Title of Invention	NEW RETINOIDS OF FORMULA I
Abstract	The present invention relates to a novel retinoid compounds and method for their synthesis,the use of such compounds for the preparation of medicaments for treting or preventing emphysema, cancer anddermatological disorder, methods for such deseaes and pharmaceutical compositions suitable for the treatment or prevention of emphysema,cancer and dermatological disorders.

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NEW RETINOIDS FOR THE TREATMENT OF EMPHYSEMA The invention relates to novel retinoid compounds and methods of synthesis thereof. The invention also relates to the use of such compounds for the preparation of medicaments for treating or preventing different diseases, methods of using these novel retinoid compounds, and pharmaceutical compositions thereof. The retinoids are structural analogues of vitamin A and include both natural and synthetic compounds. Retinoid compounds such as all trans retinoic acid ("ATRA"), 9~cis-retinoic acid, trans 3-4 didehydroretinoic acid, 4-oxo retinoic acid, 13-cw-retinoic acid and retinol are pleiotrophic regulatory compounds that influence a large number of inflammatory, immune and structural cells. For example, retinoids modulate epithelial cell proliferation, morphogenesis in lung and differentiation through a series of hormone nuclear receptors that belong to the steroid/thyroid receptor superfamily. The retinoid receptors are classified into the retinoic acid receptors (RAR) and the retinoid X receptors (RXR) each of which consists of three distinct subtypes (a, p and y). ATRA is the natural ligand for the retinoic acid receptors and binds with similar affinity to the a, p and y subtypes. A quantitative structure-activity relationship has been established for a number of synthetic RAR cc, p and y retinoid agonists, which has elucidated the principal electronic and structural characteristics that provide selective affinity for each RAR subtype (Douget et aL9 Quant. Struct Act. Relat, 18,107,1999). ATRA does not bind to RXR, for which 9-cis-retinoic acid is the natural ligand. A number of synthetic RXR a, p and y retinoid agonists have also been described in the art (See, e.g., Billoni et aL, U.S. Patent No. 5,962,508; Klaus et al, U.S. Patent No. 5,986,131. In tissues other than pulmonary tissues, retinoids typically have anti-inflammatory effects, can alter the progression of epithelial cell differentiation and may inhibit stromal cell matrix production. These biological effects of retinoids have led to the development of many topical agents for dermatological disorders such as psoriasis, acne, and hypertrophic cutaneous scars. Retinoids have also been used in the treatment of light and age damaged skin, the healing of wounds caused, for example, by surgery and burns (Mustoe etaL, Science 237,1333 1987; Sprugel et al., J. Pathol, 129,601,1987; Boyd, Am. J. Med., 86,568,1989) and as antiinflammatory agents for treatment of arthritis. Other medicinal applications of retinoids include the control of acute promyelocyte leukemia, adeno and squamous cell carcinoma and hepatic fibrosis. Retinoids have also been used extensively in treatment of premalignant epithelial lesions and malignant tumors (carcinomas) of epithelial origin (Bollag etaL, United States PatentNo. 5,248,071; Sporn et al, Fed. Proc. 1976,1332; Hong etal., "Retinoids and Human Cancer" in The Retinoids: Biology, Chemistry and Medicine, M. B. Sporn, A. B. Roberts and D.S. Goodman (eds.) Raven Press, New York, 1994,597-630). However, many retinoids previously studied often lack selectivity and consequently exert harmful pleiotrophic effects and may cause patient death when used in therapeutically effective amounts. Thus, the therapeutic use of retinoids in diseases other then cancer has been limited by toxic side effects. A general review of retinoids can be found in Goodman & Gilman's *The Pharmacological Basis of Therapeutics", 9th edition (1996, McGraw-Hill) Chapters 63-64. Chronic Obstructive Pulmonary Disease ("COPD") refers to a large group of lung diseases which prevent normal respiration. Approximately 11 % of the population of the United States has COPD and available data suggests that the incidence of COPD is increasing. Currently, COPD is the fourth leading cause of mortality in the United States. COPD is a disease in which the lungs are obstructed due to the presence of at least one disease selected from asthma, emphysema and chronic bronchitis. The term COPD was introduced because these conditions often co-exist and in individual cases it may be difficult to ascertain which disease is responsible for causing the lung obstruction (1987 Merck Manual). Clinically, COPD is diagnosed by reduced expiratory flow from the lungs that is constant over several months and in the case of chronic bronchitis persists for two or more consecutive years. The most severe manifestations of COPD typically include symptoms characteristic of emphysema. Emphysema is a disease where the gas-exchange structures (e.g., alveoli) of the lung are destroyed, which causes inadequate oxygenation that may lead to disability and death. Anatomically, emphysema is defined by permanent airspace enlargement distal to terminal bronchioles (e.g., breathing tubes) which is characterized by reduced lung elasticity, decreased alveolar surface area and gas exchange and alveolar destruction that results in decreased respiration. Thus, the characteristic physiological abnormalities of emphysema are reduced gas exchange and expiratory gas flow-Cigarette smoking is the most common cause of emphysema although other environmental toxins may also contribute to alveoli destruction. The injurious compounds present in these harmfril agents can activate destructive processes that include, for example, the release of excessive amounts of proteases that overwhelm normal protective mechanisms, such as protease inhibitors present in the lung. The imbalance between proteases and protease inhibitors present in the lung may lead to elastin matrix destruction, elastic recoil loss, tissue damage, and continuous lung function decline. The rate of lung damage may be decreased by reducing the amounts of toxins in the lung (Le.9 by quitting smoking). However, the damaged alveolar structures are not repaired and lung function is not regained At least four different types of emphysema have been described according to their locations in the secondary lobule; panlobar emphysema, centrilobular emphysema, distal lobular emphysema and paracicatrical emphysema. The major symptom of emphysema is chronic shortness of breath. Other important symptoms of emphysema include but are not limited to chronic cough, coloration of the skin caused by lack of oxygen, shortness of breath with minimal physical activity and wheezing. Additional symptoms that may be associated with emphysema include but are not limited to vision abnormalities, dizziness, temporary cessation of respiration, anxiety, swelling, fatigue, insomnia and memory loss. Emphysema is typically diagnosed by a physical examination that shows decreased and abnormal breathing sounds, wheezing and prolonged exhalation. Pulmonary function tests, reduced oxygen levels in the blood and a chest X-ray may be used to confirm a diagnosis of emphysema. No effective methods for reversing the clinical indications of emphysema currently exist in the act In some instances, medications such as bronchodilators, p-agonists, theophylline, anticholinergics, diuretics and corticosteroids delivered to the lung by an inhaler or nebulizer may improve respiration impaired by emphysema. Oxygen treatment is frequently used in situations where lung function has been so severely impaired that sufficient oxygen cannot be absorbed from the air. Lung reduction surgery may be used to treat patients with severe emphysema. Here, damaged portions of the lung are removed, which allows the normal portions of the lung to expand more fully and benefit from increased aeration. Finally, lung transplantation is another surgical alternative available to individuals with emphysema, which may increase quality of life but does not significantly improve life expectancy. Alveoli are formed during development by division of sacchules that constitute the gas-exchange elements of the immature lung. The precise mechanisms governing formation of septa and their spacing remain currently unknown in primates. Retinoids such as ATRA, which is a multifunctional modulator of cellular behavior that may alter both extracellular matrix metabolism and normal epithelial differentiation, have a critical regulatory role in mammals such as the rat For example, ATRA modulates critical aspects of lung differentiation through binding to specific retinoic acid receptors that are selectively temporally and spatially expressed. Coordinated activation of different retinoic acid receptors subtypes has been associated with lung branching, alveoli2ation/septation and gene activation of tropoelastin in neonatal rats. During alveolar septation, retinoic acid storage granules increase in the fibroblastic mesenchyme surrounding alveolar walls (Liu et al, Am. J. Physiol 1993,265, L430; McGowan et aL9 Am. J. Physiol, 1995,269, L463) and retinoic acid receptor expression in the lung peaks (Ong et al, Proc. Natl Acad. ofScl, 1976,73,3976; Grummer et al.9 Pediatr. Pulm. 1994,17,234). The deposition of new elastin matrix and septation parallels depletion of these retinoic acid storage granules. Postnatal administration of retinoic acid has been shown to increase the number of alveoli in rats, which supports the concept that ATRA and other retinoids may induces alveoli formation (Massaro et ai, Anu J. Physiol, 270, L305,1996). Treatment of newborn rat pups with dexamethasone, a glucocorticosteroid, prevents septation and decreases expression of some sub-types of retinoic acid receptor. Supplemental amounts of ATRA have been shown to prevent dexamethasone inhibition of alveoli formation. Further, ATRA prevents dexamethasone from diminishing retinoic acid receptor expression and subsequent alveolar septation in developing rat lung. ATRA has been reported to induce formation of new alveoli and returns elastic recoil in the lung to approximately normal values in animal models of emphysema (Massaro et aL9 Nature Med., 1997,3,675; "Strategies to Augment Alveolization," National Heart, Lung, and Blood Institute, RFA: HL-98-011,1998; Massaro et al9 United States PatentNo. 5,998,486). However, the mechanism of action of ATRA in these studies remains undefined, although Massaro reports that ATRA generates new alveoli. More importantly, the use of ATRA presents several toxicity or adverse effects concerns. Thus, novel retinoid agonists useful for treating dermatological disorders, emphysema and cancer without the toxicity problems of ATRA or other retinoids are highly desirable. The current invention provides novel retinoid agonists, a method for the synthesis, the use of such compounds for the preparation of medicaments for treating or preventing emphysema, cancer and dermatological disorders, methods of treating or preventing such diseases, pharmaceutical compositions suitable for the treatment or prevention of such diseases, and methods for delivering formulations of novel retinoids into the lung of a mammal suffering from emphysema, cancer and dermatological disorders. In one embodiment, the invention provides compounds having the structural formula or a pharmaceutical^ acceptable salt, solvate or hydrate thereof wherein: n is an integer from 0 to 2; cisOorl; disOorl; A is -C(=0>, -C(=CH2H »C(=NR4)- or -CR^6-; R4 is hydrogen, alkyl, hydroxy, aBcoxy or amino; and R5 and R6 are independently hydrogen, alkyl or together, along with the carbon to which they are both attached, are cycloalkyl; with the proviso that when Ac-Bd is -C(=0)-CR7=CR8-, then L is not heteroalkyl; or (d) -CRI4=CR15-L1 where Li is S(0)2R17 or S02NR18R19 where R17 is alkyl and R18 and R19 are independently hydrogen or alkyl; each R3 is independently hydrogen, alkyl, hydroxy or oxo; and t is 1 or 2 for n = 1 or 2, and tis 1 forn = 0. "Acyl" means a radical -C(0)R, where R is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl or arylalkyl wherein alkyl, cycloalkyl, cycloalkyl-alkyl, aryl and arylalkyl are as defined herein. Representative examples include, but are not limited to fonnyl, acetyl, cylcohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, and the like. "Acylamino" means a radical -NR'C(0)R, where R' is hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl or arylalkyl wherein alkyl, cycloalkyl, cycloalkyl-alkyl, aryl and arylalkyl are as defined herein. Representative examples include, but are not limited to formylamino, acetylamino, cylcohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino, benzylcarbonylamino, and the like. "Alkoxy" means a radical -OR where R is an alkyl group as defined herein e.g., methoxy, ethoxy, propoxy, butoxy, and the like. "Alkoxycarbonyl" means a radical -C(0)-R where R is aflcoxy is as defined herein. "Alkyl" means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, n-butyl, fro-butyl, tert-butyl, pentyl, and the like. "Alkylamino" means a radical -NHR where R represents an alkyl, cycloalkyl or cycloalkyl-alkyl group as defined herein. Representative examples include, but are not limited to methylamino, ethylamino, 1-methylethylamino, cyclohexylamino, and the like. "Alkylene" means a linear saturated divalent hydrocarbon radical of one to ten carbon atoms or a branched saturated divalent hydrocarbon radical of three to ten carbon atoms, e.g., methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene, and the like. "ABeylsulfonyl" means a radical -SCQhR where R is an alkyl, cycloalkyl or cycloalkyl-alkyl group as defined herein, e.g., methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, cyclohexylsulfonyl and the like. "ADcylsulfinyl" means a radical -S(0)R where R is an alkyl, cycloalkyl or cycloalkyl-alkyl group as defined herein e.g., methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, cyclohexylsulfinyl and the like. "Alkylthio" means a radical -SR where R is an alkyl, cycloalkyl or cycloalkyl-alkyl group as defined herein e.g., methylthio, ethylthio, propylthio, butylthio, cyclohexylthio and the like. "Aryl" means a monocyclic or bicyclic aromatic hydrocarbon radical which is optionally substituted with one or more substitnents, preferably one, two or three, substituents preferably selected from the group consisting of alkyl, acyl, acylamino, aflcoxycarbonyl, alkylamino, alkylsulfinyl, alkylsulfonyl, -SC^NR'R" (where R' and R" are independently hydrogen or alkyl), alkylthio, aBcoxy, amino, aryloxy, carbamoyl, cyano, dialkylamino, halo, haloalkyl, heteroalkyl, heterocyclyl, hydroxy, hydroxyaBcyl, methylenedioxy, ethylenedioxy, nitro and thio. More specifically the term aryl includes, but is not limited to, phenyl, chlorophenyl, fluorophenyl, methoxyphenyl, 1-naphthyl, 2-naphthyl,and the derivatives thereof. "Arylalkyl" refers to an alkyl radical as defined herein in which one of the hydrogen atoms of the alkyl group is replaced with an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenyIethan-l-yl, naphthylmethyl, 2-naphthylethan-l-yl, naphthobenzyl, 2-naphthophenylethan-l-yl and the like. "Aryloxy5* means a radical -OR where R is an aryl group as defined herein. "Arylalkyloxy" means a radical -O-R where R is arylalkyl as defined herein. "Carbamoyl" means the radical -C(0)N(R)2 where each R group is independently hydrogen, alkyl or aryl as defined herein. "Carboxy" means the radical -C(0)OH. "Cyano" means the radical -CN. "Cycloalkyl" refers to a saturated monovalent cyclic hydrocarbon radical of three to seven ring carbons e.g., cyclopropyl, cyclobutyl, cyclohexyl, 4-methylcyclohexyl and the like. "Cycloalkyl-alkyr means a radical -RaRb where Ra is an alkylene group and Rb is a cycloalkyl group as defined herein, e.g.9 cyclohexylmethyl and the like. "Substituted cycloaBcyl" means a cycloalkyl radical as defined herein with one, two or three (preferably one) hydrogen atoms replaced by -Y-C(0)R (where, Y is absent or an alkylene group and R is hydrogen, acyl, acylamino, alkyl, alkoxycarbonyl, alkyamino, alkylsulfinyl, alkylsulfonyl, alkylthio, aBcoxy, amino, aryloxy, arylaBcyloxy, carbamoyl, cyano, diaflcylamino, halo, haloalkyl, heteroalkyl, hydroxy, hydroxyalkyl, nitro or thio) 'TtiaBcylamino" means a radical -NRR1 where R and R1 independently represent an alkyl, cycloalkyl or cycloalkyl-alkyl group as defined herein. Representative examples include, but are not limited to dimethylamino, methylethylamino, di-(l-methylethyl)amino, (cyclohexyl)(methyl)amino, (cyclohexyl)(ethyl)amino, (cyclohexyl)(propyl)amino, (cyclohexylmethyl)(methyl)amino, (cyclohexyImethyl)(ethyl)amino and the like. "Halo" means fluoro, chloro, bromo, or iodo, preferably fluoro and chloro. "Haloalkyr means an alkyl group substituted with one or more same or different halo atoms, e.g., -CH2C1, «CF3, -CH2CF3, -CH2CC13 and the like. "Heteroaryl" means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring. The heteroaryl ring is optionally substituted independently with one or more substituents, preferably one or two substituents, selected from acyl, acylamino, alkyl, alkoxycarbonyl, alkyamino, alkylsulfinyl, alkylsulfonyl, -SChNR'R" (where R' and R" are independently hydrogen or alkyl), alkylthio, alkoxy, amino, aryloxy, carbamoyl, cyano, dialkylamino, ethylenedioxy, halo, haloalkyl, heteroalkyl, heterocyclyl, hydroxy, hydroxyalkyl, methylenedioxy, nitro and thio. More specifically the term heteroaryl includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyirolyl, pyrazolyl, pyrimidinyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolyl, tetrahydroquinolinyl, isoquinolyl, benzimidazolyl, benzisoxazolyl or benzothienyl and derivatives thereof. fiCHeteroarylalkyl means an alkyl radical as defined herein in which one of the hydrogen atoms of the alkyl group is replaced with a heteroaryl group. "Heteroalkyl" means an alkyl radical as defined herein wherein one or more hydrogen atoms have been replaced with a substituent independently selected from the group consisting of -ORa, -NR^0, and -S(0)nRd (where n is an integer from 0 to 2), with the understanding that the point of attachment of the heteroalkyl radical is through a carbon atom, wherein Ra is hydrogen, acyl, alkyl, cycloalkyl, or cycloalkyl-alkyl; Rb and Rc are independently of each other hydrogen, acyl, alkyl, cycloalkyl, or cycloalkyl-alkyl; and when n is 0, Rd is hydrogen, alkyl, cycloalkyl, or cycloalkyl-alkyl, and when n is 1 or 2, Rd is alkyl, cycloalkyl, cycloalkyl-alkyl, amino, acylamino, monoalkylamino, or dialkylamino. Representative examples include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-l-hydroxymetliylethyl, 2,3-dihydroxypropyl, 1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl, 2-hydroxy-l-methylpropyl, 2-aminoethyl, 3-aminopropyl, 2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl, aminosulfonylpropyl, methylaminosulfonylmethyl, methylaminosulfonylefcyl, methylaminosulfonylpropyl, and the like. "HeteroaBcylamino" means a radical -NHR where R is a heteroalkyl group as defined herein. "Heteroalkyloxy" means a radical -O-R where R is a heteroalkyl group as defined herein. 4CHeteroalkylsubsituted cycloalkyr means a cycloalkyl radical as defined herein wherein one, two or three hydrogen atoms in the cycloalkyl radical have been independently replaced with a heteroalkyl group with the understanding that the heteroalkyl radical is attached to the cycloalkyl radical via a carbon-carbon bond.. Representative examples include, but are not limited to, 1-hydroxymethylcyclopentyl, 2-hydroxymethylcyclohexyl, and the like. 'THeterosubstituted cycloalkyl" means a cycloalkyl radical as defined herein wherein one, two or three hydrogen atoms in the cycloalkyl radical have been replaced with a substituent independently selected from the group consisting of hydroxy, alkoxy, amino, acylamino, monoalkylamino, dialkylamino, oxo (C=0), imino, hydroximino (=NOH), NR'SO2Rd (where R' is hydrogen or alkyl and Rd is alkyl, cycloalkyl, amino, monoalkylamino or dialkylamino), -X-C(0)R (where X is O or NR\ R is hydrogen, alkyl, haloaBcyl, hydroxy, alkoxy, amino, monoalkylamino, dialkylamino,, or optionally substituted phenyl, and R' is H or alkyl) or -S(0)nR (where n is an integer from 0 to 2) such that when n is 0, R is hydrogen, alkyl, cycloalkyl, or cycloalkyl-alkyl, and when n is 1 or 2, R is alkyl, cycloalkyl, cycloalkyl- alkyl, amino, acylamino, monoalkylamino or dialkylamino. Representative examples include, but are not limited to, 2-, 3- or 4-hydroxycyclohexyl, 2-, 3- or 4-aminocyclohexyl, 2-, 3- or 4-sulfonamidocyclohexyl, and the like, preferably 4-hydroxycyclohexyl, 2-aminocyclohexyl, 4-sulfonamidocyclohexyl. "Heterosubstituted cycloalkyl-alkyl" means a radical RaRb- where Ra is a heterosubstituted cycloalkyl radical and Rb is an alkylene radical. tcHeterocyclyl" means a saturated or unsaturated non-aromatic cyclic radical of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S(0)n (where n is an integer from 0 to 2), the remaining ring atoms being C, where one or two C atoms may optionally be replaced by a carbonyl group. The heterocyclyl ring may be optionally substituted independently with one, two, or three substituents selected from alkyl, haloalkyl, heteroalkyl, halo, nitro, cyanoalkyl, hydroxy, alkoxy, amino, monoalkylamino, dialkylamino, arylalkyl, -(X)n-C(0)R (where, X is O or NR\ n is 0 or 1, R is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, amino, monoalkylamino, dialkylamino, or optionally substituted phenyl and R' is H or alkyl), -alkylene-C(0)R (where, R is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, amino, monoalkylamino, dialkylamino, or optionally substituted phenyl) or -S(0)nRd (where n is an integer from 0 to 2, and Rd is hydrogen (provided that n is 0), alkyl, haloalkyl, cycloalkyl, cycloalkyl-alkyl, amino, monoalkylamino, dialkylamino, or hydroxyalkyl). More specifically the term heterocyclyl includes, but is not limited to, tetrahydropyranyl, piperidino, N-methylpiperidin-3-yl, piperazino, N-methylpyrrolidin-3-yl, 3-pyrrolidino, morpholino, thiomorpholino, thiomorpholino-1-oxide, thiomorpholino-l,l-dioxide, pyrrolinyl, imidazolinyl, and the derivatives thereof. "Heterocyclylalkyl" means a radical -RaR^ where Ra is an alkylene group and R^ is a heterocyclyl group as defined above, e.g., tetrahydropyran-2-ylmethyl, 1,2-, or 3-piperidinylmethyl, 1-piperazinylmethyl, 4-methyl-piperazin-l-ylmethyl, and the like. ceHydroxyalkyl" means an alkyl radical as defined herein, substituted with one or more hydroxy groups, provided that the same carbon atom does not carry more than one hydroxy group. Representative examples include, but are not limited to, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, l-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-l-hydroxymethylethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl and l-(hydroxymethyl)-2-hydroxyethyL Accordingly, as used herein, fee term "hydroxyalkyl" is used to define a subset of heteroalkyl groups. "Leaving group" has the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or a group capable of being displaced by a nucleophile and includes halo (such as chloro, bromo, and iodo), alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (e.g., acetoxy), arylcarbonyloxy, mesyloxy, tosyloxy, trifluoromethanesulfonyloxy, aryloxy (e.g., 2,4-dinitrophenoxy), methoxy, N,0-dimethylhydroxylamino, and the like. "Oxo" means divalent radical (C=0). "Pharmaceutical^ acceptable excipient" means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A "pharmaceutical^ acceptable excipient" as used in the specification and claims includes both one and more than one such excipient "Phaimaceutically acceptable salt9' of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2^^]-oct-2-ene-l-carboxyhc acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. The terms "pro-drug" and "prodrug" are used interchangeably herein and refer to any compound which releases an active parent drug according to structural formula (I-VII) in vivo when such prodrug is administered to a mammalian subject Prodrugs of a compound of structural formula (I-VH) are prepared by modifying one or more functional group(s) present in the compound of structural formula (I-VII) in such a way that the modifications) may be cleaved in vivo to release the parent compound. Prodrugs include compounds of structural formula (I-VII) wherein a hydroxy, amino, or sulfhydryl group in a compound of structural formula (I-VH) is bonded to any group that may be cleaved in vivo to regenerate the free hydroxy!, amino, or sulfhydryl group, respectively* Examples of prodrugs include, but are not limited to, esters(e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds of structural formula (I-VHT), N-acyl derivatives (e.g. N-acetyl) N-Mannich bases, Schiff bases and enaminones of amino functional groups, oximes, acetals, ketals and enol esters of ketone and aldehyde functional groups in compounds of Formula I-VII, and the like, see Bundegaard, H. "Design of Prodrugs" pl-92, Elesevier, New York-Oxford (1985). and the like. "Protecting group" refers to a grouping of atoms that when attached to a reactive group in a molecule masks, reduces or prevents that reactivity. Examples of protecting groups can be found in T.W. Green and P.G. Futs, "Protective Groups in Organic Chemistry", (Wiley, 2nd ed. 1991) and Harrison et aU "Compendium of Synthetic Organic Methods", Vols. 1-8 (John Wiley and Sons, 1971-1996). Representative amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trimethylsilyl (TMS), 2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), nitro-veratryloxycarbonyl (NVOC and the like. Representative hydroxy protecting groups include but are not limited to, those where the hydroxy group is either acylated or alkylated such as benzyl, and trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers. As used herein, the term "mammal" includes human. The terms "human" and "patient" are used interchangeably herein. "Treating" or "treatment" of emphysema, cancer or a dermatological disorder includes preventing the disease, (i.e., causing at least one of the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease) inhibiting the disease (Le., arresting or reducing the development of the disease or at least one of the clinical symptoms) or relieving the disease, (ie.9 causing regression of the disease or at least one of the clinical symptoms). Preventing or prevention encompasses administration administration prior to manifestation of the disease or disorder. "A therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount9, will vary depending on the compound, the disease and its severity and the age, weight, etc.,of the mammal to be treated. As used herein the term "compounds of fee invention" means the compounds of generic formula (I-VH) including but not limited to specific compounds within those formulas disclosed herein. The compounds of the invention are identified herein by their chemical structure and/or chemical name. Where a compound is referred to by both a chemical structure and a chemical name and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity. The compounds of the invention may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (Le., geometric isomers), enantiomers, or diastereomers. According to the invention, the chemical structures depicted herein, and therefore the compounds of the invention, encompass all of the corresponding compound's enantiomers and stereoisomers, that is, the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers using either separation techniques or chiral synthesis techniques known in the art. Preferred compounds of the invention are RAR agonists, particularly RAR-gamma selective agonists and bind to the RAR-gamma receptor at least five fold better than they bind to the RAR-alpha receptor. Binding affinities for RAR agonists are typically less than 10 micromolar, preferably less than 1 micromolar. In one embodiment, n is 1. In another embodiment, A is -C(=0)-. In yet another embodiment, c is 0. Preferably, B is -NHC(0)NH-, -CR7=CR8-, -R7C=CR8-C(OH -GC-, -CsC-C(O)- or -CH2O-, most preferably -CR7=CR8-, and particularly R7 and R8 are hydrogen where B is trans -CH=CH-, i.e., the alkene moiety has the E-stereochemistry. In one embodiment, X is phenyl In another embodiment, X is thienyl. In one embodiment, R3 is hydrogen. In another embodiment, R3 is hydroxy or oxo. In one embodiment, R9 is alkoxy, aryloxy or arylalkyloxy. In another embodiment, R9 is hydroxy. In one preferred embodiment, the invention provides compounds having structural formula (II): or a pharmaceuticallyacceptable salt, solvate or hydrate thereof, wherein A, B, c, d, X, R1, R3, n, R10, R11, m, Y, p and R12 are as previously defined. Preferably, m is 1 to 4. In one embodiment, p is 0. In another embodiment, p is 1. In a preferred embodiment of compounds having structural formula (II), m is 1, p is 1 and Y is -O-. Preferably, R12 is hydrogen, acyl, alkyl carbamoyl, cycloalkyl, aryl, heteroaryl, or heteroalkyL Compounds 1,5 and 15 in Table 10 exemplify this embodiment In another preferred embodiment of compounds having structural formula (II), m is 1, p is 1 and Y is -S(0)q-. In one embodiment, R12 is alkyl, cycloalkyl or heteroalkyl. Compounds 2,3,4,9,17 and 18 in Table 1 exemplify this embodiment In another embodiment, R12 is heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl. Compounds 8,19,22,23,25,32, 34 and 35 in Table 1 exemplify this embodiment In still another preferred embodiment of compounds having structural formula (ID, m is 3, p is 1 and Y is -0-. Preferably, R12 is hydrogen, acyl, alkyl, carbamoyl, cycloalkyl, aryl, heteroaryl, or heteroalkyL Compounds 10,11 and 12 in Table 1 exemplify this embodiment 1 In still another preferred embodiment of compounds having structural formula (II), m is 3, p is 1 and Y is -NR13-. Preferably, R12 is acyl, alky!, cycloalkyl, aryl, heteroaryl, or heterocyclyl. Compound 33 in Table 1 exemplifies this embodiment In still another preferred embodiment of compounds having structural formula (II), m is 3, p is 1 and Y is -S(0)q-. Preferably, R12 is aryl, arylalkyl, heteroaryl, heteroaDcyl, heterocyclyl or heterocyclylalkyl. Compounds 24 and 28 in Table 1 exemplify this embodiment In still another preferred embodiment of compounds having structural formula (IT), m is 2, p is 1 and Y is -0-. Preferably, R12 is hydrogen, acyl, alkyl, carbamoyl, cycloalkyl, aryl, heteroaryl, or heteroalkyL Compound 31 in Table 1 exemplifies this embodiment In still another preferred embodiment of compounds having structural formula (IT), m is 2, p is 1 and Y is -S(0)q-. Preferably, R12 is aryl, arylalkyl, heteroaryl, heteroalkyl, heterocyclyl or heterocyclylalkyL Compounds 26 and 27 in Table 1 exemplify this embodiment In still another preferred embodiment of compounds having structural formula (II), m is 4, p is 1 and Y is -(O) -. Preferably, R12 is hydrogen, acyl, alkyl, carbamoyl, cycloalkyl, aryl, heteroaryl, or heteroalkyL Compound 51 in Table 1 exemplifies this embodiment In still another preferred embodiment of compounds having structural formula (II), m is 1 and p is 0. In one embodiment R12 is heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyL Compounds 6,7,44,45,47,50,53,54,55,138,139,143,146,149 and 150 in Table 1 exemplify this embodiment Compound 6 is a particularly preferred member of the above group of compounds. In another embodiment, R12 is aryl, arylalkyl, cycloalkyl or substituted cycloalkyl. Compounds 42 and 54 in Table 1 exemplify this embodiment In still another preferred embodiment of compounds having structural formula (IT), m is 2 and p is 0. Preferably, R12 is aryl, arylalkyl, heteroaryl, heteroarylalkyl, heteroalkyl, heterocyclyl or heterocyclylalkyL Compounds 29,37,38,40,41,132,134,140,147 and 152 in Table 1 exemplify this embodiment In still another preferred embodiment of compounds having structural formula (II), m is 3 and p is 0. Preferably, R12 is aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyL Compounds 30,36,46,52,130,131,135,141 and 142 in Table 1 exemplify this embodiment hypervitaminosis A, such as headache, fever, skin and membrane dryness, bone pain, nausea and vomiting, psychiatric disorders and gastrointestinal disorders. The present invention also encompasses the use of the compounds of the invention to treat or prevent certain chronic obstructive airway disorders, particularly chronic obstructive pulmonary disease including chronic bronchitis, emphysema and asthma in mammals, especially humans that smoke or smoked cigarettes. In a preferred embodiment, the invention encompasses the treatment or prevention of panlobar emphysema, centrilobular emphysema or distal lobular emphysema in mammals using therapeutically effective doses of the compounds of the invention. In one embodiment, the present invention encompasses the use of the compounds of the invention for treating or preventing emphysema. Further, the instant invention encompasses the use of pharmaceutical compositions of the compounds of the invention to treat or prevent emphysema. Moreover, the invention encompasses the use of electrohydrodynamic aerosol devices, aerosol devices and nebulizers to deliver formulations of compounds of the invention into the lung of a mammal suffering from or at risk of emphysema. The invention encompasses the systemic use as well as the local use of the compounds of the invention or both in combination. Either or both can be achieved by the oral, mucosal or parenteral modes of administration. As mentioned above, means of delivering compounds of the invention directly into die lung by nebulizer, inhaler or other known delivery devices are encompassed by the invention. A method for treating emphysema by combining compounds of the invention with one or more additional therapies such as smoking cessation (where appropriate) bronchodilators, antibiotics, oxygen therapy and the like is also encompassed by the invention. In another aspect, the current invention encompasses methods for preventing emphysema in a human at risk of emphysema through administration of an amount of a compound of the invention, or pro-drug thereof, that is sufficient to prevent emphysema. In a . another aspect, the current invention encompasses pharmaceutical compositions for preventing emphysema in a human at risk of emphysema through administration of a amount of a compound of the invention or prodrug thereof, in a pharmaceutically acceptable carrier, that is sufficient to prevent emphysema. In another aspect, the present invention encompasses the use of compounds of the invention for treating or preventing cancer. Further, the instant invention encompasses the use of pharmaceutical compositions of compounds of the invention to treat or prevent cancer. Moreover, the current invention encompasses the use of electrohydrodynamic aerosol devices, aerosol devices and nebulizers to deliver formulations of compounds of the invention into the lung of a mammal suffering from or at risk of cancer. Cancers include solid tumours such as breast, lung, prostate and liver cancer, promyelocytary leukaemias, precancerous changes of the mucosa in the mouth, tongue, larynx, oesophagus, bladder, cervix and colon. A method for treating cancer by combining compounds of the invention with one or more additional therapies is also encompassed by the invention. Additional therapies include DNA intercalating agents such as cis-platin and immunotherapeutic agents such as gamma interferons and other cytokines. In another aspect, the current invention encompasses methods for preventing cancer in a human at risk of cancer through administration of an amount of a compound of the invention, or a pro-drug thereof, that is sufficient to prevent cancer. In another aspect, the current invention encompasses pharmaceutical compositions for preventing cancer in a human at risk of cancer through administration of a amount of a compound of the invention or pro-drug thereof, in a pharmaceutical^ acceptable carrier, that is sufficient to prevent cancer. In another aspect, the present invention encompasses the use of compounds of the invention for treating or preventing dermatological disorders. Further, the instant invention encompasses the use of pharmaceutical compositions of compounds of the invention to treat or prevent dermatological disorders. Dermatological disorders include acne, psoriasis, photodamaged skin and other dermatoses accompanied by cornification. Also included are wound healing, e.g., cuts, burns, operation wounds and other wounds associated with cutaneous trauma. A method for treating dermatological disorders by combining compounds of the invention with one or more additional therapies and the like is also encompassed by the invention. In another aspect, the current invention encompasses methods for preventing dermatological disorders in a human at risk from dermatological disorders through administration of an amount of a compound of the invention, or a pro-drug thereof, that is sufficient to prevent dennatological disorders. In a final aspect, the current invention encompasses pharmaceutical compositions for preventing emphysema in a human at risk from dennatological disorders through administration of a amount of a compound of the invention or pro-drug thereof, in a pharmaceutical^ acceptable carrier, that is sufficient to prevent dennatological disorders. Also part of the present invention is the use of compounds of formula I for the preparation of medicaments for treating or preventing emphysema, cancer and dennatological disorders. Whenever within the present invention it is refened to a method for the prevention or treatment of above-mentioned diseases, also part of the present invention is the use of compounds of formula I for the preparation of medicaments for treating or preventing the above-mentioned diseases. Another aspect of the invention encompasses a method of treating emphysema in a mammal which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the invention, or pro-drug thereof. In one embodiment, the emphysema is panlobar emphysema, centrilobular emphysema or distal emphysema. Preferably, the therapeutically effective amount of a compound of the invention or prodrug thereof, for treating emphysema, is between about 0.1 |ig/qd and about 30.0 mg/qd, more preferably between about 1.0 fig/qd and about 1.0 mg/qd. In one embodiment, especially for oral administration, the therapeutically effective amount of a compound of the invention or prodrug thereof is between about 10.0 pg/qd and about 30 mg/qd, preferably 30.0 jig/qd to about 300.0 [ig/qd. In another embodiment, especially for administration by inhalation, the therapeutically effective amount of a compound of the invention or pro-drug thereof, is between about 0.1 fig/qd and about 100.0 |ig/qd, more preferably between about 10.0 pg/qd and about 100.0 |Jg/qd, most preferably between about 1.0 jig/qd and about 30.0 jig/qd. This aspect of the invention encompasses a method of treating emphysema in a mammal by repairing alveoli in a mammal In a preferred embodiment, the mammal is human. Preferably, the human was or is a cigarette smoker. In another prefened embodiment, an electrohydrodynamic aerosol device or a nebulizer device or an aerosol device is used to administer the therapeutically effective amount of a compound of the invention, or pro-drug thereof. Another aspect of the invention encompasses a pharmaceutical composition for the treatment of a mammal suffering from emphysema comprising an amount of a compound of the invention or pro-drug thereof in a pharmaceutical^ acceptable carrier, with the amount of the compound being sufficient to alleviate one symptom of emphysema. In one embodiment, the emphysema is panlobar emphysema, centrilobular emphysema or distal emphysema. In a preferred embodiment, the mammal is human. Preferably, the human was or is a cigarette smoker. The major symptoms of emphysema include but are not limited to chronic shortness of breath, chronic cough, coloration of the skin caused by lack of oxygen, shortness of breath with minimal physical activity and wheezing. Additional symptoms that may be associated with emphysema include, but are not limited to vision abnormalities, dizziness, temporary cessation of respiration, anxiety, swelling, fatigue, insomnia and memory loss. Preferably, the amount of a compound of the invention or pro-drug thereof, in the pharmaceutical composition, is between about 0.1 \xg and about 30.0 mg, more preferably between about 1.0 jig and about 1.0 mg, most preferably between about 100.0 |ig and about 300.0 pg. In one embodiment, the pharmaceutically acceptable carrier is suitable for an electrohydrodynamic aerosol device, a nebulizer device or a aerosol device. In one preferred embodiment, the pharmaceutically acceptable carrier is a liquid such as water, alcohol, polyefliylene glycol or perfluorocarbon. The amount of a compound of the invention, or prodrug thereof in the pharmaceutical composition in this pref axed embodiment is between about 0.1 jig and about 1.0 mg, more preferably between about 1.0 pg and about 100.0 pg, most preferably between about 50.0 pg and about 150.0 |ig. Another aspect of the invention encompasses a method for treating emphysema and related disorders by delivering a formulation of a compound of the invention or pro-drug thereof, into the lungs of a mammal. Preferably, the mammal is a human, more preferably, the human was or is a cigarette smoker. In one embodiment, the formulation is delivered into the lungs of the mammal with a nebulizer device. In a second embodiment, the formulation is delivered into the lungs of the mammal with an aerosol device. In a third embodiment, the formulation is delivered into the lungs of the mammal with an electrohydrodynamic aerosol device In an exemplary embodiment, the formulation is a pharmaceutical composition of a compound of the invention. Preferably, the amount of a compound of the invention, or phannaceutically acceptable salt, hydrate, solvate, or pro-drug thereof in the pharmaceutical composition is between about 1.0 \xg and about 10.0 mg, more preferably between about 10.0 |ig and about 1.0 mg, most preferably between about 50.0 pg and about 150.0 jig. In one preferred embodiment, the pharmaceutical^ acceptable vehicle is a liquid such as water, alcohol, polyethylene glycol or perfluorocarbon. In another preferred embodiment, a material that alters the aerosol properties of the formulation is added to the formulation. Preferably, the material is an alcohol, glycol, polyglycol or fatty acid. In still another aspect, the present invention encompasses a method for treating emphysema that combines use of a compound of the invention with one or more additional therapies. The additional therapies include, but are not limited to, smoking cessation, antibiotics, bronchodilators and oxygen therapy. In a preferred embodiment, a pharmaceutical composition of a compound of the invention is used in combination with other therapies. In a still another aspect, the current invention provides a method for preventing emphysema in a human at risk of emphysema by administering a amount of a compound of the invention or pro-drug thereof, sufficient to prevent emphysema. In a preferred embodiment, the human was or is a cigarette smoker. In another aspect, the present invention provides a pharmaceutical composition that prevents emphysema in a human at ride of emphysema. The composition comprises an amount of a compound of the invention or pro-drug thereof, and a phannaceutically acceptable carrier that is sufficient to prevent emphysema. Another aspect of the invention encompasses a method of treating cancer in a mammal which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the invention or pro-drug thereof. Preferably, the cancer is of epithelial origin and includes, but is not limited to breast cancer, skin cancer, colon cancer, stomach tumors, laryngeal cancer and lung cancer. Preferably, the therapeutically effective amount of a compound of the invention or prodrug thereof for treating cancer, is between about 50μg/qd and about 500 mg/qd, more preferably between about 300μg/qd and about 30 mg/qd. In one embodiment, especially for oral administration, the therapeutically effective amount of a compound of the invention or prodrug thereof is between about 3 mg/qd and about 120 mg/qd In another embodiment, especially for administration by inhalation, the therapeutically effective amount of a compound of the invention or pro-drug thereof, is between about 50 \ig/qd and about 500 (lg/qd, more preferably between about 50 μg/qd and about 150 μg/qd. In a preferred embodiment, the mammal is human. In another preferred embodiment, a electrohydrodynamic aerosol device or a nebulizer device or a aerosol device is used to administer the therapeutically effective amount of a compound of the invention or pro-drug thereof. Another aspect of the invention encompasses a pharmaceutical composition for the treatment of a mammal suffering from cancer comprising an amount of a compound of the invention or pro-drug thereof in a pharmaceutically acceptable carrier, with the amount of the compound being sufficient to alleviate one symptom of cancer. Preferably, the cancer is of epithelial origin and includes, but is not limited to breast cancer, skin cancer, colon cancer, stomach tumors, laryngeal cancer and lung cancer. In a preferred embodiment, the mammal is human. Preferably, the amount of a compound of the invention or pro-drug thereof, in the pharmaceutical composition, is between about 250 jig and about 500 mg, more preferably between about 25 mg and about 100 mg, most preferably between about 10 mg and about 50 mg. In one embodiment, the pharmaceutical^ acceptable carrier is suitable for a electrohydrodynamic aerosol device, a nebulizer device or a aerosol device. In one preferred embodiment, the pharmaceutical^ acceptable carrier is a liquid such as water, alcohol, polyethylene glycol or perfluorocarbon. The amount of a compound of the invention or prodrug thereof, in the pharmaceutical composition in this preferred embodiment is between about 50 |xg and about 1.5 mg, more preferably between about 150 jig and about 1.5 mg, most preferably between about 150 μg and about 300 μg. Another aspect of the invention encompasses a method for treating cancer by delivering a formulation of a compound of the invention or pro-drug thereof, into the lungs of a mammal. Preferably, the mammal is a human, more preferably, the human has lung cancer. In one embodiment, the formulation is delivered into the lungs of the mammal with a nebulizer device. In a second embodiment, the formulation is delivered into the lungs of the mammal with an aerosol device. In a third embodiment, the formulation is delivered into the lungs of the mammal with an electrohydrodynamic aerosol device In an exemplary embodiment, the formulation is a pharmaceutical composition of a compound of the invention. Preferably, the amount of a compound of the invention or pro-drug thereof, in the pharmaceutical composition is between about 50 \ig and about 1.5 mg, more preferably between about 50 \ig and about 1.5 jig, most preferably between about 100 jig and about 300 jig. In one preferred embodiment, the pharmaceutically acceptable vehicle is a liquid such as water, alcohol, polyethylene glycol or perfluorocarbon. In another preferred embodiment, a material that alters the aerosol properties of the formulation is added to the formulation. Preferably, the material is an alcohol, glycol, polyglycol or fatty acid. In still another aspect, the present invention encompasses a method for treating cancer that combines use of a compound of the invention with one or more additional therapies. The additional therapies include, but are not limited to, chemotherapy, radiation or surgery. In a preferred embodiment, a pharmaceutical composition of a compound of the invention is used in combination with other therapies. In a still another aspect, the cunrent invention provides a method for preventing cancer in a human at risk of cancer (e.g., smokers, asbestos workers and uranium workers) by administering a amount of a compound of the invention or pro-drug thereof, sufficient to prevent cancer. Examples of premalignant and precancerous lesions or tumors which may be prevented by compounds of the invention include, but are not limited to, actinic and arsenic keratoses, dysplasias and papillomas of mucous membranes and precancerous changes of the bladder Another aspect of the present invention provides a pharmaceutical composition that prevents cancer in a human at risk of cancer. The composition comprises an amount of a compound of the invention or pro-drug thereof, and a pharmaceutically acceptable carrier that is sufficient to prevent cancer. provide compounds 71. Bromides 71 can be converted to aldehydes 72 in one step (Le.9 halogen-metal exchange with n-butyl lithium, followed by treatment with N-formylpiperidine). Alternatively, aldehydes 72 may be made from bromides 70 by a two step procedure (Le.9 CuCOCN to provide a nitrile and reduction with di-isobutyl aluminum hydride). Other methods for effecting conversion of bromides 70 to aldehydes 72 are within the capability of those of skill in the art Homer-Emmons olefination of aldehydes 72 with an appropriate phosphonate ester may be used to provide E olefins 74. The protecting group may be removed from compounds 74 (Le., aqueous tetrabutyl ammonium fluoride) to provide alcohols 76. In a preferred embodiment, alcohols 76 may be converted by Mitsonobu reaction* (£.£., aBcylthiols, triphenylphosphine and diisopropyl azodicarboxylate) to thiol analogs 78 (R = alkylthio). Alternatively, the hydroxyl functionality of compounds 76 may be activated by conversion to the mesylate (MsCl, Et3N) followed by displacement reactions with nitrogen or oxygen nucleophiles to provide compounds 78 (R = alkoxy, amino, alkylamino, dialkyamino etc.). Other methods for effecting conversion of alcohols 76 to compounds of the invention are known to the skilled artisan. Ester hydrolysis may be used to provide the free acids of compounds 78. which is followed by reaction with halogenatedheteroaromatics, dichlorobis(triphenylphosphine) palladium (II), cuprous iodide and triethylamine to yield acetylenic heteroaromatic intennediates 88. Catalytic hydrogenation of acetylenes 88 afforded the saturated heteroaromatic intermediates 90. Horner-Emmons olefination of 90 with the appropriate phosphonate ester yields E olefins 92. The ester may then be hydrolyzed to provide retinoid analogs 94. For compounds of Formula 1 where Z = acetylene and L = heteroaryl, as shown in Scheme 3b, intermediate 88 may be treated under Horner-Emmons olefination conditions with the appropriate phosphonate to give E olefins and subsequently hydrolyzed to provide retinoid analogs 81. For compounds of Formula 1 where Z = olefin and L = heteroaryl, intermediate 82 may be treated with trans-l,2-bis (tti-n-butylstannyl)ethylene and tetrakis (triphenylphosphine)palladium in toluene under reflux, followed by addition of halo heteroaromatics to afford olefin 83. Horner-Emmons olefination of 83 with the appropriate phosphonate ester followed by hydrolysis provides retinoid analogs 85. Alternatively for R2 = vinylsulfone, treatment of intermediate 82 with methyl vinyl sulfone, tetrakis(triphenylphosphine)palladium and TEA in DMF affords vinyl sulfone intermediate 87. Olefination, followed by hydrolysis provides retinoid analogs 89. Alternatively for R2 = vinylsulfonamide, treatment of intermediate 82 with tert-butyl[diphenylphosphoryl)methyl]sulfonylcarbamate and NaH in DMF affords vinylsulfonamide intermediate 91. Treatment of 91 with tributylstannylmethane and tetrakis(triphenyl phosphine) palladium in dioxane gave hydroxymethyl intermediate 93. Oxidation of 93 with l,l,l-triacetoxy-l,l,l-l,l-dihydro-l,2-benziiodoxol-3(lH)-one, affords aldehyde 95 and olefination, followed by hydrolysis gives retinoid analog 97. to provide compounds where m = 1 or may be homologated witfT approbated carbon nucleophiles to provide compounds where m is greater than 1. Alternatively, compounds of formula I where R3 is a diol may be prepared as exemplified in Scheme 12. Olefin 198 can be treated with osmium tetroxide to afford the cis diol 212. Protection of 212 as ketal 214 was followed by conversion to aldehyde 216 by sequential treatment with n-butyl lithium and N-formylpiperidine. Horner-Emmons olefination with the appropriated phosphonate provided 218 and deprotection was followed by reprotection to the bis-acetate 220 with acetic anhydride in pyridine. Free radical bromination of 220 gives bromide 222 which may be directly displaced with an appropriate nucleophile to provide compounds where m = 1 or may be homologated with appropriate carbon nucleophiles to provide compounds where m is greater than 1. Compounds of Formula 1 where A = CH2 and B = CH2O may be prepared as described in Scheme 13. Treatment of intermediate 80 with an appropriate heteroaromatic micleqphile under basic conditians(e.g. pyrazole, and potassium tert-butoxide in THF) affords 224. Treatment of 224 with tiiniethoxyvinylsilane, palladium acetate, tri-o-tolulyphopsine in NMP gives vinyl intermediate 226. HydroboraticHi-oxidalicHi of 226 with 9BBN in THF, followed by oxidation with 30% hydrogen peroxide gave hydroxyethyl intermediate 228. Mitsonobu coupling of 228 with methyl -4-hydroxybenxoate with triphenylphosphine and diethylazodicarboxylate in THF? followed by ester saponication affords retinoid analogs 230. Also provided is method of preparing a compound of Formula VI, where n and t are 1, R1 is CO2H or C02-alkyl, R2 is -(CR10Rn)m-R12 and R3 is H and R12 is heteroaiyL where G is a leaving group with a nucleophile R12-H; and when R is COz-alkyl, hydrolysis with abase. Compounds of the invention disclosed herein are useful for promoting the repair of damaged alveoli and septation of alveoli. Thus, methods of the invention may be employed to treat pulmonary diseases such as emphysema. The methods of treatment using a compound of the invention disclosed herein also may be used to treat cancer and dermatological disorders. The retinoic acid receptor agonist selectivity of a compound of the invention may be determined by using ligand binding assays known to the skilled artisan (Apfel et aL7 Proc. Natl Acad. ScL9 (1992), 89,7129; Teng et aL9 /. Med Chenu, (1997), 40,2445; Bryce et aU United States Patent No. 5,807,900 which are herein incorporated by reference). Treatment with RAR agonists, particularly RAR y agonists may promote repair of alveolar matrix and septation, which are in important in treating emphysema. Preferably, compounds of the invention are y selective agonists that bind to the y receptor with affinities between about 25 nm and about compositions may be formulated in conventional maimer using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries, which facilitate processing of compounds of the invention into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. For topical administration a compound of the invention may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art. Systemic formulations include those designed for administration by injection, e.g.7 subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral or pulmonary administration. Systemic formulations may be made in combination with a further active agent that improves mucociliary clearance of airway mucus or reduces mucous viscosity. These active agents include but are not limited to sodium channel blockers, antibiotics, N-acetyl cysteine, * homocysteine and phospholipids. For injection, a compound of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer. The solution may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, compounds of the invention may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. For oral administration, a compound of the invention can be readily formulated by combination with pharmaceutically acceptable carriers well known in the art Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. For oral solid formulations such as, for example, powders, capsules and tablets, suitable excipients include fillers such as sugars, such as lactose, sucrose, mannitol and sorbitol; cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP); granulating agents and binding agents. If desired, disintegrating agents may be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. If desired, solid dosage forms may be sugar-coated or enteric-coated using standard techniques. Methods for formulating retinoid agonists for oral administration have been described in the art (See, e.g., the formulation of Accutane®, Physicians * Desk Reference 54th Ed., p. 2610,2000). For oral liquid preparations such as, for example, suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, saline, alkyleneglycols (e.g., propylene glycol), polyalkylene glycols (e.g., polyethylene glycol) oils, alcohols, slightly acidic buffers between pH 4 and pH 6 (e.g.9 acetate, citrate, ascorbate at between about 5.0 mM to about 50.0 mM) etc. Additionally, flavoring agents, preservatives, coloring agents, bile salts, acylcarnitines and the like may be added. For buccal administration, the compositions may take the form of tablets, lozenges, etc. formulated in conventional manner. A compounds of the invention may also be administered directly to the lung by inhalation for the treatment of emphysema (see e.g., Tong et al, PCT Application, WO 97/39745; Clark et cd., PCT Application, WO 99/47196, which are herein incorporated by reference). For administration by inhalation, a compound of the invention may be conveniently delivered to the lung by a number of different devices. For example, a Metered Dose Inhaler C"MDI') which utilizes canisters that contain a suitable low boiling propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas may be used to deliver compounds of the invention directly to the lung. MDI devices are available from a number of suppliers such as 3M Corporation, Aventis, Boehringer Ingleheim, Forest Laboratories, Glaxo-Wellcome, Schering Plough and Vectura. Alternatively, a Dry Powder Inhaler (DPI) device may be used to administer a compound of the invention to the lung (See, e.g.,. Raleigh et al., Proc. Amer. Assoc. Cancer Research Annual Meeting, (1999), 40,397, which is herein incorporated by reference). DPI devices typically use a mechanism such as a burst of gas to create a cloud of dry powder inside a container, which may then be inhaled by the patient DPI devices are also well known in the art and may be purchased from a number of vendors which include, for example, Rsons, Glaxo-Wellcome, Inhale Therapeutic Systems, ML Laboratories, Qdose and Vectura. A popular variation is the multiple dose DPI ("MDDPF) system, which allows for the delivery of more than one therapeutic dose. MDDPI devices are available from companies such as AstraZeneca, GlaxoWellcome, IVAX, Schering Plough, SkyePharma and Vectura. For example, capsules and cartridges of gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch for these systems. Another type of device that may be used to deliver a compound of the invention to the lung is a liquid spray device supplied, for example, by Aradigm Corporation. Liquid spray systems use extremely small nozzle holes to aerosolize liquid drug formulations that may then be directly inhaled into the lung. In one preferred embodiment, a nebulizer device is used to deliver a compound of the invention to the lung. Nebulizers create aerosols from liquid drug formulations by using, for example, ultrasonic energy to form fine particles that may be readily inhaled (see e.g., Verschoyle et aL9 British /. Cancer, (1999), u, SuppL 2,96, which is herein incorporated by reference). Examples of nebulizers include devices supplied by Sheffield/Systemic Pulmonary Delivery Ltd. (See, Armer et aL9 United States Patent No. 5,954,047; van der linden et aL, United States Patent No. 5,950,619; van der Linden et al, United States Patent No. 5,970,974, which are herein incorporated by reference), Aventis and Batelle Pulmonary Therapeutics. In another preferred embodiment, an electrohydrodynamic ("EHD") aerosol device is used to deliver a compound of the invention to the lung. EHD aerosol devices use electrical energy to aerosolize liquid drug solutions or suspensions (see e.g., Noakes et dLt United States Patent No. 4,765,539; Coffee, United States Patent No. 4,962,885; Coffee, PCT Application, WO 94/12285; Coffee, PCT Application, WO 94/14543; Coffee, PCT Application, WO 95/26234, Coffee, PCT Application, WO 95/26235, Coffee, PCT Application, WO 95/32807, which are herein incorporated by reference). The electrochemical properties of a compound of the invention formulation may be important parameters to optimize when delivering this compound to the lung with an EHD aerosol device and such optimization is routinely performed by one of skill in the art. EHD aerosol devices may more efficiently deliver drugs to the lung than existing pulmonary delivery technologies. Other methods of intra-pulmonary delivery of a compound of the invention will be known to the skilled artisan and are within the scope of the invention. Liquid drug formulations suitable for use with nebulizers and liquid spray devices and EHD aerosol devices will typically include a compound of the invention with a pharmaceutical^ acceptable carrier. Pref erably, the pharmaceutical^ acceptable carrier is a liquid such as alcohol, water, polyethylene glycol or a perfluorocarbon* Optionally, another material may be added to alter the aerosol properties of the solution or suspension of compounds of the invention. Preferably, this material is liquid such as an alcohol, glycol, polyglycol or a fatty acid. Other methods of formulating liquid drug solutions or suspension suitable for use in aerosol devices are known to those of skill in the art (see, e.g., Biesalski, United States Patent No. 5,112,598; Biesalski, United States Patent No. 5,556,611, which are herein incorporated by reference) A compound of the invention may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. In addition to the formulations described previously, a compound of the invention may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, a compound of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt Alternatively, other pharmaceutical delivery systems may be employed. Liposomes and emulsions are well known examples of delivery vehicles that may be used to deliver a compound of the invention. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity. A compound of the invention may also be delivered in a controlled release system. In one embodiment, a pump may be used (Sefton, CRC Crit. Ref. BiomecL Eng., (1987), u, 201; Buchwald et aL, Surgery, (1980), u, 507; Saudek et al., N. Engl J. Med, (1989), 321,574), In another embodiment, polymeric materials can be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Florida (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, J. MacromoL Set Rev. Macromol. Chenu, (1983), 23,61; see also Levy et al, Science (1985), 228,190; During et al.Ann. Neurol, (1989), 25,351; Howard et al, (1989), J. Neurosurg. 71, 105). In yet another embodiment, a controlled-release system can be placed in proximity of the target of a compound of the invention, e.g., the lung, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115 (1984)). Other controlled-release system may be used (see e.g., Langer, Science, (1990), 249,1527). When a compound of the invention is acidic, it may be included in any of the above-described formulations as the free acid, a pharmaceutically acceptable salt, a pro-drug, solvate or hydrate. Pharmaceutically acceptable salts substantially retain the activity of the free acid and may be prepared by reaction with bases. Pharmaceutically acceptable salts include any known suitable salts of retinoic acids known in the art for administration to mammals. Pharmaceutical salts tend to be more soluble in aqueous and other protic solvents than the corresponding free acid form. Similarly, a compound of the invention may be included in any of the above-described formulations as a solvate, hydrate or pro-drug. Preferred pro-drugs include hydrolyzable ester derivatives such as aromatic esters, benzyl esters and lower alkyl esters such as ethyl, cyclopentyl etc. Other pro-drugs are known to those of skill in the pharmaceutical arts. A compound of the invention, or compositions thereof, will generally be used in an amount effective to achieve the intended purpose. Of course, it is to be understood that the amount used will depend on the method of administration. For use to treat or prevent emphysema, cancer or dermatological disorders, compounds of the invention or compositions thereof, are administered or applied in a therapeutically effective amount Therapeutically effective amounts of compounds of the invention for systemic administration may be found in the detailed disclosure provided herein. The pharmacokinetic profile of the compounds of the invention is predictable and can be described by using linear pharmacokinetic theory. Importantly, the pharmacokinetics of compounds of the invention in humans may be readily determined by one of skill in the art The skilled artisan may determine a range of standard pharmacokinetic parameters after single oral dosing with a compound of die invention using procedures described in the art (see e.g., Khoo et aL, 7. Clin. Pharm, (1982), 22,395; Colburn et aU J. Clin. Pharm, (1983), 23,534; Colburn et aL9 Eur. J. Clin. Pharm., (19), 23,689). The skilled artisan may also measure values of these pharmacokinetic parameters after multiple dosing, following procedures described in the art, to determine whether induction or accumulation of the compound of the invention occurs under these circumstances (Brazzel et al.y Eur. J. Clin. Pharm., (1983), 24, 695; Lucek et aL, Clin. Pharmacokinetics, (1985), 10,38). Those of skill in the art may estimate the appropriate systemic dosage levels of compounds of the invention necessary to treat emphysema, cancer or dennatological disorders in mammals (preferably, humans) using the pharmacokinetic parameters determined by the above procedures in conjunction with animal model dosage data. Dosage amounts and intervals may be adjusted individually to provide plasma levels of a compound of the invention which are sufficient to maintain therapeutic effect. Usual patient dosages for administration by injection range from 0.1 jig and about 10.0 mg, preferably, between about 1.0 \ig and about 1.0 mg, more preferably, between about 100.0 |ig and about 300.0 pg. Therapeutically effective serum levels may be achieved by administering a single daily dose or multiple doses each day. The amount of a compound of the invention administered will, of course, be dependent on, among other factors, the subject being treated, the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician. For example, the dosage may be delivered in a pharmaceutical composition by a single administration, by multiple applications or controlled release. Dosing may be repeated intermittently, may be provided alone or in combination with other drugs and will continue as long as required for effective treatment of emphysema. Preferably, a therapeutically effective dose of a compound of the invention described herein will provide therapeutic benefit without causing substantial toxicity. Toxicity of compounds of the invention may be determined using standard pharmaceutical procedures and may be readily ascertained by the skilled artisan. The dose ratio between toxic and therapeutic effect is the therapeutic index. A compound of the invention will preferably exhibit particularly high therapeutic indices in treating emphysema, cancer or dennatological disorders when compared to other retinoid agonists. The dosage of a compound of the inventions described herein will preferably be within a range of circulating concentrations that include the effective dose with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition (see, e.g., Fingl et aL, 1975, In: The Pharmacological Basis ofTherapeutics, Ch.l, p.l). For example, a therapeutically effective dose of a compound of the invention may be administered either orally or directly into the lung. The invention is further defined by reference to the following examples describing in detail the preparation of the compound and compositions of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention. EXAMPLE 10: MEASUREMENT OF ALVEOLAR REPAIR IN RAT LUNG WITH A COMPOUND OF THE INVENTION Compounds of the invention may be evaluated for their effects on alveolar repair in the rat model of elastase-induced emphysema (Massaro et aL9 Nature, 1997, Vol. 3, No. 6:675; Massaro et aL, United States Patent No. 5,998,486). Preferably, animals are divided into treatment groups of approximately eight Lung inflammation and alveolar damage may be induced in male Sprague Dawley rats by a single instillation of about 2 U/gram body mass of pancreatic elastase (porcine derived, Calbiochem). Animals may be treated with a compound of the invention prepared in Capmul at convenient oral dosage ranges (preferably, between about 10.0 mgfkg and 0.0001 mg/kg) and will be dosed orally once per day starting 21 days post injury. Control groups are challenged with elastase and 21 days later are treated with vehicle (Capmul solution) for 14 days. Animals are sacrificed 24 hours after the last dose by exsanguination under deep anesthesia. Blood was collected at time of exsanguination for analysis. The lungs are inflated with 10% neutral buffered formalin by intratracheal instillation at a constant rate (1 ml/gram body mass/min). The lung is excised and immersed in fixative for 24 hours prior to processing. Alveolar measurements are made in four regions of the lung/rat The mean value/treatment group may be determined by summing the average area/rat for all eight rats relative to the elastase* vehicle treated group. In some cases, the variability between rats within a treatment group was too large for the group average to be statistically significant Standard methods may be used to prepare 5 jim paraffin sections. Sections are stained with Hematoxylin and Eosin. Computerized Moiphometric analysis was performed to determine the average alveolar size and alveolar number. Quantitation of triglycerides contained in rat plasma may be performed using established procedures. Briefly, plasma triglycerides may be converted to dihdroxyacetone and hydrogen peroxide by sequential treatment of plasma with lipase and glycerokinase according directions described by the manufacturer of triglycerides/GPO kit (Boehringer Mannheim #1488872). Hydrogen peroxide may be quantitated colorimetrically in a Hitachi 911 Chemistry Analyzer. In rats normal triglyceride levels are between about 75 mg/dl and about 175 mg/dL Triglyceride values are a convenient measure of toxicity. The following examples describe synthesis of particular compounds of the invention, including many compounds illustrated in Table 1. EXAMPLE 11: PREPARATION OF (El METHYL^r2-G-BROMO^ TETRAMETHYI^5.6.7.8-TETRAHYDRO-NAPTTm AT F.N-2-YUVINYL1BENZOATE. STEP A: PREPARATION OF 2.5-DICH]J3RO-2,5-DIMEIHYLHEXA3SnE HC1 gas was added by bubbling through a gas dispersion tube to a solution of 100 g (684 mmol) of 2,5-dimethyl-2,5-hexanediol in 300 mL of ethanoL The reaction mixture slowly warmed from room temperature to 60 °C over 3 hours. The reaction mixture was cooled in a wet ice bath and a white solid was filtered off. The solid was washed with water and cold ethanol, then dried to give 65.2 g (65%) of 2,5-dichloro-2,5-dimethyIhexane (M* = 181). STEP B: PREPARATION OF 2-BROMO-3-METHY1-5.5.8.8-TETRAMETHYL-5,6.7.8-TETRAHYDRONAPTHALENE To a solution of 20 g (117 mmol) of 2-bromotoluene and 14.4 g (97.4 mmol) of 2,5-dichloro-2,5-dimethylhexane in 100 mL of dichloromethane was added 1.56 g (16.9 mmol) of aluminum chloride and the mixture heated at reflux. After 16 hours, the mixture was cooled to room temperature, diluted with 150 mL of hexane and 100 mL of 1 N HC1 was added. The organic layer was separated and the aqueous layer was extracted with hexane. The combined organic layers were washed with saturated NaCl solution, dried over sodium sulfate and concentrated under reduced pressure. The product was purified by filtration through a pad of silica gel with elution with hexane and afforded 23.9 g (87%) of 2-bromo-3-methyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene as a solid. (m.p.: 8L1-85 °Q. STEP C: PREPARATION OF 2-FORMYI^3-METHYI^^ TETRAHYDRONAPWTRAT .KNR 22.2 mL (35.2 mmol) of n-butyl lithium (1.6 M in hexanes) was added. After 1 hours, a solution of 3.95 mL (35.5 mmol) of N-formylpiperidine was added to a solution of 5 g (17.8 mmol) of 2-bromo-3-methyl-5,5,8,8-tetramethy 1-5,6,7,8-tetrahydronaphthelene in 50 mL of tetrahydrofuran, cooled in a dry ice/acetone bath. After 30 minutes 30 mL of saturated aqueous ammonium chloride was added to the reaction mixture. The reaction mixture was wanned to room temperature and extracted with ethyl acetate. The organic phase was separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel with gradient elution (hexane-10% ethyl acetate/hexane) to provide 3 J g (85%) of 2-formyl-3-methyl-5,5,8,8»tetramethyl-5,6,7,8-tetrahydronaphthalene (m.p.: 82.4-84.1 °Q. AN ALTERNATIVE PREPARATION OF 2-FORMYI^3-METHYL-5.5,8.8-TETRAMETHYI5.6.7,8-TETRAHYDRONAPHTHALENER 28.9 g (322 mmol) of copper(I) cyanide was added to 22.7 g (80.7 mmol) of 2-bromo-3-methyl-5,8,8,tetramethyl-5,6,7,8-tetrahydronaphthalene in 270 mL of N-methyl pyrollidine. The reaction mixture was heated at 175 °C After 16 hours, the mixture was cooled to room temperature and treated with 400 mL of 10% aqueous ammonium hydroxide. The reaction mixture was filtered to remove salts and the solids were extracted with hot ethyl acetate. The combined organic fractions were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The product was purified by gradient elution through a pad of silica gel (hexane-5 % ethyl acetate/hexane) to give 18 g (95%) of 2-cyano-3-methyI« 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (M* = 227). To a solution of 18.7 g (823 mmol) of 2-cyano-3-methyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene in 280 mL of dichloromethane, cooled at -78°, was added 123 mL (123 mmol) of diisobutyl aluminum hydride (1.0 M in toluene). The reaction mixture was stirred and allowed to gradually warm to room temperature. After 16 hours, the reaction mixture was treated with 30 mL of acetic acid added dropwise, followed by 150 mL of water. The organic layer was separated, diluted with 200 mL of hexane, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution 5-10% ethyl acetate/hexane) on silica gel to afford 11.8 g (63%) of 2-fonnyl-3-methyl-5,5,8,8-tet^ STEP D: PREPARATION OF METHY-4-[(E)-2(3,5,8,8,-PENTAMETHYL-5,6,7,8- TETRAHYDRO-NAPHIHALEN-2YL)VINYL BENZOATE To a solution of 3.5 g (13.5 mmol) of dimethyl-4-methylcarboxylbenzylphosphonate in 80 mL of toluene at 0°, was added 7.6 mL (23 mmol) of potassium tert-pentylate (Huka Chemical Co.). After 15 minutes a solution of 2.3 g (10 mmol) of 2-formyl-3-methyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen in 20 mL of toluene was added and the reaction was allowed to stir and warm to room temperature. After 16 hours, the reaction mixture was poured into 50 mL 2 N HC1, extracted with ethyl acetate, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was stirred with 100 mL of hexane, filtered and the filtrate concentrated under reduced pressure. The residue was stirred with 100 mL of methyl alcohol and the product filtered off to give 232 g (64%) of methyl-4-[(E)-2- (3,5,5,8,8-pentamethyl-5,6,7,8-t^^ (M* = 362). STEP E: PREPARATION OF METHYI^rteV2-(3-BROM TETRAMETHYI^5.6.7.8-TEIKA^ A mixture of 1.0 g (2.76 mmol) of (E)-methyl-4-[2-(3-methyl«5^,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoate, 0.64 g (3.6 mmol) of N- bromosuccinimide and 0.033 g (0.13 mmol) of benzoyl peroxide in 20 mL of carbon tetrachloride was heated under reflux, under a high intensity lamp. After 2 hours, the reaction was cooled to room temperature and poured into 10% aqueous sodium bisulfite solution. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was stirred with methyl alcohol to afford 0.88 g of Methyl-4-[2-(3-bromomethyI-5,5,8,8-tetramethyl-5,6,7^ (M+=440). sodium sulfate and concentrated under reduced pressure. The residue was recrystallized (ethyl acetate/hexane) to give 50 mg (12%) of 4-{(E)-2-[3-(2-methoxy-ethoxymethyl-5^,8,8-tetramethyl-5,6J,8-tetrahydro-naphthalen»2-yl]vinyl}benzoic acid (m.p. = 55.9-58.2 °C) 5. EXAMPLE 17: PREPARATION OF4-((EV2-r3-G-HYDROXYPROPYLV5.5.8.8-TETRAMETHYI^5.6.7.8-TBTRAHYDRO-NAPWTH AT KNT-2-YLIVINYLmENZOIC ACID STEP A: PREPARATION OF 2-(3-HYDROXYPROPYLV53.8.8-TETRAMETHYI^5.6.7.8-TETRAHYDRO-N APHTRAT .BMR To a solution of 14 g (103 mmol) of 3- phenyl-1-propanol and 18.2 g (123 mmol) of 2,5-dicMoro-2,5-dimethyIhexane in 100 mL of dichloromethane was added 15 g (113 mmol) of aluminum chloride. After the addition of aluminum chloride was complete, the reaction was heated to reflux. After 16 hours, the reaction mixture was cooled to room temperature and 100 mL of water was added, followed by 100 mL of IN HCL The reaction mixture was stirred for 2 hours, filtered through a Celite pad and the layers were separated. The aqueous layer was extracted with diethyl ether and the combined organic fractions were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (30% ethyl acetate/hexane) to afford 13.45 g (53%) of 2~(3-hydroxj^ropyl>5^3*8-tetramefa concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient elution: 1-2% ethyl acetate/hexane) to afford 9.17 g (66%) of 2-bromo-3-(3« t-butyldtoe&ylsUoxyp^ STEP D: PREPARATION OF 2-CYANO-3-(3-t~BUTY^ 5.5.8.8-TETRAMETHYI^5 A7.8-TETRAHYDRO-N APMTff AT F.NF. To a solution of 9.0 g (20.5 mmol) of 2-bromo-3-(3-t-butyldimethylsiloxypropyl)-5^,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene in 70 mL of N-methyl pyrollidine was added 7.36 g (82 mmol) of copper (I) cyanide and the reaction mixture was heated to 175 °C. After 16 hours the reaction mixture was cooled to room temperature and diluted with 10% aqueous ammonium hydroxide. The resulting salts wore removed by filtration and washed with hot ethyl acetate. The filtrate was extracted with ethyl acetate and the combined organic fractions were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient elution: 3-25% ethyl acetate/hexane) to give 4.8 g (61%) of 2-cyano-3-(3-t-butyldimethylsiloxypropyl> 5,5,8,8"tetramethyl-5,6,7,8-tetrahydro-naphthalene. STEP E: PREPARATION OF 2-FORMYL -3-(3-t-BUTYIJ3IMETHYI^ILOXYPROPYLV 5.5.8.8-TETRAMETHYI^5A7.8^ To a solution of 4.6 g (11.9 mmol) of 2-cyano-3-(3-t-butyldimethylsiloxypropyI)- 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalenein 40 mL of dichloromethane at -78 °C was added 17.9 mL (17.9 mmol) of diisobutylaluminum hydride (1.0 M in toluene). The reaction mixture was stirred and allowed to slowly warm to room temperature. After 16 hours, acetic acid was added dropwise, followed by addition of water and dichloromethane. The organic fraction was separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient elution: 4-25% ethyl acetate/hexane) to afford 2.48 g (53%) of 2-formyl -3-(3-t- butyldimethylsttoxypropyl)-5,5,8,8- M*= 389). AN ALTERNATIVE PREPARATION OF 2-FORMYI^3-f3-t-BUTY^ SIIJmXlTROPYL^ To a solution of 14 g (32 mmol) of 2-bromo-3-(3-t-butyldimethylsililoxypropyl)- 5,5,8,8-tetramethyl-5,6,7,8-taahydro-naphthalene in 200 mL of dry tetrahydrofiiran at -78 °C was added 24.9 mL (64 mmol) of n-BuLi (2.5 M in hexane) via syringe under N2 atmosphere. The reaction mixture was stirred at this condition for 1 hour. Thai it was quenched with a solution of 7 mL (64 mmol) of N-formyl piperidine in 10 mL of dry tetrahydrofuran. The resulting solution was stirred for an additional 30 minutes, when it was quenched with 100 mL of NH4CI solution. The reaction mixture was extracted with 3 x 100 mL of ethyl acetate. The organic layers were combined, dried over MgS04 and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient elution : 30% ethyl acetate/hexanes) to afford 11.1 g (90%) of 2-formyl-3-(3-t- butyldimethylsihloxypropyl)-5,5,8,8-tet^ (M*= 386). EXAMPLE 19: PREPARATION OF 4-1 fEV2-rS,5,8.8-TETRAMETHYI^3-rPYiaMIDIN-2-YLTfflOPROPYLV5,6 J.8-TETRAHYDR0-NAPHTR AT FN-2-YL1VINYL)BENZOIC ACID A mixture of 250 mg (0.62 mmol) of methyl-4-{(E>2-[3-(3-hydroxypropyl)-5,5,8,8-tetramethyl-5,6 J3-tetrahydro-naphthalen-2-yl]vinyl}beiizoate, 1 mL (4.9 mmol) of diisopropyl azodicarboxylate, 13 g (4.9 mmol) of triphenylphosphine and 550 mg (4.9 mmol) of 2-mercaptopyrimidine in 10 mL tetrahydroforan was stirred at room temperature. After 48 hours, the reaction mixture was poured into brine and extracted with ethyl acetate, the organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure* The residue was purified by flash chromatography on silica gel (10% ethyl acetate/hexane). The purified material was taken up in 20 mL of methyl alcohol and 10 mL of 1N IiOH and heated to reflux. After 1 hour the reaction mixture was cooled and methanol was removed under reduced pressure. The solution was acidified with acetic acid, extracted with ethyl acetate, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient elution:10-20% ethyl acetate/hexane) and the product was recrystallized (ethyl acetate/hexane) to give 160 mg (55%) of4-{(E)-2-[5,5,8,8-tetramethyl-3-fe^ yl]vinyl}benzoic acid 24 (m.p. =177-177.5 °Q. Proceeding as above but substituting 2-mercaptopyrimidine with 5-methyl-13,4- thiadiazole2-thiol gave 4-((E)-2-{5,5,8,8-Tettamethyl-3^ ylsulfanyl)-propyl]-5,6,7,8-tetr^ acid 28. Proceeding as above but substituting (E> methyl-4-[2-(3-{3-hydroxypropyl}-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthal^-2-yl)vinyl]benzoate 3-[2-(3,5-dimethyl-py^ 147 respectively. EXAMPLE 21: PREPARATION OF3-BROMO-5J.8.8-TETRAMETHYL-5.6.7.8-TETRAHYDR(>2-NAPHTHALDEHYDE To a solution of 12.0 g (281 mmol) of 2-bromo-3-methyl-5,5,8,8-tetrametiiyl-5,6,7,8-tetrahydronaphthalene in 84 mL carbon tetrachloride was added 7.59 g (42.7 mmol) of N-bromosuccinimide and 0310 g (1.28 mmol) of benzoyl peroxide. This was heated to reflux for 40 minutes and then cooled to room temperature. To the cooled solution was added 170 mL petroleum ether and the solution was filtered and concentrated in vacuo to give 17.3 g of 2-bromo-S-bromomethyl-S^^^-tetramethyl-S^JjS-tetrahydronaphthalene which was used without further purification. StepB 0.981 g (42.7 mmol) of sodium was dissolved in 50 mL of ethanol. To this solution was added 4.94 g (55.5 mmol) of 2-nitropropane followed by 17.3 g (42.7 mmol) of crude 2-bromo-3-bromomethyl-5,5,83-tetramethyl-5,6,7,8-tetrahydronaphthalene in 75 mL ethanol. After 8 hours, this mixture was concentrated in vacuo and then partitioned between ethyl acetate and water. The organic layer was sequentially washed with 1M aqueous sodium hydroxide, water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The product was purified by flash chromatography on silica gel with gradient elution (1-2% ethyl acetate/hexane) to afford 7.63 g (61%) of 3-bromo-5,5,8,8-tetcamethyl-5,6,7,8-tetrahydro-2-naphthaldehyde (m.p.=l 13.9-114.3 °Q. EXAMPLE 22: PREPARATION OF 3-f2-TRIMETHYLSILYErHYNYLV5.5.8.8-TETRAMETHYI^5.6.7.8-TF^TlAHYDRO-2-NAPHTHALDEHYDE A solution of 6.97 g (23.6 mmol) of 3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaldehyde, 4.66 g (47.4 mmol) of trimethylsilyacetylene, 700 mg (0.997 mmol) of dichlorobis(triphenylphospbine) palladium(II), 350 mg (1.84 mmol) of cuprous iodide, and 3.60 g (35.5 mmol) of triethylamine in 95 mL dimethylfonnamide was heated to 45 DC for 2.5 hours, cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The product was purified by filtration through a pad of silica gel with elution with 10% ethyl acetate/hexane and afforded 7.23 g (98%) of 3-(2-trimemylsilyl-emynyl)-5,5,8,8-tetramemyl-5,6,7,8-tetrahydro-2-naphthaldehyde (m.p. = 78.4-82.0 °Q. EXAMPLE 23: PREPARATION OF 3-ETHYNYI^5.5.8.8-TETRAMETHYL-5.6.7.8-TETRAHYDRO-2-NAPHTHALDEHYDE To a solution of 7.21 g (23.1 mmol) of 3-(2-trimethylsilyl-ethynyl)-5^,8,8-tetramethyl-5,6,7,8-teteahydro-2-naphthaldehyde in 150 mL of methanol was added 638 g (46.2 mmol) of potassium carbonate. After 1 hour, the reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The product was purified by flash chromatography on silica gel (3% ethyl acetate/hexane) to afford 4.04 g (73%) of 3-ethynyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaldehyde (m.p. = 94.0-94.6 °C). EXAMPLE 24:4-rOEV2-( 5.5.8.8-TEmAMEnTYI^3-((PYRIMroiN-2-YL)ETHYNYLV 5.6.7.8-TERAHYDRq2-NAPHTHAI£N-2-YL)VINYL1BENZOICACID STEP A: PREPARATION OF 5.5.8.8-TEntAMETHY1^3-PYRI\flND^ 5.6.7.8-TETRAHYDRO-2-NAPHTHALDEHYDE A solution of 0.400 g (1.66 mmol) of 3-ethynyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaldehyde, 0.278 g (1.75 mmol) of 2-bromopyrimidine, 0.053 g (0.075 mmol) of dichlorobis(triphenylphosphine)palladium(n), 0.026 g (0.14 mmol) of cuprous iodide, and on carbon and the suspension was shaken under 40psi hydrogen gas for 3 hours. The resulting solution was filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel (30% ethyl acetate/hexane) to afford 0.251 g (68%) of 3-(2-(2-pyrimidyl)ethyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaldehyde (m.p. = 78.0-84 5 °Q. Replacement of 2-bromo-pyridine with 2-bromo-thiazole gave 2-formyl-3-[2-(thiazol-2-yl)ethyl]-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-napthalene. EXAMPLE 26: PREPARATION OF 4-((E>2-r53.8.8-TETRAMEnm^ YI^Enrm-5,6.7.8-TETRAHYDRaN^ STEP A: PREPARATION OF ETHYLS raV2-r5.5.8.8-TETRAMETHYL-3-(2-T^^ 2-YL-ETHYLV5.6.7.8-TBTRAHYDRO-NAPmHAI^^^ A 0 °C, .3 M tetrahydrofuran solution of 229 mg (.699 mmol) of 2-formyl-3-[2-(thiazol-2-yI) ethyl]-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-napthalene and 202 mg (.706 mmol) of diethyl 4-carboethoxybenzyl phosphonate was treated with 30 mg (.768 mmol, 60% wt. in mineral oil) NaH in 5 mg portions over ten minutes. The solution was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was then dried over magnesium sulfate, concentrated under reduced pressure and the resulting residue triturated with methanol to provide 278 mg(86%) of Emyl-4-{(E>-2-[5,5;8,8-tetramemyl-3K2-thiazol-2-yl-ethyl)-5,6J,8-tetrahydro-naphthalen-2-yl]vinyl}benzoate. STEP B: PREPARATION OF4-{fEV245.5.8,8-TETCAM^^ ETHYLV5.6.7.8-TETRAHYDRqNAPHTH AT .KM-O-VT JVINYLiBENZYL ACID A slurry containing 278 mg (.604 mmol) of ethyl-4-{(E)-2-[5,5,8,8-tetramethy^ tMazol-2-yl-eihyl)-5,6,7,8-tetrahydro-naphtMen-2-yl]viny in 2.3 mL of ethanol and 1.7 mL of 2M aqueous sodium hydroxide was stirred for 7 hours. The reaction mixture was neutralized and washed with a saturated solution of aqueous ammonium chloride. The resulting precipitate was extracted several times with ethyl acetate. The organic layers were combined, washed with brine and dried over magnesium sulfate before being concentrated in vacuo. The residue (95 mg) obtained was then dissolved in dichloromethane and precipitated out by adding excess hexane resulting in 25 mg (10%) of 4-{ (E)-2-[5,5,8,8-tetramethyl-3-(2-thiazol-2-yl-ethyl)-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoic acid 40 (m.p. = 215.8-217.5° 0,^=446). EXAMPLE 27: PREPARATION OF 2-FLUORO-3-METHYI^5.5.^^ 5.6.7.8-TETRAHYDRONAPHTH AT ,FMF. To a solution of 15 g (136 mmol) of 2-fluorotoluene and 24.9 g (136 mmol) of 2,5-dichloro-2,5-dimeihylhexane in 120 mL dichloromethane was added 1.82 g (13.6 mmol) of aluminum chloride and the solution heated at reflux. After 18 hours the reaction mixture was cooled to room temperature and 5% aqueous HC1 was addedL This was partitioned between hexane and water. The aqueous phase was washed once with hexane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford 25.8 g (86%) of 2-fluoro-3-methyl-5,5,8,8-tetramethyI-5,6,7,8-tetrahydronaphthalene (m.p. = 90.0-91.8 °Q. EXAMPLE 28: PREPARATION OF 3-FLUORO-5.5,8,8-TETRAMETHYL-S-6.7,8-TETRAHYDRO-2-NAPHTHALDEHYDE STEP A To a solution of 10.0 g (45.4 mmol) of 2-fluoro-3-methyl-5,5,8,8-tetramethyl«5,6,7,8-tetrahydronaphthalene in 91 mL of carbon tetrachloride was added 8.48 g (47.7 mmol) of N-bromosuccinimide and 0.330 g (1.36 mmol) of benzoyl peroxide. The solution was heated at reflux for 35 minutes and then cooled to room temperature. 200 mL petroleum ether was added and the solution filtered and concentrated in vacuo to afford 16.9 g of 2-fluoro-3-bromomethyl-5^,8»8-tetramethyl-5,6,7,8-tetrahydronaphthalene which was used without farther purification. STEPB 5.26 g (59.0 mmol) of 2-nitropropane was added to a solution prepared by dissolving 1.04 g (45.4 mmol) of sodium in 60 mL of ethanol. The resulting solution was added to a solution of 16.9 g (45.4 mmol) of crude 2-fluoro-3-bromomethyl-5,5,8,8-tetrametiiyl»5,6,7,8-tetrahydronaphthalene in 60 mL of ethanol. After 5 hours the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with 1M aqueous sodium hydroxide, water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The product was purified by flash chromatography on silica gel (1% ethyl acetate/hexane) to afford 6.17 g (58%) of 3-fluoro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaldehyde (m.p. = 119.4-120.0 °Q. EXAMPLE 29: PREPARATION OF 5^.8,8-TETRAMETHYL^3-PYRAZOL^l-YL-5.6.7,8-TETRAHYDRO-2-NAPHTHALDEHYDE A solution of 0.200 g (0.845 mmol) of 3-fluoro-5^,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaldehyde, 0.058 g (0.854 mmol) of pyrazole, and 0.130 g (0.939 mmol) of potassium carbonate in 2 mL dimethylsulfoxide was heated to 95 CC for 18 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The product was purified on flash chromatography on silica gel (5% ethyl acetate/hexane) to afford 0.101 g (42%) of 5,5,8,8-tetramethyl-3-pyrazol-l-yl-5,6,7,8-tetrahydro-2-naphthaldehyde. (mp = 95.7-97.6). Horner-Emmons olefination, followed by ester saponification gave 4-{(E)-2-[5,5,8,8-Tetramethyl-3-(pyrazol -1-yl) -5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoic acid 156 (MH+ = 401). Substitution of pyrazole with 3-methylpyrazole gave 4-{(E>2-[5,5,8,8-Tetramethyl-3-(3-methylpyrazol -1-yl) -5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoic acid 157 (MH+ = 415). EXAMPLE 30: PREPARATION OF 5.5.8.8-TETRAMETHYI^3-fPYRIMINDIN-2^ TTnOV5.6.7.8-TETRAHYDRa2-NAPmHALDEYHDE mmoD of pyrazole in 15 mL of N-methyl pyrrolidine was heated to 100 °C. After 2 hours the reaction was cooled to room temperature, poured into brine and extracted with ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution, hexane-16% ethyl acetate/hexane) to afford 32 g (73%) of ethyl-4-[(E)-2-(5,5,8,8-tetramethyl-3pyrazoH-ylmemyl^acetoxy-5,6,7,8-tetrahydbroH^ STEP GiPREPARATION OF 4-ffEV2-(5,5.8.8-TETRAMETHYI^3PY^ YmETHYL-6-HYDRO:XT-5.6.7^^ YLWINYL1BENZOIC ACID A mixture of 0.32 g (0.64 mmol) of ethyl-4-[(E)-2-(5,5,8,8-tetramethyl-3pyrazol-l-ylmemyl-6^acetoxy-5,6,7,8-terrahydro-naphthalen-2-yl)vinyl]benzoate in 10 mL of 1N LiOH solution and 20 mL of ethyl alcohol was heated to reflux. After 1 hour the reaction was cooled to room temperature, concentrated under reduced pressure and acidified with 2 N HCL The aqueous solution was extracted with ethyl acetate, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/ hexane to afford 0.22 g (82%) of 4-[(E>2-(5^,8,8-tetramethyl-3pyrazol-l-ylmethyl-6-hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoic acid 55 (mp = 241.6-242.0°). EXAMPLE38 : PREPARATION OF 4-r(EV2-(5^.8.8-TETRAMETHYL-3PYRAZOL-l> YUvlF^iriT^7-HYDROXY-5.6.7.8-TETRAHYDRO-NAPHTHALEN-2-YLVvTNYLIBENZOIC ACID tetramethyl-3-(2,4-difluorobenzyl)-5,6 J3-tetrahydrc>-naphthalen-2-yl]vinyl}benzoate gave 4~ {(E>2-[5,5,8,8-tetramethyl-3-(2,4-^^ yl]vinyl}benzoic acid (230 mg, 72%) as a white crystalline solid (m.p. 204.3-205.7 ° Q recrystallized from (Cl^Cb/hexane) 43. EXAMPLE 36: PREPARATION OF 4-ifEV245.5.8,8-TEmAMETHYI^3-rTHIOPHEN-3-YLV5,6,7.8-TETRAHYDRONAPHTH AT F.N-7-VT JVINYL1BENZOIC ACID A 0° C, -3M tetrahydrofuran solution of L832 g (6.21 mmol) of 2-fonnyl-3-bromo-5,5,8,8»tetramethyl-5,6,7,8-tetrahydro-naphthylene and diethyl 4-carboethoxybenzyl phosphonate was treated with 301 mg (7.51 mmol, 60% wt in mineral oil) NaH in 30 mg portions over ten minutes. The mixture was then stirred at room temperature for 2 hours before diluting with ethyl acetate and washing with water. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was triturated with methanol yielding 1334 g (50%) Ethyl 4-[(E)-2-(3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthylen-2-yl)vinyl]benzoate. To a solution of 375 mg (.825 mmol) of Ethyl 4-[(E)-2-(3-bromo-5^,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthylen-2-yl)vinyl]benzoate and 48 mg (.0413 mmol) of tetra]ris(triphenylphosphine)palladium(0) in 17 mL of toluene were added 158 mg of 3-thiophene boronic acid(Aldrich) in 5 mL of ethanol followed by 8.5 mL of a saturated aqueous sodium bicarbonate. The mixture was refluxed for 16 hours before diluting with ethyl acetate and washing with water. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo yielding 504 mg of crude residue. The crude mixture was purified by preparatory thin layer chromatography on silica gel (2% ethyl acetate in hexane) yielding 160 mg (44%) of E±y\4-{(E)-2-l5&S,$-t!Stiam tetrahydro-naphtfaylen-2-yl]vinyl}bOTZoatB* A sluny of 160 mg (359 mmol) of Ethyl 4-{(E)-2-[5,5,8t8-tetram^tyl-3-(^iophen-3-yl)-5,6 >7,8-tetrahydro-naphthylen-2-yl]vinyl}beii2oate, 1.5 mL ethanol, and 1 mL of 2M aqueous NaOH was stirred for 16 hours before neutralizing with ammonium chloride and extracting with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo yielding 115 mg of crude residue. The residue was purified by preparatory thin layer chromatography on silica gel (10% MeOH-dichlororaethane) to provide 42 mg of 4-{(E)-2-[5^,8»8-tetramediyl-3-(thio0i«i-3-yl)-5,6,7,8-tetrahydro-naphthalen-2-yl]vinyl}benzoic acid 48. EXAMPLE 37: PREPARATION OF 4-rmV2-f5.5.8,8-TETRAMETHYL-3-PYRAZOL-l- YIJS4ETHYI^6-HYPROXY-5 A7 JTOAYLlVINYLl- BENZOIC ACID STEP A: PREPARATION OF 1,1 A4.7^PE^^^AMETF^fI^2^IETRALONE To a solution of 20 g (140,6 mmol) of dihyrdo^2,2^,5-tetramethtyl-3(2H)-furanone in 240 mL of toluene, cooled in a wet ice bath, was added 38.4 g (288 mmol) of aluminum chloride portionwise ova* 15 minutes. After the addition was complete the reaction mixture was allowed to warm to roomtemperature. After 16 hours the reaction was carefully poured onto ice and the resulting aqueous solution was extracted with ethyl acetate. The organic purified by flash chromatography (gradient elation with hcxane-15% ethyl acetate/hexane) to give 6 g (97%) of 2-biomo-3-methyl-6-acetoxy -53,8»8-teteamefoy]r5,6,7,8-tetrahydronaphthalene.(M+ = 338). STEP D: PREPARATION OF ETHYI^mBV2-fS.5.8.8-T^^ A mixture of 1 M w „ XJ.X4.VS A / XSX M UlV/tllV fcS UlVVltl X V^ MVVkV/1 T •—' »*-' >U , 3-tetramethyl- 5,6,7,8-tetrahydronaphthalene, 0.68 ml (4.42 mmol) of trimethoxyvinyl silane, 0.12 g (0.53 mmol) of palladium acetate 0.36 g of Tri-o-tolylphosphine (1.2 mmol) and 0.82 mL of triethylamine (5.9 mmol) in 10 mL of N-methyl pyrollidinie was heated at 90°C. After 3 hours, the reaction was cooled to room temperature and 0.57 mL (3.5 mmol) of ethyl-4-bromobenzoate, 0.82 mL of triethylamine (5.9 mmol) and 5 mL (5 mmol) of tetrabutylammonium fluoride were added. The reaction mixture was heated to 90° again. After 2.5 hours, the reaction was cooled to room temperature, poured into brine and extracted with ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution 2-5 % ethyl acetate/hexane) to afford 0.2 g (20%) of Ethyl-4[(E)-2-(5,5,8,8-Tetramethyl-3-methyl-6-acetoxy-5,6,7,8-tetrahydro-naphthalen-2yl)vinyl]benzoate (M+ =434)

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