Dimer-selective RXR modulators and methods for their use

Abstract

Dimer-selective RXR modulator compounds having agonist, partial agonist and/or antagonist activity in the context of an RXR homodimer and/or RXR heterodimers are provided. Also provided are pharmaceutical compositions incorporating such dimer-selective RXR modulator compounds and methods for their therapeutic use.

What is claimed is:  
     
         1 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein, 
 R 1  through R 4  each independently are hydrogen, a C 1 -C 6  alkyl or a C 7 -C 15  arylalkyl or heteroarylalkyl;  
 R 5  is a C 5 -C 10  alkyl, heteroalkyl, aryl, heteroaryl, a C 7 -C 15  arylalkyl or heteroarylalkyl, N 6 R 7 , or OR 8 , where R 6  and R 7  each independently are a C 7 -C 10  alkyl, heteroalkyl, a C 7 -C 15  arylalkyl or heteroarylalkyl, a C 3 -C 10  acyl, provided that only one of R 6  or R 7  can be acyl, or R 6  and R 7  taken together are C 3 -C 6  cycloalkyl, and where R 8  is a C 7 -C 10  alkyl, heteroalkyl, aryl, heteroaryl, or a C 7 -C 15  arylalkyl or heteroarylalkyl;  
 R 9  and R 10  each independently are hydrogen, a C 1 -C 10  alkyl, halogen, heteroalkyl, NR 11 R 12 , NO 2  or OR 13 , where R 11  and R 12  each independently are hydrogen, a C 1 -C 10  alkyl, heteroalkyl, a C 7 -C 15  arylalkyl or heteroarylalkyl, a C 1 -C 8  acyl, provided that only one of R 11  or R 12  can be acyl, or R 11  and R 12  taken together are a C 3 -C 6  cycloalkyl, and where R 13  is hydrogen or a C 1 -C 10  alkyl, heteroalkyl or a C 7 -C 15  arylalkyl or heteroarylalkyl;  
 R 14  and R 15  each independently are hydrogen, a C 1 -C 10  alkyl, a C 1 -C 8  acyl, or OR 16  where R 16  is hydrogen or a C 1 -C 10  alkyl; or R 14  and R 15  taken together are keto, methano, optionally substituted oxime, optionally substituted hydrazone, optionally substituted epoxy, 1,3-dioxolane, 1,3-dioxane, 1,3-dithiolane, 1,3-dithiane, oxazolidine or:  
                     
 where R 17  through R 23  have the definitions given below and the dashed lines crossing the bonds indicate the attachment bonds to the rings adjacent to R 14  and R 15 ;  
 R 17  and R 18  each independently are hydrogen, a C 1 -C 10  alkyl, heteroalkyl, aryl, a C 7 -C 15  arylalkyl or heteroarylalkyl or R 17  and R 18  taken together are a C 3 -C 6  cycloalkyl;  
 R 19  is hydrogen, a C 1 -C 10  alkyl, heteroalkyl, aryl, heteroaryl, a C 7 -C 15  arylalkyl or heteroarylalkyl;  
 R 20  through R 23  each independently are hydrogen, halogen, a C 1 -C 10  alkyl, heteroalkyl, aryl, heteroaryl, a C 7 -C 15  arylalkyl or heteroarylalkyl, NR 24 R 25 , NO 2 , or OR 26 , where R 24  and R 25  each independently are hydrogen, a C 1 -C 10  alkyl, heteroalkyl, a C 7 -C 15  arylalkyl or heteroarylalkyl or a C 1 -C 8  acyl, provided that only one of R 24  or R 25  can be acyl, and where R 26  is hydrogen or a C 1 -C 10  alkyl, heteroalkyl, aryl, heteroaryl, or a C 7 -C 15  arylalkyl or heteroarylalkyl;  
 R 27  through R 31  each independently are hydrogen, a C 1 -C 10  alkyl, heteroalkyl, halogen, NR 32 R 33 , NO 2  or OR 34 , where R 32  and R 33  each independently are hydrogen, a C 1 -C 10  alkyl, a C 7 -C 15  arylalkyl or heteroarylalkyl, a C 1 -C 8  acyl, provided that only one of R 32  or R 33  can be acyl, or R 32  and R 33  taken together are a C 3 -C 6  cycloalkyl, and where R 34  is hydrogen or a C 1 -C 10  alkyl, heteroalkyl or a C 7 -C 15  arylalkyl or heteroarylalkyl and can only exist when W is C;  
 R 35  through R 38  each independently are hydrogen, a C 1 -C 2  alkyl or OR 39  where R 39  is hydrogen or a C 1 -C 10  alkyl, or R 35  and R 36  or R 37  and R 38  taken together are keto, or R 35  and R 36 , R 37  and R 38 , R 35  and R 37  or R 36  and R 38  taken together are epoxy;  
 COR 40  can originate from any W, when the originating W is C, and R 40  is OR 41  or NR 42 R 43 , with R 41  being hydrogen, a C 1 -C 6  alkyl or a C 7 -C 15  arylalkyl or heteroarylalkyl, and with R 42  and R 43  each independently being hydrogen, a C 1 -C 6  alkyl, a C 7 -C 15  arylalkyl or heteroarylalkyl, aryl, ortho-, meta-, or para-substituted hydroxyaryl, or taken together are a C 3 -C 6  cycloalkyl;  
 R 44  and R 45  each independently-are hydrogen, a C 1 -C 4  alkyl or CH 2 OR 46 , where R 46  is hydrogen or a C 1 -C 6  alkyl, or R 44  and R 45  taken together are a C 3 -C 6  cycloalkyl or cycloheteroalkyl;  
 R 47  is hydrogen, a C 1 -C 4  alkyl, or when n=1, R 47  taken together with R 44  or R 45  are a C 3 -C 6  cycloalkyl or cycloheteroalkyl;  
 R 48  and R 49  each independently are C 1 -C 4  alkyl;  
 R 50  is a C 4 -C 10  alkyl, heteroalkyl, aryl, heteroaryl, a C 7 -C 15  arylalkyl or heteroarylalkyl, NR 51 R 52 , or OR 53 , where R 51  and R 52  each independently are a C 2 -C 10  alkyl, heteroalkyl, a C 7 -C 15  arylalkyl or heteroarylalkyl, a C 3 -C 10  acyl, provided that only one of R 51  or R 52  can be acyl, or R 51  and R 52  taken together are C 3 -C 6  cycloalkyl, and where R 53  is a C 7 -C 10  alkyl, heteroalkyl, aryl, heteroaryl, a C 3 -C 6  alkyl, heteroalkyl, aryl or heteroalkyl or a C 7 -C 15  arylalkyl or heteroarylalkyl;  
 R 54  represents:  
                     
 where R 9 , R 10 , R 14 , R 15  and R 40  have the definitions given above;  
 R 55  through R 58  each independently are hydrogen, halogen, a C 1 -C 10  alkyl, heteroalkyl, aryl, heteroaryl, a C 7 -C 15  arylalkyl or heteroarylalkyl, NR 59 R 60  or OR 61 , where R 59  and R 60  each independently are hydrogen, a C 1 -C 10  alkyl or heteroalkyl, a C 7 -C 15  arylalkyl or heteroarylalkyl, a C 1 -C 8  acyl, provided that only one of R 59  or R 60  can be acyl, or R 59  and R 60  taken together are C 3 -C 6  cycloalkyl, and where R 61  is hydrogen or a C 1 -C  10  alkyl, heteroalkyl, aryl, heteroaryl, or a C 7 -C 15  arylalkyl or heteroarylalkyl, or where R 55  and R 56  or R 57  and R 58  taken together are keto, methano, a C 1 -C 10  alkyl methylene, a C 1 -C 10  dialkylmethylene, C 7 -C 15  arylalkyl or heteroarylalkylmethylene, oxime, O-alkyl oxime, hydrazone, 1,3-dioxolane, 1,3-dioxane, 1,3-dithiolane, 1,3-dithiane, oxazolidine, or R 55  and R 57  or R 56  and R 58  taken together are epoxy;  
 R 62  through R 64  each independently are hydrogen, aryl, heteroaryl, CF 3 , a C 2  -C 6  alkyl, C 2 -C 6  heteroalkyl or NR 51 R 52 , where R 51  and R 52  have the definitions given above;  
 R 65  is hydrogen, a C 1 -C 2  alkyl or OR 66 , where R 66  is a C 1 -C 2  alkyl;  
 R 67  is a C 4 -C 10  alkyl, heteroalkyl, aryl, heteroaryl, a C 7 -C 15  arylalkyl or heteroarylalkyl, NR 51 R 52 , or OR 68 , where R 51  and R 52  have the definitions described above, and where R 68  is a C 3 -C 10  alkyl, heteroalkyl, aryl, heteroaryl, or a C 7 -C 15  arylalkyl or heteroarylalkyl;  
 X and Y each independently represent C, O, S, N, SO or SO 2 , provided, however, that when X or Y are O, S, SO or SO 2 , then either R 1  and R 2  or R 3  and R 4  respectively do not exist, and further provided, that when X or Y is N, then one each of R 1  and R 2  or R 3  and R 4  respectively, do not exist;  
 M is N or C;  
 Q is N or C;  
 Z is O, S, SO, SO 2 , CR 69 R 70  or NR 71 , where R 69  through R 71  each independently are hydrogen or a C 1 -C 10  alkyl, heteroalkyl, aryl, heteroaryl, a C 7 -C 15  arylalkyl or heteroarylalkyl, or R 69  and R 70  each independently are OR 71 , or R 69  and R 70  taken together are a cycloalkyl;  
 each W is independently C, N, S or O, or a pharmaceutically acceptable salt, but is not O or S if attached by a double bond to another W or if attached to another such W which is O or S, and is not N if attached by a single bond to another such W which is N;  
 m is 0, 1 or 2 carbon atoms;  
 n is 0 or 1 carbon atoms;  
 k is 1 to 5 carbon atoms;  
 the dashed lines in the structures, other than at R 14  and R 15 , represent optional double bonds, provided, however, that the double bonds cannot be contiguous, and further provided that when such optional double bonds exist then the substitution patterns around such bonds cannot violate double bond valency; and  
 the wavy lines represent olefin geometry that is either cis (Z) or trans (E), and unless otherwise indicated, for substituents R 1  through R 71 , all olefin geometric Isomers (i.e., cis (Z) or trans (E)) of the above compounds are included.  
 
     
     
         2 . A compound according to  claim 1 , wherein the compound is a dimer-selective RXR modulator.  
     
     
         3 . A compound according to  claim 2 , wherein the compound is effective in modulating RXR homodimer interactions.  
     
     
         4 . A compound according to  claim 3 , wherein the compound is a RXR homodimer antagonist.  
     
     
         5 . A compound according to  claim 2 , wherein the compound is effective in modulating RXR heterodimer interactions, and wherein the RXR heterodimer comprises an RXR complexed with another intracellular receptor that forms a heterodimer with RXR.  
     
     
         6 . A compound according to  claim 5 , wherein the compound is a RXR, heterodimer antagonist.  
     
     
         7 . A compound according to  claim 5 , wherein the RXR is selected from the group consisting of RXRα, RXRβ and RXRγ.  
     
     
         8 . A compound according to  claim 5 , wherein the other intracelluar receptor is selected from the group consisting of PPARα, PPARβ, PPARγ1, PPARγ2, TRα, TRβ, VDRs, RARα, RARβ, RARγ, NGFIBs, NURR1s, LXRα, LXRβ and DAXs.  
     
     
         9 . A compound according to  claim 2 , wherein the compound is effective in treating skin-related diseases and conditions, cancerous and pre-cancerous conditions, diseases of the eye, cardiovascular diseases, metabolic diseases, obesity, inflammatory diseases, neurodegenerative diseases, diseases involving modulation of apoptosis, diseases involving modulation of cellular proliferation, diseases involving modulation of cellular differentiation, diseases of the immune system, improper pituitary function, diseases involving human papilloma virus, wound healing br restoration of hair growth.  
     
     
         10 . A compound according to  claim 9 , wherein the compound is effective in treating non-insulin dependent diabetes mellitus and insulin dependent diabetes mellitus.  
     
     
         11 . A compound according to  claim 2  selected from the group consisting of 4-[(3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid (Compound 101); 4-[(3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethenyl]benzoic acid (Compound 102); 4-[(3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)cyclopropyl] benzoic acid (Compound 103); 4-[(3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid oxime (Compound 104); 4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl]benzoic acid O-benzyloxime (Compound 105); 4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl]benzoic acid O-hexyloxime (Compound 106); 4-[(3-ethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethenyl]benzoic acid (Compound 107); 4-[(3-ethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid O-methyloxime (Compound 108); 4-[(3-propoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid oxime (Compound 109); 4-[(3-propoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid O-methyloxime (Compound 110); 4-[(3-butyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid (Compound 111); 4-[(3-butyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethenyl]benzoic acid (Compound 112); 4-[(3-butyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid O-methyloxime (Compound 113); 4-[(3-hexyloxy-5,6,7,8-tetrahydro-5,5,8,8 -tetramethyl-2-naphthyl)carbonyl]benzoic acid oxime (Compound 114); 4-[(3-heptyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid oxime (Compound 115); 4-[(3-heptyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethenyl]benzoic acid (Compound 116); cis-4-[(3-benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid oxime (Compound 117); trans-4-[(3-benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid oxime (Compound 118); (2E, 4E, 6E)-7-[3-butyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2-yl]-3-methylocta-2,4,6-trienoic acid (Compound 119); (2Z, 4E, 6E)-7-[3-(butyl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2-yl]-3-methylocta-2,4,6-trienoic acid (Compound 120); (2E, 4E, 6E)-7-[3-propoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalen-2-yl]-3-methylocta-2,4,6-trienoic acid (Compound 121); (2E, 4E, 6Z)-7-[3-propoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalen-2-yl]-3-methylocta-2,4,6-trienoic acid (Compound 122); (2Z, 4E, 6E)-7-(3-ethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2-yl)-3-methylocta-2,4,6-trienoic acid (Compound 123); (2E, 4E, 6Z)-7-[3-hexyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2-yl]-3-methylocta-2,4,6-trienoic acid (Compound 124); (2E, 4E, 6E)-7-[3-hexyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2-yl]-3-methylocta-2,4,6-trienoic acid (Compound 125); (2E, 4E, 6E)-7-[3-(3-methylbutyl-2-enyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2-yl]-3-methylocta-2,4,6-trienoic acid (Compound 126); (2E, 4E, 6E)-7-[3-benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2-yl]-3-methylocta-2,4,6-trienoic acid (Compound 127); (2E, 4E, 6Z)-7-[3-benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2-yl]-3-methylocta-2,4,6-trienoic acid (Compound 128); (2E, 4E, 6E)-7-[3-(4-methylbenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2-yl]-3-methylocta-2,4,6-trienoic acid (Compound 129); (2E, 4E, 6Z)-7-[3-(4-methylbenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2-yl]-3-methylocta-2,4,6-trienoic acid (Compound 130); 4-(3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-anthracen-1-ylmethyl)-benzoic acid (Compound 131); 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3H-cyclopenta[b]naphthalen-1-ylmethyl)-benzoic acid (Compound 132); 4-(6,7,8,9-tetrahydro-6,6,9,9-tetramethyl-2H-benzo[g]chromen-4-ylmethyl)-benzoic acid (Compound 133); 4-(3,4,6,7,8,9-hexahydro-2-oxo-6,6,9,9-tetramethyl-2H-benzo[g]quinolin-1-ylmethyl-)-benzoic acid (Compound 134); 4-(3,4,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-2H-benzo[g]quinolin-1-ylmethyl)-benzoic acid (Compound 135); 4-(2,3,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-naphtho[2,3-b][1,4]oxazin-4-ylmethyl)-benzoic acid (Compound 136); 4-(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracene-1-carbonyl)-benzoic acid (Compound 137); 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracen-1-yl)-hydroxymethyl]-benzoic acid (Compound 138); 4(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracen-1-ylmethyl)-benzoic acid (Compound 139); 4-[1-hydroxy-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracen-1-yl)-ethyl)-benzoic acid (Compound 140); 4-[1-methoxy-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracen-1-yl)-ethyl)-benzoic acid (Compound 141); 4-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracen-1-yl)-vinyl)-benzoic acid (Compound 142); (trans)4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracene-1-carbonyl oxime)-benzoic acid. (Compound 143); (cis)-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracene-1-carbonyl oxime)-benzoic acid (Compound 144); (trans)-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracene-1-carbonyl O-methyloxime)-benzoic acid (Compound 145); (2E, 4E, 6E)-7-(3,5-diisopropyl-2-n-heptyloxyphenyl)-3-methylocta-2,4,6-trienoic acid (Compound 146); (2E, 4E, 6Z)-7-(3,5-diisopropyl-2-n-heptyloxyphenyl)-3-methylocta-2,4,6-trienoic acid (Compound 147); (2E, 4E,)-7-(3,5-diisopropyl-2-n-heptyloxyphenyl)-3-methylocta-2,4-dienoic acid (Compound 148); (2Z, 4E,)-7-(3,5-diisopropyl-2-n-heptyloxyphenyl)-3-methylocta-2,4,dienoic acid (Compound 149); (2E, 4E, 6E)-7-(3,5-diisopropyl-2-benzyloxyphenyl)-3-methylocta-2,4,6-trienoic acid (Compound 150); (2E, 4E, 6E)-7-(3,5-diisopropyl-2-n-butyloxyphenyl)-3-methylocta-2,4,6-trienoic acid (Compound 151); (2E, 4E)-6-[2-(5,5,8,8-Tetramethyl-3-propyloxy-5,6,7,8-tetrahydronaphthalen-2-yl) cyclopropan-1-yl]-3-methyl hexadienoic acid (Compound 152); (2E, 4E)-6-[2-(5,5,8,8-Tetramethyl-3-heptyloxy-5,6,7,8-tetrahydronaphthalen-2-yl) cyclopropan-1-yl]-3-methyl hexadienoic acid (Compound 153); (2E, 4E)-6-[2-(5,5,8,8-Tetramethyl-3-benzyloxy-5,6,7,8-tetrahydronaphthalen-2-yl) cyclopropan-1-yl]-3-methyl hexadienoic acid (Compound 154); (2E, 4E)-7-[(5,5,8,8-Tetramethyl-3-propyloxy-5,6,7,8-tetrahydronaphtha-len-2-yl) cyclopropan-1-yl]-3-methyl heptadienoic acid (Compound 155); (2E, 4E)-7-[(5,5,8,8-Tetramethyl-3-heptyloxy-5,6,7,8-tetrahydronaphtha-len-2-yl) cyclopropan-1-yl]-3-methyl heptadienoic acid (Compound 156); (2E, 4E)-7-[(5,5,8,8-Tetramethyl-3-benzyloxy-5,6,7,8-tetrahydronaphtha-len-2-yl) cyclopropan-1-yl]-3-methyl heptadienoic acid (Compound 157); (2E, 4E)-5-[2-(5,5,8,8-Tetramethyl-3-propyloxy-5,6,7,8-tetrahydronaphthalen-2-yl) cyclopent-1-en-1-yl]-3-methyl pentadienoic acid (Compound 158); cis (2E, 4E)-5-[2-(5,5,8,8-Tetramethyl-3-propyloxy-5,6,7,8-tetrahydro-2-naphthyl) cyclopentan-1-yl]-3-methyl pentadienoic acid (Compound 159); 4-[(3-(4-t-Butylbenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid oxime (Compound 160); 4-[(3-(4-Bromobenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid oxime (Compound 161); cis-4-[(3-Benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid O-methyloxime (Compound 162); trans-4-[(3-Benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid O-methyloxime (Compound 163); 4-[2-(3-Benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-[1,3]dioxolan-2-yl]benzoic acid (Compound 164); 4-[2-Methyl-1-(3-benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]benzoic acid (Compound 165); (2E, 4E, 6E)-7-[3-(4-tert-butylbenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2-yl]-3-methyl-octa-2,4,6-trienoic acid. (Compound 166); (2E, 4E, 6Z)-7-[3-(4-tert-butylbenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2-yl]-3-methyl-octa-2,4,6-trienoic acid. (Compound 167); (2E, 4E, 6E)-7-[3-isobutyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2-yl]-3-methyl-octa-2,4,6-trienoic acid. (Compound 168); (2E, 4E, 6Z)-7-[3-isobutyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2-yl]-3-methyl-octa-2,4,6-trienoic acid. (Compound 169); (2E, 4E, 6E)-7-[3-pentyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2-yl]-3-methyl-octa-2,4,6-trienoic acid. (Compound 170); (2E, 4E, 6Z)-7-[3-pentyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2-yl]-3-methyl-octa-2,4,6-trienoic acid. (Compound 171); (2E, 4E, 6E)-7-[3-heptyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2-yl]-3-methyl-octa-2,4,6-trienoic acid. (Compound 172); (2E, 4E, 6Z)-7-[3-heptyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2-yl]-3-methyl-octa-2,4,6-trienoic acid. (Compound 173); (2E, 4E, 6E)-7-[3-(4-methoxybenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2-yl]-3-methyl-octa-2,4,6-trienoic acid. (Compound 174) and (2E, 4E)-7-[3-propoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2-yl]-3-methyl-octa-2,4-dienoic acid. (Compound 175).  
     
     
         12 . A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to  claim 2  and a pharmaceutically acceptable carrier.  
     
     
         13 . A pharmaceutical composition according to  claim 12 , wherein the composition is formulated for oral, topical, intravenous, suppository or parental administration.  
     
     
         14 . A pharmaceutical composition according to  claim 13 , wherein the composition is effective to treat skin-related diseases and conditions, cancerous and pre-cancerous conditions, diseases of the eye, cardiovascular diseases, metabolic diseases, obesity, inflammatory diseases, neurodegenerative diseases, diseases involving modulation of apoptosis, diseases involving modulation of cellular proliferation, diseases involving modulation of cellular differentiation, diseases of the immune system, improper pituitary function, diseases involving human papilloma virus, wound healing or restoration of hair growth.  
     
     
         15 . A compound according to  claim 14 , wherein the compound is effective in treating non-insulin dependent diabetes mellitus and insulin dependent diabetes mellitus.  
     
     
         16 . A pharmaceutical composition according to  claim 12 , wherein the composition 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.  
     
     
         17 . A pharmaceutical composition according to  claim 12 , wherein the composition is administered to a patient as a dosage unit at from about 10 μg/kg of body weight to about 250 mg/kg of body weight.  
     
     
         18 . A pharmaceutical composition according to  claim 12 , wherein the composition 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.  
     
     
         19 . A method of modulating processes mediated by RXR homodimers and/or RXR heterodimers comprising administering to a patient an effective amount a dimer-selective RXR modulator compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein, 
 R 1  through R 71 , M, Q, W, X, Y, Z, k, m and n each have the definitions provided in  claim 1;   
 R 72  is a C 3 -C 10  alkyl, heteroalkyl, aryl, heteroaryl, a C 7 -C 15  arylalkyl or heteroarylalkyl, NR 73 R 74 , or OR 75 , where R 73  and R 74  each independently are a C 7 -C 10  alkyl, heteroalkyl, a C 7 -C 15  arylalkyl or heteroarylalkyl, a C 3 -C 10  acyl, provided that only one of R 73  or R 74  can be acyl, or R 73  and R 74  taken together are C 3 -C 6  cycloalkyl, and where R 72  is a C 2 -C 10  alkyl, heteroalkyl, aryl, heteroaryl, or a C 7 -C 15  arylalkyl or heteroarylalkyl;  
 the dashed lines in the structures, other than at R 14  and R 15 , represent optional double bonds, provided, however, that the double bonds cannot be contiguous, and further provided that when such optional double bonds exist then the substitution patterns around such bonds cannot violate double bond valency; and  
 the wavy lines represent olefin geometry that is either cis (Z) or trans (E), and unless otherwise indicated, for substituents R 1  through R 75 , all olefin geometric isomers (i.e., cis (Z) or trans (E)) of the above compounds are included.  
 
     
     
         20 . A method of modulating according to  claim 19 , wherein the process is mediated by RXR homodimers.  
     
     
         21 . A method of modulating according to  claim 19 , wherein the process is mediated by RXR heterodimers.  
     
     
         22 . A method of modulating according to  claim 19 , wherein the process is selected from the group consisting of skin-related diseases and conditions, cancerous and pre-cancerous conditions, diseases of the eye, cardiovascular diseases, metabolic diseases, obesity, inflammatory diseases, neurodegenerative diseases, diseases involving modulation of apoptosis, modulation of diseases involving cellular proliferation, modulation of diseases involving cellular differentiation, diseases of the immune system, improper pituitary function, diseases involving human papilloma virus, wound healing and restoration of hair growth.  
     
     
         23 . A method of modulating according to  claim 22 , wherein the metabolic disease process is selected from the group consisting of non-insulin dependent diabetes mellitus and insulin dependent diabetes mellitus.  
     
     
         24 . A method of modulating according to  claim 19 , wherein the dimer-selective RXR modulator compound is combined with a pharmaceutically acceptable carrier to form a pharmaceutical composition.  
     
     
         25 . A method of modulating according to  claim 24 , wherein the pharmaceutical composition is formulated for oral, topical, intravenous, suppository or parental administration.  
     
     
         26 . A method of modulating according to  claim 24 , wherein the pharmaceutical composition is effective to treat processes selected from the group consisting of skin-related diseases and conditions, cancerous and pre-cancerous conditions, diseases of the eye, cardiovascular diseases, metabolic diseases, obesity, inflammatory diseases, neurodegenerative diseases, diseases involving modulation of apoptosis, diseases involving modulation of cellular proliferation, diseases involving modulation of cellular differentiation, diseases of the immune system, improper pituitary function, diseases involving human papilloma virus, wound healing and restoration of hair growth.  
     
     
         27 . A method of modulating according to  claim 26 , wherein the metabolic disease process is selected from the group consisting of non-insulin dependent diabetes mellitus and insulin dependent diabetes mellitus.  
     
     
         28 . A method of modulating according to  claim 24 , wherein the composition 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 method of modulating according to  claim 24 , wherein the composition is administered to a patient as a dosage unit at from about 10 μg/kg of body weight to about 250 mg/kg of body weight.  
     
     
         30 . A method of modulating according to  claim 24 , wherein the composition 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 method of modulating a process mediated by RXR homodimers and/or RXR heterodimers comprising administering to a patient an effective amount of a dimer-selective RXR modulator compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein, 
 R 44  through R 47  and R 62  through R 68 , M, W and n each have the definitions given in  claim 1 , or R 62  and R 63 , R 63  and R 65 , or R 65  and R 64  taken together are:  
                     
 where R 1  through R 4 , R 35  through R 39 , X, Y and m have the definitions given in  claim 1  and the dashed lines crossing the bonds adjacent X and Y indicate the points of attachment at R 62  and R 63 , R 63  and R 65 , or R 65  and R 64 ;  
                     
 where R 27  through R 34 , R 40  through R 43 , R 49 , W and n have the same definitions given in  claim 1  and the dashed lines crossing the bonds adjacent R 49  and R 27 /R 31  indicate the points of attachment at R 76 ;  
 other than as indicated above for points of attachment, the dashed lines in the structures represent optional double bonds, provided, however, that the double bonds cannot be contiguous, and further provided that when such optional double bonds exist then the substitution patterns around such bonds cannot violate double bond valency; and  
 the wavy lines represent olefin geometry that is either cis (Z) or trans (E), and unless otherwise indicated, for substituents R 1  through R 76 , all olefin geometric isomers (i.e., cis (Z) or trans (E)) of the above compounds are included.  
 
     
     
         32 . A method of modulating according to  claim 31 , wherein the process is mediated by RXR homodimers.  
     
     
         33 . A method of modulating according to  claim 31 , wherein the process is mediated by RXR heterodimers.  
     
     
         34 . A method of modulating according to  claim 31 , wherein the process is selected from the group consisting of skin-related diseases and conditions, cancerous and pre-cancerous conditions, diseases of the eye, cardiovascular diseases, metabolic diseases, obesity, inflammatory diseases. neurodegenerative diseases, diseases involving modulation of apoptosis, diseases involving modulation of cellular proliferation, diseases involving modulation of cellular differentiation, diseases of the immune system, improper pituitary function, diseases involving human papilloma virus, wound healing and restoration of hair growth.  
     
     
         35 . A method of modulating according to  claim 34 , wherein the metabolic disease process is selected from the group consisting of non-insulin dependent diabetes mellitus and insulin dependent diabetes mellitus.  
     
     
         36 . A method of modulating according to  claim 31 , wherein the dimer-selective RXR modulator compound is combined with a pharmaceutically acceptable carrier to form a pharmaceutical composition.  
     
     
         37 . A method of modulating according to  claim 36 , wherein the pharmaceutical composition is formulated for oral, topical, intravenous, suppository or parental administration.  
     
     
         38 . A method of modulating according to  claim 36 , wherein the pharmaceutical composition is effective to treat processes selected from the group consisting of skin-related diseases and conditions, cancerous and pre-cancerous conditions, diseases of the eye, cardiovascular diseases, metabolic diseases, obesity, inflammatory diseases, neurodegenerative diseases, diseases involving modulation of apoptosis, diseases involving modulation of cellular proliferation, diseases involving modulation of cellular differentiation, diseases of the immune system, improper pituitary function, diseases involving human papilloma virus, wound healing and restoration of hair growth.  
     
     
         39 . A method of modulating according to  claim 38 , wherein the metabolic disease process is selected from the group consisting of non-insulin dependent diabetes mellitus insulin dependent diabetes mellitus.  
     
     
         40 . A RXR homodimer antagonist compound.  
     
     
         41 . A RXR homodimer antagonist according to  claim 40 , wherein the compound also antagonizes a RXR heterodimer.  
     
     
         42 . A RXR homodimner antagonist according to  claim 40 , wherein the compound antagonizes a RXR homodimner, but does not antagonize a RXR heterodimer.  
     
     
         43 . A RXR homodimer antagonist according to  claim 42 , wherein the compound activates RXR heterodimers.  
     
     
         44 . A RXR homodimer antagonist according to  claim 43 , wherein the compound activates RXR hetrodimers comprising a RXR selected from the group consisting of RXRα, RXRβ and RXRγ complexed with another intracellular receptor selected from the group consisting of PPARα, PPARβ, PPARγ1, PPARγ2, TRα, TRβ, VRDs, RARα, RARβ, RARγ, NGFIBs, NURR1s, LXRα, LXRβ and DAXs.  
     
     
         45 . A RXR homodimer antagonist according to  claim 44 , wherein the compound activates the RXR heterodimer in the absence of an activator for the other intracellular receptor complexed with RXR.  
     
     
         46 . A RXR homodimer antagonist according to  claim 45 , wherein the compound activates a RXR:RAR heterodimer in the absence of a RAR activator.  
     
     
         47 . A RXR homodimer antagonist according to  claim 44 , wherein the compound and an activator for the other intracellular receptor complexed with RXR activate the RXR heterodimer to a significantly greater extent than either the compound or activator alone.  
     
     
         48 . A RXR homodimer antagonist according to  claim 44 , wherein the compound activates the RXR heterodimer in the presence or absence of an activator for the other intracellular receptor complexed with RXR.  
     
     
         49 . A RXR homodimer antagonist according to  claim 48 , wherein the other intracellular receptor is selected from the group consisting of PPARα, PPARβ, PPARγ1, PPARγ2, NGFIBs LXRα and LXRβ.  
     
     
         50 . A RXR homodimer antagonist compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein, 
 R 44  through R 47  and R 62  through R 68 , M, W and n each have the definitions given in  claim 1 , or R 62  and R 63 , R 63  and R 65 , or R 65  and R 64  taken together are:  
                     
 where R 1  through R 4 , R 35  through R 39 , X, Y and m have the definitions given in  claim 1  and the dashed lines crossing the bonds adjacent X and Y indicate the points of attachment at R 62  and R 63 , R 63  and R 65 , or R 65  and R 64 ;  
 R76 is:  
                     
 where R 27  through R 34 , R 40  through R 43 , R 49 , W and n have the same definitions given in  claim 1  and the dashed lines crossing the bonds adjacent R 49  and R 27 /R 31  indicate the points of attachment at R 76 ;  
 other than as indicated above for points of attachment, the dashed lines in the structures represent optional double bonds, provided, however, that the double bonds cannot be contiguous, and further provided that when such optional double bonds exist then the substitution patterns around such bonds cannot violate double bond valency; and  
 the wavy lines represent olefin geometry that is either cis (Z) or trans (E), and unless otherwise indicated, for substituents R 1  through R 76 , all olefin geometric isomers (i.e., cis (Z) or trans (E)) of the above compounds are included.  
 
     
     
         51 . A RXR homodimer antagonist according to  claim 50 , wherein the compound antagonizes a RXR homodimer, but does not antagonize a RXR heterodimer.  
     
     
         52 . A RXR homodimer antagonist according to  claim 51 , wherein the compound activates RXR heterodimers.  
     
     
         53 . A RXR homodimner antagonist according to  claim 52 , wherein the compound activates RXR hetrodimers comprising a RXR selected from the group consisting of RXRα, RXRβ and RXRγ complexed with another intracellular receptor selected from the group consisting of PPARα, PPARβ, PPARγ1, PPARγ2, TRα, TRβ, VRDs, RARα, RARβ, RARγ, NGFIBs, NURR1s, LXRα, LXRβ and DAXs.  
     
     
         54 . A RXR homodimer antagonist according to  claim 53 , wherein the compound activates the RXR heterodimer in the absence of an activator for the other intracellular receptor complexed with RXR.  
     
     
         55 . A RXR homodimer antagonist according to  claim 54 , wherein the compound activates a RXR:RAR heterodimer in the absence of a RAR activator.  
     
     
         56 . A RXR homodimer antagonist according to  claim 53 , wherein the compound and an activator for the other intracellular receptor complexed with RXR activate the RXR heterodimer to a significantly greater extent than either the compound or activator alone.  
     
     
         57 . A RXR homodimer anatagonist according to  claim 50 , wherein a pharmaceutically effective amount of the compound is combined with a pharmaceutically acceptable carrier to form a pharmaceutical composition.  
     
     
         58 . A pharmaceutical composition according to  claim 57 , wherein the composition is formulated for oral, topical, intravenous, suppository or parental administration.  
     
     
         59 . A pharmaceutical composition according to  claim 58 , wherein the composition is effective to treat skin-related diseases and conditions, cancerous and pre-cancerous conditions, diseases of the eye, cardiovascular diseases, metabolic diseases, obesity, inflammatory diseases, neurodegenerative diseases, diseases involving modulation of apoptosis, diseases involving modulation of cellular proliferation, diseases involving modulation of cellular differentiation, diseases of the immune system, improper pituitary function, diseases involving human papilloma virus, wound healing or restoration of hair growth.  
     
     
         60 . A compound according to  claim 59 , wherein the compound is effective in treating non-insulin dependent diabetes mellitus or insulin dependent diabetes mellitus.  
     
     
         61 . A pharmaceutical composition according to  claim 57 , wherein the composition 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.  
     
     
         62 . A pharmaceutical composition according to  claim 57 , wherein the composition is administered to a patient as a dosage unit at from about 10 μg/kg of body weight to about 250 mg/kg of body weight.  
     
     
         63 . A pharmaceutical composition according to  claim 57 , wherein the composition 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.  
     
     
         64 . A method of modulating a process mediated by a RXR homodimer comprising administering an effective amount of a RXR homodimer antagonist.  
     
     
         65 . A method of modulating a process mediated by a RXR heterodimer comprising administering an effective amount of a RXR homodimer antagonist.  
     
     
         66 . A method of modulating a process mediated by a RXR heterodimer comprising administering an effective amount of a RXR heterodimer antagonist.  
     
     
         67 . A method of treating a disease process mediated by RXR heterodimers comprising administering to a patient a therapeutically effective amount of a RXR homodimer antagonist.  
     
     
         68 . A method of treating a disease according to  claim 67 , wherein the RXR homodimer antagonist activates the RXR heterodimer in the absence of an activator for the other intracellular receptor complexed with RXR.  
     
     
         69 . A method of treating a disease according to  claim 68 , wherein the RXR homodimer antagonist activates a RXR:RAR heterodimer in the absence of a RAR activator.  
     
     
         70 . A method of treating a disease according to  claim 67 , wherein the RXR homodimer antagonist and an activator for the other intracellular receptor complexed with RXR activate the RXR heterodimer to a significantly greater extent than either the RXR homodimer antagonist or activator alone.  
     
     
         71 . A method of treating a disease according to  claim 67 , wherein the disease process is selected from the group consisting of skin-related diseases and conditions, cancerous and pre-cancerous conditions, diseases of the eye, cardiovascular diseases, metabolic diseases, obesity inflammatory diseases, neurodegenerative diseases, diseases involving modulation of apoptosis, diseases involving modulation of cellular proliferation, diseases involving modulation of cellular differentiation, diseases of the immune system, improper pituitary function, diseases involving human papilloma virus, wound healing and restoration of hair growth.  
     
     
         72 . A method of treating a disease according to  claim 71 , wherein the disease process is selected from the group consisting of non-insulin dependent diabetes mellitus and insulin dependent diabetes mellitus.  
     
     
         73 . A method of treating a disease according to  claim 68 , wherein the disease process is selected from the group consisting of skin-related diseases and conditions, cancerous and pre-cancerous conditions, diseases of the eye, cardiovascular diseases, metabolic diseases, obesity inflammatory diseases, neurodegenerative diseases, diseases involving modulation of apoptosis, diseases involving modulation of cellular proliferation, diseases involving modulation of cellular differentiation, diseases of the immune system, improper pituitary function, diseases involving human papilloma virus, wound healing and restoration of hair growth.  
     
     
         74 . A method of treating a disease according to  claim 73 , wherein the disease process is selected from the group consisting of non-insulin dependent diabetes mellitus and insulin dependent diabetes mellitus.  
     
     
         75 . A method of treating a disease according to  claim 67 , wherein the RXR homodimer antagonist is a compound according to  claim 1.