of the compounds of the present invention, a transactivation assay of a chimeric receptor which tests activity similar to that of an agonist in the subtypes of RARa, RARβ, RAR receptors. ?, RxRa, and which is based on the work published by Feigner P. L. and Holm M. (1989) Focus, 112 is described in detail in U.S. Patent No. 5,455,265. The specification of U.S. Patent No. 5,455,265 is hereby expressly incorporated by reference. A holoreceptor transactivation assay and a ligand binding assay which measure activity similar to that of an antagonist / agonist of the compounds of the invention, or their ability to bind to the different subtypes of retinoid receptors, respectively, are described in published PCT Application No. WO W093 / 11755 (particularly pages 30-33 and 37-41) published on June 24, 1993, the specification of which is also incorporated here as a reference. A detailed experimental procedure for holoreceptor transactivations has been described by Heyman et al. Cell 68, 397-406, (1992); Allegreto et al. J. Biol. Chem. 268, 26625-26633, and Mangelsdorf et al. The Retinoids: Biology, Chemistry and Medicine, pp. 319-349, Raven Press Ltd., New York, which are expressly incorporated herein by reference. The results obtained in this test are expressed in EC50 numbers, as they are also in the transactivation assay of a chimeric receptor. The results of the ligand binding assay are expressed in Kd numbers. (See Cheng et al.

Biochemical Pharmacology Vol. 22 pp 3099-3108, expressly incorporated herein by reference). Yet another transactivation assay, the "PGR assay" is described in the Klein et al. J. Biol. Chem. 271, 22692-22696 (1996), which is expressly incorporated herein by reference, and a detailed description is provided below. The results of the PGR assay are also expressed in EC5o numbers (nanomolar concentration). RAR-P-GR holopreceptor transactivation assay CV-1 cells were transiently transfected (4 x 10 5 cells / well) with the luciferase reporter plasmid MTV-4 (R5G) -Luc (0.7 ug / well) containing four copies of the DNA response element of retinoid R5G together with the expression plasmid pRS-hRXRa of RXRa (0.1 ug / well) and one of the expression plasmids RAR-P-GR (0.05 ug / well) in 12-well plates via precipitation with calcium phosphate Chen et al. (1987) Mol. Cell. Biol. 7, 2745-2752 according to that described by Klein et al. in J. Biol. Chem. 271, 22692, to which reference was made above. The three different expression plasmids RAR-P-PGR, pRS-RARa-P-GR, pcDNA3-RARβ-P-GR and pcDNA3-RAR? -P-GR, express receptors RARa, RARβ and RAR ?, respectively, which contain modified DNA binding domains so that their "boxes P "have been altered to those of the glucocorticoid receptor.

These RAR-P-GR receptors bind to DNA as heterodimeric complexes with RXR. Specifically, RAR-P-GR receptors bind to retinoic acid in response to elements designated as R5G, comprised of two semisites of RAR (nucleotide sequence 5 '-GGTTCA-3') separated by five base pairs in which the 3 'semisite has been modified from a semisite of the glucocorticoid receptor, 5' -AGAACA-3 '. To allow variations in the efficiency of the transfection, a β-galactosidase expression plasmid (0.01 ug / well) was used as an internal control. Alternatively, the assay was performed in a 96-well microtiter plate format (5000 cells / well) in a form that was identical to that described above except that 1/5 of the amount of the calcium phosphate precipitant was applied to the DNA (20 μl instead of 100 μl) to each well. Eighteen hours after the introduction of the DNA precipitants, the cells were rinsed with phosphate buffered saline (PBS) and fed with D-MEM (Gibco-BRL) containing 10% fetal bovine serum extracted with activated carbon ( Gemini Bio-Products). The cells were treated for 18 hours with the compounds indicated in the figures. After rinsing with PBS, the cells were used and the luciferase activity was measured as described previously in Wet (1987) Mol. Cell. Biol. 7, 725-737. The luciferase values represent the mean of + SEM of triplicate determinations normalized to the activity of the β-galactosidase. Inverse agonists are ligands that are capable of inhibiting receptor activity based on unbound receptors. Recently, retinoic acid receptors (RAR) have been shown to respond to inverse retinoid agonists in the regulation of the transcriptional activity of the basal gene. In addition, the biological effects associated with inverse retinoid agonists are different from those of retinoid agonists or antagonists. For example, inverse RAR agonists, but not neutral RAR antagonists, produce a dose-dependent inhibition of the MRP-8 protein in cultured human keratinocytes differentiated with serum. MRP-8 is a specific marker of cell differentiation, which is also highly expressed in the psoriatic epidermis, but is not detectable in normal human skin. Thus, inverse retinoid agonists may offer a unique form of treatment of diseases such as psoriasis. The activity of inverse retinoid 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, the inverse retinoid agonists are capable of repressing the basal activity of a chimeric RAR? -VP-16 receptor, where the constitutively active domain of the herpes simplex virus (HSV) VP-16 is fused to the N terminus of the RAR ? CV-1 cells are cotransfected with RAR? -VP-16, a chimeric AR-RXRa receptor and a chimeric reporter gene ERE-tk-luc to produce a luciferase activity level, as demonstrated by Nagpal et al. EMBO J. 12, 2349-2360 (1993) expressly incorporated herein by reference. The inverse retinoid agonists are able to inhibit basal luciferase activity in these cells in a dose-dependent manner and the IC 50 was measured. Table 1 describes data demonstrating the ability of exemplary compounds of the invention to bind to and transactivate via RXR receptors.

TABLE 1 UNION AND TRANSACTIVATION DATA OF THE RXR RECEIVER ND - not determined Modes of Administration The compounds of this invention can be administered systemically or topically, depending on considerations such as the condition to be treated, the need for specific treatment at the site, the amount of drug to be administered, and numerous other considerations. While the preferred compounds of the invention are primarily RXr selective agonists, the preferred compounds are administered as retinoids. Thus, in the treatment of dermatosis, it will generally be preferred to administer the drug topically, although in certain cases, such as the treatment of severe cystic acne or psoriasis, it may also be used for oral administration. Any such common topical formulation can be used with a similar solution, suspension, gel, ointment or ointment. The preparation of such topical formulations is well described in the prior art of pharmaceutical formulations as exemplified, for example, by Remington's Pharmaceutical Science, Issue 17, Mack Publishing Company, Easton, Pennsylvania. For topical application, those compounds could also be administered as a powder or spray, particularly in the form of an aerosol. If the drug is to be administered systemically, it can be made up as a powder, a pill, a tablet or the like or as a syrup or elixir suitable for oral administration. For intravenous or intraperitoneal administration, the compound will be prepared as a solution or suspension capable of being administered by injection. In certain cases, it may be useful to formulate those compounds by injection. In certain cases, it may be useful to formulate those compounds in suppository form or as a prolonged release formulation to be deposited under the skin or for intramuscular injection. Other drugs may be added to such a topical formulation for secondary purposes such as the treatment of skin dryness; provide protection against light; other medications to treat dermatosis; medicines to prevent infections, reduce irritation, inflammation and the like. The treatment of dermatoses or any other known indications or that is discovered to be susceptible to treatment by compounds similar to retinoic acid will be effected by administration of the therapeutically effective dose of one or more of the compounds of the present invention. A therapeutic concentration will be that concentration which effects the reduction of the particular condition, or retards its expansion. In certain cases, the compound can potentially be used prophylactically to prevent the appearance of a particular condition. A useful therapeutic or prophylactic concentration will vary from condition to condition and in certain cases may vary with the severity of the condition being treated and the patient's susceptibility to treatment. In consecuense, a single concentration will not be uniformly useful, but will require modifications depending on the particularities of the disease that is being treated. It can be reached at such concentrations through routine experimentation. However, it was anticipated that in the treatment of, for example, acne or similar dermatoses, that a formulation containing between 0.01 and 1.0 milligrams per milliliter of formulation will constitute a therapeutically effective concentration for the total application. If administered systemically, it is expected that an amount between 0.01 and 5 mg per kg per day of body weight will produce a therapeutic result in the treatment of many diseases for which these compounds are useful. The retinoid partial agonists or antagonists and / or reverse panagonists or retinoid partial reverse agonists of the invention, when used to take advantage of their antagonist and / or inverse agonist property, can be co-administered to mammals, including humans, with agonists retinoids and, by means of pharmacological selectivity or site-specific release, preferably prevent the undesirable effects of certain retinoid agonists. The antagonist and / or inverse agonist compounds of the invention can also be used to treat overdose of Vitamin A, acute or chronic, resulting from the excessive consumption of Vitamin A supplements or the ingestion of liver of certain fish and animals containing high Vitamin A levels. Moreover, the antagonist and / or inverse agonist compounds of the invention can also be used to treat acute or chronic toxicity caused by retinoid drugs. It has been known in the art that the toxicities observed with the hypervitaminosis A syndrome (headache, skin exfoliation, bone toxicity, dyslipidemia) are similar or identical to the toxicities observed with other retinoids, suggesting a common biological cause, i.e. the activation of the RAR. Because the antagonist or inverse agonist compounds of the present invention block or decrease the activation of the RAR, they are suitable for treating the above toxicities. Generally speaking, for therapeutic applications in mammals, the antagonist and / or inverse agonist compounds of the invention can be administered enterally or topically as an antidote to Vitamin A, or antidote for retinoid toxicity resulting from overdosage or prolonged exposure , after the consumption of the causative factor (Vitamin A, precursor of Vitamin A, or another retinoid) has been discontinued. Alternatively, the antagonist and / or inverse agonist compounds of the invention are coadministered with retinoid drugs, in situations where the retinoid provides the therapeutic benefit, and wherein the antagonist and / or coadministered reverse agonist compounds alleviates or eliminates one or more of the undesirable side effects of the retinoid. For this type of application the antagonist and / or inverse agonist compound may be administered in a site-specific manner, for example, a cream or lotion applied topically while the co-administered retinoid may be given enterally. For therapeutic applications, the agonist compounds of the invention, such as the retinoid agonist compounds, are incorporated into pharmaceutical compositions, such as tablets, pills, capsules, solutions, suspensions, creams, ointments, gels, taken, lotions and the like, using excipient and pharmaceutically acceptable carriers which per se are well known in the art. For topical application, the antagonist and / or inverse agonist compounds of the invention could also be administered as a powder or spray, particularly in the form of an aerosol. If the drug is to be administered systemically, it can be made up as a powder, a pill, a tablet or the like or as a syrup or elixir suitable for oral administration. For intravenous or intraperitoneal administration, the compound will be prepared as a solution or suspension capable of being administered by injection. In certain cases, it may be useful to formulate those compounds by injection. In certain cases, it may be useful to formulate those compounds in suppository form or as a prolonged release formulation to be deposited under the skin or by intramuscular injection. The antagonist and / or inverse agonist compounds also, like the retinoid agonists of the invention, will be administered in a therapeutically effective dose. A therapeutic concentration will be that concentration which effects the reduction of the particular condition, or retards its expansion. When the compounds of the invention are coadministered to block the toxicity or side effects induced by a retinoid, the antagonist and / or inverse agonist compounds of the invention are used prophylactically to prevent the appearance of a particular condition, such as irritation of the skin. A useful therapeutic or prophylactic concentration will vary from condition to condition and in certain cases may vary with the severity of the condition being treated and the patient's susceptibility to treatment. Consequently, a single concentration will not be uniformly useful, but will require modifications depending on the particularities of chronic or acute retinoid toxicity or the related condition being treated. It can be reached at such concentrations through routine experimentation. However, it was anticipated that a formulation containing between 0.01 and 1.0 milligrams per milliliter of the active compound of formulation will constitute a therapeutically effective concentration for the total application. If administered systemically, an amount between 0.01 and 5 mg per kg per day of body weight would be expected to produce a therapeutic result.

GENERAL MODALITIES AND SYNTHETIC METHODOLOGY Definitions The term alkyl refers to and covers any and all groups that are known as alkyl, branched chain alkyl and cycloalkyl normal. The term "alkenyl" refers to and covers normal alkenyl, branched chain alkenyl and cycloalkenyl groups having one or more sites of unsaturation. Similarly, the term "alkynyl" refers to and covers normal branched chain alkynyl and alkynyl groups having one or more triple bonds. "Lower alkyl" means the broad definition defined above of alkyl groups having from 1 to 6 carbons in the case of the normal lower alkyl, and applying from 3 to 6 carbons for the lower branched chain and cycloalkyl groups. Lower alkenyl is defined in a similar manner having from 2 to 6 carbons for the normal lower alkenyl groups, and 3 to 6 carbons for the lower branched chain cycloalkenyl groups. Lower alkynyl is also defined in a similar manner, having from 2 to 6 carbons for the normal lower alkynyl groups, and from 4 to 6 carbons for the lower branched chain alkynyl groups. The term "ester" as used herein refers to and covers any compound that falls within the definition of that term as it is used in a classical manner in organic chemistry. This includes organic and inorganic esters. Where A of Formula 1, 2 or 3 is -COOH, this term covers the products derived from the treatment of this function with alcohols or thiols, preferably with aliphatic alcohols having 1-6 carbons. Where the ester is derived from the compounds where A is -CH2OH, this term covers compounds derived from organic acids capable of forming esters, including phosphorus based on sulfur-based acids, or compounds of the formula -CH2OCORn where Rn is any group aliphatic, aromatic, heteroaromatic or aliphatic substituted or unsubstituted aromatic, preferably with 1-6 carbons in the aliphatic portions. Unless otherwise stated in this application, preferred esters are derived from saturated aliphatic alcohols or acids of ten or fewer carbon atoms or saturated aliphatic cyclic or cyclic alcohols and acids of 5 to 10 carbon atoms. Particularly preferred aliphatic esters are those derived from lower alkyl acids and alcohols. Phenyl or lower alkyl phenyl esters are also preferred. Amides have the meaning agreed in a classical way, that the term in organic chemistry. In this case it includes the unsubstituted amides and all the aliphatic and aromatic mono- and di-substituted amides. Unless otherwise stated in this application, preferred amides are mono- and di-substituted amides derived from saturated aliphatic radicals of ten or fewer carbon atoms or saturated cyclic or cyclic aliphatic radicals of from 5 to 10 carbon atoms. carbon. Particularly preferred amides are those derived from substituted or unsubstituted lower alkylamines. Also preferred are mono- and disubstituted amides derived from substituted or unsubstituted phenyl or lower alkyl phenyl amines. Unsubstituted amides are also preferred. Acetals and ketals include the radicals of formula -CK where K is (-OR) 2. Here, R is lower alkyl. Also, K can be -0R70- where R7 is lower alkyl of 2-5 carbon atoms, straight or branched chain. A pharmaceutically acceptable salt can be prepared by any of the compounds of this invention having a functionality capable of forming a salt, for example an acid functionality. A pharmaceutically acceptable salt is any salt that retains the activity of the parent compound and does not impart any harmful or adverse effect on the subject to which it is administered in the context in which it is administered. The pharmaceutically acceptable salts can be derived from organic or inorganic bases. The salt can be mono- or polyvalent. Of particular interest are inorganic ions, sodium, potassium, calcium and magnesium. The organic salts can be made with amines, particularly ammonium salts such as the mono-, di- and trialkylamines or ethanol amines. The salts can also be formed with protein, tromethamine and similar molecules. Where there is a sufficiently basic nitrogen to be able to form acid addition salts, such can be formed with any inorganic or organic acids or alkylating agents such as methyl iodide. Preferred salts are those formed with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid. Any of a number of simple organic acids such as mono-, di- or tri-acids may also be used. Many compounds of the present invention have trans and cis (E and Z) isomers. The specific orientation of the substituents relative to a double bond is indicated in the name of the respective compound and / or specifically showing in the structural formula the orientation of the substituents relative to the double bond.

Some of the compounds of the present invention may contain one or more chiral centers and therefore may exist in enantiomeric and diastereomeric forms. It is intended that the scope of the present invention cover all isomers per se, as well as mixtures of cis and trans isomers, mixtures of diastereomers and racemic mixtures of enantiomers (optical isomers) as well. (a) fr-Br r Formula 6 o ^ Formula 9 Peroxidation Oxidation / »• • • CRr-CR, R" CH CHO Formula 14 (C) c., Br- "-CO; et [H] 'Formula 7» »R * -R" - CO? E? »R'-R" -CHjOH Pd (°) Reduction Formula is Formula 16 R ** = divalent cycloalkyl, aryl or heteroaryl radical Reaction Scheme 1 A generalized method for obtaining compounds of the invention is illustrated in Reaction Scheme 1. As shown in section (a) of this scheme, the compounds of the invention wherein Z is a cyclopropyl function within the definitions of Formulas 1, 2 and 3 are generally obtained in a sequence of reactions which usually involves a multi-step synthesis of a halogen-substituted compound (Formula 6), wherein the halogen atom, preferably bromine, is placed on the aromatic nucleus of the dihydronaphthalene, indene, chrom-3-ene, thiochrom-3-ene (Formula 1), 2,3-benzobicyclooctane (Formula 3) or the phenyl group (compounds of Formula 2). In the compounds of Formula 1 the 8-position of the dihydronaphthalene nucleus or the 4-position of the nucleus of chrom-3-ene or thiocrom-3-ene contains a substituent designated as Ri4. Generally speaking, the Ri4 group and the double bond 7.8 or 3.4, as applicable, obtain these compounds by reacting the corresponding tetrahydronaphthalen-8-one or chroman-4-one or thiochroman-4-one. corresponding with a Grignard reagent (Ri4-Mg-Br) or similar organometallic reagent, followed by dehydration of the intermediate tertiary alcohol. The introduction of the Ri4 group and the formation of the double bond are not shown in Reaction Scheme 1. According to the general synthetic methodology the halogen-substituted compound noted above, preferably bromine, Formula 6 is reacted with trimethoxy boron (( CH30) 3B) in the presence of tertiary butyl lithium. The dihydronaphthalen-2-yl, chromen-6-yl, thiochromen-6-yl, [2, 3] benzo-4-ylbicyclooctane, or resultant phenyl boronic acid (as applicable, Formula 7) is subsequently reacted in the presence of palladium catalyst of (Pd (0)) with a 3-iodo-allyl alcohol derivative (Formula 8) to produce a prop-2-en-1-ol derivative (Formula 9) which is substituted at the 3-position of the propene portion with dihydronaphthalen-2-yl derivative, chrom-3-en-6-yl, thiochrom-3-en-6-yl, [2, 3] benzo-4-ylbicyclooctane, or phenyl, as applicable. The cyclopropane ring is introduced into the prop-2-en-l-ol derivative of Formula 9 in a cyclopropylation reaction with diiodomethane in the presence of an appropriate catalyst to produce a cyclopropyl derivative of Formula 10. Subsequently, the alcohol function of the compound of Formula 10 is oxidized to the aldehyde stage (Formula 11), and the aldehyde compound of Formula 11 is reacted in a Homer Emmons reaction with diethylphosphono reagent (Formula 12) having a double bond on a carbon adjacent to the carbon containing the diethylphosphono group. Consequently, as a result of the Horner Emmons reaction, the conjugated diene portion of the compounds of the invention is formed (Formula 13). Since the diethylphosphono reagent (Formula 12) also contains function A (as defined above) of the compounds of the invention, or such precursors of function A that can be easily converted to group A by reactions well known in the art , the Horner-Emmons reaction described above provides compounds of the invention where the group Y of the formulas 1, 2 and 3 represents cyclopropyl. Section (b) of Reaction Scheme 1 shows that the compounds of the invention where Y represents an oxiranyl (epoxide) ring in place of cyclopropyl can be produced by methods similar to the methodology described above except that instead of cyclopropyl, the Compounds of Formula 9 are epoxidized using reagents well known in the art, for example, meta-chloroperoxybenzoic acid. The resulting oxirane (epoxide) compound having a primary alcohol is oxidized to the step of (Formula 14) with the reagents of the state of the art, and the aldehyde is subjected to a Horner Emmons reaction, as shown above, for producing the oxiranyl (epoxide) compounds of the invention. The Horner Emmons reaction that is carried out on the oxiranyl compounds of Formula 14 is not shown in the reaction scheme. The compounds of the invention wherein the group Y is aryl, heteroaryl or cycloalkyl other than cyclopropyl, can generally be referred to as boronic acid derivatives as shown in section (c) of Reaction Scheme 1. In this scheme R ** represents a divalent aryl, heteroaryl or cycloalkyl radical, other than cyclopropyl, radicals such as these are defined in relation to Formulas 1, 2 and 3. According to this generalized scheme, the boronic acid derivative of Formula 7 is coupled to presence of palladium catalyst (Pd (0)) with an ester of cycloalkyl, aryl or heteroaryl carboxylic acid, halogenated, preferably brominated. The ester carboxylic acid function of the resulting compound, (Formula 15) is reduced to the primary alcohol stage (Formula 16). The primary alcohol of Formula 16 is subsequently treated in the same reaction sequence (oxidation followed by Horner Emmons reaction) as described above, to provide the compounds of the invention. The details of the generalized synthetic schemes described above are given below in connection with the description of the specific modalities.

The synthetic methodology employed for the synthesis of the compounds of the present invention may also include transformations of the group designated as A in Formulas 1, 2 and 3. Generally speaking, those transformations involve reactions also within the experience of an organic chemist. practicing. In this regard, the well-known and published general principles and methodology are briefly described. The carboxylic acids are typically esterified by refluxing the acid in an appropriate alcohol solution in the presence of an acid catalyst such as hydrogen chloride or thionyl chloride. Alternatively, the carboxylic acid can be condensed with the alcohol in the presence of cyclohexylcarbodiimide (DCC) and 4- (dimethylamino) pyridine (DMAP). The ester is covered and purified by conventional means. Acétals and ketals are easily produced by the method described in March, "Advanced Organic Chemistry," 2nd Edition, McGraw-Hill Book Company, p 810). The alcohols, aldehydes and ketones can be protected by forming, respectively, ethers and esters, acetals or ketals by the known methods such as those described in McOmie, Plenum Publeshing Press, 1973 and Protecting Groups, Ed. Greene, John Wiley & Sons, 1981. The acids and salts derived from the compounds of the invention can be easily obtained from the corresponding esters. Basic saponification with an alkali metal base will provide the acid. For example, an ester of the invention can be dissolved in a polar solvent such as an alkanol, preferably under an inert atmosphere at room temperature, with approximately a three molar excess of base, for example lithium hydroxide or potassium hydroxide. The solution is stirred for a prolonged period of time, between 15 and 20 hours, cooled, acidified and the hydrolyzate recovered by conventional means. The amide may be formed by any suitable amidation means known in the art from the corresponding esters or carboxylic acids. One way to prepare such compounds is to convert an acid to an acid chloride and then treat that compound with ammonium hydroxide or an appropriate amine. For example, the ester is treated with a basic alcohol solution such as ethanolic KOH (in about a 10% molar excess) at room temperature for about 30 minutes. The solvent is removed and the residue is removed from the organic solvent such as diethyl ether, treated with the dialkylformamide and then a 10-fold excess of oxalyl chloride. All this is effected at a moderately reduced temperature of between about -10 degrees and +10 degrees C. The last mentioned solution is then stirred at the reduced temperature for 1 to 4 hours, preferably 2 hours. Removal of the solvent provides a residue which is removed in an inert organic solvent such as benzene, cooled to about 0 degrees C and treated with concentrated ammonium hydroxide. The resulting mixture is stirred at room temperature for 1-4 hours. The product is recovered by conventional means. The alcohols are produced by converting the corresponding acids to the acid chloride with thionyl chloride or other means (J. March, "Advanced Organic Chemestry", 2nd Edition, McGraw-Hill Book Company), then reducing an acid chloride with borohydride of sodium (March, Ibid, page 1124), which gives the corresponding alcohols. Alternatively, the esters can be reduced with lithium aluminum hydride at reduced temperatures. Alkylation of these alcohols with the appropriate alkyl halides under the Williamson reaction conditions (March, Ibid, pg 357) gives the corresponding ethers. These alcohols can be converted to esters by reacting them with suitable esters in the presence of acid catalysts or dicyclohexylcarbodiimide and dimethylaminopyridine. The aldehydes can be prepared from the corresponding primary alcohols using moderate oxidizing agents such as pyridine dichromate in methylene chloride (Corey, E. J., Schmidt, G., Tet. Lett. , 399, 1979), or dimethyl sulfoxide / oxalyl chloride in methylene chloride (Omura, K., Swern, D., Tetrahedron, 1978, 34, 1651). Ketones can be prepared from an appropriate aldehyde by treating the aldehyde with an alkyl Grignard reagent or similar reagent followed by oxidation. The acetals or ketals can be prepared from the corresponding aldehyde or ketone by the method described in March, Ibid, p 810.

SPECIFIC MODALITIES With reference to the symbol X in Formula 1, the preferred compounds of the invention are those where X is O (chromene derivatives), S (thiochromene derivatives) and where X is (CR? R?) Nyn is 1 ( dihydronaphthalene derivatives). The 5,5-dimethyldihydronaphthalene derivatives where Ri of CRiRi is CH 3 are particularly preferred. The R2 groups of the compounds of Formula 1 and of Formula 3 are preferably independently of each other H or lower alkyl, and even more preferably independently of each other are H and methyl. When X is S or O, then the groups R2 in the 2-position of the chromene or thiochromen core are preferably CH3. The R3 groups of the preferred compounds of the invention are H or lower alkyl; among them lower alkyl methyl is preferred. The R2 groups of the preferred compounds of Formula 2 are H or lower alkyl. Those R2 groups which are in the meta position relative to the group Y in the compounds of Formula 2 preferably are branched chain lower alkyl. The Ri groups of the cycloalkyl and oxiranyl rings, as shown in Formulas 4 and 5 are preferably H or lower alkyl, even more preferably H, methyl, ethyl or n-propyl. The Ri groups attached to the diene portion are also preferably H or lower alkyl, even more preferably H or methyl. The group Y is preferably cyclopropyl, according to that presented by Formula 4 where o is 1 and the broken line represents the absence of a bond, or Y is oxyranyl according to that represented by Formula 5. Alternatively the group And it is preferably cyclohexyl, cyclopentyl, phenyl, pyridyl, thienyl, furyl or thiazolyl. When the group Y is cycloalkyl, according to that represented by Formula 4, then the portion of the diene and the aromatic residue of the condensed cyclic group or the phenyl group, as applicable, are preferably in the cis orientation relative to the ring of the cycloalkyl. When the group Y is aryl or heteroaryl then the portion of the diene and the aromatic residue of the condensed cyclic group or the phenyl group, as applicable, are preferably in ortho or 1,2 orientation in relation to the aryl or heteroaryl ring, as applicable. The group A is preferably COOH, a pharmaceutically acceptable salt of the carboxylic acid, COOR8 or CONR9R10 where R8 is preferably lower alkyl, even more preferably methyl or ethyl. The double bonds of the diene portion are preferably in trans orientation. Joining the junction of the Y portion to the aromatic residue of the condensed cyclic group is preferably in the 2 or 3 position of the dihydronaphthalene, to the 6 or 7 position of the chromene or thiochromen, and to the 4 or 5 position of the bicyclooctane portion, as applicable. Even more preferred is the binding of group Y to position 2 of dihydronaphthalene and to position 6 of chromene or thiochromen. Preferred Ri4 groups are lower alkyl, particularly methyl and ethyl, and branched chain lower alkyl, particularly i-propyl and t-butyl groups. In a highly preferred class of compounds of the invention the portion that is attached to the condensed cyclic group as shown in Formulas 1 and 3, or to the phenyl group, as shown in Formula 2, is the group described below. in Formula 17. Ri * is methyl, ethyl or n-propyl. It can be seen that in this portion the orientation around the cyclopropane ring is cis, the orientation of both double bonds of the diene portion is trans. Formula 17 also shows the numbering of the cyclopropane ring and the pentadienoic acid moiety.

R, '= CH3 or C2Hs or C3H7 Formula n The most preferred class of compounds of the invention is shown below in Formulas 18, 19, 20 and 21 where the Ri * group represents lower alkyl, X * represents 0 or S and R8 * represents H, a salt of the carboxylic acid, or lower alkyl, and R * x is methyl, ethyl or n-propyl. Formulas 18, 19 and 21 also show the numbering of the condensed cyclic portions of those formulas, numbering which is used consistently for the description of the compounds of the invention.

R, * = CH3 or C2H5 or C3H? Rn * = CH3 or C2H5 or C3H7 X * = O u S or NR Formula 18 Formula 19 FV = CH3 or C2HS or C3H7 FV > CHs? C2H5 or C3H7 R * = iso-propyl. t-butyl. H and 1 -adamantilo Formula 20 Formula 21 The most preferred exemplary compounds of the invention hitherto are designated as Compounds 6, 7, 13, 14, 21, 22, 27, 28, 33, 34, 43 and 44. The chemical names are described and the respective structures are shown in the experimental section. The compounds of this invention can be produced by the general procedures set forth above under the heading "GENERAL MODALITIES AND SYNTHETIC METHODOLOGY". The following chemical pathways represent the synthetic routes preferred up to now for certain classes of the compounds of the invention and for certain specific exemplary compounds. However, the synthetic chemical will readily appreciate that the conditions set forth herein for those specific embodiments can be generalized to any and all compounds of the invention.

Formula 22 Formula 23 Formula 24 Formula 25 Formula 26 Formula 27 Reaction Scheme 2 Referring now to Reaction Scheme 2, the synthesis of a preferred class of compounds of the present invention is shown, which fall within the general definition of Formula 1, and where the group X * in Formula 19 represents 0 or S, R2 and R3 are defined as in relation to Formula 1 above, and R '? is alkyl, aryl or heteroaryl. The initial compound (Formula 22) in this scheme is, generally speaking, available in accordance with the scientific and chemical patent literature and / or can be obtained in synthetic steps within the experience of the practicing organic chemist. Examples of starting compounds of Formula 22 are 2,2-dimethyl-6-bromochroman-4-one and 2,2-dimethyl-6-bromothiochroman-4-one or its 7-bromo position isomers. The initial compounds may be maintained in accordance with the scientific and chemical patent literature, particularly the teachings of U.S. Patent No. 5,728,846, the specification of which is expressly incorporated herein by reference. Other examples for the initial compounds of Formula 22 with 6-bromochroman-4-one and 6-bromothiochroman-4-one. According to Reaction Scheme 2, the compound of Formula 22 is reacted with a Grignard reagent of the formula R '? 4-MgBr to provide an intermediate tertiary alcohol not shown in the reaction scheme. The tertiary alcohol can also be obtained by the reaction of the compound of Formula 22 as a reagent of the formula R '? - X2, wherein X2 is halogen, preferably bromine, in the presence of a strong base, such as tertiary butyl lithium or butyl normal lithium, as described in U.S. Patent No. 5,728,846. The group R '? in it described in the example is lower alkyl, aryl or heteroaryl but in other examples its scope can be as broad as the definition of the group Ri4 in relation to Formula 1. The Grignard reaction or the reaction with the reagent R 'i4- X2 is typically conducted in an inert aprotic solvent, such as diethyl ether or tetrahydrofuran (THF). Specific examples for obtaining the preferred compounds of the invention with the reagent R 'i4-MgBr are the Grignard reagents obtained from iodomethane or bromoethane, iodoethane or bromoethane, t-butyl chloride and i-propyl chloride. The tertiary alcohol is then dehydrated, typically without first being isolated, by heating with an acid such as toluene sulfonic acid (p-TsA) to produce the 4-alkyl or 4-aryl-6-bromo-chromium derivative. 3-ene or its analog thiocrom-3-ene (Formula 23). The compounds of Formula 23 can also be obtained from the 4-trifluoromethylsulfonyloxy (triflate) derivatives obtained from the ketone compounds of Formula 22 by reacting the latter with sodium bis (trimethylsilyl) amide and 2- [N, N-bis (trifluoromethylsulfonyl) amino] -5-chloropyridine in a solvent of the inert ether type such as tetrahydrofuran at low temperatures (-78 ° C and 0 ° C). This reaction is followed by the treatment of the resulting trifluoromethylsulfonyloxy (triflate) derivatives with an organometallic derivative obtained from the alkyl, aryl or heteroaryl compound R '1 -X2 (X2 is halogen) or R'? H so that the formula organometallic derivative is R 'i4-Met (Met means metal), preferably Li, as described in U.S. Patent No. 5,648,514. The specification of U.S. Patent No. 5,648,514 is incorporated herein by reference. The reactions leading from the compounds of Formula 22 to the compounds of Formula 23 via the triflate derivative are not shown in Reaction Scheme 2. The compounds of Formula 23 are further reacted with trimethoxyboron (CH30) 3B) to providing the (2,2-dialkyl-4-alkyl, aryl or heteroaryl-2H-chromen-6-yl) boronic acid compounds of Formula 24. Alternatively, when the starting compound of Formula 22 is a thiochroman-4 The thiochromene analogs of Formula 24 are then obtained. In the following description, and in this and other reaction schemes, as applicable, the disclosure is directed primarily to the synthesis of chromene derivatives. However, it should be understood that those reaction steps are equally applicable to thiochroman analogs as well. The reaction with trimethoxyboron is typically conducted in a solvent of the aprotic ether type, preferably diethyl ether or THF at low temperature (-78 ° C). The boronic acid derivatives of Formula 24 are subsequently reacted in an inert solvent, or mixture of solvents, such as a 10: 1 mixture of toluene and methanol, with the 3-iodo-allyl alcohol derivative in the presence of palladium catalyst (Pd (0)) at elevated temperature (approximately 95 ° C), in the presence of some water and an acid receptor. Reaction Scheme 2 describes the specific example where the 3-iodo allyl alcohol derivative is 3-iodo-but-2-en-1-ol the resulting description of the scheme is directed to the use of this specific reagent, although it should be understood that homologs and analogues of this reagent can be used in the reactions, which will be apparent to those skilled in the art in light of the present disclosure. The products of the coupling reaction with 3-iodo-but-2-en-l-ol are 3- (2,2-dialkyl-4-alkyl, aryl or heteroaryl-2H-chromen-6-yl) -but - 2 (Z) -in-l-ol of Formula 25. The double bond in the butene portion is in the cis orientation when the allyl 3-iodo alcohol derivative has the cis orientation as shown in the reaction scheme. Trans-targeting compounds can also be obtained as long as the orientation of the allyl 3-iodo alcohol reagent is trans. The 3- (2, 2-dialkyl-4-alkyl, aryl or heteroaryl-2H-chromen-6-yl) -but-2 (Z) -en-l-ol derivatives of Formula 25 are then converted to the derivatives of cyclopropyl, [2-methyl-2- (2, 2-dialkyl-4-alkyl, aryl or heteroaryl-2H-chromen-6-yl) -cyclopropyl] methanol of Formula 26. This "cyclopropylation" reaction employs the Diiodomethane reagent in the presence of a suitable catalyst. The cyclopropylation reaction is usually conducted at a cold temperature (-25 ° C), in an inert solvent such as tetrahydrofuran in an inert gas atmosphere (argon). In the cyclopropylation reaction the orientation (cis or trans) of the double bond to which the methyl group is attached is maintained, so that a cis-cyclopropyl derivative of Formula 26 is obtained from the cis-allylic alcohol of Formula 25, while the trans allylic alcohol of Formula 25 would produce a trans-cyclopropyl derivative. A suitable catalyst for the cyclopropylation reaction is the presence of both of the mercury (II) chloride, and samarium. Nevertheless, the presence of this catalytic mixture does not provide enantio selectivity to the resulting cyclopropyl derivatives. When enantio selectivity is desired, optically active tartrate catalysts are used, specifically N, β-tetramethyl tartramide borrolidine, shown in Reaction Scheme 2, and diethyl zinc (Et 2 Zn). This cyclopropylation reaction using active tartrate catalysts is analogous to a similar reaction (performed on different materials) described in Journal of Organi c Chemistry (1995) 60 1081-1083. In the next reaction step the derivatives of [2-methyl-2- (2, 2-dialkyl-4-alkyl, aryl or heteroaryl-2H-chromen-6-yl) -cyclopropyl] methanol of Formula 26 are oxidized to the "aldehyde stage" to produce derivatives of [2-methyl-2- (2, 2-dialkyl-4-alkyl, aryl or heteroaryl-2H-chromen-6-yl) -cyclopropyl] carbaldehyde of Formula 27. It will be recognized by those skilled in the art that various reagents are suitable for this oxidation steps. The reactions and conditions preferred heretofore for this reaction include the use of methylene chloride as a solvent, and tetrapropylamine perruthenate and N-methyl morpholine N-oxide as the reagent and catalyst. The oxidation reaction is typically conducted at room temperature. Other suitable reagents for this oxidation reaction include, as will be readily understood by those skilled in the art, pyridinium dichromate, oxalyl chloride and dimethyl sulfoxide or trifluoroacetic anhydride and dimethylsulfoxide. The [2-methyl-2- (2, 2-dialkyl-4-alkyl, aryl or heteroaryl-2H-chromen-6-yl) -cyclopropyl] carbaldehyde of Formula 27 are subsequently reacted with a diethylphosphono reagent. The diethylphosphono reagent shown in the reaction scheme for the examples herein is ethyl diethylphosphonium-3-methyl-2 (E) -butenoate, which can be obtained according to the chemical literature (J. Org. Chem. 1974 Volume 39 pp. 821). The reaction with the diethylphosphono reagent is known in the art as the Hormer Emmons reaction. This is conducted in the presence of a strong base (such as n-butyl lithium) in an inert solvent, such as tetrahydrofuran, usually at low temperature (typically -78 ° C) and results in the formation of a double bond to replace the oxo function of the reagent Formula 27. The resulting products in this example are the 3-methyl-5- [2-methyl-2- (2, 2-dialkyl-4-alkyl, aryl or heteroaryl-2H-chromen-6-ester. il) -cyclopropyl] -2,4-dienoic of Formula 28. In place of the diethylphosphon Horner Emmons reagent an analogous Wi t ting reagent can also be used in the coupling reaction. The structure of such Wi t ting reagent will be readily apparent to those skilled in the art in light of the present disclosure. The Horner Emmons coupling reaction described herein typically provides as the predominant product the isomer where the orientation around the newly formed double bond (A4 of pentadienoic acid) is trans, and normally only this trans isomer, or predominantly the trans isomer, is isolated from the reaction mixture. However, it is also possible to obtain a greater proportion of the corresponding cis isomer by adjusting the conditions of the Horner Emmons reaction. The ester compounds of Formula 28 are readily saponified to give the free carboxylic acid derivatives of Formula 29. Other readily apparent transformations can also be made to those skilled in the art in light of the present disclosure on the acid ester functions carboxylic or carboxylic acid of the compounds of Formula 28 and Formula 29, as applicable, as described in relation to Formula 13 of Reaction Scheme 1.

Stages Multiples X = O or S Formula 25 Formula 30 Formula 31 C ° 2 Reaction Scheme Referring now to Reaction Scheme 3, the reaction step is important for the preparation of oxirane derivatives of the compounds of the invention, for exemplary compounds which are derivatives of chromene or thiochromene. In this reaction the derivatives of 3- (2, 2-dialkyl-4-alkyl, aryl or heteroaryl-2H-chromen-6-yl) -but-2 (Z) -en-l-ol, or the analogues of thiochromen of Formula 25 are subjected to an epoxidation reaction to provide derivatives of [2-methyl-2- (2,2-dialkyl-4-alkyl, aryl or heteroaryl-2H-chromen-6-yl) -oxiranyl] methanol , or their thiochromen analogs of Formula 30. The allyl alcohol compounds of Formula 25 can be obtained as described in relation to Reaction Scheme 2. The epoxidation reaction can be carried out with reagents and under reaction conditions normally used for this purpose in the art, for example, with meta-chloroperoxybenzoic acid in methylene chloride solution. There are other epoxidizing agents well known in the art and available to practicing organic chemists, which are also suitable for the epoxidation reactions of this invention. Some of the known epoxidizing agents are selective enantium. The resulting epoxidized primary alcohols of Formula 30 are then subjected to the same reaction sequence of the cyclopropylmethanol derivatives of Formula 26 -: cr.et ..dos according to Reaction Scheme 2, to provide 3-methyl acid derivatives -5- [2-methyl-2- (2, 2-di aiq? Il-4-alkyl, aryl or heteroari.l-2H-chromen-6-yl) -cxiranii] -2,4-dienoic of Formula 31 Formula 32 Formula 33 Formula 34 Formula 35 Formula 36 Formula 35 Formula 39 Reaction Scheme 4 Reaction Scheme 4 describes the preferred process hitherto for the synthesis of a preferred class of the compound of the present invention which is derived from 8-alkyl, aryl or heteroaryl 5,5-dimethyl- 5,6-dihydronaphthalene. The initial compounds of this reaction scheme are 1- (2H) -naphthalenones substituted with bromine (or similar halogen) in positions 6 or 7. Of these only the derivatives of 7-Bromine are shown in the scheme by Formula 32. It will be readily understood in this respect by those skilled in the art that the compounds used as starting compounds in this scheme where the bromo substituent is in position 6 or 7 of 1 (2H) -naphthalenone gives rise to positional isomers of the compounds of the invention preferred hitherto. In the exemplary synthetic route illustrated in Reaction Scheme 4 a preferred starting material according to Formula 32 is 3-dihydro-4, -dimethyl-7-bromo-1 (2H) -naphthalenone. The latter compound can be obtained according to the scientific literature (Johnson et al., J. Med. Chem. 1995, 38, 4764-4767) and patents (US Pat. No. 5,543,534) of chemistry. The publication of Johnson et al. and the specification of U.S. Patent No. 5,543,534 are expressly incorporated herein by reference. The isomeric compound 3, 4-dihydro-4,4-dimethyl-6-bromo-l (2H) -naphthalenone can also be obtained according to the scientific literature (Mathur et al., Tetrahedron, 41, 1509 1516 (1985)) and patent (US Pat. No. 5,543,534) of chemistry. The numbering system employed for those simple naphthalenone derivatives are shown in Formula 32. As shown in Reaction Scheme 4, the bromonaphthalenone compounds of Formula 32 are subjected substantially in the same sequence of reactions, under substantially similar conditions, as the chroman-4-one or thiochroman-4-one derivatives according to Reaction Scheme 2. The adaptation of the reaction scheme described in relation to Reaction Scheme 2 of the compounds shown in Reaction Scheme 4 also it is within the experience of the synthetic organic chemistry expert. For these reasons, the reaction sequence shown in Reaction Scheme 4 is described here only briefly. Thus, the compounds of 3- (5,5-dimethyl-8-alkyl, aryl or heteroaryl-5,6-dihydronaphthalen-2-yl) -but-2 (Z) -en-l-ol of the Formula 35 are obtained through the intermediates 7-bromo-3,4-dihydro-4,4-dimethyl-1-alkyl-aryl or heteroaryl) -naphthalene (Formula 33) and acid (3,4-dihydro-4,4) -dimethyl-l-alkyl, aryl or heteroaryl) -naphthalen-7-yl) boronic acid (Formula 34). The allyl alcohol derivatives of Formula 35 are subjected to a cyclopropylation reaction with Reaction Scheme 2, to give the derivatives of [2-methyl-2- (5,5-dimethyl-8-alkyl, aryl or heteroaryl 5,6-dihydro-naphthalen-2-yl) -cyclopropyl] -methanol of Formula 36. The methanol compounds of Formula 36 are then further oxidized to the aldehyde step of (Formula 37) and then reacted in a reaction of Homer Emmons diethylphosphono-3-methyl-2 (E) -butenoate ethyl to provide the 3-methyl-5- [2-methyl-2- (5,5-dimethyl-8-alkyl, aryl or heteroaryl-5,6-dihydro-naphthalen-2-yl) -cyclopropyl] -pentadienoic of Formula 38. As described above, the esters of Formula 38 can be saponified or converted to other derivatives, such as amides or alcohols, within the scope of the invention. As shown in Reaction Scheme 4, the intermediate 3- (5,5-dimethyl-8-alkyl, aryl or heteroaryl-5,6-dihydronaphthalen-2-yl) -but-2 (Z) -in-1 -ol of Formula 35 is epoxidized according to the present invention to provide the derivatives [2-methyl-2- (5,5-dimethyl-8-alkyl, aryl or heteroaryl-5,6-dihydro-naphthalene-2-yl) ) -oxiranyl] -methanol of Formula 39. As in Reaction Scheme 3, the latter are converted in several steps, to the derivatives of 3-methyl-5- [2-methyl-2- (5,5-dimethyl) -8-alkyl, aryl or heteroaryl-5,6-dihydro-naphthalen-2-yl) -oxiranyl] -pentadienoic of Formula 40.

Formula 43 Formula 44 Fopular 45 Reaction Scheme 5 Reaction Scheme 5 describes a synthetic route for the preparation of a preferred class of compounds of the invention which are derivatives of the [2, 3] benzobicyclooctane. The initial compounds for the synthesis of these compounds are preferred examples are [2, 3] benzobicyclooctane derivatives where the positions 1 and 4 of the saturated ring are either unsubstituted or substituted with a lower alkyl group. In addition, one of these two positions may be substituted with an aryl or heteroaryl group. This is symbolized in the reaction scheme R '? 4, which is thus designated as lower alkyl, aryl or heteroaryl. However, in the most preferred examples the positions 1 to 4 are both substituted with a lower alkyl group, preferably a methyl group. An example for an initial material according to Formula 41 is 1,4-dimethyl- [2,3] benzobicyclooctane. The last compound can be prepared according to the chemical literature, as described for example by Kagechika et al. J. Med. Chem. 1988 31, 2182, where it is named as 1,4-ethane-1,2,3,4-tetrahydro-1,4-dimethylnaphthalene (see page 2190 of the reference by Kagechika et al. .). The [2,3] substituted benzobicyclooctane compounds of Formula 41 are brominated according to Reaction Scheme 5. The ratio can be conducted in any number of suitable solvents for the bromination of aromatic compounds, for example acetic acid. Depending on the nature of the substituents R '? , R '2 and R' 3 the bromination reaction can give rise to a mixture of positional isomers, of which only one is shown in Formula 42. It will be readily understood by those skilled in the art that in those and other schemes of reaction described herein the positional isomers on the aromatic portion (benzene ring) of chromene, thiochromen, dihydronaphthalene and benzobicyclooctane will give rise to the corresponding positional isomers of the preferred compounds of the invention described herein. As shown in Formulas 1, 2, and 3, those isomers are still within the scope of the invention. The 1, -disubstituted-4-bromo- [2,3] benzobicyclooctane compounds of Formula 42 are then subjected substantially in the same sequence of reactions which is described in relation to Reaction Schemes 2 and 4, to produce the derivatives of 1,4-disubstituted [2, 3] [(benzo -yl) -2-methyl-cyclopropyl] pentadienoic] bicyclooctane and 1,4-disubstituted acid [2, 3] [(benzo-4-yl)] acid 2-methyl-oxiranyl-pentadienoic acid] bicyclooctane of Formulas 47 and 49, respectively.

Formula 50 Formula 51 Formula 52 Reaction Scheme 6 Reaction Scheme 6 describes the synthetic route preferred heretofore for a preferred class of compounds of the invention in which the phenyl-cyclopropyl-pentadienoic acid derivatives are disubstituted. Suitable starting materials for the synthesis are the disubstituted benzoic acid derivatives at the 3,5-positions shown in reaction scheme 5 by Formula 50, where the R * 2 group may represent any group defined as R2 in connection with the Formula 2, but is preferably an alkyl group, more preferably tertiary butyl, iso-propyl or 1-adamantyl. The compounds of Formula 50 are, generally speaking, available according to the chemical literature. 3, 5-Di-t-butylbenzoic acid and 3,5-di-i-propylbenzoic acid serve as preferred examples; these compounds are commercially available from Aldrich Chemical Company. As shown in Reaction Scheme 6, the disubstituted benzoic acids at positions 3,5 of Formula 50 are subjected to a Hunsdiecker or analogous reaction where the carboxylic acid function is replaced by halogen, preferably bromine. The Hunsdiecker reaction (or similar reactions) per se are well known in the art. The product of the Hunsdiecker reaction or the like is a disubstituted bromobenzene at the 3,5 positions shown by Formula 51. As is well known in the art, disubstituted bromobenzenes at the 3,5-positions of Formula 51 can also be obtained by other chemical reactions than those described, and some may be commercially available as well. The disubstituted bromobenzenes at the 3,5-positions of Formula 51 are converted to the corresponding boronic acid derivatives of Formula 52 as in the previously described reaction schemes. The boronic acid derivatives of Formula 52 are subjected to the same sequence of reactions as described in Reaction Schemes 2, 4 and 5. The final products of those reactions, shown in Reaction Scheme 6 by Formulas 56 and 58 , respectively, are derivatives of 5- [2- (3,5-dialkyl-phenyl) -2-methyl-cyclopropyl) -3-methyl-penta-2, -dienoic acid] and 5- [2- (3, 5-dialkyl-phenyl) -2-methyl-oxiranyl) -3-methyl-penta-2,4-dienoic acid]. As noted above, the preferred compounds according to this reaction scheme are those where both R * 2 groups represent tertiary butyl, or both R * 2 groups are iso-propyl or where one of the two R2 * groups is H and 1-adamantyl. The adamantyl derivative is heretofore preferably made from an analogous but somewhat different reaction sequence involving a coupling reaction between 4- (l-adamantyl) phenyltrifluoromethanesulfonate and 3-iodo-O-triesopropylsilyl-but-2 acid (Z -en-ol-3-boronic. This reaction sequence is described in detail in the experimental section.

Formula 61 Formula 62 Formula 63 Reaction Scheme 7 Reaction Scheme 7 describes the preferred synthesis hitherto of a class of preferred compounds of the invention which includes an aryl, heteroaryl or cycloalkyl group (other than cyclopropyl) covalently linked to the pentadienoic acid moiety . The reaction scheme specifically shows this synthetic route applied to the derivatives of crom-3-ene and thiocrom-3-ene in the situation where the aryl group is phenyl substituted in positions 1,2. Those skilled in the art, however, will readily understand that by analogy this synthetic scheme is applicable to the synthesis of numerous other compounds of the invention.

As shown in the reaction scheme, (2, 2-dialkyl-4-alkyl, aryl or heteroaryl-2H-chromen-6-yl) boronic acid compounds of Formula 24 (or their thiochrom-3-ene analogs) corresponding) are reacted with ethyl 2-bromobenzoate in the presence of Pd (0) catalyst in solvent or mixture of inert solvents such as toluene and methanol, to provide 2- (2, 2-dialkyl-4-alkyl, aryl or heteroaryl-2H-chromen-6-yl) benzoic acid ethyl ester compounds of Formula 60. The ethyl 2-bromobenzoate reagent is available from according to the chemical literature, see for example J. Org. Chem. 14 (1949) 509, 512 and Helv. Chim. Minutes 39 (1956) 505-511. Other examples of reagents that can be used in this reaction in place of ethyl 2-bromobenzoate are: ethyl 2-bromopyridine-3-carboxylate, ethyl 4-bromopyridine-3-carboxylate, ethyl 3-bromothiophen-2-carboxylate , Ethyl 2-bromothiophene-3-carboxylate, ethyl 3-bromofuran-2-carboxylate, ethyl 2-bromofuran-3-carboxylate, ethyl cis-2-bromo-cyclopentanecarboxylate and ethyl cis-2-bromo-cyclohexanecarboxylate. However, in the resulting description the main emphasis remains on the substituted phenyl derivative at positions 1,2 currently shown in the reaction scheme.

The carboxylic acid ester function of the 2- (2,2-dialkyl-4-alkyl, aryl or heteroaryl-2H-chromen-6-yl) benzoic acid ethyl ester compounds of Formula 60 is then reduced with a reducing agent suitable, such as di-iso-butyl aluminum hydride (diBAl H) in an ether-like solvent, to provide 2- (2,2-dialkyl-4-alkyl, aryl or heteroaryl-2H-chromen-6-yl) ) -phenylmethanols (corresponding primary alcohols) of Formula 61. The primary alcohols of Formula 61 are subsequently oxidized to the corresponding 2- (2,2-dialkyl-4-alkyl, aryl or heteroaryl-2H-chromen-6-yl) benzaldehydes) of Formula 62 in an oxidation reaction which is analogous to the oxidation of the methanol derivatives of Formula 26 in Reaction Scheme 2. The benzaldehyde derivatives of Formula 62 are subsequently subjected to a reaction of Horner Emmons with the diethylphosphono- Ethyl 3-methyl-2 (E) -butenoate by analogy with the related reaction desc rite in the Reaction Scheme 2. Ethyl esters of 3-methyl-5- [2- (2, 2-dialkyl-4-alkyl, aryl or heteroaryl-2H-chromen-6-yl) -phenyl] -penta Resulting 2,4-dienoic are a preferred class of the compounds of the present invention. The ester function of these compounds is to saponify to provide the corresponding carboxylic acids, or their salts. The acid ester or carboxylic acid functions can also be subjected to other transformations well known in the art to provide still further compounds of the invention. It will be readily recognized by those skilled in the art that the reactions described in connection with Reaction Scheme 7 can also be used by initiating with the acid derivatives (3,4-dihydro-4,4-dimethyl-8-alkyl, aryl or heteroaryl). ) -naphthalen-7-yl) boronic of Formula 34, with the derivatives of [2,3] benzobicyclooctane boronic acid of Formula 43, and with the boronic acid derivatives disubstituted at positions 3,5 Formula 52, to produce the compounds corresponding preferred embodiments of the invention.

Nal, H -C02 and DibAI-H AcOH H) - \ C02Me CHjOH R = CH3 or lower alkyl Formula 64 Formula 65 Formula 65 Reaction Scheme 8 describes an example for preparing a compound of the invention where, with reference to Formula 1, the R2 groups comprise an oxo group (0 =) and where X is 0 or S (chromene derivatives, or thiochromene) . The exemplary starting material in this scheme is a compound of Formula 64 which is a 4-methyl-6-bromo-3-chromen-2-one or a thio analogue. Both of these compounds are available according to the chemical literature; for 4-methyl-6-bromo-3-chromen-2-one see J. Ind. Chem. Soc. (1940) 17 65-67, and for his analog uncle see Bull. Chem. Soc. Jap. (1986) 53 2046-2049. These two publications are expressly incorporated here, as a reference. In the first reaction shown in the scheme, the ketone function of the compounds of Formula 64 are reduced with a suitable reducing agent (such as DIBAL-H) and a methyl ether methanol is formed in the presence of acid, such as para-acid. toluenesulfonic. The resulting methyl ether of Formula 65 is reacted with trimethoxyboron, and the resulting boronic acid compound (analogous to the compounds of Formula 24 in Reaction Scheme 2) is subjected to the same sequence of reactions as the boronic acid compound of Formula 24 in Reaction Scheme 2. The resulting 2,4-dienoic acid derivatives where the chromene core retains the methoxy protecting group at position 2 are shown in Formula 66. The compounds of Formula 66 are oxidized with pyridinium chlorochromate (PCC) to form the corresponding chromen-2-one derivatives or their thio analogs of Formula 67. The reaction sequence described above can also be employed, with modifications such that they will become readily apparent to those skilled in organic chemistry synthetic, for the synthesis of dihydronaphatalene analog compounds of the invention within the scope of Formula 1 where the two group R 2 together form an oxo group.

SPECIFIC PROCEDURES 3-Iodo-pent-2 (Z) -en-l-ol (Compound 1) A solution of ethyl pent-2-inosate (2.0 g, 15.9 mmol), acetic acid (15 mL) and sodium iodide (3.1 g, 20.7 mmol) was heated for 36 hours at 95 ° C. The reaction was cooled to room temperature and the major portion of the solvent was removed under reduced pressure. The crude mixture was diluted with ether (100 mL), washed with water (20 mL), aqueous sodium thiosulfate (2 mL), brine (2 mL), dried and the solvent was removed under reduced pressure to give 3- iodine. pent-2 (Z) ethyl enoate. To a cold (-78 ° C.) Solution of ethyl 3-iodo-pent-2 (Z) enoate (3.1 g, prepared as described above) in dichloromethane (15 mL), diisobutylaluminum hydride (ÍM solution) was added. in dichloromethane, 27 mL, 27 mmol). The resulting mixture was gradually heated to -10 ° C. , and cooled by adding methanol (2 mL), water (10 mL) and 10% HCl (10 mL). The mixture was washed with water, 10% sodium carbonate, brine, dried with MgSO4 and the solvent was distilled to give the title compound as a colorless oil. XH NMR (300 MHz, CDC13): d 1.10 (t, J = 7.3 Hz, 3H), 2.55 (c, J = 7.3 Hz, 2H), 4.21 (d, J = 5.5 Hz, 2H), 5.84 (t, J = 5.5 Hz, 1H). (3, 5-Diisopropylphenyl) boronic acid (Compound 2) 3,5-Diisopropyl bromobenzene was prepared by the procedure reported in Le Noble, W. J. et al. J. Org.

Chem. 36, (1971) 193-196. To a cold solution (-78 ° C.) Of 3,5-diisopropyl bromobenzene (2.4 g, 10 mmol) in tetrahydrofuran (THF) (20 mL) was added dropwise t-BuLi (1.7M solution in pentane, 12.9 mL, 22 mmol). The mixture was stirred for 1 hour between -78 ° C. and -20 ° C. The reaction mixture was then cooled to -78 ° C. and trimethyl borate (2.3 g, 22 mmol) was added via drip via a syringe. The mixture was stirred and gradually warmed to room temperature for 1 hour and cooled with aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate (3 times, 30 mL), the combined organic layers were washed with brine, dried and the solvent removed by evaporation. The resulting residue, the crude product was used in the next step without further purification. 3- (3,5-Diisopropylphenyl) -pent-2 (Z) -en-l-ol (Compound 3) Argon was bubbled for 5 minutes in a solution of 3,5-diisopropylphenylboronate (Compound 2, 2.4 g crude), toluene (8 mL), methanol (8 mL), K2C03 (3 g) in water (10 mL) and 3-iodo-pent-2 (Z) -en-l-ol (Compound 1). Then Pd (PPh3) 4 (66 mg) was added and the mixture was heated to 95 ° C. for 16 hours. Subsequently, the reaction mixture was cooled to room temperature and washed with brine and dried with MgSO 4, and the solvent was removed by evaporation. The residual product was purified by column chromatography (silica gel, hexane: EtAc 9: 1) to obtain the title compound as a pale yellow oil.

XHRMN (CDC13): 1.03 (t, J = 7.1 Hz, 3H), 1.25 (d, J = 7.0 Hz, 12H), 2.40 (c, 7.1 Hz, 2H), 2.88 (s, J = 7.0 Hz, 2H), 4. 08 (d, J = 6.6 Hz, 2H), 5.65 (t, J = 6.6, 1H), 6.79 (d, J = l .5 Hz, 2H), 6.99 (broad s, 1H). (-) -2 (R), 3 (S) -Metano-3- (3, 5-diisopropylphenyl) -pentan-1-ol (Compound 4) To a cold mixture (-50 ° C.) Of 3- ( 3,5-diisopropylphenyl) -pent-2 (Z) -en-l-ol (Compound 3, 600 mg, 2.4 mmol), 1,3-dioxa-2-butyl-4,5-dicarbo-N, N- dimethylamide-2-borolane (1.75 g, 6.4 mmol), (derivative of O- (-) - N, N-tetramethyltartaramide and n-butylboronic acid, for the preparation of this test reagent see, J. Org. Chem. 1995 , 60, 1081), molecular sieves (1.8 g), dichloromethane (15 mL), complex drip of Zn (CH2 I) 2. Freshly prepared DME in dichloromethane (8M solution, 64 mmol, for the preparation see; J. Org. Chem. 1995, 60, 1081), via a cannula (15 min). The mixture was stirred at 20 ° C. for 16 hours and then cooled by adding ammonium chloride solution. The mixture was extracted with dichloromethane, the combined organic layers were washed with ammonium chloride, brine, dried and the solvent was removed by evaporation. Purification by chromatography gave the title compound as a colorless oil. [a] D20 ° C. = -9.9 °; c = 0.9 g / 100 mL; solvent-di clor orneño; * HRMN (CDC13): d 0.72-0.82 (m, 5H), 1.23 (d, J = 7.0 Hz, 12H), 1.88-2.00 (m, 1H), 2.66 (s, J = 7.0 Hz, 2H), 3.26 (d, J = 7.1 Hz, 2H), 6.91 (broad s, 1H), 6.95 (d, J = 1.9 Hz, 2H). (-) -2 (R), 3 (S) -Metano-3- (3,5-diisopropylphenyl) -pentanal (Compound 5) To a solution of (-) -2 (R), 3 (S) -methane -3- (3,5-diisopropylphenyl) -pentan-1-ol (Compound 4, 180 mg, 0.7 mmol), in dichloromethane (8 mL), acetonitrile (0.5 mL) was added N-methylmorpholen-N-oxide (234) mg, 2 mmol), molecular sieves (500 mg) and tetrapropylammonium perruthenate (5 mg). The mixture was stirred for 1 hour and then passed through a column of silica gel eluting with hexane and ethyl acetate (9: 1). The collected fractions containing the product were combined and the solvent was distilled to give the title compound as a colorless oil. The product was used in the next step without further purification. XHRMN (CDC13): d 0.82 (t, J = 7.1 Hz, 3H), 1.23 (d, J = 7.0 Hz, 12H), 1.35-1.45 (m, 2H), 1.75-1.97 (m, 3H), 2.83 ( s, J = 7.0 Hz, 2H), 6.91 (broad s, 3H), 8.38 (d, J = 7.4 Hz, 1H).

Ethyl ^ 7- [3,5-diisopropylphenyl] -6 (S), 7 (S) -methyl-3-methyl-2 (E), 4 (E) -nonadienoate (Compound 6) To a solution of diethyl (E) -3-ethoxycarbonyl-2-methylallylphosphonate (950 mg, 3.6 mmol) in THF (12 ml), 1,3-dimethyl-3,, 5,6-tetrahydro-2 (1H) - pyrimidenone (2.7 ml) at -78 ° C. n-BuLi (2.3 ml, 3.6 mmol) was added dropwise. The mixture was stirred for five minutes. Then (-) -2 (R), 3 (S) -methane-3- (3,5-diisopropylphenyl) -pentanal (Compound 5, 187 mg, 0.72 mmol) in THF (2 + 2 ml) was added dropwise. ). The mixture was stirred and gradually the reaction temperature was allowed to rise to -10 ° C. At this time, thin layer chromatography indicated that the reaction was complete, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water, brine, then dried (MgSO ,.) and the solvent was removed by evaporation. Column chromatography on silica gel (3% ethyl acetate in hexane) gave a mixture of two isomers, the title compound and the 13-cis isomer. The title compound was isolated as a colorless oil by high pressure liquid chromatography (CLAP, semi-preparative column, Partyl-10, 1% ethyl acetate in hexane). * H NMR (300 MHz, CDC13): d? .83 (t, J = 7.5 Hz, 3H), 1.03 (t, J = 4.9 Hz, 1H), 1.15-1.20 (m, 1H), 1.21 (d, J = 7.5 Hz, 12H), 1.26 (t, J = 7.2 Hz, 3H), 1.30-1.42 (m, 1H), 1.6 * 5-1.80 (m, 2H), 1.98 (s, 3H), 2.84 (m , 2H), 4.13 (c, J = 7.2 Hz, 2H), 5.24 (dd, J = 9.9 Hz, 15.6 Hz, 1H), 5.62 (s, 1H), 6.19 (d, J = 15.6 Hz, 1H), 6.86 (s, 2H), 6.89 (s, H).

Acid (+) 7- [3,5-Diesopropylphenyl] -6 (S), 7 (S) -methane-3-methyl-2 (E), 4 (E) -nonadienoic (Compound 7) To a solution of 7- [3,5-diisopropylphenyl] -6 (S), 7 (S) -methane-3-methyl-2 (E), ethyl 4 (E) -nononandienate (Compound 6, 235 mg, 0.64 mmole) in THF (4.1 ml) and methanol (8.2 ml) was added NaOH (IM solution, 3.4 ml). The mixture was heated at 75 ° C for 15 hours. At that time, thin-layer chromatography indicated that the reaction was complete. The solvents, THF and methanol were removed under reduced pressure and the residue was diluted with ethyl acetate. The mixture was acidified with 10% HCl to pH 2. The aqueous and organic layers were separated and the organic layer was washed with water and brine and then dried with MgSO.j. The solvent was removed by evaporation. The title compound (white solid) was isolated from the residue by chromatography on silica gel. Optical Rotation [a] 20oCD = + 25.7 °, solvent, dichloromethane, c = 0.0025 g / mL, 1 = 1; X NMR (300 MHz, CDC13): d 0.86 (t, J = 7.2 Hz, 3H), 1. 07 (t, J = 5.0 Hz, 1H), 1.15-1.23 (m, 1H), 1.21 (d, J = 7.2 Hz, 12H), 1.35-1.45 (m, 1H), 1.68-1.80 (m, 2H) , 1.98 (s, 3H), 2.75-2.90 (m, 2H), 5.33 (dd, J = 10.0, 15.5 Hz, 1H), 5.65 (s, 1H), 6.21 (d, J = 15.5 Hz, 1H), 6.86 (s, 2H), 6.89 (s, 1H). 3, 5-Di-tert-butylphenylboronic acid (Compound 9) To a cold solution (-78 ° C) of 3,5-tert-butyl bromobenzene (available from Lancaster Co., 2.1 g, 8.2 mmol) in tetrahydrofuran (THF) ) (20 mL) was added dropwise t-BuLi (1.7M solution in pentane, 9.7 mL, 16.4 mmol). The mixture was stirred for 1 hour between -78 ° C and -20 ° C. The reaction was cooled to -78 ° C and trimethyl borate (1.7 g, 16.4 mmol) was added by drip via a syringe. The mixture was stirred and gradually warmed to room temperature for 1 hour and cooled with aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate (3 x 30 mL), the combined organic layer was washed with brine, dried, and the solvent was removed. The crude product was used in the next step without further purification. 3- (3, 5-Di-tert-butylphenyl) -hex-2 (Z) -en-l-ol (Compound 10) Using the procedure used for the preparation of 3- (3,5-diisopropylphenyl) -pent- 2 (Z) -in-l-ol (Compound 3), 3,5-di-tert-butylphenylboronic acid (Compound 9) was converted to the title compound using 3-iodo-hex-2 (Z) -in- ol (Compound 15) as a coupling agent. XHRMN (CDC13): d 0.90 (t, J = 7.1 Hz, 3H), 1.33 (s, 18H), 1.33-1.45 (m, 2H), 2.37 (t, J = 7.1 Hz, 2H), 4.08 (d, J = 6.7 Hz, 2H), 5.66 (t, J = 6.6, 1H), 6.94 (d, J = 1.5 Hz, 2H), 7.32 (broad s, 1H). (-) -2 (R), 3 (S) -Metano-3- (3, 5-di-tert-butylphenyl) -hexan-1-ol (Compound 11) Using the procedure used for the preparation of (-) -2 (R), 3 (S) -methane-3- (3,5-diisopropylphenyl) -pentan-1-ol (Compound 4), 3- (3,5-di-tert-butylphenyl) -hex-2 (Z) -in-l-ol (Compound 10) was converted to the title compound. [a] D20oC = -48.5 °; c = 0.55 g / 100 mL; solvent-dichloromethane; It was determined that the% yield was > 95% XHRMN (CDCI3): d 0.78-0.90 (m, 5H), 1.32 (s, 18H), 1.20-1.34 (m, 6H), 1.85 (m, 1H), 3.35 (broad s, 2H), 7.12 (d, J = 1.8 Hz, 2H), 7.24 (d, J = 1.8 Hz, 1H). (-) - 2 (R), 3 (S) -Metano-3- (3,5-di-tert-butylphenyl) -hexanal (Compound 12) Using the procedure used for the preparation of (-) -2 (R ), 3 (S) -methane-3- (3,5-diisopropylphenyl) -pentanal (Compound 5), (-) -2 (R), 3 (S) -Metano-3- (3, 5-di) -tert-butylphenyl) -hexan-1-ol (Compound 11) was converted to the title compound. [a] D20oC = -20.5 °; c = 0.42 g / 100 mL; solvent-dichloromethane; XHRMN (CDC13): d 0.84 (t, J = 7.1 Hz, 3H), 1.23 (s, 18H), 1.25-1.45 (m, 4H), 1.75-1.97 (m, 3H), 7.00 (d, J = 1.7 Hz, 2H), 7.27 (d, J = 1.7 Hz, 1H), 8.36 (d, J = 7.4 Hz, 1H).

(+) Ethyl-7- [3,5-di-tert-butylphenyl] -6 (S), 7 (S) -me a or-3-methyl-2 (E), 4 (E) -decadienoate (Compound 13) Using the procedure used for the preparation of ethyl-7- [3,5-diisopropylphenyl] -6 (S), 7 (S) -methane-3-methyl-2 (E), (E) -nonandienate (Compound 6) , (-) - 2 (R), 3 (S) -methane-3- (3,5-di-tert-butylphenyl) -hexanal Compound 12) was converted into the title compound. [a] D20oC = + 70.5 °; c = 0.24 g / 100 mL; solvent-dichloromethane; XH NMR (300 MHz, CDC13): d 0.84 (t, J = 7.5 Hz, 3H), 1.05 (t, J = 4.9 Hz, 1H), 1.21 (dd, J = 4.5, 8.3 Hz, 1H), 1.28 ( t, J = 7.5 Hz, 3H), 1.30 (s, 18H), 1.30-1.40 (m, 3H), 1.64-1.76 (m, 2H), 2.00 (s, 3H), 4.14 (c, J = 7.2 Hz , 2H), 5.24 (dd, J = 9.9 Hz, 15.6 Hz, 1H), 5.64 (s, 1H), 6.20 (d, J = 15.6 Hz, 1H), 7.03 (d, J = 1.8 Hz, 2H), 7.23 (d, J = 1.8 Hz, 1H).

Acid (+) 7- [3,5-di-tert-butylphenyl] -6 (S), 7 (S) -methyl-3-methyl-2 (E), 4 (E) -decadienoic (Compound 14) Using the procedure used for the preparation of (+) 7- [3,5-diisopropylphenyl] -6 (S), 7 (S) -methane-3-methyl-2 (E), 4 (E) -nonadienoic acid ( Compound 7), (+) ethyl-7- [3,5-di-tert-butylphenyl] -6 (S), 7 (S) -methane-3-methyl-2 (E), 4 (E) - decadienoate (Compound 13) was converted into the title compound. Optical Rotation [a] 20oCD = + 80.4 °, the solvent is dichloromethane, c = 0.0035 g / mL, 1 = 1; ? ti NMR (300 MHz, CDC13): d 0.87 (t, J = 7.2 Hz, 3H), 1.23 (t, J = 5.0 Hz, 1H), 1.20-1.45 (m, 4H), 1.31 (s, 18H) , 1.65-1.80 (m, 2H), 2.00 (s, 3H), 5.31 (dd, J = 10.0, 15.5 Hz, 1H), 5.66 (s, 1H), 6.23 (d, J = 15.5 Hz, 1H), 7.03 (d, J = 1.7 Hz, 2H), 7.24 (d, J = 1.7 Hz, 1H). 3-Iodo-hex-2 (Z) -en-l-ol (Compound 15) Using the procedure used for the preparation of 3-iodo-pent-2 (Z) -in-l-ol (Compound 1), the ethyl-hex-2-inoato was converted to 3-iodo-hex-2 (Z) -en-l-ol. X NMR (300 MHz, CDCl 3): d 1.10 (t, J = 7.3 Hz, 3H), 2. 55 (c, J = 7.3 Hz, 2H), 4.21 (d, J = 5.5 Hz, 2H), 5.84 (t, J = 5.5 Hz, 1H).

L-tert-Butyl-4,4-dimethyl-3,4-dihydro-naphthalene-7-boronic acid (Compound 17) Using the procedure used for the preparation of 3,5-diisopropylphenylboronic acid (Compound 2), the l- tert-butyl-4, -dimethyl-3, -dihydro-7-bromonaphthalene (Compound 16) was converted to the title compound. The resulting crude product was used in the next step without further purification. The l-tert-butyl-4, -dimethyl-3, 4-dihydro-7-bromonaphthalene (Compound 16) can be obtained according to the description of U.S. Patent No. 5,741,896, incorporated herein by reference. 3- (l-Tert-Butyl-4,4-dimethyl-3,4-dihydro-naphthalen-7-yl) -hex-2 (Z) -en-l-ol (Compound 18) Using the procedure used for the Preparation of 3- (3,5-di-tert-butylphenyl) -hex-2 (Z) -en-l-ol (Compound 10), l-tert-butyl-4,4-dimethyl-3, - dihydro-naphthalene-7-boronic acid (Compound 17) was converted to the title compound. XHRMN (CDC13): d 0.88 (t, J = 8.0 Hz, 3H), 1.21 (s, 6H), 1.33 (s, 9H), 1.39 (m, 2H), 2.14 (d, J = 5.0 Hz, 2H) , 2.36 (t, J = 6.8 Hz, 2H), 4.11 (t, J = 6.6 Hz, 2H), 5.66 (t, J = 6.6 Hz, 1H), 5.95 (t, J = 5.0 Hz, 1H), 6.93 (dd, J = 1.8, 7.9 Hz, 1H), 7. 25 (d, J = 7.9 Hz, 1H), 7.39 (d, J = 1.8 Hz, 1H). (-) 2 (R), 3 (S) -Metano-3- (l-tert-butyl-4,4-dimethyl-3, -dihydro-naphthalen-7-yl) -hexan-1-ol (Compound 19 ) Using the procedure used for the preparation of (-) -2 (R), 3 (S) -methane-3- (3, 5-diisopropylphenyl) -pentan-1-ol (Compound 4), the 3- (l) -tert-butyl-4, -dimethyl-3, 4-dihydro-naphthalen-7-yl) -hex-2 (Z) -en-l-ol (Compound 18) was converted to the title compound. Optical Rotation [a] 20oCD = -26.25 °, the solvent is dichloromethane, c = 0.0045 g / mL, 1 = 1; 2H NMR (CDCl 3): d 0.82 (t, J = 7.0 Hz, 3H), 0.77-0.84 (m, 2H), 1.19 (s, 6H), 1.34 (s, 9H), 1.18-1.38 (m, 4H), 1.84- 1.95 (m, 1H), 2.11 (d, J = 7.0 Hz, 2H), 3.28 (bre, 2H), 5.93 (t, J = 7.0 Hz, 1H), 7.06 (dd, J = 1.8, 8.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 1.8 Hz, 1H). 2 (R), 3 (S) -Metano-3- (l-tert-butyl-, -dimethyl-3, -dihydronaphthalen-7-yl) -hexanal (Compound 20) Using the procedure used for the preparation of (- ) -2 (R), 3 (S) -methane-3- (3,5-diisopropylphenyl) -pentanal (Compound 5), the (-) 2 (R), 3 (S) -methane-3- (I -tert -butyl-4,4-dimethyl-3,4-dihydro-naphthalen-7-yl) -hexan-1-ol (Compound 19) was converted to the title compound.

Ethyl-6 (S), 7 (S) -methane-3- (1-tert-butyl-4, -dimethyl-3, 4-dihydro-naphthalen-7-yl) -deca-2 (E), (E ) -dienoato (Compound 21) OjEt Using the procedure used for the preparation of ethyl-7- [3,5-diisopropylphenyl] -6 (S), 7 (S) -methane-3-methyl-2 (E), 4 (E) -nonandienoate (Compound 6 ), 2 (R), 3 (S) -methane-3- (l-tert-butyl-4,4-dimethyl-3,4-dihydro-naphthalen-7-yl) -hexanal 20 was converted to the compound of the title. 'HRMN (CDC13): d 0.84 (t, J = 6.9 Hz, 3H), 1.06 (t, J = 5.0 Hz, 1H), 1.17 (s, 3H), 1.21 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.29 (s, 9H), 1.24-1.39 (m, 4H), 1.62-1.78 (m, 2H), 1.94 (d, J = 1.2 Hz, 3H), 2.04 (s, 3) , 2.05-2.15 (m, 2), 4.15 (c, J = 7.1 Hz, 2H), 5.23 (dd, J = 10.0, 15.5 Hz, 1H), 5.60 (s, 1H), 5.91 (t, J = 5.0 Hz, 1H), 6.18 (d, J = 15.5 Hz, 1H), 7.00 (dd, J = 1.8, 8.1 Hz, 1H), 7.21 (d, J = 8.1 Hz, 1H), 7.45 (d, J = 1.8 Hz, 1H). (+) 6 (S), 7 (S) -Metano-3- (l-tert-butyl-4,4-dimethyl-3, 4-dihydro-naphthalen-7-yl) -deca-2 (E) acid , 4 (E) -dienoic (Compound 22) Using the procedure used for the preparation of the acid (+) 7- [3,5-diisopropylphenyl] -6 (S), 7 (S) -methane-3-methyl-2 (E), 4 (E) -nonadienoic Compound 7), ethyl-6 (S), 7 (S) -methane-3- (l-tert-butyl-4,4-dimethyl-3,4-dihydro-naphthalen-7-yl) -deca-2 ( E), 4 (E) -dienoate 21, was converted into the title compound. Optical Rotation [a] 20oCD = + 14.2 °, the solvent is dichloromethane; XHRMN (CDC1): d 0.86 (t, J = 6.9 Hz, 3H), 1.10 (t, J = 4.4 Hz, 1H), 1.18 (s, 3H), 1.23 (s, 3H), 1.21-1.40 (m, 4H), 1.30 (s, 9H), 1.70-1.81 (m, 2H), 1.96 (s, 3H), 2.11-2.15 (m, 2H), 5.30 (dd, J = 10.0, 15.5 Hz, 1H), 5.65 (s, 1H), 5.93 (t, J = 4.8 Hz, 1H), 6.23 (d, J = 15.5 Hz, 1H), 7.03 (dd, J = 1.5, 7.8 Hz, 1H), 7.44 (d, J = 1.5 Hz, 1H). 7-Bromo-2, 2-4-trimethyl-2H-chromene (Compound 23) A 3.0 M solution of MeMgBr in ether (14 mL, 42.9 mmol) was slowly added to a solution of cerium chloride (10.6 g, 42.9 mmol. ) in 30 mL of anhydrous THF at 0 ° C. The mixture was stirred for 2 hours at room temperature. The mixture was cooled to 0 ° C. and a solution of 7-bromo-2,2-dimethyl-chroman-4-one (available according to J. Med. Chem. 33 1990, 3028-3034, incorporated herein by reference) in THF (20 mL) was added. ). The reaction mixture was stirred for 20 hours at room temperature. The reaction was quenched with 1% H2SO4 at 0 ° C. and extracted with ether (3 x 50 mL). The organic layer was washed with water (2 x 100 mL) and brine (2 x 100 mL), dried with MgSO 4 and the solvent was removed by distillation. The residue was then refluxed with 20mL of 20% H2SO4 for 14 hours. The reaction mixture was extracted with ether (3 x 20 mL), the organic layer was washed with water, brine, dried, and the solvent was removed by distillation. The title compound was isolated as an oil after chromatography. 2H NMR (CDCl 3): d 1.38 (s, 6H), 1.97 (d, J = 1.5 Hz, 3H), 5.41 (d, J = 1.5 Hz, 1H), 6.94-6.99 (m, 3H). 3- (2,2-4-Trimethyl-2H-chromen-7-yl) -but-2 (Z) -en-l-ol (Compound 24) Using the procedure for the preparation of 3- (3, 5-di-tert-butylphenyl) -hex-2 (Z) -en-l-ol (Compound 10), 7-bromo-2, 2-4-trimethyl-2H-chromenne (Compound 23) ) was converted to the title compound. XHRMN (CDC13): d 1.38 (s, 6H), 1.97 (s, 3H), 2.05 (s, 3H), 4.11 (t, J = 4.5 Hz, 2H), 5.48 (s, 1H), 5.67 (t, J = 4.5 Hz, 1H), 6.50 (s, 1H), 6.58 (d, J = 7.8 Hz, 1H), 7.09 (d, J = 7.8 Hz, 1H). 2 (R), 3 (S) -Metano-3- (2, 2-4-trimethyl-2H-chromen-7-yl) -butan-1-ol (Compound 25) Using the procedure for the preparation of (- ) -2 (R), 3 (S) -methane-3- (3,5-diisopropylphenyl) -pentan-1-ol (Compound 4), 3- (2, 2-4-trimethyl-2H-chromen-7) -yl) -but-2 (Z) -in-l-ol (Compound 24) was converted to the title compound. XHRMN (CDC13): d 0.73 (dd, J = 4.9, 8.4 Hz, 1H), 0.87 (t, J = 5.1 Hz, 1H), 1.37 (s, 6H), 1.38 (s, 3H), 1.97 (d, J = l.6 Hz, 1H), 3.15-3.34 (m, 2H), 5.35 ( s, 1H), 6.73 (d, J = 1.8 Hz, 1H), 6.82 (dd, J = 1.8, 7.8 Hz, 1H), 7.05 (d, J = 7.8 Hz, 1H). 2 (R), 3 (S) -Metano-3- (2, 2-4-trimethyl-2H-chromen-7-yl) -butanal (Compound 26) Using the procedure for the preparation of (-) -2 ( R), 3 (S) -methane-3- (3, 5-diesopropylphenyl) -pentanal (Compound 5), 2 (R), 3 (S) -methane-3- (2, 2-4-trimethyl-2H -chromen-7-yl) -butan-1-ol (Compound 25) was converted to the title compound. XHRMN (CDC13): d 1.36 (s, 3H), 1.38 (s, 3H), 1.43 (s, 3H), 1.75-1.93 (m, 3H), 1.95 (d, J = 1.5 Hz, 3H), 5.37 ( d, J = 1.5 Hz, 1H), 6.74 (d, J = 1.8 Hz, 1H), 6.80 (dd, J = 1.8, 7.8 Hz, 1H), 7.04 (d, J = 7.8 Hz, 1H), 8.42 ( d, J = 6.8 Hz, 1H).

Ethyl-6 (S), 7 (S) -methane-3- (2, 2-4-trimethyl-2H-chromen-7-yl) -octa-2 (E), 4 (E) -dienoate (Compound 27 ) Using the procedure for the preparation of ethyl-7- [3,5-diisopropylphenyl] -6 (S), 7 (S) -methane-3-methyl-2 (E), 4 (E) -nonadienoate (Compound 6) , 2 (R), 3 (S) -methane-3- (2, 2-4-trimethyl-2H-chromen-7-yl) -butanal (Compound 26) was converted to the title compound.

XHRMN (CDC13): d 1.14-1.17 (m, 2H), 1.26 (t, J = 7.0 Hz, 3H), 1.35 (s, 3H), 1.40 (s, 3H), 1.41 (s, 3H), 1.68- 1.78 (m, 1H), 1.99 (broad s, 6H), 4.10 (c, J = 7.0 Hz, 2H), 5.23 (d, J = 11.0, 15.5 Hz, 1H), 5.38 (d, J = 2.0 Hz, 1H), 5.62 (s, 1H), 6.18 (d, J = 15.5 Hz, 1H), 6.70 (d, J = 1.8 Hz, 1H), 6.76 (dd, J = 1.8, 7.8 Hz, 1H), 7.05 ( d, J = 7.8 Hz, 1H).

Acid 6 (S), 7 (S) -Metano-3- (2, 2-4-trimethyl-2H-chromen-7-yl) -octa-2 (E), 4 (E) -dienoic acid 28 Using the procedure for the preparation of (+) 7- [3,5-diesopropylphenyl] -6 (S), 7 (S) -methane-3-methyl-2 (E), (E) -nonadienoic acid (Compound 7) ), ethyl-6 (S), 7 (S) -methane-3- (2, 2-4-trimethyl-2H-chromen-7-yl) -octa-2 (E), 4 (E) -dienoate ( Compound 27), was converted to the title compound. XHRMN (CDC13): d 1.12 (broad s, 1H), 1.14 (broad s, 1H), 1.33 (s, 3H), 1.39 (s, 6H), 1.65-1.74 (m, 1H), 1. 97 (s, 6H), 5.24 (dd, J = 11.0, 15.5 Hz, 1H), 5.36 (s, 1H), . 62 (s, 1H), 6.18 (d, J = 15.5 Hz, 1H), 6.68 (s, 1H), 6.73 (dd, J = 1.5, 8.0 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H). 4, 4-Dimethyl-l-isopropyl-7-bromo-3,4-dihydronaphthalene (Compound 29) Using the procedure for the preparation of 7-bromo-2, 2-4-trimethyl-2H-chromene (Compound 23), 4,4-dimethyl-7-bromo-3,4-dihydro-2 (H) -naphalene-1-one was converted to composed of the title. THRMN (CDCI3): d 1.15 (d, J = 6.7 Hz, 6H), 1.21 (s, 6H), 2.17 (d, J = 4.6 Hz, 2H), 2.89 (sept, J = 6.7 Hz, 1H), 5.82 (t, J = 4.6 Hz, 1H), 7.17 (d, J = 8.3 Hz, 1H), 7.30 (d, J = 2.1, 8.3 Hz, 1H), 7.43 (d, J = 2.1 Hz, 1H). 3- (l-Iso-Propyl-4,4-dimethyl-3, 4-dihydro-naphthalen-7-yl) -hex-2 (Z) -en-l-ol (Compound 30) Using the procedure for the preparation of 3- (3,5-di-tert-butylphenyl) -hex-2 (Z) -en-l-ol (Compound 10), 4-dimethyl-1-propyl-7-bromo-3, 4-dihydronaphthalene (Compound 29) was converted to the title compound. XHRMN (CDC13): d 0.88 (t, J = 7.5 Hz, 3H), 1.15 (d, J = 6.9 Hz, 6H), 1.23 (s, 6H), 1.31-1.45 (m, 2H), 2.17 (d, J = 4.4 Hz, 2H), 2.35 (t, J = 6.9 Hz, 2H), 2.92 (sept, J = 6.9 Hz, 1H), 4.08 (t, J = 6.0 Hz, 2H), 5.66 (t, J = 6.0 Hz, 1H), 5.78 (t, J = 4.4 Hz, 1H), 6.95 (dd, J = 1.7, 7.8 Hz, 1H), 7.06 (d, J = 1.7 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H). (-) 2 (R), 3 (S) -Metano-3- (l-iso-propyl-4,4-dimethyl-3,4-dihydro-naphthalen-7-yl) -hexan-1-ol (Compound 31) Using the procedure for the preparation of (-) -2 (R), 3 (S) -methane-3- (3,5-diisopropylphenyl) -pentan-1-ol (Compound 4), the 3- (1) -iso-propyl-4,4-dimethyl-3, -dihydro-naphthalen-7-yl) -hex-2 (Z) -en-l-ol (Compound 30) was converted to the title compound Optical Rotation [ot] 20oCD = -26.67 °, the solvent is dichloromethane; 2HRMN (CDC13): d 0.75-0.85 (m, 5H), 1.12-1.34 (m, 13H), 1.85-1.94 (m, 1H), 2.15 (d, J = 4.4 Hz, 2H), 2.96 (sept, J = 6.9 Hz, 1H), 3.26 (t, J = 7.1 Hz, 2H), 5.72 ( t, J = 4.4 Hz, 1H), 7.09 (dd, J = 1.7, 7.9 Hz, 1H), 7.20 (d, J = 7.9 Hz, 1H), 7.26 (d, J = 1.7 Hz, 1H). (+) 2 (R), 3 (S) -Metano-3- (l-iso-propyl-4,4-dimethyl-3,4-dihydro-naphthalen-7-yl) -hexanal (Compound 32) Using the procedure for the preparation of (-) -2 (R), 3 (S) -methane-3- (3,5-diisopropylphenyl) -pentanal (Compound 5), (-) 2 (R), 3 (S) - methane-3- (1-iso-propyl-4,4-dimethyl-3,4-dihydro-naphthalen-7-yl) -hexan-1-ol (Compound 31) was converted to the title compound. Optical Rotation [a] 20oCD = + 8.7 °, the solvent is dichloromethane.

XHRMN (CDC13): d 0.80-0.90 (m, 5H), 1.15-1.40 (m, 14H), 1.43-1.47 (m, 1H), 1.80-1.95 (m, 3H), 2.17 (d, J = 4.4 Hz, 2H), 2.94 (sept.J = 6.9 Hz, 1H), 5.78 (t, J = 4.4 Hz, 1H), 7. 10 (dd, J = 1.8, 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.27 (broad s, 1H), 8.44 (d, J = 7.6 Hz, 1H).

Ethyl-6 (S), 7 (S) -methane-3- (l-iso-propyl-4,4-dimethyl-3,4-dihydro-naph talen-7-yl) -deca-2 (E), 4 (E) -dienoate (Compound 33) Using the procedure for the preparation of ethyl-7- [3,5-diisopropylphenyl] -6 (S), 7 (S) -methane-3-methyl-2 (E), (E) -nonadienoate (Compound 6), 2 (R), 3 (S) -methane-3- (1-iso-propyl-4,4-dimethyl-3,4-dihydro-naphthalen-7-yl) -hexanal (Compound 32) was converted to the compound of the Title. Optical Rotation [a] 20oCD = + 96.30 °, the solvent is dichloromethane. : HRMN (CDC13): d 0.84 (t, J = 6.9 Hz, 3H), 1.08 (d, J = 6.9 Hz, 3H), 1.15 (d, J = 6.9 Hz, 3H), 1.09 (s, 3H), 1.18-1.32 (m, 5H), 1.25 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H), 1.70-1.82 (m, 2H), 1.95 (s, 3H), 2.15 (t, J = 4.4 Hz, 2H), 2.90 (sept.

J = 6.9 Hz, 1H), 4.14 (c, J = 7.2 Hz, 2H), 5.21 (dd, J = 11.0, 15.5 Hz, 1H), 5.61 (s, 1H), 5.74 (t, J = 4.4 Hz, 1H), 6.17 (d, J = 15.5 Hz, 1H), 7.00 (dd, J = 1.8, 7.9 Hz, 1H), 7.16 (d, J = 1.8 Hz, 1H), 7.19 (d, J = 7.9) Hz, 1H).

Acid (+) 6 (S), 7 (S) -Metano-3- (l-iso-propyl-4,4-dimethyl-3,4-dihydro-naphthalen-7-yl) -deca-2 (E) , 4 (E) -dienoic (Compound 34) Using the procedure for the preparation of (+) 7- [3,5-diisopropylphenyl] -6 (S), 7 (S) -methane-3-methyl-2 (E), 4 (E) -nonadienoic acid (Compound 7), (+) ethyl-6 (S), 7 (S) -methyl-3- (l-iso-propyl-, 4-dimethyl-3,4-dihydronaphthalen-7-yl) -deca-2 (E) ), 4 (E) -dioate (Compound 33), was converted to the title compound. Optical Rotation [a] 20oCD = + 46.26 °, the solvent is dichloromethane; ^ RN (CDC13): d 0.84 (t, J = 6.9 Hz, 3H), 1.08 (d, J = 6.9 Hz, 3H), 1.15 (d, J = 6.9 Hz, 3H), 1.09 (s, 3H), 1.18-1.32 (m, 5H), 1.25 (s, 3H), 1.70-1.82 (, 2H), 1.95 (s, 3H), 2.15 (t, J = 4.4 Hz, 2H), 2.90 (Sept. J = 6.9) Hz, 1H), 4.14 (c, J = 7.2 Hz, 2H), 5.21 (dd, J = 11.0, 15.5 Hz, 1H), 5.61 (s, 1H), 5.74 (t, J = 4.-i Hz, 1K., 6.17 (d, J = 15.5 Hz, 1H), 7.00 (d, J = 1.8, 7.9 Hz, 1H), 7.16 (d, J = 1.8 Hz, 1H;, 7.19 (d, J = 7.9 Hz, 1 HOUR) 3-Iodo-0-triisopropylsilyl-but-2 (Z) -en-ol (Compound 36) A solution, with stirring, cooled (rneloi bath of 3-iodo-α at-2 (z) -in-ol ( Compound 35, lC g, 5 mmcl) and 10 mL of anhydrous dichloromethane was treated sequentially with 2,6-latidine (0.88 mL, 7.5 mmoi, and tri-iso-p-cypi isintrifluoromer.anesulfon-ito (1.36 mL, 5 mmoi i under argon. (Compound 35 can be obtained by analogy to the presence of 3-iodo-pent-2 (Z) -en-i-ol (Compound 1.). 1 hour, the sc-reaction mixture was diluted with 10 mL of hexane and purified by flash column chromatography on silica gel (230-40 C mesh) using 2.5% acetate and ethyl in nexane as the eluent to give the Compounding the title as. \ n Colorless oil (1.62 g, 91%;.: HRMN (300 MHz, CDCI3); d 1.05-1.15 (rn, 21F), 2.51 (d, Hz, iH;, 4.25 (dd, J = 3.6, 5.2 K .., 2H.}., 5.73 (ct, J-1.7, 5.0 Hz. 1H). 4- (1-Adamantyl) phenyltrifluoromethanesulfonate (Compound 37) A stirred solution, cooled (0 ° C) of 4- (1-adamantyl) phenol (3.2 g, 14 mmol, obtained according to the chemical literature) and triethylamine ( 3.3 mL, 22.4 mmol) in 40 mL of anhydrous dichloromethane was treated with 2- [N, N-bes (trifluoromethanesulfonyl) amino] -5-chloropyridine (5.6 g, 14.2 mmol). The resulting solution was warmed to room temperature for 0.5 hours, then diluted with 20 mL of dichloromethane and washed with 30 mL of 3M HCl followed by 30 mL of brine. The organic phase was dried over anhydrous sodium sulfate and evaporated in vacuo to yield an orange solid which on flash column chromatography on silica gel (230-400 mesh) using 5% ethyl acetate in hexane as eluent, gave title compound as a white solid (3.72 g, 73%). XHRMN (300 MHz, CDC13): d 1.78 (dd, J = 10.0, 19.9 Hz, 6H), 1.91 (d, J = 2.4 Hz, 6H), 2.12 (s, 3H), 7.21 (dd, J = 2.3, 8.9 Hz, 2H), 7.43 (dd, J = 8.9, 2.2 Hz, 2H). 3- (4-Adamantan-l-yl-phenyl) -1-O-triisopropylsilyl-but-2 (Z) -en-ol (Compound 38) 3-iodo-0-triisopropylsilyl-but-2 (Z) - en-ol (Compound 36, 1.22 g, 3.44 mmol)) was converted to O-triiso? ropilsilyl-but-2 (Z) -en-ol-3-boronic acid by analogy to the preparation of the boronic acid derivatives described previously, and it was used without any purification. Its proton NMR spectrum revealed that a considerable amount existed (~ 60%) of the rearranged product and that the desired product was formed in a small amount. A solution of a mixture of the crude boronic acid derivative, 4- (1-adamantyl) phenyltrifluoromethanesulfonate (Compound 37, 0.36 g, 1 mmol), lithium chloride (0.29 g, 7 mmol), sodium carbonate (0.42 g, mmol) and tetracis (triphenylphosphine) palladium (0) (0.078 g) in a combination of 2 mL of water, 5 L of methanol and 10 mL of toluene was degassed with argon for 10 minutes and refluxed under argon for 24 hours . The volatile solvents were removed by evaporation in vacuo and the residue was diluted with 20 mL of water and extracted with diethyl ether (2 x 25 mL). The combined organic extracts were dried over sodium sulfate and the solvent was evaporated to give a residual yellow oil in which the flash column chromatography on silica gel (230-400 mesh) using 3% ethyl acetate in hexane as eluent, gave the title compound (0.275 g, 62% yield based on Compound 37) as a yellow oil.

XH-NMR (300 MHz, CDC13): d 1.02-1.13 (m, 21H), 1.75-1.82 (m, 6H), 1.91-1.93 (m, 6H), 2.08 (s, 6H), 4.18 (d, J = 5.5 Hz, 2H), 5.66 (unresolved t, 1H), 7.14 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.2 Hz, 1H). 3- (4-Adamantan-l-yl-phenyl) -but-2 (Z) -en-ol (Compound 39) It was dissolved 3- (4-Adamantan-l-yl-phenyl) -1-0-triisopropylsilyl- but-2 (Z) -en-ol (Compound 38, 0.27 g, 0.62 mmol) in 10 mL of 1: 1 methanol: tetrahydrofuran and treated with 3 mL of IN HCl. After stirring at room temperature for 0.5 hours, the volatile solvents were removed by evaporation in vacuo and the residue was distilled with water (15 mL) and extracted with ethyl ether (2 x 20 mL). The combined organic extracts were dried over anhydrous sodium sulfate and evaporated in vacuo to provide a residual oil. Flash column chromatography on silica gel (230-400 mesh) using 20% ethyl acetate in hexane as the eluent gave the title compound (0.082 g, 49%) as a white off-white solid. XH-NMR (300 MHz, CDC13): d 1.59 (s, 1H), 1.74-1.84 (m, 6H), 1.94 (d, J = 2.8 Hz, 6H), 2.09-2.12 (m, 6H), 4.10 ( d, J = 7.0 Hz, 2H), 5.69 (dt, J = 1.4, 7.0 Hz, lH), 7.14 (dd, J = 8.3, 2.0 Hz, 2H), 7.34 (dd, J = 8.3, 2.0 Hz, 1H ). 3- [4- (I-Adamantan-1-yl-phenyl)] -2, 3-methane-butylalcohol (Compound 40) 3- (4-adamantan-lyl-phenyl) -but-2 (Z) -en -ol (Compound 39, 0.32 g, 1.2 mmol) was converted into the title compound (viscous oil, 0.32 g, 94%), enriched in the 2S, 3S isomer, by analogy with the cyclopropylation reactions described above. XH-NMR (300 MHz, CDC13): d 0.78 (dd, J = 4.8, 8.4 Hz, 1H), 0.89 (t, J = 5.0 Hz, 1H), 1.25-1.38 (m, 1H), 1.40 (s, 3H), 1.72-1.82 (m, 6H), 1.90 (d, J = 2.6 Hz, 6H), 2.09 (s, 3H), 3.17-3.26 (m, 1H), 3.28-3.32 (m, 1H), 7.24 -7.31 (m, 4H).

Ester of (SS) -Camfanate of (2S, 3S) -3- [4- (1-adamantan-1-yl-phenyl)] -2, 3-methane-butylalcohol (Compound 41) 3- [4- ( 1-Adamantan-l-yl-phenyl)] -2, 3-methane-butylalcohol (enriched in the 2S, 3S isomer (Compound 40, 0.32 g, 1.1 mmol) was converted to the title compound with (S) -camphanic chloride , in anhydrous dichloromethane, in the presence of triethylamine by stirring overnight at room temperature under a protective argon stream.The product obtained by evaporation of the solvents and extraction of the residue was recrystallized from hot ethyl acetate 1: 1 hexane (0.35 g). g, 65%).

XH-NMR (300 MHz, CDC13): d 0.87 (dd, J = 5.0, 8.4 Hz, 1H), 0.93-0.99 (m, 1H), 0.95 (s, 3H), 1.04 (s, 3H), 1.12 ( s, 3H), 1.30-1.41 (m, 1) 1.39 (s, 3H), 1.65-1.82 (m, 7H), 1.85-2.10 (m, 2H), 1.89 (d, J = 2.44 Hz, 6H), 2.09 (s, 3H), 2.33-2.42 (m, 1H), 3.77 (dd, J = 7.5, 11.5 Hz, 1H), 3.91 (dd, J = 7.6, 11.5 Hz, 1H), 7.21-7.29 (m, 4H). (2S, 3S) -3- [4- (I-Adamantan-1-yl-phenyl)] -2, 3-methano-butylalcohol (Compound 40) The ester (1S) -Camfanate of (2S, 3S) -3 - [4- (1-adamantan-1-yl-phenyl)] -2, 3-methane-butylalcohol (Compound 41, 0. 35 g, 0.75 mmol) was converted to the optically pure title compound by saponification of the ester with lithium hydroxide in a mixture of methanol and tetrahydrofuran followed by evaporation of the volatile solvents, extraction of the residue with diethyl ether, washing, drying (MgSO4) and the evaporation of the solvents to give the product as a viscous oil (0.2 g, 94%). XH-NMR (300 MHz, CDC13): d 0.78 (dd, J = 4.8, 8.4 Hz, 1H), 0.89 (t, J = 5.0 Hz, 1H), 1.25-1.38 (m, 1H), 1.40 (s, 3H), 1.72-1.82 (m, 6H), 1.90 (d, J = 2.6 Hz, 6H), 2.09 (s, 3H), 3.17-3.26 (m, 1H), 3.28-3.32 (m, 1H), 7.24 -7.31 (m, 4H). (2S, 3S) -3- [4- (I-Adamantan-1-yl-phenyl)] -2,3-methane-l-oxo-butane (Compound 42) The (2S, 3S) -3- [4 - (1-Adamantan-l-yl-phenyl)] -2, 3-methane-butylalcohol (Compound 40, 0.2 g, 0.7 mmol) was converted to the title compound (0.19 g, 97%) by analogy to the reactions of oxidation described above. ^ -RMN (300 MHz, CDC13): d 1.41 (dd, J = 4.8, 7.6 Hz, 1H), 1.46 (s, 3H), 1.68-1.84 (m, 7H), 1.8501.98 (m, 7H), 2.C9 (s, 3H), 7.28 (ABc, J = 12 Hz, 4H), 8.41 (d, J = 7.1 Hz, 1F). Ethyl ester of (6S, 7S) -7- [4- (Admantan-1-yl-f-enyl)] -6,7-methane-3-methyl-octa-2E, 4E-diethyl (Compound 43) Ei (2S, 5S) -3- [4- -Adamantan-1-yl-yl)] -2, 3-methano-1-oxo-butane (Compound 42, 0.19 g, 0.68 mmol) was 0 converted to the compound of the title (0.25 g, 91%) by analogy to the Horner Emmons reactions described above. XH-NMR (300 MHz, CDC13): d 1.16-1.19 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H), 1.42IS, 3H), 1.68-1.84 (, 8H), i. 1 (d, = 2.P Hz, 6H), 1.96 (s, 3H), 2.09 (s, 3H), 4.14 (c, J = 7.1 Hz, 2H), 5.11 (dd, J = 10.0, 15.4 Hz, 1H), 5.62 (s, 1H), 6.17 (d, J = 15.5 Hz, 1H), 7.19 (dd, J = 2.0, 8.4 Hz, 2H), 7.27 (dd, J = 1.9, 8.4 Hz, 2H). Acid (6S, 7S) -7- [4- (Adamantan-1-yl-phenyl)] -6,7-methano-3-methyl-octa-2E, 4E-dienoic (Compound 44) The ethyl ester of (6S, 7S) -7- [4- (Adamantan-1-yl-phenyl)] -6,7-methane-3-methyl-octa-2E, 4E-dienoic acid (Compound 43, 0.18 g , 0.44 mmol) was converted to the title compound by saponification as described above (0.038 g, 22% after recrystallization of hot isopropanol isopropanol: hexane 1: 7). XH-NMR (300 MHz, CDC13): d 1.20 (d, J = 7.0 Hz, 2H), 1.44 (s, 3H), 1.68-1.84 (m, 8H), 1.91 (d, J = 2.48 Hz, 6H) , 1.97 (s, 3H), 2.10 (s, 3H), 5.23 (dd, J = 10.1, 15.5 Hz, 1H), 5.64 (s, 1H), 6.44 (d, J = 15.6 Hz, 1H), 7.19 ( dd, J = 2.0, 8.4 Hz, 2H), 7.29 (dd, J = 2.0, 8.4 Hz, 2H). It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates.

? «« MÍßgk

Claims (27)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A compound of Formula 1, Formula 2 or Formula 3 Formula 1 Formula 2 Formula 3 characterized in that X is O, S, or (CR? Rx) n where n is 0, 1 or 2; Y is a bivalent radical having the Formula 4 or Formula 5 where o is a number of 1 to 4 Formula 4 Formula 5 or Y is a bivalent aryl or a 5- or 6-membered heteroaryl radical having from 1 to 3 selected heteroatoms of N, S and 0, the aryl or heteroaryl groups are unsubstituted, or substituted with 1 to 3 C? _6 alkyl or with 1 to 3 C? -6 fluoroalkyl groups; with the proviso that when the compound is in accordance with Formula 2, then Y is not a ring of 5 or 6 members; Xi is 0, S or NH; Ri is independently H, lower alkyl of 1 to 6 carbons, or lower fluoroalkyl of 1 to 6 carbons; R2 is independently H, lower alkyl of 1 to 6 carbons, ORi, 1-adamantyl or lower fluoroalkyl of 1 to 6 carbons, or the two R2 groups together represent an oxo group (= 0); with the proviso that when the compound is in accordance with Formula 2, then at least one of the substituents R 2 is a branched chain alkyl or an adamantyl; R3 is hydrogen, lower alkyl of 1 to 6 carbons, ORi, lower alkyl substituted with fluorine of 1 to 6 carbons or halogen, N02, NH2, NHCOalkyl of (C? -C6), or NHCOalkenyl of (C? -C6); A is COOH or a pharmaceutically acceptable salt thereof, COORg, CONR9R10, -CH2OH, CH2ORn, CH2OCORn, CHO, CH (OR12) 2, CH (OR? 30), -COR7, CR7 (OR? 2) 2, CR7 (OR130), or Si (C? -6 alkyl) 3, where R7 is an alkyl, cycloalkyl or alkenyl group containing from 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl) alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 10 carbons, or phenyl, hydroxyphenyl or lower alkylphenyl, Rn is lower alkyl, phenyl or lower alkylphenyl, Ri2 is lower alkyl, and R13 is a divalent alkyl radical of 2-5 carbons, and R? 4 is alkyl of 1 to 10 carbons , alkyl substituted with fluorine of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, aryl or carbocyclic selected from the group consisting of phenyl, C?-C? alkylphenyl, naphthyl, C--Cio alqu alkylnaphthyl, C fen-Cio fen phenyl-alkyl, C--C na na naphthyl-C,-Cio alquilo alkyl, C al-C al-alkenylphenyl Cio having 1 to 3 double bonds, C1-C10 alkynylphenyl having from 1 to 3 triple bonds, phenyl-alkenyl of C? -C? 0 having from 1 to 3 double bonds, phenyl-alkynyl Ci-Cio having has from 1 to 3 triple bonds, hydroxyalkyl of 1 to 10 carbons, hydroxyalkenyl having 2 to 10 carbons and 1 to 3 double bonds, hydroxyalkynyl having 2 to 10 carbons and 1 to 3 triple bonds, acyloxyalkyl of 1 to 10 carbons , acyloxyalkenyl having 2 to 10 carbons and 1 to 3 double bonds, or acyloxyalkynyl of 2 to 10 carbons and of 1 to 3 triple bonds wherein the acyl group is represented by COR8, or Ri4 is a heteroaryl group of 5 or 6 members having 1 to 3 heteroatoms, the heteroatoms being selected from a group consisting of O, S, and N, the heteroaryl group being unsubstituted or substituted by a C 1 to C 1 0 alkyl group, with a Ci to C 1 fluoroalkyl group, or with halogen, and with the dashed line in Formula 4 represents a bond or the absence of a bond.

2. The compound according to claim 1, characterized in that it is in accordance with Formula 1.

3. The compound according to claim 1, characterized in that it is in accordance with Formula 2. .

The compound according to claim 1, characterized in that it is according to Formula 3.

5. The compound according to claim 1, characterized in that the group Y is in accordance with Formula 4.

6. The compound in accordance with claim 1, characterized in that the group Y is in accordance with Formula 5.

7. The compound according to claim 5, characterized in that 0 is 1.

The compound according to claim 7, characterized in that it is in agreement with the Formula 1.

The compound according to claim 7, characterized in that it is in accordance with the Formula 2.

The compound according to claim 7, characterized in that it is according to Formula 3.

11. The compound according to claim 2, characterized in that Ri4 is lower alkyl.

12. The compound according to claim 2, characterized in that Ri 4 is carbocyclic aryl, or heteroaryl.

13. A mule character or because R is a monovalent radical of formula (i), (ii) or (iii) (0 (H) ("0 where * shows the aromatic carbon covalently bound to the cyclopropyl ring; X is O, S, or CRiRi, - Ri R2 R3 and Ri4 are independently H, lower alkyl of 1 to 6 carbons or adamantyl, with the proviso that when R is in accordance with formula (ii) at least one of the substituents R2 is branched chain alkyl or adamantyl, and A is COOH, a pharmaceutically acceptable salt thereof, COOR8 or CONR9R10 where R8 is lower alkyl of 1 to 6 carbons.

14. The compound according to claim 13, characterized in that it is in accordance with formula (i).

15. The compound according to claim 14, characterized in that it is 0 or S.

16. The compound according to claim 14, characterized in that X is C (CH3) 2.

17. The compound according to claim 13, characterized in that it is in accordance with formula (ii).

18. The compound according to claim 17, characterized in that the R2 groups are branched chain alkyl.

19. The compound according to claim 13, characterized in that it is in accordance with formula (iii).

20. A compound of formula where R * is H or CH3; R *? is methyl, ethyl or n-propyl, and R * 8 is H. Lower alkyl of 1 to 6 carbons, a pharmaceutically acceptable salt of the compound.

21. The compound according to claim 20, characterized in that R * 8 is H or ethyl or a pharmaceutically acceptable salt of such compound.

22. The compound of formula where R * is H or CH3; R *? is methyl, ethyl or n-propyl, and R * 8 is H, or lower alkyl of 1 to 6 carbons, or a pharmaceutically acceptable salt of the compound.

23. The compound according to claim 22, characterized in that R * 8 is H or ethyl or a pharmaceutically acceptable salt of such compound. n:

24. A compound of formula where R * is H or CH3; R *? is methyl, ethyl or n-propyl, and R * 8 is H, or lower alkyl of 1 to 6 carbons, or a pharmaceutically acceptable salt of the compound.

25. The compound according to claim 24, characterized in that R * 8 is H or ethyl or a pharmaceutically acceptable salt of such compound.

26. A compound of formula R *? is methyl, ethyl or n-propyl, and R * 8 is H, lower alkyl of 1 to 6 carbons, or a pharmaceutically acceptable salt of the compound.

27. The compound according to claim 25, characterized in that R * 8 is H or ethyl or a pharmaceutically acceptable salt of such compound.