NOVEL TRIENOIC RETINOID COMPOUNDS AND METHODS

Abstract: Novel trienoic retinoid compounds having activity for retinoic acid receptors and retinoid X receptors are provided. Also provided are pharmaceutical compositions incorporating such compounds and methods for their use.

Description: NOVEL TRΓENOIC RETINOID COMPOUNDS AND METHODS Field of the Invention The present invention relates to compounds having activity for retinoic acid receptors and retinoid X receptors, and to methods for the therapeutic use of such compounds. Background of the Invention The vitamin A metabolite, retinoic acid, has long been recognized to induce a broad spectrum of biological effects. In addition, a variety of structural analogues of retinoic acid have been synthesized that also have been found to be bioactive. Some, such as Retin-A ® and Accutane* , have found utility as therapeutic agents for the treatment of various pathological conditions. In addition, synthetic retinoids have been found to mimic many of the pharmacological actions of retinoic acid. Medical professionals have become very interested in the therapeutic applications of retinoids. Among their uses approved by the FDA is the treatment of severe forms of acne and psoriasis. A large body of evidence also exists that these compounds can be used to arrest and, to an extent, reverse the effects of skin damage arising from prolonged exposure to the sun. Other evidence exists that these compounds may be useful in the treatment and prevention of a variety of cancerous and pre-cancerous conditions, such as melanoma, cervical cancer, some forms of leukemia, oral leukoplakia and basal and squamous cell carcinomas. Retinoids have also shown an ability to be efficacious in treating and preventing diseases of the eye, cardiovascular system, immune system, skin, respiratory and digestive tracts, and as agents to facilitate wound healing and modulate programmed cell death (apoptosis). Major insight into the molecular mechanism of retinoic acid signal transduction was gained in 1988, when a member of the steroid/thyroid hormone intracellular receptor superfamily was shown to transduce a retinoic acid signal. Evans, Science, 240:889-95 (1988); Giguere et al., Nature, 330:624-29 (1987); Petkovich et al.. Nature, 330: 444-50 (1987). It is now known that retinoids regulate the activity of two distinct intracellular receptor subfamilies, the Retinoic Acid Receptors (RARs) and the Retinoid X Receptors (RXRs), including their isoforms, RARα, β, γ and RXRα, β, γ In this regard, an endogenous low-molecular- weight ligand which modulates the transcriptional activity of the RARs is all-trαΛS-retinoic acid (ATRA), while an endogenous ligand for the RXRs is 9-as retinoic acid (9-c/s) Heyman et al., Cell, 68 397-406 ( 1992) and Levin et al Nature, 355 359-61 (1992). Although both the RARs and RXRs respond to ATRA m vivo, due to the in vivo conversion of some of the ATRA to 9-cιs, the receptors differ in several important aspects First, the RARs and RXRs are significantly divergent in primary structure (e.g , the ligand binding domains of RARα and RXRα have only 27% amino acid identity) These structural differences are reflected in the different relative degrees of responsiveness of RARs and RXRs to various vitamin A metabolites and synthetic retinoids In addition, distinctly different patterns of tissue distribution are seen for RARs and RXRs For example, in contrast to the RARs, which are not expressed at high levels in the visceral tissues, RXRα mRNA has been shown to be most abundant in the liver, kidney, lung, muscle and intestine Finally, the RARs and RXRs have different target gene specificity For example, response elements have recently been identified in the cellular retinal binding protein type II (CRBPII) and Apolipoprotein Al genes which confer responsiveness to RXR, but not RAR Furthermore, RAR has also been recently shown to repress RXR-mediated activation through the CRBPII RXR response element (Manglesdorf et al , Cell, 66 555-61 ( 1991 )) These data indicate that two retinoic acid responsive pathways are not simply redundant, but instead manifest a complex interplay In view of the related, but clearly distinct, nature of these receptors, retinoids which are more selective for the RAR subfamily or the RXR subfamily would be of great value for selectively controlling processes mediated by one or more of the RAR or RXR isoforms, and would provide the capacity for independent control of the physiologic processes mediated by the RARs or RXRs In addition, pan-agonist retinoids that activate one or more isoforms of both the RARs and RXRs would also be valuable for controlling processes mediated by both of these subfamilies of retinoid receptors Furthermore, retinoids which preferentially affect one or more but not all of the receptor isoforms also offer the possibility of increased therapeutic efficacy and reduced side effect profiles when used for therapeutic applications. Various polyene compounds have been disclosed to be useful in the treatment of inflammatory conditions, psoriasis, allergic reactions, and for use in sunscreens in cosmetic preparations. gee e ^ g., U.S. patent Numbers 4,534,979 and 5,320,833. In addition, trienediolates of hexadienoic acids have proved useful in the synthesis of retinoic and nor- retinoic acids. See M.J. Aurell, et al., 49 Tetrahedron, 6089 (1993). However, no retinoid activity has been ascribed to these compounds. Summary of the Invention The present invention provides novel trienoic compounds that have selective activity on RARs and RXRs or pan-agonist activity on one or more each of the RAR and RXR iso¬ forms The present invention also provides labeled retinoid compounds, pharmaceutical compositions incorporating these novel trienoic compounds and methods for the therapeutic use of such compounds and pharmaceutical compositions. These and various other advantages and features of novelty which characterize the invention are pointed out with particularity in the claims annexed hereto and forming a part hereof However, for a better understanding of the invention, its advantages, and objects obtained by its use, reference should be had to the accompanying descriptive matter, in which there is illustrated and described preferred embodiments of the invention Definitions In accordance with the present invention and as used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise The term alkyl refers to straight-chain, branched-chain or cyclic structures that are optionally saturated or unsaturated (thereby resulting in alkenyl and alkynyl struc¬ tures), as well as combinations thereof The term aryl refers to an optionally substituted six-membered aromatic ring The term heteroaryl refers to an optionally substituted five-membered or six- membered heterocyclic ring containing one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur The terms retinoid or retinoids refer to compound(s) that bind and/or activate one or more retinoid receptors, thereby affecting the transcriptional activity of a target gene to which the activated receptor and compound complex binds The term pan-agonist refers to a retinoid that activates at least one member of both the RAR subfamily (i e , RARα, RARβ, or RARγ) and the RXR subfamily (i e , RXRα, RXRβ, or RXRγ) Preferably such pan-agonist retinoids activate all members of both the RAR and RXR subfamilies of retinoid receptors As used herein, isotopic labels or radiolabels refer to substituents labeled with deuterium, tritium, carbon 13 and/or carbon 14, including, but not limited to 1 CH 3; 13 CH 3 , CD 3 , C 3 H 3 , and 13 CD 3 . Detailed Description of Embodiments of the Invention In accordance with a first aspect of the present invention, we have developed novel trienoic compounds having the formulae: (I) OR (II) OR (III) OR (IV) OR (V) wherein: and R each independently are hydrogen, aryl, heteroaryl, CF3 or a C2 - C ( , alkyl, fluoroalkyl or perfluoroalkyl optionally substituted with 14 CH3 % 13 CH3, CD3, C 3 H3, and/or 13 CD3; 3 5 R and R each independently are hydrogen, CF3, a Cj - C3 alkyl, a Ci to C3 fluoroalkyl or perfluoroalkyl, or OR , where R is hydrogen, CF3, a Cj - C2 alkyl or a C\ to C2 fluoroalkyl or perfluoroalkyl, provided, however, that R and R cannot be CF3 or alkyl, 3 fluoroalkyl or perfluoroalkyl when R is CF3 or alkyl, fluoroalkyl or perfluoroalkyl; R 7 is a Ci - C4 alkyl optionally substituted with 14 CH 3> 13 CH 3 , CD3, C 3 H 3 , and/or 8 8 13 CD3 or CH2OR , where R represents hydrogen, a C\ - Cf, alkyl, a C3 - C7 saturated or unsaturated cycloalkyl optionally substituted with a C\ - C4 alkyl, F, Cl, Br, I, OH, CF3, OR , NR , where R has the definition given above; 9 R is a Ci - C4 alkyl; R through R each independently are hydrogen, a C 1 - β alkyl or CF3; X is COOR 16 , CONR 17 , or CONHR 17 R 18 where R 16 represents hydrogen or a C ] - 17 18 C alkyl, and where R and R each independently represent a Ci - C alkyl, or an aryl or heteroaryl optionally substituted with OH, F, Br, Cl or I, provided, however, that R 17 and 18 R both cannot be an aryl or heteroaryl; 14 15 Y is C, O, S or N, provided that, when Y is O, then R and R do not exist, and 14 15 14 15 when Y is N, then R and R cannot be CF3, and when Y is S, then R and R can inde¬ pendently or together represent O, or may be absent altogether; W is N or CR , where R has the same definition given above; 19 R is an aryl or heteroaryl optionally substituted with one or more substituents selected from the group consisting of hydrogen, F, Cl, Br, I or a Ci - Cg alkyl, wherein X has the same definition given above; n is 0, 1 or 2; the dotted lines designate optional double bonds; and the wavy lines depict carbon to carbon bonds in either the cis or trans configurations, provided, however, that when R , R , R and R are all hydrogen, then R cannot be aryl. 1 2 4 Preferably, R , R and R independently represent C3 - C branched alkyls, fluoro- 2 4 alkyls or perfluoroalkyls, more preferably R and R independently represent C3 - CO branched alkyls, fluoroalkyls or perfluoroalkyls, while R , R and R are all hydrogen, and 2 4 most preferably R and R are selected from the group consisting of isopropyl, t-butyl and CF3, while R 1 , R3 and R 5 are all hydrogen. The compounds of the present invention also include all pharmaceutically acceptable salts, as well as esters, amides and prodrugs. Preferably, such salts, esters and amides, will lft 17 18 be formed at the R , R and/or R positions. As used in this disclosure, pharmaceutically acceptable salts include, but are not limited to: pyridine, ammonium, piperazine, diethyl - amine, nicotinamide, formic, urea, sodium, potassium, calcium, magnesium, zinc, lithium, cinnamic, methylamino, methanesulfonic, picric, tartaric, triethylamino, dimethylamino, and tris(hydoxymethyl)aminomethane. Additional pharmaceutically acceptable salts are known to those skilled in the art. The compounds of the present invention exhibit retinoid activity and are particularly useful in the treatment of skin-related diseases, including, without limitation, actinic kerato- ses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage (steroid atrophy), as a topical anti-microbial, as skin pigmentation agents and to treat and reverse the effects of age and photo damage to the skin. The compounds are also useful for the preven¬ tion and treatment of cancerous and pre-cancerous conditions, including, premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of Kaposis sarcoma. In addition, the present compounds can be used as agents to treat diseases of the eye, including, without limitation, proliferative vitreoretinopathy (PVR), retinal detachment, dry eye and other corneopathies, as well as in the treatment and prevention of various cardiovascular diseases, including, without limita¬ tion, diseases associated with lipid metabolism such as dyslipidemias, prevention of resteno- sis and as an agent to increase the level of circulating tissue plasminogen activator (TPA). Other uses for the compounds of the present invention include the prevention and treatment of conditions and diseases associated with human papilloma virus (HPV), including warts and genital warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn's disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Amyotrophic Lateral Sclerosis (ALS), improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis and inhibition of T-Cell activated apoptosis, restoration of hair growth, including combination therapies with the present compounds and other agents such as Minoxidil ® , diseases associated with the immune system, including use of the present compounds as immunosuppressants and immunostimulants, modulation of organ transplant rejection and facilitation of wound healing, including modulation of chelosis. It will also be understood by those skilled in the art that the retinoid compounds of the present invention will prove useful in any therapy in which retinoids, including RAR selective retinoids, RXR selective retinoids, and pan-agonist retinoids will find application. Furthermore, it will be understood by those skilled in the art that the compounds of the present invention, including pharmaceutical compositions and formulations containing these compounds, can be used in a wide variety of combination therapies to treat the condi¬ tions and diseases described above. Thus, the compounds of the present invention can be used in combination with other therapies, including, without limitation, chemotherapeutic agents such as cytostatic and cytotoxic agents, immunological modifiers such as interferons, interleukins, growth hormones and other cytokines, hormone therapies, surgery and radiation therapy. Representative compounds of the present invention include, without limitation, ethyl (2E, 4E, 6E 7-(3,5-di-t-butylphenyl)-3-methylocta-2,4,6-trienoate; ethyl (2E, 4E, 6ZJ -7- (3,5-di-t-butylphenyl)-3-methylocta-2,4,6-trienoate; (2E, 4E, 6E 7-(3,5-di-t-butylphenyl)-3- methylocta-2,4,6-trienoic acid; (2E, 4E, 6Z 7-(3,5-di-t-butylphenyl)-3-methylocta-2,4,6- trienoic acid; ethyl (2E, 4Ej-7-(3,5-di-t-butylphenyl)-3-methylocta-2,4-dienoate; (2E, 4E)-1- (3,5-di-t-butylphenyl)-3-methylocta-2,4-dienoic acid; ethyl (2E, 4E, 6EJ-7-(3,5-di-t- butylphenyl)-3-methyldeca-2,4,6-trienoate; ethyl (2E, 4E, 6E)-7-(3,5-di-t-butylphenyl)-3- methyldeca-2,4,6-trienoate; (IE, 4E, 6E, ) -7-(3,5-di-t-butylphenyl)-3-methyldeca-2,4,6- trienoic acid; (2E, 4E, 6Z 7-(3,5-di-t-butylphenyl)-3-methyldeca-2,4,6-trienoic acid; ethyl (2E,4E,6E -6-(6,8-di-t-butylchroman-4-ylidene)-3-methylhexa-2,4,6-trienoate; ethyl (2E,4E,6Z 6-(6,8-di-t-butylchroman-4-ylidene)-3-methylhexa-2,4,6-trienoate; (2E,4E,6E 6-(6,8-di-t-butylchroman-4-ylidene)-3-methylhexa-2,4,6-trienoic acid; (2E,4E,6Z 6-(6,8-di- t-butylc--roman-4-y-idene)-3-methylhexa-2,4,6-trienoic acid; (2E, 4E, 6£ 7-(3,5-di- trifluoromethylphenyl)-3-methylocta-2,4,6-trienoic acid; (2E, 4E, 6Z 7-(3,5-di- trifluoromethylphenyl)-3-methylocta-2,4,6-trienoic acid; (2E, 4E, 6_ζ -7-(3,5-di- isopropylphenyl)-3-methylocta-2,4,6-trienoic acid; (2E, 4E, 6Z 7-(3,5-di-isopropylphenyl)- 3-methylocta-2,4,6-trienoic acid; (2E, 4E, 6E 7-(4-t-butylphenyl)-3-methylocta-2,4,6- trienoic acid; (2E, 4E, 6E 7-(3,5-di-t-butyl-4-methoxyphenyl)-3-methylocta-2,4,6-trienoic acid; (2E, 4E, 6E -3-methyl-7-(3,5-di-t-butyl-4-methoxyphenyl)octa-2,4,6-trienoic acid; (2E,4E,6£)-3-methyl-7-(3,4-diethylphenyl)octa-2,4,6-trienoic acid; (2E,4E,6Z)-3-methyl-7- (3,4-di-ethylphenyl)octa-2,4,6-trienoic acid; (2E, 4£, 6E)-3-methyl-7-(3,5-di-t-butyl-4- ethoxyphenyl)octa-2,4,6-trienoic acid; (2E,4E,6E)-3-methyl-7-(3,4-di-t-butylphenyl)octa- 2,4,6-trienoic acid; (2E,4E,6E)-3-methyl-7-cyclohexyl-7-(3,5-di-t-butylphenyl)hepta-2,4,6- trienoic acid; (2E,4E,6£)-3-methyl-7-(3,5-di-t-butylphenyl)nona-2,4,6-trienoic acid; and (2E,4E,6Z)-3-methyl-7-(3,4-diethyl-6-methylphenyl)nona-2,4,6-trienoic acid. The compounds of the present invention can be obtained by routine chemical synthe¬ sis by those skilled in the art, e.g., by modification of the compounds disclosed or by a total synthesis approach. In this regard, the synthesis of the compounds of the present invention follows well established retinoid synthesis schemes and techniques as described in M.I. Daw- son and W.H. Okamura, "Chemistry and Biology of Synthetic Retinoids", Chapters 3, 8, 14 and 16, CRC Press, Inc., Florida (1990); M.I. Dawson and P.D. Hobbs, The Synthetic Chemistry of Retinoids, In Chapter 2: "The Retinoids, Biology, Chemistry and Medicine", M B. Sporn et al., Eds. (2nd ed ), Raven Press, New York, New York, pp. 5-178 (1994) and R.S.H. Liu and A. E. Asato, "Photochemistry and Synthesis of Stereoisomers of Vitamin A," 40 Tetrahedron, 1931 (1984), the disclosures of which are herein incorporated by refer¬ ence. The sequence of steps of the general methods of synthesizing the compounds of the present invention are shown below. In addition, more detailed and illustrative synthetic schemes for specific compounds of the present invention will be found in the Examples included herein. General Method 1 B In General Method 1, the compounds of the present invention may be prepared by treatment of an aryl ketone A with a phosphonate, such as diethylcyanomethylphosphonate, to give the nitrile B, followed by reduction of B (where the optional single or double bonds are illustrated with dashed lines) in the presence of a reducing agent, such as diisobutyl alu¬ minum hydride (Dibal) to provide the aldehyde C. The cis and trans isomers of aldehyde C may be separated at this stage via thin-layer chromatography (TLC), or other recognized procedures known to those skilled in the art. These separated aldehydes C are then treated with a phosphonate, such as triethyl-3-alkyl-4-phosphonocrotonate, to give the trienoate esters D, which in turn can be saponified under basic conditions to give the carboxylic acid E Alternatively, utilizing General Method 2, shown below, the cis isomer of aldehyde C may be prepared from the alkyne F. Specifically, aryl alkyne F is prepared from aryl aceto- phenone A by treatment with a phosphorylating agent, such as ClPO(EtO) 2 , in the presence of a strong base, such as lithium diisopropylamide (LDA). Aryl alkyne F is then treated with a suitable nitrile source, such as PhOCN, in the presence of base, such as nBuLi, to give nitrile G, which is then subjected to reductive methylation to give exclusively the cis isomer of nitrile B. Nitrile B is then reduced to the corresponding aldehyde C and homologated in the same fashion as described in General Method 1 above to yield compounds D and E. General Method 2 PhOCN nBuLi DIBAL hexanes Other analogs of compounds of the present invention may be prepared via General Method 3, by first reducing the double bond of nitrile B (where the single or double optional bonds are illustrated with dashed lines) to give nitrile I. Thereafter nitrile I is reduced in the presence of Dibal to yield aldehyde J, which in turn is treated with a phosphonate, such as triethyl-3-alkyl-4-phosphonocrotonate, to give dienoate ester K. Saponification of dienoate ester K via base, such as KOH MeOH, gives the dienoic acid L. General Method 3 B K Radiolabeled homologs of the compounds of the present invention may be prepared by the General Method 4 shown below Specifically, compound A is oxidized to methyl ester B which is then reduced with a tritium hydride source, such as LiAl 3 H 4 , to alcohol C Oxidation of the tritiated alcohol C to aldehyde D, followed by condensation with the ylide of triethylphosphonocrotonate gives the tritiated ester E Ester E may then be saponified to give the final tritium labeled acid F in high yield with high (>20 Ci/mmol) specific activity This methodology is described in detail in Boehm et al , "Synthesis of High Specific Activity [ H]-9-c.s-Retinoic Acid and Its Application for Identifying Retinoids with Unusual Binding Properties", 37 J Med Chem . 408-414 (1994), the disclosure of which is herein incor¬ porated by reference General Method 4; Preparation of Radiolabeled Homoloes B It will be understood by those skilled in the art that certain modifications can be made to the above-described methods that remain within the scope of the present invention. For example, the compounds of the present invention may also be produced in the form of the corresponding amides or esters, appropriate phosphoranes may be substituted for phos- 3 phonates, and reducing agents other than LiAl H4 may be utilized in the syntheses outlined above. Furthermore, it will be understood that other isotopic labels may be employed, 13 13 including CH3, CD3 and the like. These labels may be introduced using the appropriate 13 labeled MeLi (e.g., CH3Li)as shown in Scheme 1. Thereafter, the remainder of the syn¬ thesis is as shown in Scheme 1. In another aspect, the retinoid compounds, their pharmaceutically acceptable salts or hydrolyzable esters of the present invention are combined in a mixture with a pharmaceuti¬ cally acceptable carrier to provide pharmaceutical compositions useful for treating the bio¬ logical conditions or disorders noted herein in mammalian species, and more preferably, in human patients. The particular carrier employed in these phaπnaceutical compositions may take a wide variety of forms depending upon the type of administration desired, e.g., intrave¬ nous, oral, topical, suppository or parenteral. In preparing the compositions in oral liquid dosage forms (e.g., suspensions, elixirs and solutions), typical pharmaceutical media, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be employed. Similarly, when prepar¬ ing oral solid dosage forms (e.g., powders, tablets and capsules), carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like will be employed. Due to their ease of administration, tablets and capsules represent the most advantageous oral dosage form for the pharmaceutical compositions of the present invention For parenteral administration, the carrier will typically comprise sterile water, although other ingredients that aid in solubility or serve as preservatives, may also be included. Furthermore, injectable suspensions may also be prepared, in which case appro¬ priate liquid carriers, suspending agents and the like will be employed. For topical administration, the compounds of the present invention may be formulated using bland, moisturizing bases, such as ointments or creams. Examples of suitable ointment bases are petrolatum, petrolatum plus volatile silicones, lanolin, and water in oil emulsions suc as Eucerin™ (Beiersdorf). Examples of suitable cream bases are Nivea™ Cream (Beiersdorf), cold cream (USP), Purpose Cream™ (Johnson & Johnson) hydrophilic ointment (USP), and Lubriderm™ (Warner-Lambert). The pharmaceutical compositions and compounds of the present invention will gen¬ erally be administered in the form of a dosage unit (e.g., tablet, capsule etc.) at from about 1 μg/kg of body weight to about 500 mg/kg of body weight, more preferably from about 10 μg/kg to about 250 mg/kg, and most preferably from about 20 μg kg to about 100 mg/kg As recognized by those skilled in the art, the particular quantity of pharmaceutical composi- tion according to the present invention administered to a patient will depend upon a number of factors, including, without limitation, the biological activity desired, the condition of the patient, and tolerance for the drug. The compounds of this invention also have utility when labeled and used in assays to determine the presence of RARs and RXRs. They are particularly useful due to their ability to selectively bind to members of the RAR and RXR subfamilies and can therefore be used to determine the presence of RAR and RXR isoforms in the presence of other retinoid receptors or related intracellular receptors. Thus, the present invention also provides isotopically labeled and radiolabeled compounds, and methods for their synthesis, including deuterium, tritium, carbon 13 and carbon 14 labeled homologs. In a preferred aspect, the labeled compounds of the present invention display a specific activity of at least 15 Ci/mmol, and more preferably at least 25 Ci/mmol, and most preferably, at least 40 Ci/mmol. Such labeled compounds will also prove useful in the identification of compound metabolites in animal metabolism studies. Due to the selective specificity of the compounds of this invention for retinoid receptors, these compounds can also be used to purify samples of RARs and RXRs in vitro. Such purification can be carried out by mixing samples containing retinoid recep¬ tors with one of more of the compounds of the present invention, so that the compound (ligand) binds to the receptor, and then separating out the bound ligand receptor combi- nation by separation techniques which are known to those of skill in the art. These techniques include column separation, filtration, centrifugation, tagging and physical separation, and antibody complexing, among others. The compounds of the present invention also include racemate, individual stereoiso- mers and mixtures thereof. These isomers are then isolated by standard resolution tech- niques, including fractional crystallization and chiral column chromatography. The compounds and pharmaceutical compositions of the present invention can advantageously be used in the treatment of the diseases and conditions described herein. In this regard, the compounds and compositions will prove particularly useful in the treatment of skin-related diseases and conditions, such as acne, psoriasis, and photo damage, cancerous and precancerous conditions, diseases of the eye, cardiovascular diseases, inflammatory and neurodegenerative diseases, diseases associated with human papilloma virus, improper pitui¬ tary function, modulation of apoptosis, diseases of the immune system, wound healing and restoration of hair growth. Furthermore, the compounds and pharmaceutical compositions of the present inven- tion possess a number of advantages over previously identified retinoid compounds. For example, the compounds are extremely potent activators of RARs and RXRs as demon¬ strated in the co-transfection assay further described herein, preferably displaying 50% maximal activation (i.e., EC5 0 ) of one or more of the retinoid receptors at a concentration of less than 100 nM, more preferably at a concentration of less than 50 nM, more preferably yet at a concentration of less than 20 nM, and most preferably at a concentration of less than 10 nM. Also, the RAR and RXR selective compounds of the present invention preferentially activate one subfamily of retinoid receptors at a potency level at least 2 times greater, pref¬ erably at least 5 times greater, more preferably at least 10 times greater, and most preferably at a potency level at least 100 times greater than the other subfamily of retinoid receptors. In addition, the compounds of the present invention also are easier to synthesize, provide greater stability and bioavailability, and appear to be less teratogenic in comparison to all- trans retinoic acid and 9-cis retinoic acid, known RAR and RXR active compounds, respec¬ tively. The invention will be further illustrated by reference to the following non-limiting Examples. [rest of page left purposely blank] EXAMPLES 1-2 (2E, 4E, 6E -7-(3,5-Di-t-butylphenyl)-3-methylocta-2,4,6-trienoic acid (9) and (2E, 4E, 6Z)-7-(3,5-di-t-butylphenyl)-3-methylocta-2,4,6-trienoic acid (10), prepared according to Scheme 1 illustrated and described below. Scheme 1 3 trans 4 cis 5 trans 7 trans 9 trans β cis β cis 10 cis 3.5-Di-t-butylacetophenone (D To 20 g (85.5 mmol) of 3,5-di-tertbutylbenzoic acid 1 in 100 mL of dry THF at -78 °C was added 94.0 mL (188.0 mmol) of a 2 N ether solution of MeLi. The reaction mixture was slowly warmed to room temperature and stirred for an additional 30 min., then poured into saturated aqueous NH4CI (200 mL). The organic prod¬ uct was extracted with hexanes (2 X 100 mL) dried (MgSO4), filtered, concentrated and purified by chromatography (Siθ2, 2 ΕtOAc-hexanes) to give 15 g (64.7 mmol) of ketone 2 (75 7% yield) TLC (5% EtOAc-95% hexanes) Rf 0 8, Ϊ H-NMR (CDCI3) δ 1 39 (s, 18H, 6(CH3)), 2 61 (s, 3H, CH3), 7 64 (t, J = 1 Hz, IH, Ar-H), 7 80 (d, J = 1 Hz, 2H, Ar-H) 3-(3.5-Di-t-butylphenyl.but-2-enitrile (3) (trans) and (4. (cis) To 2 43 g (13 7 mmol) of diethylcyanomethyl phosphonate in 10 mL of dry THF was added 440 mg (10 96 mmol) of NaH (60% in mineral oil) The reaction was stirred for 30 min followed by addition of 1 59 g (6 85 mmol) of ketone 2 in 5 mL of dry THF After stirring for 12 h, the mixture was quenched with saturated aqueous NH4CI (50 mL) and the products were extracted with ether (2 X 50 mL) The ether extracts were washed (water then brine), dried (MgSO4), fil- tered, concentrated and purified by preparative TLC (Siθ2, 2 5 % EtOAc-hexanes) to give 1 1 g (44 mmol) of the trans isomer 3 and 104 mg (0 4 mmol) of the cis isomer 4 (70% combined yield ) Trans isomer 3: TLC (5% EtOAc-95% hexanes) Rf 0 9, 1H-NMR (CDCI3) 6 1 32 (s, 18H, 6(CH3)), 2 49 (s, 3H, CH3), 5 59 (s, IH, =CH), 7 25 (d, J = 1 Hz, 2H, Ar-H), 7 50 (d, J = 1 Hz, IH, Ar-H) Cis isomer 4: TLC (5% EtOAc-95% hexanes) Rf 0 8, 1H-NMR (CDCI3) δ 1 42 (s, 18H, 6(CH3)), 2 31 (s, 3H, CH3), 5 34 (s, IH, =CH), 7 39 (d, J = 1 Hz, 2H, Ar-H), 7 49 (d, J = 1 Hz, IH, Ar-H) 3-(3.5-Di-t-butylphenyl.but-2-enal (5) (trans isomer. To 736 mg (2 89 mmol) of 3 in 5 mL of CH2CI2 at -78 °C was added 2 31 mL (3 47 mmol) of a 1 5 M solution of DIBAL in toluene After stirring for 15 min at -78 °C, the reaction mixture was quenched with 10 mL of a saturated aqueous solution of Rochelle salt The product was extracted with ether (2 X 20 mL), washed (water, then brine), dried (MgSO4), filtered, concentrated and purified by chromatography (Siθ2, 3 % EtOAc-hexanes) to give 462 3 mg (1 80 mmol) of 5 (62 % yield) TLC (10% EtOAc-90% hexanes) Rf 0 5, 1H-NMR (CDCI3) δ 1 34 (s, 18H, 6(CH3)), 2 59 (s, 3H, CH3), 6 50 (d, J = 8 0 Hz, IH, =CH), 7 39 (d, J = 1 Hz, 2H, Ar-H), 7 51 (d, J = 1 Hz, IH, Ar-H), 10 18 (d, J = 8 0 Hz, IH, CHO) 3-(3.5-Dι-t-butylphenyl.but-2-enal (6) (cis isomer. The as isomer 6 was prepared from the corresponding as isomer 4 using the same method as described for 5 TLC (10% EtOAc- 90% hexanes) Rf 0.55; iH-NMR (CDCI3) δ 1.34 (s, 18H, 6(CH3)), 2.34 (s, 3H, CH3), 6.12 (d, J = 8.0 Hz, IH, =CH), 7.10 (d, J = 1 Hz, 2H, Ar-H), 7.46 (t, J = 1 Hz, IH Ar-H), 9.45 (d, J = 8.0 Hz, IH, CHO). Ethyl (2£. 4E. 6EJ-7-(3.5-di-t-butylphenvn-3-methylocta-2.4.6-trienoate f7V To 790 mg (3.0 mmol) of triethyl-3-methyl-4-phosphonocrotonate in 8 mL of dry THF at -78 °C was added 1.2 mL of a 2.5 M nBuLi solution in hexanes. After stirring for 15 min., the solution containing the ylide of triethylphosphonocrotonate was added to 258 mg (1.0 mmol) of the trans isomer 5 in 8 mL of dry THF at -78 °C. The reaction mixture was warmed to RT, quenched with saturated aqueous NH4CI (20 mL) and the products were extracted with ether (2 X 50 mL). The ether extracts were washed (water, then brine), dried (MgSO4), fil¬ tered, concentrated and purified by column chromatography (Siθ2, 5 % EtOAc-hexanes) to give 294 mg (0.8 mmol) of the £,E,£isomer of 7 (49% yield): TLC (5% EtOAc-95% hex¬ anes) Rf 0.78; !H-NMR (CDCI3) δ 1.30 (t, J = 7.7 Hz, 3H, CH2CH3), 1.34 (s, 18H, 6(CH3)), 2.28, (s, 3H, CH3), 2.39 (s, 3H, CH3), 4.17 (m, 2H, CH2CH3), 5.82 (s, IH, =CH), 6.40 (d, J = 15 Hz, IH, =CH), 6.54 (d, J = 15 Hz, IH, =CH), 7.04 (m, IH, =CH), 7.21 (d, J = 1Hz, 2H, Ar-H), 7.39 (d, J = 1 Hz, IH, Ar-H). Ethyl (2E. 4E. 6Z>-7-(3.5-di-t-butylphenvn-3-methylocta-2.4.6-trienoate (8V The 2E, 4E, 6Z isomer 8 was prepared in the same manner as the 2E,4E,6__.-isomer 7, except that 6 was used instead of the 5: TLC (5% ΕtOAc-95% hexanes) Rf 0.82; Ϊ H-NMR (CDCI3) δ 1.27 (t, J = 7.7 Hz, 3H, CH2CH3), 1.34 (s, 18H, 6(CH3)), 2.17, (s, 3H, CH3), 2.22 (s, 3H, CH3), 4.15 (m, 2H, CH2CH3), 5.74 (s, IH, =CH), 6.26 (dd, J = 8 Hz, 2H, =CH), 6.80 (m, IH, =CH), 7.10 (d, J = 1 Hz, 2H, Ar-H), 7.37 (t, J = 1 Hz, IH, Ar-H). (2E. 4E. 6EJ-7-r3.5-Di-t-butylρhenyl.-3-methylocta-2.4.6-trienoic acid (9V To 180 mg (0.49 mmol) of the IE, ΛE, 6E-ethyl ester 7 in 5 mL of MeOH was added 1 mL of 5N aque¬ ous NaOH solution. The mixture was heated to reflux for 10 min., cooled to RT, acidified with 20% aqueous HCI solution and the organics extracted with ether (2 x 10 mL). The ether layer was washed (H2O, brine), dried (MgSO4), filtered and concentrated. Purification by column chromatography (Siθ2, 20% EtOAc-hexanes) gave 157 mg (0.46 mmol) of the 2£,4£,6E-isomer 9 (93% yield): TLC (10% MeOH-90% CHCI3) Rf 0.6; mp 196-198 °C; iH-NMR (CDCI3) δ 1.35 (s, 18H, 6(CH3)), 2.29, (s, 3H, CH3), 2.41 (s, 3H, CH3), 5.84 (s, IH, =CH), 6.41 (d, J = 15 Hz, IH, =CH), 6.54 (d, J = 15 Hz, IH, =CH), 7.08 (m, IH, =CH), 7.32 (d, J = 1Hz, 2H Ar-H), 7.39 (t, J = 1 Hz, IH, Ar-H). (2E. 4E. 6Z)-7-(3.5-Di-t-bu lphenyl.-3-methylocta-2.4.6-trienoic acid f 10V The 2E, 4E, 6Z-isomer 10 was prepared in the same manner as 9 except that 8 was used instead of 7: TLC (10% MeOH-90% CHCI3) Rf 0.57; mp 221-222 >C; iH-NMR (CDCI3) δ 1.34 (s, 18H 6(CH3)), 2.18, (s, 3H CH3), 2.23 (s, 3H, CH3), 5.77 (s, IH, =CH), 6.27 (m, 2H, =CH), 6.84 (m, IH, =CH), 7.10 (d, J = 1 Hz, 2H, Ar-H), 7.37 (t, J = 1 Hz, IH, Ar-H). [rest of page left purposely blank] EXAMPLE 3 (IE, 4£ 7-(3,5-Di-t-butylphenyl)-3-π-ethyIocta-2,4-dienoic acid (14), prepared accord¬ ing to Scheme 2 illustrated and described below. Scheme 2 11 12 80 % yield 13 14 3-(3.5-Di-t-butylphenyl .butanitrile ( 11 V To 300 mg (1.18 mmol) of 3-(3,5-di-t- butylphenyl)-but-2-enitrile 3 in 5 mL of EtOAc was added 20 mg (catalytic quantity) of 10% Pd/C. The mixture was placed under vacuum for 0.5 min., followed by addition of H2 gas. After stirring for 2 h under H2 gas, the solution was filtered through celite, the celite washed with EtOAc (3 x 5 mL) and the solution concentrated to give 300 mg (1.17 mmol) of the reduced product 11 (99% yield): TLC (5% EtOAc-95% hexanes) Rf 0.8; iH-NMR (CDCI3) δ 1.34 (s, 18H, 6(CH3)), 1 50 (d, 3H, CH3), 2.60 (m, 2H, CH2), 3.15 (m, IH, CH), 7.05 (d, J = 1 Hz, 2H, Ar-H), 7.33 (t, J = 1 Hz, IH, Ar-H). 3-(3.5-Di-t-butylphenyl.butanai i2V To 300 mg (1.17 mmol) of the nitrile 11 in 5 mL of CH2CI2 at -78 °C was added 0.93 mL (1.4 mmol) of a 1.5 M DIBAL solution in toluene. The reaction mixture was stirred for 5 min., quenched with saturated aqueous NH4CI (10 mL), extracted with ether (2 x 20 mL), dried (MgSO4), filtered, concentrated and purified by chromatography (Siθ2, 5% EtOAc-hexanes) to give 188 mg (0 72 mmol) of the desired aldehyde 12 (62% yield) TLC (5% EtOAc-95% hexanes) Rf 0 8, iH-NMR (CDCI3) δ 1 34 (s, 18H 6(CH3)), 1 35 (d, 3H, CH3), 2 70 (m, 2H, CH2), 3 36 (m, IH, CH), 7 06 (d, J = 1 Hz, 2H, Ar-H), 7 28 (t, J = 1 Hz, IH, Ar-H), 9 70 (t, IH, CHO) Ethyl (IE. 4EJ-7-f3.5-di-t-butylphenylV3-methylocta-2.4-dιenoate (13. Compound 13 was prepared from 12 in a similar manner as described for compound 7 TLC (5% ΕtOAc-95% hexanes) Rf 0 88, H-NMR (CDCI3) δ 1 30 (m, 6H, CH2CH3+CH3), 1 34 (s, 18H, 6(CH3)), 2 20, (s, 3H, CH3), 2 40 (m, 2H, CH2), 2 85 (m, IH, CH), 4 14 (m, 2H, CH2CH3), 5 62 (s, IH, =CH), 6 03 (m, 2H, =CH), 7 00 (d, J = 1 Hz, 2H, Ar-H), 7 24 (t, J = 1 Hz, IH Ar-H) (2E. 4E)-7-(3.5-Di-t-butylpheny..-3-methylocta-2.4-dienoic acid (\ >) Compound 14 was prepared from 13 in a similar manner as described for compound 9: TLC (10% MeOH-90% CHCI3) Rf 0 5, mp 127-128 °C, -NMR (CDCI3) δ 1 28 (d, J = 8 Hz, 3H, CH3), 1 32 (s, 18H, 6(CH3)), 2 23, (s, 3H, CH3), 2 46 (m, 2H, CH2), 2 86 (m, IH, CH), 5 69 (s, IH, =CH), 6 10 (m, 2H, =CH), 7 01 (d, J = 1 Hz, 2H, Ar-H), 7 26 (t, J = 1 Hz, IH, Ar-H) [rest of page left purposely blank] EXAMPLE 4 (2E, 4E, 6Z)-7-(3,5-Di-t-butylphenyl)-3-methylocta-2,4,6-trienoic acid (10), alternative preparation of Compound (10) according to Scheme 3 illustrated and described below. Scheme 3 1. nBuLi, THF, -78 °C 2. PhOCN, -78 °C-RT 92 % yield 15 5N KOH, MeOH reflux 91 % yield 10 1.3-Di-t-butyl-5-ethvnylbenzene f 1SV To 9.86 mL (24.7 mmol) of a 2.5 N LDA solution in THF at -78 °C was added 4.75 g (20.47 mmol) of ketone 2 (from EXAMPLES 1-2) in 3 mL of dry THF. After stirring for 30 min., 2.96 mL (20.47 mmol) of diethylphosphonylchloride was added and the reaction mixture was warmed to RT for 1 h. The reaction mixture was again cooled to -78 °C followed by addition of 19.7 mL (49.2 mmol) of a 2.5 N LDA solu¬ tion in THF and warmed to RT. Water (50 mL) was added and the mixture was extracted with hexanes (2 x 40 mL). The combined organic extract was washed (water, then brine), dried (MgSO4), filtered, concentrated and purified by column chromatography (Siθ2, 2% EtOAc-hexanes) to give 3.02 g (14.1 mmol) of compound 15 (69% yield): TLC (hexanes) Rf 0.9; iH-NMR (CDCI3) δ 1.31 (s, 18H, 6(CH3 ), 3.02 (s, IH, C≡CH), 7.35 (d, J = 1 Hz, 2H, Ar-H), 7.42 (t, J = 1 Hz, IH, Ar-H). 3 -(3.5-Di-t-butylphenyl propynitrile (16). To 1.67 g (7.80 mmol) of propyne 15 in 25 mL of dry THF at -78 °C was added 3.75 mL (9.38 mmol) of nBuLi (2.5 M in hexanes). After stirring for 15 min., 1.12 g (9.41 mmol) of PhOCN was added and the reaction mixture was warmed to RT. The mixture was quenched by addition of 25 mL of aqueous 6N NaOH, extracted (EtOAc, 2 x 25 mL), washed (water, then brine), dried (MgSO4), filtered, con¬ centrated and purified by column chromatography (Siθ2, 5% EtOAc-hexane) to give 1.71 g (7.16 mmol) of 16 as a white solid (92% yield) : TLC (hexanes) Rf 0.4; i H-NMR (CDCI3 ) δ 1.32 (s, 18H, 6(CH3)), 7.45 (d, J = 1 Hz, 2H, Ar-H), 7.58 (t, J = 1 Hz, IH, Ar-H). 3-(3.5-Di-t-butylphenyl.but-2-enitrile (4. (cis isomer). A 250 mL flame dried round bottom flask was charged with 3.27 g (17.17 mmol) of anhydrous copper iodide and 25 mL of dry THF. The mixture was cooled to 0° C, followed by slow addition of 24.5 mL (34.3 mmol) of MeLi (1.4 M in ether). After the solution became clear and colorless, it was cooled to -78 °C and a solution of 1.71 g (7.16 mmol) of 16 in 10 mL of dry THF was added dropwise. The mixture was stirred at -78 °C for 45 min. and quenched with 40 mL of a 1 : 1 mixture of MeOH and saturated aqueous NH4CI solution. The product was extracted with EtOAc (2 x 40 mL), washed (2% NaOH followed by sat. NH4CI, then water, then brine), dried (MgSO4), filtered, concentrated and purified through a short silica gel pad to give 1.64 g (6.80 mmol) of the cis isomer 4 (95% yield): TLC (5% EtOAc-95% hexanes) Rf 0.8; iH- NMR (CDCI3) δ 1.42 (s, 18H, 6(CH3)), 2.31 (s, 3H, CH3), 5.34 (s, IH, =CH), 7.39 (d, J = 1 Hz, 2H, Ar-H), 7.49 (d, J = 1 Hz, IH, Ar-H). The remaining synthesis of Compounds 6, 8 and final product 10 were performed as described in EXAMPLES 1-2 above. EXAMPLES 5-6 (2E. 4E.6E -7-(3,5-Di-t-butyIphenyl)-3-methyldeca-2,4,6-trienoic acid (27) and {IE. 4E, 6Z)-7-(3,5-di-t-butylphenyl)-3-methyldeca-2,4,6-trienoic acid (28), prepared according to Scheme 4 illustrated and described below. Scheme 4 17 18 DΛβ/, RT-reΛux -78° C, 83 % yield 75% yield 19 20 21 trans 22 cis 23 trans 88 % yield 25 trans 27 trans 24 cis 26 cis 2β cis 3.5-Di-t-butylbenzyl alcohol 117V To 10.0 g (42.7 mmol) of acid 1 in 20 mL of dry THF at 0 °C was added 42.7 mL (42.7 mmol) of LAH (1.0 M in THF). The reaction mixture was warmed to 50 °C and stirred for 15 min After cooling the reaction to RT, 20% aqueous HCI was added until the solution turned clear. The solution was extracted with EtOAc (2 x 50 mL), and the combined EtOAc extract was washed (water, then brine), dried (MgSO4), filtered and concentrated to give 8.8 g (40.0 mmol) of 17 (94 % yield): The product was directly used in the next step. TLC (20% EtOAc-80% hexanes) Rf 0.4; iH-NMR (CDCI3) δ 1.33 (s, 18H, 6(CH3)), 4.68 (s, 2H, CH2) 7.22 (d, J = 1 Hz, 2H Ar-H), 7.38 (t, J = 1 Hz, IH, Ar-H). 3.5-Di-t-butylbenzaldehvde (18V To 8.8 g (40.0 mmol) of alcohol 17 in 20 mL of CH2CI2 was added 50.0 g (575 mmol) of Mnθ2 The reaction mixture was vigorously stirred for 8 h and filtered through a pad consisting of a top layer of celite and a bottom layer of silica. The filter was washed repeatedly with 50 mL aliquots of CH2CI2 until no more product eluted from the filter. The resulting compound 18 (8.3 g (38 1 mmol)) was determined to be pure by iHNMR and was used directly in the next step (95 % yield): TLC (20% EtOAc-80% hexanes) Rf 0.6; iH-NMR (CDCI3) δ 1.34 (s, 18H, 6(CH3)), 7.72 (m, 3H, Ar-H), 10.01 (s, IH, CHO). 1 -(3.5-Di-t-butylphenyl .butan-1-ol (19V To 2.0 g (9.17 mmol) of aldehyde 18 in 10 mL of dry ether at 0 °C was added 5.5 mL (11.0 mmol) of propylmagnesium chloride (2 0 M in ether). The reaction mixture was warmed to RT and quenched with water (50 mL), extracted (ether, 2 x 50 mL), washed (water then brine), dried (MgSO4), filtered and con¬ centrated to give 2.37 g (9.05 mmol) of alcohol 19 (pure by iH-NMR) which was directly used in the next step (98% yield): TLC (20% EtOAc-80% hexanes) Rf 0.5; iH-NMR (CDCI3) δ 0.96 (t, 3H, CH2CH3), 1 34 (s, 18H, 6(CH3)), 1.66 (m, 2H, CH2), 1 84 (m, IH, CH), 4.66 (m, IH, CHOH), 7.18 (d, J = 1 Hz, 2H, Ar-H), 7.34 (t, J = 1 Hz, IH, Ar-H). 1 -(3.5-Di-t-butylphenyl .butan- 1 -one (20V To 2.37 g (9.05 mmol) of alcohol 19 in 18 mL of CH2CI2 was added 7.86 g (90.45 mmol) of Mnθ2 The reaction mixture was stirred for 3 h, then filtered (celite over silica gel pad) and the pad was washed repeatedly with 20 mL ali¬ quots of CH2CI2 After concentration, ketone 20 was purified by chromatography (Siθ2, 3% EtOAc-hexanes) to give 941 mg (3.62 mmol) of 20 (40% yield): TLC (10% EtOAc- 90% hexanes) Rf 0.7; iH-N R (CDCI3) δ 1.01 (t, 3H, CH2CH3), 1.34 (s, 18H, 6(CH3)), 1.78 (m, 2H, CH2CH3), 2.96 (t, J = 7 Hz, 2H, CH2CH2CH3), 7.63 (t, J = 1 Hz, IH, Ar-H), 7.83 (d, J = 1 Hz, 2H, Ar-H). 3-(3.5-Di-t-butylρhenyl .hex-2-enitrile (21) (trans) and (22) (cis To 661 mg (3.73 mmol) of diethylcyanomethylphosphonate in 5 mL of dry THF was added 127 mg (3.17 mmol) of sodium hydride (60% dispersion in mineral oil). The mixture was stirred for 5 min., followed by addition of 484 mg (1.87 mmol) of ketone 20 in 2 mL of dry THF. The reaction was heated to reflux for 30 m, cooled to RT, quenched with saturated aqueous NH4CI (15 mL), extracted with ether (2 x 15 mL), washed (water then brine), dried (MgSO4), filtered and concentrated. Purification by chromatography (preparative TLC, Siθ2, 10% EtOAc- hexanes) gave 329 mg (1.16 mmol) of the trans isomer 21 and 70.5 mg (0.25 mmol) of the as isomer 22 (75 % combined yield). Trans isomer 21 TLC (10% EtOAc-90% hexanes) Rf 0.8; iH-NMR (CDCI3) δ 0.97 (t, J = 7 Hz, 3H, CH2CH3), 1.33 (s, 18H 6(CH3», 1.54 (m, 2H, CH2CH2CH3), 2.88 (t, J = 7 Hz, 2H, CH2CH2CH3), 5.50 (s, IH, =CH), 7.23 (d, J = 1 Hz, 2H, Ar-H), 7.50 (t, J = 1 Hz, IH, Ar-H). Cis isomer 22: TLC (10% EtOAc-90% hexanes) Rf 0.9; iH-NMR (CDCI3) δ 0.93 (t, J = 7 Hz, 3H, CH2CH3), 1.34 (s, 18H 6(CH3)), 1.48 (m, 2H, CH2CH2CH3), 2.57 (t, J = 7 Hz, 2H, CH2CH2CH3), 5.32 (s, IH, =CH), 7.28 (d, J = 2 Hz, 2H, Ar-H), 7.45 (t, J = 2 Hz, IH, Ar-H) 3-(3.5-Di-t-butylphenyl)hex-2-enal (23) (trans). To 166 mg (0.59 mmol) of nitrile 21 in 4 mL of CH2CI2 at -78 °C was added 0.59 mL (0.88 mmol) of DIBAL (1.5 M in toluene). The reaction mixture was stirred for 10 m and quenched with 10 mL of a saturated aqueous solution of Rochelle salt. The product was extracted with ether (2 x 20 mL), washed (water then brine), dried (MgSO4), filtered, concentrated and purified by chromatography (preparative TLC, Siθ2, 3 % EtOAc-hexanes) to give 141 mg (0.49 mmol) of 23 as an oil (83 % yield): TLC (10% EtOAc-90% hexanes) Rf 0.7; iH-NMR (CDCI3) δ 0.97 (t, J = 7 Hz, 3H, CH2CH3), 1.34 (s, 18H, 6(CH3», 1.57 (m, 2H, CH2CH2CH3), 3.03 (t, J = 7 Hz, 2H, CH2CH2CH3), 6 32 (d, J = 8 Hz, IH, =CH), 7 33 (d, J = 1 Hz, 2H, Ar-H), 7 48 (t, J = 1 Hz, IH, Ar-H), 10 15 (d, J = 8 Hz, IH, CHO) 3-(3.5-Di-t-butylphenyl)hex-2-enal (24) (as) Compound 24 was prepared in the same man- ner as 23 except that the as isomer 22 was used instead of 21 TLC (10% EtOAc-90% hexanes) Rf 0 8, iH-NMR (CDCI3) δ 0 94 (t, J = 7 Hz, 3H, CH2CH3), 1 34 (s, 9Η, CH3), 1 35 (s, 9H, CH3), 1 51 (m, 2H, CH2CH2CH3), 2 58 (t, J = 7 Hz, 2H, CH2CH2CH3), 6 10 (d, J = 8 Hz, IH, =CH), 7 04 (d, J = 2 Hz, 2H, Ar-H), 7 43 (t, J = 2 Hz, IH, Ar-H), 9 42 (d, J = 8 Hz, IH, CHO) Ethyl (2£. 4£. 6£)-7-(3.5-di-t-butylphenvn-3-methyldeca-2.4.6-trienoate (25) To 391 mg (1 48 mmol) of triethyl-3-methyl-4-phosphonocrotonate in 5 mL of dry THF at -78 °C was added 0 59 mL (1 48 mmol) of a 2 5 M nBuLi solution in hexanes and 2 5 mL of DMPU After stirring for 15 min , the solution containing the ylide of triethylphosphonocrotonate was added to 141 mg (0 49 mmol) 23 in 5 mL of dry THF at -78 °C The reaction mixture was warmed to RT, quenched with saturated aqueous NH4CI (20 mL) and the products were extracted with ether (2 x 25 mL) The ether extracts were washed (water, then brine), dried (MgSO4), filtered, concentrated and purified by column chromatography (Siθ2, 5 % EtOAc-hexanes) to give 171 mg (0 43 mmol) of the all-trans isomer 25 (88% yield) TLC (5% EtOAc-95% hexanes) Rf 0 5, iH-NMR (CDCI3) δ 0 94 (t, J = 7 Hz, 3H, CH2CH3), 1 29 (t, J = 7 Ηz, 3Η, CH2CH3), 1 34 (s, 18Η, 6(CH3)), 1 52 (m, 2H, CH2CH2CH3), 2 39 (s, 3H, CH3), 2 70 (t, J = 7 Hz, 2H, CH2CH2CH3), 4 18 (m, 2H, CH2CH3), 5 80 (s, IH, =CH), 6 42 (d, J = 15 Hz, 2H, =CH), 6 47 (d, J = 15Hz, IH, =CH), 7 03 (m, IH, =CH), 7 27 (d, J = 1 Hz, 2H, Ar-H), 7 36 (t, J = 1 Hz, IH Ar-H) Ethyl (2E. 4E. 6E.-7-(3.5-di-t-butylphenyl)-3-methyldeca-2.4.6-trienoate (26) Compound 26 was prepared in the same manner as 25, except that the as isomer 24 was used instead of 23: TLC (5% EtOAc-95% hexanes) Rf 0 5, iH-NMR (CDCI3) δ 0 94 (t, J = 7 Hz, 3H, CH2CH3), 1 29 (t, J = 7 Ηz, 3Η, CH2CH3), 1 33 (s, 8Η 6 (CΗ3)), 1 44 (m, 2H, CH2CH2CH3), 2.15 (s, 3H, CH3), 2.48 (t, J = 7 Hz, 2H, CH2CH2CH3), 4.16 (m, 2H, - COCH2CH3), 5.73 (s, IH, =CH), 6.22 (d, J = 11 Hz, IH, =CH), 6.26 (d, J = 11 Hz, IH, =CH), 6.74 (dd, J = 11 Hz, IH, =CH), 7.26 (d, J = 2 Hz, 2H, Ar-H), 7.34 (t, J = 2 Hz, IH, Ar-H). (2E. 4E. 6EJ-7-(3.5-Di-t-butylphenyl)-3-methyldeca-2.4.6-trienoic acid (27). To 171 mg (0.44 mmol) of 25 in 5 mL of MeOH was added 1 mL of 5N aqueous NaOH solution. The mixture was heated to reflux for 10 min., cooled to RT, acidified with 20% aqueous HCI solution, and the organics extracted with ether (2 x 10 mL). The ether layer was washed (water, then brine), dried (MgSO4), filtered and concentrated. Purification by chromatogra¬ phy (preparative TLC, Siθ2, 20% ΕtOAc-hexanes) gave 28 mg (0.08 mmol) of the a\\-trans isomer of 27 (80 % yield): TLC (10% MeOH-90% CHCI3) Rf 0.8; mp 143-144 °C; iH- NMR (CDCI3) δ 0.94 (t, J = 7 Hz, 3H, CH2CH3), 1 34 (s, 18H, 6(CH3)), 1.52 (m, 2H, CH2CH2CH3), 2.40 (s, 3H, CH3), 2.71 (t, J = 7 Hz, 2H, CH2CH2CH3), 5.84 (s, IH, =CH), 6.41 (d, J = 15 Hz, IH, =CH), 6.47 (d, J = 15 Hz; IH, =CH), 7.08 (m, IH, =CH), 7.26 (d, J = 1 Hz, 2H, Ar-H), 7.37 (t, J = 1 Hz, IH, Ar-H). (2E. 4E. 6ZJ-7-(3.5-Di-t-butylphenyl)-3-methyldeca-2.4.6-trienoic acid (28) Compound 28 was prepared in the same manner as 27 except that the cis isomer 26 was used instead of 25: TLC (10% MeOH-90% CHCI3) Rf 0.8; mp 166-169 °C, iH-NMR (CDCI3) δ 0.89 (t, J = 7 Hz, 3H, CH2CH3), 1.31 (s, 9Η, CH3), 1.32 (s, 9H, CH3), 1.42 (m, 2H, CH2CH2CH3), 2.15 (s, 3H CH3), 2.49 (t, J = 7 Hz, 2H, CH2CH2CH3), 5.76 (s, IH, =CH), 6.23 (d, J = 11 Hz, IH, =CH), 6.28 (d, J = 15 Hz, IH, =CH), 6.78 (dd, J = 15 Hz, IH, =CH), 7.04 (s, 2H, Ar-H), 7.35 (s, IH, Ar-H). [rest of page left purposely blank] EXAMPLES 7-8 (2E,4E,6E -6-(6,8,-Di-t-butyIchroman-4-ylidene)-3-methylhexa-2,4,6-trienoic acid (39) and (2E,4E,6Z)-6-(6,8,-di-t-butylchroman-4-ylidene)-3-methylhexa-2,4,6-trienoic acid (40), prepared as illustrated and described in Scheme 5 below. Scheme 5 29 30 31 EtOAc, 85% 32 33 trans 35 trans 34 cis 36 cis 37 trans 39 trans 38 cis 40 cis 3.5 -Di-t-butyl-2-hvdroxyacetophenone (30) . To 10 g (48.5 mmol) of 2,5-di-t-butylphenol 29 and 4.56 g (58.16 mmol) of acetyl chloride in 60 mL of dichloroethane was added 11.9 mL (97.0 mmol) of BF3#OΕt2, and the mixture was heated to reflux for 10 min. The reac- tion was cooled and poured into 1 :1 ice - 20% aqueous HCI, stirred and extracted (2 x 100 mL of EtOAc). The organic extract was washed (water, then brine), dried (MgSO4), con¬ centrated and purified (Siθ2 chromatography, 5% EtOAc-hexanes) to give 7.0 g (28.22 mmol) of 30 as an oil (58% yield): TLC (5% % EtOAc-hexane) Rf 0.1; iH-NMR (CDCI3) δ 1.32 (s, 9H, CH3), 1.42 (s, 9H 3 (CH3)), 2.68 (s, 3H, CH3), 7.55 (m, 2H, Ar-H). 6 T 8-Di-t-butyl-2-hvdroxychroman-4-one (31). To 1.8 g (78.26 mmol) of sodium metal in a flame dried 500 mL round bottom flask, was dropwise added 7.5 g (30.24 mmol) of phenol 30 in 120 mL of ethyl formate. Once addition was complete, the mixture was stirred at 40 °C for 1 h, then cooled to RT and poured into 1 N aqueous HCI. When the mixture became transparent, the organics were extracted (2 x 150 mL EtOAc), washed (water, then brine), dried (MgSO4) and concentrated to give 7.4 g (26.81 mmol) of 31 as an oil (approximate yield, 89%). This product was used directly in the next step: TLC (20% EtOAc-hex) Rf 0.4; Ϊ H-NMR (CDCI3) δ 1.30 (s, 9H 3(CH3)), 1.42 (s, 9H, 3CH3), 2.87 (dd, J = 16.0, 5.5 Hz, IH, CH2), 3.01 (dd, J = 16.0, 3.1 Hz, IH, CH2), 5.87 (dd, J = 5.5, 3.3 Hz, IH, CHOH), 7.58 (d, J = 2.5 Hz, IH, Ar-H), 7.79 (d, J = 2.5 Hz, IH, Ar-H). 4H-6.8-di-t-butyl-benzopyran-4-one (not shown). To 7.4 g (26.81 mmol) of 30 in 20 mL of MeOΗ was added 8 mL of aqueous 20% ΗCL and the mixture was heated at reflux for 20 min. After cooling to RT, water was added (30 mL) and the products were extracted (2 x 30 mL of EtOAc), washed (water, then brine), dried (MgSO4), and concentrated to give ca 6.0 g (25.00 mmol) of 4H-6,8-di-t-butyl-benzopyran-4-one as an oil which after standing for several hours, solidified (approximate yield, 93 %). This product was directly used in the next step: TLC (5% EtOAc-hex) Rf 0.5; iΗ-NMR (CDCI3) δ 1.37 (s, 9Η, 3CH3), 1.49 (s, 9H 3CH3), 6.35 (d, J = 5.6 Hz, IH, CH=CH), 7.70 (d, J = 2.4 Hz, IH, Ar-H), 7.91 (d, J = 5.6 Hz, IH, CH=CH), 8.10 (d, J = 2.4 Hz, IH, Ar-H). 6.8-Di-t-butyl-chroman-4-one (32). To 1.0 g (3.87 mmol) of 4H-6,8-di-t-butyl-benzopyran- 4-one in 8 mL of EtOAc was added 200 mg of 10% Pd/C. The mixture was degassed, fol- lowed by addition of H2 gas and stirred under an H2 gas atmosphere for 2 h at RT. After filtration (celite), the product was concentrated and purified (Siθ2 chromatography, 5% EtOAc-hexanes) to give 857 mg (3.29 mmol) of 32 as a white solid (85% yield): TLC (5% EtOAc-hex) Rf 0.7; lH-NMR (CDCl3) δ 1.32 (s, 9H, CH3), 1.42 (s, 9H, CH3), 2.78 (t, J = 6.0 Hz, 2H, CH2), 4.52 (t, J = 6.0 Hz, 2H, CH2), 7.53 (d, J = 2.4 Hz, IH, Ar-H), 7.81 (d, J = 2.4 Hz, IH, Ar-H) (6.8-Di-t-butylchroman-4-ylidene)acetonitrile (33) (trans) and (34) (cis). To 891 mg (5.03 mmol) of cyanomethyl phosphonate in 6 mL of dry THF was added 188 mg (4.69 mmol) of NaH (60% in oil) and the mixture was stirred for 20 min. To this solution was added 436 mg (1.80 mmol) of 32 in 2 mL of dry THF and the reaction was heated at reflux for 2 h. After cooling to RT, the reaction was quenched with saturated NH4CI (10 mL) and extracted (2 x 10 mL EtOAc), washed (water, then brine), dried (MgSO4), concentrated and purified (Siθ2 chromatography, 5% EtOAc-hexane) to give 358 mg (1.32 mmol) of the trans isomer 33 and 95 mg (0.35 mmol) of the cis isomer 34 (93 % combined yield) Trans isomer 33,: TLC (5% EtOAc-hex) Rf 0.5; iH-NMR (CDCI3) δ 1.30 (s, 9H, 3CH3), 1.36 (s, 9H, 3CH3), 3.00 (t, J = 6.0 Hz, 2H, CH2), 4.27 (t, J = 6 0 Hz, 2H, CH2), 5.73 (s, IH, =CH- CN), 7.35 (d, J = 2.4 Ηz, 1Η, Ar-Η), 7.41 (d, J = 2.4 Ηz, 1Η, Ar-Η); Cis isomer 34: TLC (5% EtOAc-hex), Rf 0.4; iΗ-NMR (CDCI3) δ 1.34 (s, 9Η, 3CH3), 1.39 (s, 9H, 3CH3), 2.76 (t, J = 6.0 Hz, 2H, CH2), 4.29 (t, J = 6.0 Hz, 2H, CH2), 5.11 (s, IH, =CH-CN), 7.42 (d, J = 2 Ηz, 1Η, Ar-Η), 8.28 (d, J = 2 Ηz, 1Η, Ar-Η) (6.8-Di-t-butylchroman-4-ylidene)acetaldehyde (35) (trans). To 100 mg (0.36 mmol) of nitrile 33 in 5 mL of hexane at -78 °C was added 0.35 mL (0.53 mmol) of a 1.5 M solution of DIBAL in toluene. The mixture was stirred for 5 min followed by addition of 10 mL of sat. aqueous Rochelle salt and warmed to RT. The solution was extracted (2 x 10 mL of EtOAc), washed (water then brine), dried (MgSO4), filtered and concentrated to give 86 mg (0.30 mmol) of the relatively pure aldehyde 35 (83 % yield): TLC (5% EtOAc-hex) Rf 0.5, iΗ-NR (CDCI3) δ 1.32 (s, 9Η, 3CH3), 1.41 (s, 9H, 3CH3), 3.27 (t, J = 6.0 Hz, 2H, CH2), 4.30 (t, J = 6.0 Hz, 2H, Ofe), 6.57 (d, J = 8 Hz, IH, =CH-CHO), 7.41 (d, J = 2.4 Hz, IH, Ar-H), 7.51 (d, J = 2.4 Hz, IH, Ar-H), 10.14 (d, J = 8 Hz, IH, CHO). (6.8-Di-t-butylchroman-4-ylidene)acetaldehvde (36) (cis). Compound 36 was prepared in the same manner as 35, except that the cis isomer 34 was used instead of 33: TLC (5% EtOAc- hex) Rf 0.4, Ϊ H-NMR (CDCI3) δ 1.30 (s, 9H, 3CH3), 1.38 (s, 9H, 3CH3), 2.80 (t, J = 6.5 Hz, 2H, CH2), 4.42 (t, J = 6.5 Hz, 2H, CH2), 5.95 (d, J = 8 Hz, IH, =CH), 7.12 (d, J = 2.4 Hz, IH, Ar-H), 7.44 (d, J = 2.4 Hz, IH, Ar-H), 10.00 (d, J = 8 Hz, IH, CHO). Ethyl (2E.4E.6E)-6-(6.8.-di-t-butylchroman-4-ylidene)-3 -methylhexa-2.4.6-trienoate (37) To 238 mg (0.902 mmol) of triethyI-3-methyl-4-phosphonocrotonate in 3 mL of dry THF at -78 °C was added 0.36 mL (0.90 mmol) of a 2.5 M nBuLi solution in hexanes and 3 mL of DMPU. After stirring for 15 min., the solution containing the ylide of triethylphosphonocrotonate was transferred to 86 mg (0.30 mmol) of 35 in 4 mL of 1 : 1 THF-DMPU at -78 °C. The reaction mixture was warmed to RT, quenched with saturated aqueous NH4CI (20 mL), and the products were extracted with EtOAc (2 x 20 mL). The extracts were washed (water then brine), dried (MgSO4), filtered, concentrated and purified by column chromatography (Siθ2, 5 % EtOAc-hexanes) to give 85.3 mg (0.22 mmol) of the 2£,4E,6£-isomer of 37 (73 % yield) and 5.6 mg (0.014 mmol) of the 2Z,4E,6E isomer (5 % yield). Compound 37: TLC (5% EtOAc-hex) Rf 0.5, iH-NMR (CDCI3) δ 1.30 (t, J = 7 Hz, 3H, CH2CH3), 1.33 (s, 9H, 3CH3), 1.37 (s, 9H, 3CH3), 2.37 (s, 3H, CH3), 2.88 (t, J = 6.0 Hz, 2H CH2), 4.17 (q, 2H, CH2), 4.23 (t, J = 6.0 Hz, 2H, CH2), 5.81 (s, IH, =CH), 6.43 (d, J = 15 Hz, IH, =CH), 6.73 (d, J = 15 Hz, IH, =CH), 6.96 (m, IH, =CH), 7.25 (d, J = 2.4 Hz, IH, Ar-H), 7.50 (d, J = 2.4 Hz, IH, Ar-H). Ethyl (2E.4E.6Z)-6-(6.8.-di-t-butylchroman-4-ylidene)-3-methylhexa-2.4.6-trienoate (38). Compound 38 was prepared in the same manner as 37 except that the cis isomer 36 was used instead of 35, Compound 36: TLC (5% EtOAc-hex) Rf 0.5, iH-NMR (CDCI3) δ 1.30 (t, J = 7 Hz, 3H, CH2CH3), 1.30 (s, 9Η, 3CH3), 1.38 (s, 9H, 3CH3), 2.32 (s, 3H CH3), 2.66 (t, J = 6.0 Hz, 2H, CH2), 4.16 (m, 2H, CH2), 4.35 (t, J = 6.0 Hz, 2H, CH2), 5.80 (s, IH, =CH), 6.08 (d, J = 11 Hz, IH, =CH), 6.36 (d, J = 15 Hz, IH, =CH), 7.27 (d, J = 2 Hz, IH, Ar-H), 7.29 (d, J = 2 Hz, IH, Ar-H), 7.28 (dd, J = 15, 11 Hz, IH, Ar-H). (2E.4E.6EJ-6-(6.8.-Di-t-butylchroman-4-ylidene)-3-methylhexa-2.4.6-trienoic acid (39). To 85.3 mg (0.22 mmol) of ester 37 in 6 mL of 1 : 1 THF-MeOH was added 3 mL of an aqueous 5N KOH solution. The solution was heated at reflux for 10 min., cooled to RT, acidified (20% aqueous HCI) and extracted (2 x 6 mL of ΕtOAc). The extracts were combined, washed (water then brine), dried (MgSO4), filtered and concentrated. Purification by preparative TLC (5% MeOH-CHCl3), followed by crystallization (ΕtOAc-hexane, 1 4) gave 74.5 mg (0.20 mmol) of acid 39 as a pale yellow solid (94 % yield): TLC (5% ΕtOAc-hex) Rf 0.5; mp 237-239 O iH-NMR (CDCI3) δ 1.33 (s, 9H, 3CH3), 1.38 (s, 9H, 3CH3), 2.37 (s, 3H, CH3). 2.89 (t, J = 6.0 Hz, 2H, CH2), 4.23 (t, J = 6.0 Hz, 2H, CH2), 5.86 (s, IH, =CH), 6.43 (d, J = 15 Hz, IH, =CH), 6.74 (d, J = 11 Hz, IH, =CH), 6.97 (dd, 11, 15 Hz, IH, =CH), 7.25 (d, J = 2.3 Hz, IH, Ar-H), 7.50 (d, J = 2.3 Hz, IH, Ar-H). (2E.4E.6Z -6-(6.8.-Di-t-butylchroman-4-ylidene)-3-methylhexa-2.4.6-trienoic acid (40). Compound 40 was prepared in the same manner as 39, except that the cis isomer 37 was used instead of 36, Compound 37: TLC (5% ΕtOAc-hex) Rf0.5; mp 233-235 °C; iH- NMR (CDCI3) δ 1.32 (s, 9H, 3CH3), 1 37 (s, 9H, 3CH3), 2.33 (s, 3H, CH3). 2.68 (t, J = 6.0 Hz, 2H, CH2), 4.35 (t, J = 6.0 Hz, 2H, CH2), 5.83 (s, IH, =CH), 6.10 (d, J = 11 Hz, IH, =CH), 6.39 (d, J = 15 Hz, IH, =CH), 7.26 (d, J = 2 Hz, IH, Ar-H), 7.30 (d, J = 2 Hz, IH, Ar-H), 7.35 (dd, J = 11, 15 Hz, IH, =CH). [rest of page left purposely blank] EXAMPLE 9 (2E, 4E, 6E -7-(3,5-Di-triπuoromethylphenyl)-3-methylocta-2,4,6-trienoic acid (41), prepared according to Scheme 1. This compound was synthesized in an analogous manner as 9, except that 3,5-di- trifluoromethylacetophenone was used instead of 3,5-di-t-butylacetophenone: TLC (5% ΕtOAc-hex) Rf 0.5; mp 225-227 °C; iH-NMR (CDCI3) δ 2.30 (s, 3H, CH3). 2.40 (s, 3H, CH3), 5.90 (s, IH, =CH), 6.52 (d, J = 15 Hz, IH, =CH), 6.66 (d, J = 12 Hz, IH =CH), 7.03 (m, IH, =CH), 7.78 (s, IH, Ar-H), 7.87 (s, IH Ar-H). EXAMPLE 10 (22s, 4EA 6E)-7-(3,5-Di-isopropylphenyl)-3-methylocta-2,4,6-trienoic acid (42), pre¬ pared according to Scheme 1. This compound was synthesized in an analogous manner as 9, except that 3,5-di- isopropylacetophenone was used instead of 3,5-di-t-butylacetophenone: TLC (5% EtOAc- hex) Rf 0.5; mp 157-160 iH-NMR (CDCI3) δ 1.28 (d, J = 8 Hz, 12 H, CH3), 2.27 (s, 3H, CH3). 2.42 (s, 3H, CH3), 2.90 (p, J = 8 Hz, 2H, CH), 5.83 (s, IH, =CH), 6.42 (d, J = 15 Hz, IH, =CH), 6.60 (d, J = 15 Hz, IH =CH), 7.02 (s, IH, Ar-H), 7.08 (m, IH, =CH), 7.45 (s, 2H, Ar-H). EXAMPLE 11 (IE, 4E, 6Z)-7-(3,5-Di-isopropylphenyl)-3-methylocta-2,4,6-trienoic acid (43), pre¬ pared according to Scheme 1. This compound was synthesized in an analogous manner as 10, except that 3,5-di- isopropylacetophenone was used in the first step instead of 3,5-di-t-butylacetophenone: TLC (5% EtOAc-hex) R f 0.5; mp 177-179 °C; i H-NMR (CDCI3) δ 1.25 (d, J = 7 Hz, 12 H, CH 3 ), 2.18 (s, 3H, CH3). 2.21 (s, 3H, CH 3 ), 2.90 (p, J = 7 Hz, 2H, CH), 5.77 (s, IH, =CH), 6.25 (d, J = 11 Hz, IH, =CH), 6.27 (d, J = 15 Hz, IH =CH), 6.85 (dd, J = 11, 15 Hz, IH, Ar-H), 6.94 (d, J = 2 Hz, 2H, Ar-H), 7.02 (bs, H, Ar-H). EXAMPLE 12 (2E, 4£, 6E -7-(4-T-butyl-phenyl)-3-methylocta-2,4,6-trienoic acid (44), prepared according to Scheme 1. This compound was synthesized in an analogous manner as 9, except that 4-t- butylacetophenone was used instead of 3,5-di-t-butylacetophenone. TLC (5% ΕtO Ac-hex) Rf 0.5; mp 198-200 O C; 1H-NMR (CDCI3) δ 1.33 (s, 9H, 3CH3), 2.26 (s, 3H, CH3). 2.39 (s, 3H, CH3), 5.84 (s, IH, =CH), 6.40 (d, J = 15 Hz, IH, =CH), 6 60 (d, J = 12 Hz, IH =CH), 7.07 (m, IH, =CH), 7.38 (s, IH, Ar-H), 7.43 (s, IH, Ar-H). EXAMPLE 13 (2E, 4E, 6£ -7-(3,5-Di-t-butyl-4-methoxyphenyl)-3-methyIocta-2,4,6-trienoic acid (45), prepared according to Scheme 1. This compound was synthesized in an analogous manner as 9, except that 3,5-di-t-butyl-4- methoxyacetophenone was used instead of 3,5-di-t-butyl-acetophenone: TLC (5% EtOAc- hex) Rf 0.5; mp 244-246 °C; iH-NMR (CDCI3) δ 1.30 (s, 9H, 3CH3), 1.42 (s, 9H, 3CH3), 2.27 (s, 3H, CH3). 2.42 (s, 3H, CH3), 3.67 (s, 3H, OCH3), 5.83 (s, IH, =CH), 6.34 (d, J = 15 Hz, IH, =CH), 6.35 (d, J = 15 Hz, IH =CH), 7.00 (d, J = 2Hz, IH, Ar-H), 7.06 (m, IH, =CH), 7.27 (d, J = 2 Hz, IH, Ar-H). EXAMPLE 14 (2E, 4E, 6Z)-7-(3,5-Di-trifluoromethylphenyl)-3-methylocta-2,4,6-trienoic acid (46), prepared according to Scheme 1. This compound was synthesized in an analogous manner as 10, except that 3,5-di- trifluoromethyl-acetophenone was used instead of 3,5-di-t-butyl-acetophenone. TLC (5% EtOAc-hex) Rf 0.5; mp 225-227 O iH-NMR (CDCI3) 5 2.15 (s, 3H, CH3), 2.24 (s, 3H, CH3), 5.82 (s, IH, CH=), 6.36 (d, J=15Hz, IH, CH=), 6.39 (d, J=9.7Hz, IH, CH=), 6.53 (dd, J=15Hz, 9.7Hz, IH, CH=), 7.70 (s, 2H, Ar-CH), 7.83 (s, IH, Ar-CH). EXAMPLE 15 (IE, 4-£, 6£) -3-Methyl-7-(3,5-di-t-buty_-4-metho_typhenyl)octa-2,4,6-trienoic acid (47), prepared according to Scheme 1. This compound was synthesized in an analogous manner as 9, except that 3,5-di-t-butyl-4- methoxyacetophenone was used instead of 3,5-di-t-butylacetophenone: TLC (50% EtOAc- 50% hexanes) R f 0.5; mp 213-216°C; i H-NMR (CDC1 3 ) δ 1.45 (s, 18H, 6(CH 3 )), 2.25, (s, 3H, CH 3 ), 2.40 (s, 3H, CH 3 ),3.70 (S,3H.OCH3), 5.84 (s, IH, =CH), 6.41 (d, J = 15 Hz, IH, =CH), 6.52 (d,J=l 1.2Hz, IH, =CH), 7.08 (m, IH, =CH), 7.35 (s, 2H, Ar-H). EXAMPLE 16 (2E,4E,6£>3-Methyl-7-(3,4-diethylphenyl)octa-2,4,6-trienoic acid (48), prepared according to Scheme 1. This compound was synthesized in an analogous manner as 9, except that 3,4-di- ethylacetophenone was used instead of 3,5-di-t-butylacetophenone: TLC (20% ΕtOAc-80% hexanes) R f 0.3; mp 153-155°C; i H-NMR (CDCI 3 ) δ 1.45 (dd, J=14.1Hz,7.5Hz, 6H, 2CH3), 2.25 (s,3HCH3), 2.39 (s, 3H, CH3), 2.66 (m, 4H, 2CH2), 5.83 (s, IH, =CH), 6.40 (d, J=15Hz, IH, =CH), 6.59 (d, J=l 1.2Hz, IH, =CH), 7.07 (m, IH, =CH), 7.14 ( d, J=7.8Hz, IH, Ar-H), 7.27 (d, J=7.8Hz, IH, Ar-CH), 7.28 (s, IH, Ar-CH). EXAMPLE 17 (2E,4E,6Z 3-MethyI-7-(3,4-di-ethylphenyl)octa-2,4,6-trienoic acid (49), prepared according to Scheme 1. Compound 49 was prepared in the same manner as 10, except that 3,4-diethylacetophenone was used instead of 3,5-di-t-butylacetophenone: TLC (20% ΕtOAc-80% hexanes) R f 0.32; i H-NMR (CDCI3) δ 1.23 (dd, J=14. lHz,7.5Hz, 6H, 2CH3), 2.18 (s,6H,2CH3), 2.67 (m, 4H, 2CH2), 5.76 (s, IH, =CH), 6.23(d, J=l 1.8Hz, IH, =CH), 6.28 (d, J=15Hz, IH, =CH), 6.83 (m, IH, =CH), 7.04 ( d, J=7.8Hz, IH, Ar-H), 7.06 ( s, IH, Ar-CH), 7.17 (d, J=7.8Hz, IH, Ar-CH). EXAMPLE 18 (2£, 4£, 6_E)-3-Methyl-7-(3,5-di-t-butyl-4-etho__yphenyl)octa-2,4,6-trienoic acid (50), prepared according to Scheme 1. This compound was synthesized in an analogous manner as 9, except that 3,5-di-t-butyl-4- ethoxyacetophenone was used instead of 3,5-di-t-butylacetophenone TLC (50% EtOAc- 50% hexanes) Rf 0.5; mp 236-239 0 C, iH-NMR (CDC1 3 ) δ 1 41 (t, J = 7 0 Hz, 3H, CH3), 1 44 (s, 18H, 6(CH 3 », 2.26 (s, 3H, CH3), 2.40 (s, 3H, CH3), 3 77 (q, J = 7 Hz, 2H OCH2CH3), 5.84 (s, IH, =CH), 6 41 (d, J = 15 Hz, IH, =CH), 6 51 (d,J=l 1 2Hz, IH, =CH), 7 08 (m, IH, =CH), 7.35 (s, 2H, Ar-H) EXAMPLE 19 (2£,4£,6£)-3-Methyl-7-(3,4-di-t-butylphenyl)octa-2,4,6-trienoic acid (51), prepared according to Scheme 1. This compound was synthesized in an analogous manner as 9, except that 3,4-di-t- butylacetophenone was used instead of 3,5-di-t-butylacetophenone TLC (20% EtOAc-80% hexanes) Rf 0.3, mp 195-199 0 C, iH-NMR (CDCI3) d 1 56 (s, 9H, 3CH 3 ), 1 58 (s, 9H, 3CH 3 ), 2.26 (s, 3H, CH3), 2 40 (s, 3H, CH3), 5 84 (s, IH, =CH), 641 (d, J = 15 Hz, IH, =CH), 6 59 (d, J = 11Hz, IH, =CH), 7 08 (m, IH, =CH), 7 23 (dd, J = 8 5, 2 3 Hz, IH, Ar- H), 7 57 (d, J = 8 5 Hz, IH, Ar-H), 7 72 (d, J = 2 3 Hz, IH, Ar-H) EXAMPLE 20 (2£,4£,6£)-3-Methyl-7-cyclohe--yl-7-(3,5-di-t-butylphenyl)hepta-2,4,6-trienoic acid (52), prepared according to Scheme 4. This compound was synthesized in an analogous manner as 27, except that 3,4-di-t-butylphenylcyclohexyl ketone was used instead of 3,5-di- t-butylbutan- 1 -one TLC (20% EtOAc-80% hexanes) Rf 0 3 , iH-NMR (CDCI3) l U NMR (CDCI3) δ 1 35 (s, 9H), 1 9-1 1 (m,m, 8 H), 2 40 (s, 3 H), 2 85 (m, IH), 5 81 (s, 1 H), 6 08 (d, IH, J = 11.3 Hz), 6 30 (d, IH, J = 15 8 Hz), 7 02 (s, 2H Ar-H), 7 14 (dd, IH, J = 15 2, 15 2 Hz), 7 33 (s, IH, Ar-H), EXAMPLE 21 (2E,4E,6£)-3-MethyI-7-(3,5-di-t-butylphenyI)nona-2,4,6-trienoic acid (53), prepared according to Scheme 1. This compound was synthesized in an analogous manner as 9, except that 3,5-di-t-butyl-4- methoxyacetophenone was used instead of 3,5-di-t-butylacetophenone: TLC (50% EtOAc- 50% hexanes) Rf 0.5; mp 213-216 0 C; i H-NMR (CDCI3) δ 1.45 (s, 18H, 6(CH )), 2.25, (s, 3H, CH 3 ), 2.40 (s, 3H, CH 3 ),3.70 (S,3H, OCH3), 5.84 (s, IH, =CH), 6.41 (d, J = 15 Hz, IH, =CH), 6.52 (d,J=l 1.2Hz, IH, =CH), 7.08 (m, IH, =CH), 7.35 (s, 2H, Ar-H). EXAMPLE 22 (2E,4E,6Z)-3-Methyl-7-(3,4-diethyl-6-methylphenyl)nona-2,4,6-trienoic acid (54), pre¬ pared according to Scheme 1. This compound was synthesized in an analogous manner as 10, except that 3,4-diethyl-6-methylacetophenone was used instead of 3,5-di-t- butylacetophenone: TLC (20% ΕtOAc-80% hexanes) R f 0.3; i H-NMR (CDCI 3 ) δ 1.22 (t, J = 7.5 Hz, 3H, CH 3 ), 1.24 (t, J = 7.5 Hz, 3H, CH3), 2.08 (s, 3H, CH 3 ), 2.09 (s, 3H, CH 3 ), 2.17 (s, 3H CH3), 2.60 (m, 4H 2(CH 2 )), 5.73 (s, IH, =CH), 6.25 (m, 3H 3(=CH)), 6.81 (s, IH, Ar-H), 7.01 (s, IH, Ar-H). [rest of page left purposely blank] EXAMPLE 23 (2E, 4E, 6£>-7-(3,5-Di-t-butylphenyl)-3-methylocta-2,4,6-trienoic acid (69), prepared according to Scheme 6 illustrated and described below. Scheme 6 NaH, THF TBSiCI , 1. n-BuLi; THF R 1 OH (Et0) 2 P(0)CH 2 N=CHPh R 1 OTBS J i PCC/Celite: DCM ^ H f 0TBS OHC R 4 2 n-BuLi: THF :' R Λ 4 - R Λ" 5 3. Mel 59 58 60 4. H 3 0 * 1. NaBH 4 ; MeOH (CONTINUED) 1. n-Buϋ. THF, DMPU (EtO)^(0)CH 2 C(CH3)=CHCθ2Et 2. Bu 4 NF; THF 67 66 TsNHNH 2 ; EtOH, HCI(cat) 5-tert-Butyl- 1.3 -benzene dimethanol (56). A solution of 5-tørt-butyl-l,3-benzene dicar- boxylic acid (55) 20.0 g (89.9 mmol) in THF (200 mL) was cooled at 0°C and a solution of borane-THF complex in THF (190 mL) was slowly added via an addition funnel over 20 minutes with vigorous stirring. The mixture was warmed to RT and stirred for an additional 90 min. A mixture of water-THF (1 : 1; 200 mL) was slowly added, followed by an additional 200 mL of water. The mixture was extracted with ethyl acetate. The aqueous layer was extracted with EtOAc (2 x 100 mL) and the combined organic layers washed with water (2 x 100 mL); brine (2 x 100 mL) and dried over MgSO 4 . The solvent was evaporated to give the pure diol in 98% yield: l H NMR (CDC1 3 ; 400 MHz) δ (ppm): 7.32 (s, 2 H); 7.19 (s, 1 H); 4.69 (s, 4 H); 1.75 (br. s; 2 H); 1.33 (s, 9 H) 5-tert-Butyl- 1.3-tereρhthaldehvde. 5-ftτ-/-Butyl-l,3-benzene dimethanol (56) (20.0 g; 103 mmol) was added to a vigorously stirring mixture of pyridinium chlorochromate (66.0 g; 306 mmol) and celite (130 g) in dichloromethane (DCM) (500 mL). The mixture was stiσed for 3 h at RT until completion (TLC) The reaction mixture was filtered over a short pad of silica gel (2" x 4") and eluted with DCM (1 L) The solvent was evaporated to give 18 7 g, 94% yield of the desired dialdehyde *H NMR (CDC1 3 , 400 MHz) δ (ppm) 10 11 (s, 2 H), 8 18 (s, 3 H), 1 41 (s 9 H) (R. SV5-tert-Butyl-1.3-benzene-r2.2'-diethanon (57V A solution of 5-tert-buty.-l,3- terephthaldehyde (18 7 g, 96 4 mmol) in THF (400 mL) was cooled to -78°C, and a solution of methyl magnesium bromide (80 0 mL of a 3 M solution) slowly added, and the reaction mixture was warmed to rt After stirring for 60 min , the solution was quenched with a sat NH4CI solution (100 mL), followed by HCI (1 N, 50 mL) and extraction with EtOAc The organic layer was washed with water (2 x 100 mL), bπne (2 x 100 mL) and dried over MgSO4 The solvent was evaporated The crude residue was dissolved in hot EtOAc (30 mL) and pentane (200 mL) was added The clear solution was cooled in a ~4°C refrigerator for 3 h The white solid obtained was filtered and πnsed with cold pentane The solid was dried in vaccuo to give 15 3 g (70% yield) of the desired compound ! H NMR (CDC , 400 MHz) δ (ppm) 7 32 (s, 2 H), 7 2 (s, IH), 4 92 (m, 2 H), 1 82 (d, 2 H, J=2 5 Hz), 1 52 (d, 6 H, J=6 5 Hz), 1 35 (s, 9 H) ■R. SV5-tert-Butyl-1.3-phenyl-[2-ethanol. 2'-ethane-tert-bυtyl dimethyl silyl ether] (58V Sodium hydride (2 75 g of a 60% mineral oil content mixture) was rinsed with hexanes (2 x 10 ml), suspended in THF (200 mL) and 5-/ert-butyl-l,3-benzene-2,2'-diethanol (12 69 g, 57 mmol) was added with vigorous stirring The mixture was stirred for 45 min at rt to give a white slurry then rt-butyldimethylsilyl chloride (8 61 g, 57 mmol) was added at once The reaction mixture was stirred for 2 h and water (25 mL) was added The mixture was extracted with EtOAc (350 mL) The organic layer was washed with a sat NH4CI solution (100 mL), water (2 x 100 mL), brine (2 x 100 mL) and dried over MgSO 4 The solvent was evaporated and the residue purified by flash chromatography over silica gel to give the desired monosilylated product (14 45 g, 75% yield) as an oil (2 14 g of the starting material was recovered) H NMR (CDCI3, 400 MHz) δ (ppm) 7 32 (s, 1 H), 7 28 (s, IH), 7 12 (2s, 1 H), 4 92 (m, 2 H), 1 85 (s, 1 H), 1 5 (d, 3 H, J=6 5 Hz), 1 43 (d, 3 H, J=6 5 Hz) 1 35 (s, 9 H), 0 9 (s, 9 H), 0 05 (s, 6 H) (R. SV3-(Ethyl-2-tert-butyldimethyl silyl ether)-5-tert-butylacetophenone (59V Pyridinium chlorochromate (15.0 g; 69 mmol) and celite (30 g) were mixed in DCM (500 mL) while 5- ter/-butyl-l,3-benzene-(2-ethanol, 2'-ethane-tør/-butyldimethyl silyl ether) (14.45 g; 44 mmol) in DCM (100 mL) was added with vigorous stirring. After 3 h at rt, the mixture was filtered over a short pad of silica gel (2 M x 4") and eluted with DCM (500 L). The solvent was evaporated to give the desired ketone (14.4 g, 99% yield). *H NMR (CDCI 3 ; 400 MHz) δ (ppm): 7.89 (s, 1 H); 7.73 (s, 1 H); 7.65 (s, 1 H); 4.94 (q, 1 H, J=6.3 Hz); 2.63 (s, 3 H); 1.45 (d, 3 , J=6.3 Hz); 1.37 (s, 9 H); 0.96 (s, 9 H); 0.12 (s, 3 H), -0.05 (s, 3 H). 5-tert-Butyl- 1 -(2-eth.mol . -3-(2-f 2-methylpropan- 1 -a -benzene (60V A flame-dried three- necked round bottom flask, was charged with THF (90 mL) and cooled to -78 °C «-BuLi (12.0 mL of a 2 M solution; 24 mmol) was slowly added and the mixture stirred for 10 min. A solution of N-benzylidene diethyl aminomethyl phosphonate (6.14 g; 24 mmol) in THF (15 mL) was added and the resulting mixture stirred for 60 min at -78°C. A solution of5-tert- butyl-3-(ethane-2-tert-butyIdimethylsilyl ether]acetophenone (7.0 g, 20.9 mmol) in THF (15 mL) was added to the above solution, and the mixture was warmed to room temp., stirred for 30 min., then refluxed for 2 h. The mixture was cooled to rt and the solvent was evapo¬ rated. Diethyl ether (400 mL) was added and the solution was washed with sodium chloride (200 mL). The aqueous layer was extracted with ether (200 mL) and the combined organic layers were washed with brine (200 mL) and dried over MgSO 4 The solvent was evapo¬ rated to give a yellow residue which was dried under high vaccuo (1 mm.Hg) for 1 hour. THF (90 mL) was added to this residue and cooled to -78°C. w-BuLi (12.0 mL of a 2 M solution; 24 mmol) was slowly added and the deeply colored solution was stirred for 60 min. Methyl iodide (6.52 mL) was added and the mixture was warmed to room temperature and stirred for 4 h. The reaction mixture was quenched with HCI (3 N; 100 mL) and the biphasic solution was stirred for 16 h at RT. EtOAc (300 mL) was added and the organic layer was separated and washed with water (2 x 100 mL), brine (2 x 100 mL), and dried over MgSO . The solvent was evaporated to give a residue which was purified by s.g.c. to give 3.3 g of the desired aldehyde in 65% yield: l NMR (CDCI 3 ; 400 MHz) δ (ppm): 9.5 (s, 1 H); 7.33 (s, IH), 7 17 (s, IH), 7 11 (s, IH), 4 91 (m, 1 H), 1 80 (d, 1 H, J=3 4 Hz), 1 5 (d, 3 H, J-6 3 Hz), 1 47 (s, 3 H), 1.32 (s, 9 H) 5-tert-Butyl-3-(2-methylpropan-l-ol]acetophenone (61V A solution of 5-tert-butyl-l-(2- ethanol)-3-(2-[2-methylpropan-l-al])benzene (1 77 g, 7 53 mmol) in MeOH (50 mL) was cooled to 0°C and N-1BH4 (300 mg, 7 93 mmol) was added portionwise The reaction mix¬ ture was warmed to RT and stirred for 30 min The solvent was evaporated and the residue taken up in EtOAc (50 mL) and washed with HCI (10%, 3 10 mL), water (3 x 20 mL) and brine (3 x 20 mL) The organic layer was dried over MgSO4 and evaporated to dryness to give the desired diol 1 76 g, 99% yield This diol (1 65 g, 6 78 mmol) was dissolved in DCM (20 mL) and Mnθ2 (18 7 g, 0 17 mmol) was added at once The reaction mixture was vigorously stirred for 4 h, then filtered over a short pad of celite The solvent was evapo¬ rated to givel 63 g (97 % yield) of the desired ketone *H NMR (CDCI 3 , 400 MHz) δ (ppm) 7 85 (s, 1 H), 7 8 (s, 1 H), 7 63 (s, 1 H), 3 64 (d, 2 H, J=4 5 Hz), 2 6 (s, 3 H), 1 38 (s, 6 H), 1 35 (s, 9 H) 5-tert-Butyl-3-(2-[2-methylpropan- 1 -tert-butyldiphenylsilylether ])acetophenone (62V To a solution of 5-t-τt-butyl-3-(2-methylpropan-l-ol]acetophenone (1 63 g, 6 96 mmol) in DCM (30 mL) was added imidazole (500 mg, 7 35 mmol), a drop of DMF and tert- butyldiphenylsilyl chloride (2 01 g, 7 33 mmol) The mixture was stirred overnight at RT and quenched with excess sat NH4CI DCM (50 mL) was added and the organic layer washed with water (3 x 20 mL) and brine (3 x 20 mL) The organic layer was dried over MgSO 4 and evaporated to dryness to give a residue which was purified by s g c to give the desired ether 2 77 g (83% yield) l H NMR (CDCI3, 400 MHz) δ (ppm) 7 85 (s, 1 H), 7 76 (s, 1 H), 7 63 (1 H), 7 48-7 25 (mm, 10 H), 3 62 (s, 2 H), 2 56 (s, 3 H), 1 38 (s, 6 H), 1 33 (s, 9 H), 0 94 (s, 9 H) 5-tert-Butyl-3 -(2-r2-methylpropan- 1 -tert-butyldiphenylsilylether 1 1 -(2EV3 -r2-butenitrile .- benzene (63V To a solution of diethyl cyanomethyl phosphonate (1 7 g, 9 55 mmol) in THF (30 mL) at 0°C was added n-BuLi (4 64 mL of a 2 0 M solution in hexanes) The solution was stirred for 10 min., after which a solution of 5-tert-butyl-3-(2-[2,2'-dimethylpropan-tert- butyldiphenylsilyl ether])acetophenone in THF (10 mL) was added. The reaction mixture was stirred for 30 min. and quenched with a sat. NH 4 CI solution. EtOAc (50 mL) was added and the organic layer was washed with water (3 x 20 mL) and brine (3 x 20 mL). The organic layer was dried over MgSO 4 and evaporated to dryness to give a residue which was purified by s.g.c. to give the desired nitrile as a transxis mixture (~4: 1 by *H NMR). S.g.c. gave the desired trans isomer 1.70 g, 63% yield: *H NMR (CDCI 3 ; 400 MHz) δ (ppm): 7.85 (s, 1 H), 7.48-7.22 (mm, 13 H ArH); 5.5 (s, 1 H); 3.59 (s, 2 H); 2.43 (s, 3 H); 1.35 (s, 6 H); 1.27 9s, 9 H); 0.94 (s, 9 H). 5-tert-Butyl-3-(2-f2-methylpropan-l-tert-butyldiphenylsilylether1Vl-(2EV(3-f2- butenal .benzene (64). A solution of 5-/ert-butyl-3-(2-[2-methylpropan-l-/er/- butyldiphenylsilylether])-l-(3-[3-methyl-2-propenitrile)benzene (1.7 g; 3.42 mmol) in anhydrous DCM (20 mL) was cooled to -78°C and Dibal (3.5 mL of a 1 M solution in toluene) was added dropwise. The reaction mixture was stirred at -78°C for 60 min, quenched with excess Rochelle salt, then allowed to warm to RT. EtOAc (50 mL) was added and the mixture washed with water (3 x 20 mL) and brine (3 x 20 mL). The organic layer was dried over MgSO 4 and evaporated to dryness to give a residue which was purified by s.g.c. to give 1.25 g of the desired aldehyde (74% yield): J H NMR (CDCI 3 ; 400 MHz) δ (ppm): 10.17 (d, 1 H; J=8 Hz); 7.48-7.22 (mm, 13 H, ArH); 6.36 (d, 1 H J=8 Hz); 3.60 (s, 2 H); 2.54 (s, 3 H); 1.37 (s, 6 H); 1.32 (s, 9 H); 0.94 (s, 9 H). Ethyl-(2E. 4E. 6E.-7-(5-tert-butvI-3-f2-f2-methylpropan-l -ol .1-1 '-benzene .-3 -methylocta- 2.4.6-trienoate (66). A solution of diethyl 3-e_hoxycarbonyl-2-methylprop-2-enyl phosphonate (1.20 g, 4.52 mmol) in anhydrous THF (20.0 mL) was cooled to 0°C and added with anhydrous DMPU (3.5 mL) and w-BuLi in hexanes (2.15 mL of 2 o M solution, 4.50 mmol). The mixture was stirred at this temperature for 20 min., then cooled to -78°C. A solution of 5-terf-butyl-3-(2-[2-methyl propane- l-tert-butyldiphenylsilyl ether])- 1-(3-[3- methyl-2-propenal)benzene (1.25 g, 2.52 mmol) in THF (10.0 mL) was slowly added and the reaction mixture stirred at -78°C for an additional 60 min. The mixture was allowed to warm to 23 °C for 1 h with stirring A sat solution of ammonium chloride (5 mL) was added and the mixture extracted using EtOAc (3x 10 mL) The organic layer was with water (2x 25 mL) and brine (50 mL), dried over MgSO4 and concentrated The reidue was purified on a short sgc column to give 1 35 g (86% yield) of the desired ester (65) The above silyl ether (1 05 g, 1 68 mmol) was dissolved in THF (20 mL) and tetrabutylammonium fluoride (17 mL of 1 M solution in THF) was added The reaction mixture was stirred at room tempera¬ ture for 12 h, and EtOAc (50 mL) was added, followed by wash with water (2 x 20 mL), brine (20 mL) The organic layer was separated, dried over MgSO4 and evaporated to dry¬ ness The residue was purified by s g c to give 479 mg (80% yield) of the desired alcohol *H NMR (CDC1 3 , 400 MHz) δ (ppm) 7 9 (d, 1 H, J= 16 Hz, 2 cis isomer, -15%), 7 34 (s, 2 H), 7 29 (s, 1 H), 7 03 (dd, 1 H, J=16 Hz), 6 53 (d, 1 H, J=12 Hz), 6 38 (d, 1 H, J=16 Hz), 5 72 (s, 1 H), 5 68 (s, 1 H, 2 cis isomer, -15%), 4 15 (q, 2 H, J=6 7 Hz), 3.62 (s 2 H), 2 38 (s, 3 H), 2 28 (s, 3 H), 1 6 (br s, 1 H), 1 37 (s, 6 H), 1 33 (s, 9 H), 1 26 (t, 3 H, J=6 7 Hz) Ethyl-(2E. 4E. 6E)-7-(5-tert-butyl-3-f 2-(2-methylpropan- 1 -al)]- 1 '-phenyl . -3 -methylocta- 2.4.6-trienoate (67). To a vigorously stirred mixture of pyridinium chlorochromate(350 mg, 1.39 mmol) and celite (750 mg) in DCM (20 mL) was added a solution of ethyl-(2E, 4E, 6E)-7-(5-tert-butyl-3-[2-(2-methylpropan-l-ol)]-l'-phenyl)-3-methylocta-2,4,6-trienoate (330 mg, 0 889 mmol) in DCM (10 mL) The mixture was stirred for 3 h at rt and filtered over a short pad of silica gel The solvent was evaporated and the residue purified by s g c to give the desired aldehyde 290 mg (87% yield) *H NMR (CDCI3, 400 MHz) δ (ppm) 9 5 (s, IH), 7 9 (d, 1 H, J= 16 Hz, 2 cis isomer, -15%), 7 34 (s, 2 H), 7 29 (s, 1 H), 7 03 (dd, 1 H, J=16 Hz), 6 53 (d, 1 H, J=12 Hz), 6 38 (d, 1 H, J=16 Hz), 5 79 (s, 1 H), 5 68 (s, 1 H, 2 cis isomer, -15%), 4 15 (q, 2 H, J=6 7 Hz), 3 62 (s 2 H), 2 38 (s, 3 H), 2 28 (s, 3 H), 1 37 (s, 6 H), 1 33 (s, 9 H), 1 26 (t, 3 H, J=6 7 Hz) Ethyl-(2E. 4E. 6EV7-(5-tert-butyl-3- 2- ( 2-methylpropan-l-al ) 1-l'-phenyl ) -3-methylocta- 2.4.6-trienoate p-toluenesulfonyl hydrazone (68). To a solution of ethyl-(2E, 4E, 6E)-7-(5- /er/-butyl-3-[2-(2-methyl propanal)]-r-phenyl)-3-methylocta-2,4,6-trienoate (250 mg, 0 67 mmol) in ethanol (5 mL) was added p-toluenesulfonyl hydrazide (137 mg, 0 73 mmol) and -10 ml of cone. HCI. The mixture was heated at 40-45°C for 15 min. The solvent was evaporated and the residue purified by s. g. c. to give 330 mg (89% yield): *H NMR (CDCI 3 ; 400 MHz) δ (ppm): 7.82 (d, 2 H, J=7.4 Hz); 7.5 (2s, 2 H); 7.3 (d, 2 H, J=7.4 Hz); 7.18 (s, 1 H); 7.05 (s, 1 H); 7.0 (dd, 1 H, J=16 Hz); 6.45 (d, 1 H, J=12 Hz); 6.38 (d, 1 H, J=12 Hz); 5.82 (s, 1 H); 4.2 (q, 2 H, J= 6.7 Hz); 3.62 (s 2 H); 2.42 (s, 3 H); 2.38 (s, 3 H); 2.28 (s, 3 H); 1.37 (s, 6 H); 1.33 (s, 9 H), 1.26 (t, 3 H, J=6.7 Hz). (2E. 4E. 6EV7-(3. 5-Di-tert-butylphenvn-3-methylocta-2.4.6-trienoic acid (69)**. To a solution of ethyl-(2E, 4E, 6E)-7-(5-tert-butyl-3-[2-(2-methylpropan-l-al)]-l'-ρhenyl)-3- methylocta-2,4,6-trienoate p-toluenesulfonyl hydrazone (68) (80 mg) in acetic acid (2.0 mL) was added sodium borohydride* (80 mg) in small portions. The mixture was heated at 50°C for 1 h, cooled to RT and added to ice; allowed to warm to ambient temperature and extracted with EtOAc (3 x 10 mL). The organic layer was washed with water (3 x 10 mL); N-1HCO 3 (2 x 10 mL); water (3 x 10 mL); brine (3 x 10 mL); dried over MgSO 4 and evaporated. The residue was purified by s.g.c. to give the desired ester. This ester (20 mg) was dissolved in EtOH and KOH 1 M (1 mL) was added and the mixture heated at reflux for 3 h. The reaction mixture was cooled to RT; neutralized with HCI (10%) and extracted with EtOAc. The organic layer was washed with water (3 x 10 mL); brine (3 x 10 mL); dried over MgSO 4 and evaporated to give the desired acid. Those skilled in the art will recognize that the above protocol can be adapted to use labeled and radiolabeled NaB n H 4 (n=l, 2, 3) to generate the labeled (i.e., tritium labeled) compounds shown in Scheme 6. Furthermore, those skilled in the art will also recognize that the same labeled (deuterio and tritio)-compound (69) can be obtained from hyrazone (68) with heating for 8 h in methanol in the presence of NaCNB n H 3 (n=l, 2, 3) and ZnCtø, followed by saponification (KOH, EtOH). In another alternative embodiment, aldehyde (67) is reduced with radiolabeled NaB n H 4 (n=l, 2, 3), and the resulting alcohol is then oxidized to the corresponding tritiated aldehyde. Conversion of such an aldehyde to its tosyl hydrazone, followed by reduction with sodium cyanoborohydride and ZnCl2 in methanol, and saponifi¬ cation yields the corresponding acid (See 68 to 69 of Scheme 6) Evaluation of Retinoid Receptor Subfamily Activity Utilizing the "cis-trans" or "co-transfection" assay described by Evans et al , Science. 240 889-95 (May 13, 1988), the disclosure of which is herein incorporated by reference, the retinoid compounds of the present invention were tested and found to have strong, specific activity as either selective RAR agonists, selective RXR agonists, or as pan-agonist activat¬ ors of both RAR and RXR receptors This assay is described in further detail in U S Patent Nos 4,981,784 and 5,071,773, the disclosures of which are incorporated herein by refer¬ ence The co-transfection assay provides a method for identifying functional agonists which mimic, or antagonists which inhibit, the effect of native hormones, and quantifying their activity for responsive IR proteins In this regard, the co-transfection assay mimics an in vivo system in the laboratory Importantly, activity in the co-transfection assay correlates very well with known m vivo activity, such that the co-transfection assay functions as a qualitative and quantitative predictor of a tested compoundsjw vivo pharmacology See. e g . T Berger et al 41 J Steroid Biochem Molec Biol 773 (1992), the disclosure of which is herein incorporated by reference In the co-transfection assay, a cloned cDNA for an IR (e g , human RARα, RARβ, RXRγ) under the control of a constitutive promoter (e g , the SV 40 promoter) is introduced by transfection (a procedure to induce cells to take up foreign genes) into a background cell substantially devoid of endogenous IRs This introduced gene directs the recipient cells to make the IR protein of interest A second gene is also introduced (co-transfected) into the same cells in conjunction with the IR gene This second gene, comprising the cDNA for a reporter protein, such as firefly luciferase (LUC), is controlled by an appropriate hormone responsive promoter containing a hormone response element (HRE) This reporter plasmid functions as a reporter for the transcription-modulating activity of the target IR Thus, the reporter acts as a surrogate for the products (mRNA then protein) normally expressed by a gene under control of the target receptor and its native hormone. The co-transfection assay can detect small molecule agonists or antagonists of target IRs. Exposing the transfected cells to an agonist ligand compound increases reporter activity in the transfected cells. This activity can be conveniently measured, e.g., by increasing luciferase production, which reflects compound-dependent, IR-mediated increases in reporter transcription. To detect antagonists, the co-transfection assay is carried out in the presence of a constant concentration of an agonist to the target IR (e.g., ail-trans retinoic acid for RARα) known to induce a defined reporter signal. Increasing concentrations of a suspected antagonist will decrease the reporter signal (e.g., luciferase production) The co-transfection assay is therefore useful to detect both agonists and antagonists of specific IRs. Further¬ more, it determines not only whether a compound interacts with a particular IR, but whether this interaction mimics (agonizes) or blocks (antagonizes) the effects of the native regulatory molecules on target gene expression, as well as the specificity and strength of this interac- tion. The activity of the retinoid compounds of the present invention were evaluated utiliz¬ ing the co-transfection assay according to the following illustrative Example 23. EXAMPLE 23 Co-transfection assay CV-1 cells (African green monkey kidney fibroblasts) were cultured in the presence of Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% charcoal resin- stripped fetal bovine serum then transferred to 96-well microtiter plates one day prior to transfection. To determine RAR and/or RXR agonist activity of the compounds of the present invention, the CV-1 cells were transiently transfected by calcium phosphate coprecipitation according to the procedure of Berger et al., 41 J. Steroid Biochem. Mol. Biol, 733 (1992) with the following receptor expressing plasmids: pRShRARα: Giguere et al., 330 Nature. 624 (1987); pRShRARβ and pRShRARγ, Ishikawa et al, 4 Mol. Endocrin.. 837 (1990); pRShRXRα, Mangelsdorf et al, 345 Nature. 224 (1990); and pRSmRXRβ and pRSmRXRγ, Mangelsdorf etal, 6 Genes & DeveL 329 (1992), the disclosures of which are herein incorporated by reference. Each of these receptor expressing plasmids was co- transfected at a concentration of 5 ng/well, along with a basal reporter plasmid at 100 ng well, the internal control plasmid pRS-β-Gal at 50 ng/well and filler DNA , pGEM at 45 ng/well. The basal reporter plasmid D-MTV-LUC (Hollenberg and Evans, 55 CeU, 899 (1988), the disclosure of which is herein incorporated by reference) containing two copies of the TRE-palindromic response element described in Umesono etal, 336 Nature. 262 (1988), the disclosure of which is herein incorporated by reference, was used in transfections for the RARs, and the reporter plasmid CRBPIIFKLUC, which contains an RXRE (retinoid X receptor response element, as described in Mangelsdorf et al, 66 Cell, 555 (1991), the disclosure of which is herein incorporated by reference), was used in transfections for the RXRs. Each of these reporter plasmids contains the cDNA for firefly luciferase (LUC) under constitutive promoter containing the appropriate RAR or RXR response element. As noted above, pRS-β-Gal, coding for constitutive expression of E. coli β-galactosidase (β- Gal), was included as an internal control for evaluation of transfection efficiency and com¬ pound toxicity. Six hours after transfection, media was removed and the cells were washed with phosphate-buffered saline (PBS). Media containing compounds of the present invention in concentrations ranging from 10" 12 to 10"^ M were added to the cells. Similarly, the refer¬ ence compounds all-trans retinoic acid (ATRA)(Sigma Chemical), a known RAR selective compound, and 9-cis retinoic acid (9-cis) (synthesized as described in Heyman et al. Cell, 68:397-406 (1992)), a compound with known activity on RXRs, were added at similar con¬ centrations to provide a reference point for analysis of the activity of the compounds of the present invention. Retinoid purity was established as greater than 99% by reverse phase high-performance liquid chromatography. Retinoids were dissolved in dimethylsulfoxide for use in the transcriptional activation assays. Three to four replicates were used for each sample. After 40 hours, the cells were washed with PBS, lysed with a Triton X-100-based buffer and assayed for LUC and β-Gal activities using a luminometer or spectrophotometer, respectively. For each replicate, the normalized response (NR) was calculated as: LUC response/β-Gal rate where β-Gal rate = β-GaMxlO'5/β-Gal incubation time. The mean and standard error of the mean (SEM) of the NR were calculated. Data was plotted as the response of the compound compared to the reference compounds over the range of the dose-response curve. For the agonist compounds of the present invention, the effective concentration that produced 50% of the maximum response (EC50) was quantified The potency (nM) of selected retinoid compounds of the present invention are in Table 1 below. [rest of page left purposely blank] Table 1: Potency (nM) of selected retinoid compounds of the present invention on RARα,β,γ and RXRα,β,γ , in comparison to the known RAR-active retinoid compound all-trans retinoic acid (ATRA) and RXR-active retinoid compound 9-cis retinoic acid (9-cis), and in comparison to comparative example compounds A, B, C and D. na = not active (potency of > 10,000 and/or efficacy of <20%) As can been seen in Table 1, Compounds 9, 39, 41 and 47 are extremely potent RAR active compounds, with Compound 9 displaying sub-nanomolar activity on RARγ, and Compound 47 displaying selectivity on RARβ and RARγ. In fact, these Compounds are 10 to over 100 times more potent than the known RAR active compound ATRA on the RARs. Likewise, Compound 28 is a very potent and selective RXR active compound. Furthermore, pan-agonist Compounds 10 and 43 display a superior potency profile to that of the known RX active pan-agonist compound 9-c/s retinoic acid. While efficacy is not reported in Table 1, th compounds displaying an efficacy of less than 20 percent are considered to be inactive as retin activators (potency defined as >10,000), even if the compounds display marginal potency. In this regard, except for comparative compound A on RARβ, the comparative example compounds all displayed efficacies of less than 20 percent. The retinoid activity of the compounds of the present invention for RAR and/or RXR receptors is not exhibited by other known structurally similar compounds. As further shown in Table 1, comparative example compounds that appear structurally similar to the compounds of the present invention, such as (2E,4-_?,6£)-3-methyl-7-(3,4-dimethoxyphenyl)octa-2,4,6-trienoic acid (A) and (_-£,4E,6E)-3-methyl-7-(4-methoxyphenyl)octa-2,4,6-trienoic acid (B) described in M.J. Aurell, et al., 49 Tetrahedron, 6089 (1993) (Scheme 2, compounds d and e), (2E,4E,6E)-2- methyl-7-(2,3,6-trimethyl-4-methoxyphenyl)hepta-2,4,6-trienoic acid (C) disclosed in U.S. patent No. 4,534,979 (Example 17), and (2E,4-__ ' ,6£)-3-methoxy-7-(4-t-butylphenyl)octa-2,4,6- trienoic acid (D) disclosed in U.S. Patent No. 5,320,833 (Compound 80), have no, or virtually no, activity on any of the RARs or RXRs. EXAMPLE 24 In addition to the cotransfection data of Example 15, the binding of selected com¬ pounds of the present invention to the RAR and RXR receptors was also investigated according to the methodology described in M.F., Boehm, et al., "Synthesis and Structure- Activity Relationships of Novel Retinoid X Receptor Selective Retinoids", 37 J. Med. Chem., 2930 (1994); M.F. Boehm, et al., "Synthesis of High Specific Activity [ 3 H]-9-c/s Retinoic Acid and Its Application for Identifying Retinoids with Unusual Binding Proper¬ ties", 37 J. Med. Chem., 408 (1994), and E. A. Allegretto, et al., "Characterization and Com- parison of Hormone-Binding and Transactivation Properties of Retinoic Acid and Retinoid X Receptors Expressed in Mammalian Cells and Yeast", 268 J. Biol Chem., 22625 (1993), the disclosures of which are herein incorporated by reference. Non-specific binding was defined as that binding remaining in the presence of 500 nM of the appropriate unlabelled compound. At the end of the incubation period, bound from free ligand were separated. The amount of bound tritiated retinoids was determined by liquid scintillation counting of an aliquot (700 mL) of the supernatant fluid or the hydroxylapatite pellet. After correcting for non-specific binding, IC50 values were determined. The IC50 value is defined as the concentration of competing ligand needed to reduce specific binding by 50%. The IC50 value was determined graphically from a log-logit plot of the data. The Kj values w determined by application of the Cheng-Prussof equation to the IC50 values, the labeled ligan concentration and the Kd of the labeled ligand. The binding activity (Kd in nM) results of selected retinoid compounds of present invention, and the reference compounds ATRA, and 9-cis RA, is shown in Table 2 below. Table 2: Binding (Kd in nM) of selected retinoid compounds of the present invention on RARα,β,γ and RXRα,β,γ proteins in comparison to the known RAR-active retinoid compound all-trans retinoic acid (ATRA) and RXR-active retinoid compound 9-cis retinoic acid (9-cis). As can be seen in Table 2, Compounds 9 and 10 of the present invention show equal o superior binding to the known RAR active compound ATRA, and the known RXR active compound 9-cis. In comparison, all of the comparative example compounds of Example 14 show absolutely no binding on any of the retinoid receptors, with the exception of comparative example compound A, which shows weak binding of 312 nM on RARα. EXAMPLE 25 Yet another recognized measure of the retinoid activity of the compounds of the prese invention is the ornithine decarboxylase assay, as originally described by Verma and Boutwell, 37 Cancer Research. 2196 (1977), the disclosure of which is herein incorporated by reference. In Verma & Boutwell original work using retinoic acid, it was established that ornithine decarboxylase (ODC) activity increased in relation to polyamine biosynthesis. In turn, it had previously been established that increases in polyamine biosynthesis is correlated with cellular proliferation. Thus, if ODC activity could be inhibited, cell hyperproliferation could be modulated. Although all causes of increased OCD activity are yet unknown, it is known that 12- O-tetradecanoylphorbor-13-acetate (TPA) induces ODC activity. Importantly, retinoic acid inhibits this induction of ODC by TPA. An ODC assay essentially following the procedures set out in 35 Cancer Research. 1662 (1975), the disclosure of which is herein incorporated by reference, was used to demonstrate the inhibition of TPA induction of ODC by the compounds of the present invention. The results of this assay on selected Example Compounds, and the reference compounds ATRA and (E)-4-[2- (5,6, 7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-l-propenyl]benzoic acid (TTNPB), known RAR active compounds, are shown below in Table 3. All values are expressed as the concentration of the indicated compounds in nM required to inhibit the TPA induction of ODC by 80 percent, i.e., the IC-80 in nM. Table 3: Inhibitory concentration required to inhibit 80% of the maximally observed TPA induction of ODC (ODC ICβo) in nM for Compounds 7, 8, 9 and 10, and reference compounds ATRA and TTNBP. Compounds 7 and 8, which are the esters of Compounds 9 and 10 respectively, have been included to show that such ester analogs exhibit retinoid activity. While not being bound to a theory of operation, it is believed that such esters may operate as pro-drugs in vivo, possibly due to the cleavage of the ester to the active acid form of the compounds of the present invention. EXAMPLE 26 The in vitro affect of selected compounds of the present invention on the recognized cancer cell lines, RPMI 8226, ME 180 and AML-193, obtained from the American Type Culture Collection (ATCC, Rockville, MD), was investigated. RPMI 8226 is a human hematopoietic cell line obtained from the peripheral blood of a patient with multiple myeloma, and as such is a recognized model for multiple myelomas and related malignancies. Y. Matsuoka, G.E. Moore, Y. Yagi and D. Pressman, "Production of free light chains of immunoglobulin by a hematopoietic cell line derived from a patient with multiple myeloma", 125 Proc. Soc. Exp. Biol Med., 1246 (1967), the disclosure of which is herein incorporated by reference. The cells resemble the lymphoblastoid cells of other human lymphocyte cell lines and secretes λ-type light chains of immunoglobulin RPMI 8226 cells were grown in RPMI medium (Gibco) supplemented with 10% fetal bovine serum, glutamine and antibiotics. The cells were maintained as suspension cultures grown at 37 °C in a humidified atmosphere of 5% CO2 in air. The cells were diluted to a concentra- tion of 1 x 1 O^/mL twice a week. ME 180 is a human epidermoid carcinoma cell line derived from the cervix, and as such is a recognized model for squamous cell carcinomas and related malignancies. J A Sykes, J Whitescarver, P Jernstrom, J.F. Nolan and P Byatt, "Some properties of a new epithelial cell line of human origin", 45 MH-Adenoviridae J. Natl. Cancer Inst., 107 (1970), the disclosure of which is herein incorporated by reference. The tumor was a highly invasive squamous cell carcinoma with irregular cell clusters and no significant keratinization ME 180 cells were grown and maintained in McCoy's 5a medium (Gibco) supplemented with 10% fetal bovine serum, glutamine and antibiotics. The cells were maintained as monolayer cultures grown at 37 °C in a humidified atmosphere of 5% CO2 in air The AML-193 cell line was established from the blast cells of a patient with leukemia and was classified as M5 Acute Monocytic Leukemia, and as such is a recognized model for leukemias and related malignancies. G. Rovera, et al., 139 J. Immunol, 3348 (1987), the disclosure of which is herein incorporated by reference Over 75% of these cells are positive by immunofluorescence for the myelomonocytic antigen CS15. The cells were grown in Iscove's modified Dulbeccos's medium with 5 μg/mL transferring, 5 μg mL insulin and 2 ng/mL rh GM-CSF. The cells were maintained as suspension cultures grown at 37 °C in a humidified atmosphere of 5% CO2 in air. The cells were diluted to a concentration of 1 x lO^/mL twice a week. Incorporation of ^H-Thvmidine Measurement of the level of radiolabeled thymidine incorporated into the above- identified cell lines provides a direct measurement of the antiproliferative properties of the compounds of the present invention. The method used for determination of the incorpora¬ tion of radiolabeled thymidine was adapted from the procedure described by S. Shrivastav et al., "An in vitro assay procedure to test chemotherapeutic drugs on cells from human solid tumors", 40 Cancer Res., 4438 (1980), the disclosure of which is herein incorporated by reference. RPMI 8226 or AML-193 cells were plated in a 96 well round bottom microtiter plate (Costar) at a density of 1,000 cells/well. To appropriate wells, retinoid test compounds were added at the final concentrations indicated for a final volume of 150 uL/well. The plates were incubated for 96 hours at 37 °C in a humidified atmosphere of 5% CO2 in air. Subsequently, 1 μCi of [S'-^Hj-thymidine (Amersham, U.K, 43 Ci/mmol specific activity) in 25 μL culture medium was added to each well and the cells were incubated for an additional six hours. The cultures were further processed as described below. ME 180 cells, harvested by trypsinization were plated in a 96 well flat bottom microtiter plate (Costar) at a density of 2,000 cells/well. The cultures were treated as described above for RPMI 8226 with the following exceptions. After incubation, the super¬ natant was carefully removed, and the cells were washed with a 0.5 mM solution of thymidine in phosphate buffered saline. ME 180 cells were briefly treated with 50 μL of 2.5% trypsin to dislodge the cells from the plate. Both cell lines were then processed as fol¬ lows: the cellular DNA was precipitated with 10% trichloroacetic acid onto glass fiber filter mats using a SKATRON multi-well cell harvester (Skatron Instruments, Sterling VA). Radioactivity incorporated into DNA, as a direct measurement of cell growth, was measured by liquid scintillation counting. The mean disintegrations per minute of incorporated thymidine from triplicate wells was determined. The IC50 (nM concentration required to inhibit 50% of the maximally observed incorporation of thymidine) for Compounds 9 and 10 of the present invention, and reference compounds ATRA and TTNBP are shown below in Tables 4, 5 and 6 for the cell lines RPMI 8226, ME 180 and AML-193 respectively. Viability Selected compounds of the present invention were also measured to determine their cytotoxicity on the above-identified cell lines. The procedure used was identical, with only slight modifications, to the assay described in T. Mosmann, "Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays", 65 J. Immunol. Meth., 55 (1983), the disclosure of which is herein incorporated by reference RPMI 8226 or AML-193 cells were plated in a 96 well round bottom microtiter plate (Costar) at a density of 1,000 cells/well. To appropriate wells, retinoid test compounds were added at the final concentrations indicated for a final volume of 150 μL/well. The plates were incubated for 96 hours at 37 °C in a humidified atmosphere of 5% CO2 in air. Subse¬ quently, 15 μL of a filter sterilized tetrazolium dye in phosphate buffered saline (Promega, Madison, WI) was added to each well and the cells were incubated for an additional four hours. Subsequent manipulations of the cultures were as described below. ME 180 cells, harvested by trypsinization were plated in a 96 well flat bottom microtiter plate (Costar) at a density of 2,000 cells/well The cultures were treated as described above for RPMI 8226. After the four hours incubation, 100 μL of a solubilization/stop solution was added to each well (Promega, Madison, WI). The plates were allowed to stand overnight at 37 °C in the humidified atmosphere. The absorbance at 570 - 600 nm wavelength was recorded for each well using a Biomek ELISA plate reader (Beckman Instruments). The IC50 (nM con¬ centration required to inhibit 50% of the mitochondrial function, and ultimately, the viability of the cells) for Compounds 9 and 10 of the present invention, and reference compounds ATRA and TTNBP are also shown below in Table 4, 5 and 6 for the cell lines RPMI 8226, ME 180 and AML-193 respectively. Table 4: Inhibitory concentration required to inhibit 50% of the maximally observed radiolabeled thymidine (TdR IC5 0 ) in nM, and inhibitory concentration required to inhibit 50% of the mitochondrial function (MTS IC50) in nM, for Compounds 9 and 10, and reference compounds ATRA and TTNBP on the RPMI 8226 cell line. Table 5: Inhibitory concentration required to inhibit 50% of the maximally observed radiolabeled thymidine (TdR IC5 0 ) in nM, and inhibitory concentration required to inhibit 50% of the mitochondrial function (MTS IC50) m nM, for Compounds 9 and 10, and reference compounds ATRA and TTNBP on the ME 180 cell line. Table 6: Inhibitory concentration required to inhibit 50% of the maximally observed radiolabeled thymidine (TdR IC50) in nM, and inhibitory concentration required to inhibit 50% of the mitochondrial function (MTS ICso) in nM, for Compounds 9 and 10, and reference compounds ATRA and TTNBP on the AML-193 cell line. EXAMPLE 27 The following examples provide illustrative pharmacological composition formulation Hard gelatin capsules are prepared using the following ingredients: Quantity (mg/capsule) Compound 9 140 Starch, dried 100 Magnesium stearate _10 Total 250 mg The above ingredients are mixed and filled into hard gelatin capsules in 250 mg quantities. A tablet is prepared using the ingredients below: Quantity (mg/tablet) Compound 9 140 Cellulose, microcrystalline 200 Silicon dioxide, fumed 10 Stearic acid _K) Total 360 mg The components are blended and compressed to form tablets each weighing 360 mg. Tablets, each containing 60 mg of active ingredient, are made as follows: Quantity (mg/tablet) Compound 9 60 Starch 45 Cellulose, microcrystalline 35 Polyvinylpyrrolidone (PVP) (as 10% solution in water) 4 Sodium carboxymethyl starch (SCMS) 4.5 Magnesium stearate 0.5 Talc _L0 Total 150 mg The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of PVP is mixed with the resultant powders, which are then passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50°C and passed through a No. 18 mesh U.S. sieve. The SCMS, magnesium stearate, and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg. Suppositories, each containing 225 mg of active ingredient, may be made as follows: Compound 9 225 mg Saturated fatty acid glycerides 2.000 mg Total 2,225 mg The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of normal 2g capacity and allowed to cool An intravenous formulation may be prepared as follows. Compound 9 100 mg Isotonic saline 1 ,000 ml Glycerol 100 ml The compound is dissolved in the glycerol and then the solution is slowly diluted with isotonic saline. The solution of the above ingredients is then administered intravenously at a rate of 1 ml per minute to a patient. While in accordance with the patent statutes, description of the preferred embodi- ments and processing conditions have been provided, the scope of the invention is not to be limited thereto or thereby. Various modifications and alterations of the present invention will be apparent to those skilled in the art without departing from the scope and spirit of the pre¬ sent invention. Consequently, for an understanding of the scope of the present invention, reference is made to the following claims.

Claims: What is claimed is: A compound of the formulae: (I) OR (π) OR (III) OR (IV) OR (V) wherein: 1 2 4 R , R and R each independently are hydrogen, aryl, heteroaryl, CF3 or a C2 - C alkyl, fluoroalkyl or perfluoroalkyl optionally substituted with 14 CH 3, 13 CH 3 , CD 3 , C 3 H 3 , and/or 13 CD 3 ; 3 5 R and R each independently are hydrogen, CF3, a Cj - C3 alkyl, a Ci to C3 fluoroalkyl or perfluoroalkyl, or OR , where R is hydrogen CF3, a Ci - C2 alkyl or a Ci to C2 fluoroalkyl or perfluoroalkyl, provided, however, that R and R cannot be CF3 or alkyl, 3 fluoroalkyl or perfluoroalkyl when R is CF3 or alkyl, fluoroalkyl or perfluoroalkyl; R 7 is a Ci - C4 alkyl optionally substituted with 14 CH 3, 13 CH 3 , CD 3 , C 3 H 3 , and/or X 8 13 CD3 or CH2OR , where R represents hydrogen, a C \ - Cβ alkyl, a C3 - C7 saturated or unsaturated cycloalkyl optionally substituted with a Ci - C4 alkyl, F, Cl, Br, I, OH, CF3, OR , NR , where R has the definition given above; R 9 is a Ci - C4 alkyl; R through R each independently are hydrogen, a Ci - C6 alkyl or CF3; X is COOR 16 , CONR 17 , or CONR 17 R 18 where R 16 represents hydrogen or a Ci - 17 18 C6 alkyl, and where R and R each independently represent a Ci - C alkyl, or an aryl or 17 heteroaryl optionally substituted with OH, F, Br, Cl or I, provided, however, that R and 18 R both cannot be an aryl or heteroaryl; 14 15 Y is C, O, S or N, provided that, when Y is O, then R and R do not exist, and 14 15 14 15 when Y is N, then R and R cannot be CF3, and when Y is S, then R and R can independently or together represent O, or may be absent altogether; W is N or CR , where R has the same definition given above; 19 R is an aryl or heteroaryl optionally substituted with one or more substituents selected from the group consisting of hydrogen, F, Cl, Br, I or a Cj - CO alkyl, wherein X has the same definition given above; n is 0, 1 or 2; the dotted lines designate optional double bonds; and the wavy lines depict carbon to carbon bonds in either the cis or trans configurations, provided, however, that when R , R , R and R are all hydrogen, then R cannot be aryl 1 2 4 2. A compound according to claim 1, wherein R , R and R independently represent C3 - CO branched alkyls, fluoroalkyls or perfluoroalkyls. 2 4 3. A compound according to claim 1, wherein R and R independently 1 3 5 represent C3 - C6 branched alkyls, fluoroalkyls or perfluoroalkyls, and R , R and R are all hydrogen. 4. A compound according to claim 1, wherein R 2 and R 4 independently 1 3 5 represent isopropyl, t-butyl or CF3, and R , R and R are all hydrogen. 5. A compound according to claim 1, selected from the group consisting of ethyl (2E, 4E, 6E 7-(3,5-di-t-butylphenyl)-3-methylocta-2,4,6-trienoate; ethyl (2E, 4E, 6ZJ-7- (3,5-di-t-butylphenyl)-3-methylocta-2,4,6-trienoate; (2E, 4E, 6E 7-(3,5-di-t-butylρhenyl)-3- methylocta-2,4,6-trienoic acid; (2E, 4E, 6Z 7-(3,5-di-t-butylphenyl)-3-methylocta-2,4,6- trienoic acid; ethyl (2E, 4£ 7-(3,5-di-t-butylphenyl)-3-methylocta-2,4-dienoate; (2E, 4E)-7- (3,5-di-t-butylphenyl)-3-methylocta-2,4-dienoic acid; ethyl (IE, 4E, 6£ 7-(3,5-di-t- butylphenyl)-3-methyldeca-2,4,6-trienoate; ethyl (2£, 4E, 6£)-7-(3,5-di-t-butylphenyl)-3- methyldeca-2,4,6-trienoate; (IE, 4£, 6E -7-(3,5-di-t-butylphenyl)-3-methyldeca-2,4,6- trienoic acid; (2E, 4E, 6Z 7-(3,5-di-t-butylphenyl)-3-methyldeca-2,4,6-trienoic acid; ethyl (2E,4E,6E -6-(6,8,-di-t-butylchroman-4-ylidene)-3-methylhexa-2,4,6-trienoate; ethyl (2E,4E,6Z -6-(6,8,-di-t-butylchroman-4-ylidene)-3-methylhexa-2,4,6-trienoate; (2E,4E,6E. - 6-(6,8,-di-t-butylchroman-4-ylidene)-3-methylhexa-2,4,6-trienoic acid; (2£,4£,6^-6-(6,8,- di-t-butylchroman-4-ylidene)-3-methylhexa-2,4,6-trienoic acid; (2E, 4E, 6£ 7-(3,5-di- trifluoromethylphenyl)-3-methylocta-2,4,6-trienoic acid; (2E, 4E, 6Z 7-(3,5-di- trifluoromethylphenyl)-3-methylocta-2,4,6-trienoic acid; (2E, 4E, 6E^-7-(3,5-di- isopropylphenyl)-3-methylocta-2,4,6-trienoic acid; (2E, 4E, 6Z^-7-(3,5-di-isopropylphenyl)- 3-methylocta-2,4,6-trienoic acid; (2£, 4E, 6£ 7-(4-t-butylphenyl)-3-methylocta-2,4,6- trienoic acid; (2£, 4£, 6£ 7-(3,5-di-t-butyl-4-methoxyphenyl)-3-methylorta-2,4,6-trienoic acid; (2E, 4E, 6E)-3-methyl-7-(3,5-di-t-butyl-4-methoxy-phenyl)octa-2,4,6-trienoic acid; (2E,4E,6E)-3-methyl-7-(3,4-di-ethylρhenyl)octa-2,4,6-trienoic acid; (2E,4E,6Z)-3-methyl-7- (3,4-di-ethylphenyl)octa-2,4,6-trienoic acid; (2E, 4E, 6£)-3-methyl-7-(3,5-di-t-butyl-4- ethoxy-phenyl)octa-2,4,6-trienoic acid; (2E,4E,6___ * )-3-methyl-7-(3,4-di-t-butylphenyl)octa- 2,4,6-trienoic acid; (2E,4E,6E)-3-methyl-7-cyclohexyl(3,5-di-t-butylphenyl)hepta-2,4,6- trienoic acid; (2£,4£,6£)-3-Methyl-7-(3,5-di-t-butylphenyl)nona-2,4,6-trienoic acid; and (2E,4E,6Z)-3-Methyl-7-(3,4-diethyl-6-methylphenyl)nona-2,4,6-trienoic acid. 6. A compound according to claim 1 , wherein the compound comprises a retinoid compound. 7. A compound according to claim 6, wherein the compound exhibits 50% maximal activation potency of one or more retinoid receptors at a concentration of less than 100 nM. 8. A compound according to claim 6, wherein the compound exhibits 50% maximal activation potency of one or more retinoid receptors at a concentration of less than 50 nM. 9. A compound according to claim 6, wherein the compound exhibits 50% maximal activation potency of one or more retinoid receptors at a concentration of less than 20 nM. 10. A compound according to claim 6, wherein the compound exhibits 50% maximal activation potency of one or more retinoid receptors at a concentration of less than 10 nM. 11. A compound according to claim 6, wherein the compound exhibits activity as a selective RAR agonist. 12. A compound according to claim 11, wherein the compound is at least two times more potent an activator of RAR than of RXR. 13. A compound according to claim 11, wherein the compound is at least five times more potent an activator of RAR than of RXR. 14. A compound according to claim 11, wherein the compound is at least ten times more potent an activator of RAR than of RXR. 15. A compound according to claim 11, wherein the compound is at least one hundred times more potent an activator of RAR than of RXR. 16. A compound according to claim 6, wherein the compound exhibits activity as a selective RXR agonist. 17. A compound according to claim 16, wherein the compound is at least two times more potent an activator of RXR than of RAR. 18. A compound according to claim 16, wherein the compound is at least five times more potent an activator of RAR than of RXR. 19. A compound according to claim 16, wherein the compound is at least ten times more potent an activator of RAR than of RXR. 20. A compound according to claim 16, wherein the compound is at least one hundred times more potent an activator of RAR than of RXR. 21. A compound according to claim 6, wherein the compound exhibits pan- agonist activity as both an activator of RAR and RXR. 22. A compound according to claim 1, wherein the compound is administered to a patient as a dosage unit at from about 1 μg/kg of body weight to about 500 mg/kg of body weight. 23. A compound according to claim 1, wherein the compound is administered to a patient as a dosage unit at from about lOμg/kg of body weight to about 250 mg/kg of body weight. 24. A compound according to claim 1, wherein the compound is administered to a patient as a dosage unit at from about 20μg/kg of body weight to about 100 mg/kg of body weight. 25. A compound according to claim 1, wherein the compound is effective in treating skin-related diseases and conditions, cancerous and pre-cancerous conditions, diseases of the eye, cardiovascular diseases, inflammatory diseases, neurodegenerative diseases, diseases involving modulation of apoptosis, diseases of the immune system, improper pituitary function, diseases involving human papilloma virus, wound healing or restoration of hair growth. 26. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. 27. A pharmaceutical composition according to claim 26, wherein the composition is formulated for oral, topical, intravenous, suppository or parental administration. 28. A pharmaceutical composition according to claim 26, wherein the compound is administered to a patient as a dosage unit at from about 1 μg/kg of body weight to about 500 mg/kg of body weight. 29. A pharmaceutical composition according to claim 26, wherein the compound is administered to a patient as a dosage unit at from about lOμg/kg of body weight to about 250 mg/kg of body weight. 30. A pharmaceutical composition according to claim 26, wherein the compound is administered to a patient as a dosage unit at from about 20 μg/kg of body weight to about 100 mg/kg of body weight. 31. A pharmaceutical composition according to claim 26, wherein the composition is effective in treating skin-related diseases and conditions, cancerous and pre¬ cancerous conditions, diseases of the eye, cardiovascular diseases, inflammatory diseases, neurodegenerative diseases, diseases involving modulation of apoptosis, diseases of the immune system, improper pituitary function, diseases involving human papilloma virus, wound healing or restoration of hair growth. 32. A method of affecting RAR and/or RXR activity comprising the in vivo administration of a compound according to claim 1. 33. A method of modulating processes mediated by RAR and/or RXR receptors comprising administering to a patient an effective amount of a compound according to claim 6. 34. A method of treating a patient requiring retinoid therapy comprising administering to the patient a pharmaceutically effective amount of a compound according to claim 6. 35. A method of treating a patient according to claim 34, wherein the compound is effective in treating skin-related diseases and conditions, cancerous and pre-cancerous conditions, diseases of the eye, cardiovascular diseases, inflammatory diseases, neurodegenerative diseases, diseases involving modulation of apoptosis, diseases of the immune system, improper pituitary function, diseases involving human papilloma virus, wound healing or restoration of hair growth. 36. A method of treating a patient requiring retinoid therapy comprising administering to the patient a pharmaceutically effective amount of a pharmaceutical composition according to claim 26. 37. A method of treating a patient according to claim 36, wherein the composition is effective in treating skin-related diseases and conditions, cancerous and pre- cancerous conditions, diseases of the eye, cardiovascular diseases, inflammatory diseases, neurodegenerative diseases, diseases involving modulation of apoptosis, diseases of the immune system, improper pituitary function, diseases involving human papilloma virus, wound healing or restoration of hair growth. 38. A method for determining the presence of one or more RAR and or RXR receptors in a sample comprising combining a compound according to claim 1 with a sample containing one or more unknown retinoid receptors, and determining whether said compound binds to a receptor in the sample. 39. A ligand-retinoid receptor complex formed by the binding of a compound according to claim 1 to a RAR and/or RXR receptor. 40. A method of purifying retinoid receptors comprising combining a compound according to claim 1 with a sample containing RAR and/or RXR receptors, allowing said compound to bind said receptors, and separating out the bound combination of said compound and said RAR and or RXR receptors. 41. A method of making of tritium labeled compound according to claim 1 , structure I, comprising: (a) coupling a trienoate aldehyde of the formula: with an aryl sulfonyl hydrazide to yield the corresponding hydrazone; and (b) reducing the hydrazone with a tritide to yield the corresponding tritium labeled trienoate, wherein, R and R through R have the definitions given in claim 1. 42. A method according to claim 41 , further comprising, saponifying the tritium labeled trienoate to yield the corresponding trienoic acid of the formula: wherein, R and R through R have the definitions given in claim 1.

Inventors: BENNANI YOUSSEF L, BOEHM MARCUS F, NADZAN ALEX M, ZHANG LIN, BENNANI, YOUSSEF, L., BOEHM, MARCUS, F., NADZAN, ALEX, M., ZHANG, LIN
Applicants: LIGAND PHARM INC, LIGAND PHARMACEUTICALS INCORPORATED
Application year: 1995
Main classification: C07C57
IPC codes: A61K31, A61P3, A61P25, A61P27, A61P29, A61P35, A61P37, A61P43, C07B59, C07C15, C07C33, C07C45, C07C47, C07C49, C07C57, C07C59, C07C69, C07C255, C07C311, C07D311