Claims for Patent: 6,043,279

Summary for Patent: 6,043,279

Title:	Compounds having selective activity for retinoid X receptors, and means for modulation of processes mediated by retinoid X receptors
Abstract:	Compounds, compositions, and methods for modulating processes mediated by Retinoid X Receptors using retinoid-like compounds which have activity selective for members of the subclass of Retinoid X Receptors (RXRs), in preference to members of the subclass of Retinoic Acid Receptors (RARs). Examples of such compounds are bicyclic benzyl, pyridinyl, thiophene, furanyl, and pyrrole derivatives. The disclosed methods employ compounds for modulating processes selectively mediated by Retinoid X Receptors.
Inventor(s):	Boehm; Marcus F. (San Diego, CA), Heyman; Richard A. (Encinitas, CA)
Assignee:	Ligand Pharmaceuticals, Incorporated (San Diego, CA)
Application Number:	08/799,396
Patent Claims:	1. A compound having the formula: ##STR14## wherein R.sub.1 and R.sub.2, each independently, represent hydrogen or lower alkyl or acyl having 1-4 carbon atoms; R' and R" represent hydrogen, lower alkyl or acyl having 1-4 carbon atoms, OH, alkoxy having 1-4 carbon atoms, thiol or thio ether, or amino, or R' or R" taken together form an oxo (keto), methano, thioketo, HO--N.dbd., NC--N.dbd., (R.sub.7 R.sub.8)N--N.dbd., R,.sub.7 O--N.dbd., R.sub.17 N.dbd., epoxy, cyclopropyl, or cycloalkyl group and wherein the epoxy, cyclopropyl, and cycloalkyl groups can be substituted with lower alkyl having 1-4 carbons or halogen; R.sub.6, R.sub.10, R.sub.11, R.sub.12, R.sub.13 each independently represent hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, OR.sub.7, SR.sub.7, NR.sub.7 R.sub.8 or (CF).sub.n CF.sub.3, and exist only if the Z, Z', Z", Z'", or Z"" from which it originates is C, and where one of R.sub.6, R.sub.10, R.sub.11, R.sub.12 or R.sub.13 is X; R.sub.7 represents hydrogen or a lower alkyl having 1-6 carbons; R.sub.8 represents hydrogen or a lower alkyl having 1-6 carbons; R.sub.9 represents a lower alkyl having 1-4 carbons, phenyl, aromatic alkyl, or q-hydroxyphenyl, q-bromophenyl, q-chlorophenyl, q-fluorophenyl, or q-iodophenyl, where q=2-4; R.sub.17 represents hydrogen, lower alkyl having 1-8 carbons, alkenyl (including halogen, acyl, OR.sub.7 and SR.sub.7 substituted alkenes), R.sub.9, alkyl carboxylic acid (including halogen, acyl, OR.sub.7 and SR.sub.7 substituted alkyls), alkenyl carboxylic acid (including halogen, acyl, OR.sub.7 and SR.sub.7 substituted alkenes), alkyl amines (including halogen, acyl, OR.sub.7 and SR.sub.7 substituted alkyls), and alkenyl amines (including halogen, aryl, OR.sub.7 and SR.sub.7 substituted alkenes); R.sub.18 represents hydrogen, a lower alkyl having 1-4 carbons, halogan, nitro, OR.sub.7, SR.sub.7, NR.sub.7 R.sub.8, or (CF).sub.n CF.sub.3 ; X is COOH, tetrazole, PO.sub.3 H, SO.sub.3 H, CHO, CH.sub.2 OH, CONH.sub.2, COSH, COOR.sub.9, COSR.sub.9, CONHR.sub.9, or COOW where W is a pharmaceutically acceptable salt, and where X can originate from any C or N on the ring; Z, Z', Z", Z"' and Z"", each independently, represent C, S, O, N, or a pharmaceutically acceptable salt, but is not O or S if attached by a double bond to another such Z or if attached to another such Z which is O or S, and is not N if attached by a single bond to another such Z which is N; and n=0-3. 2. A compound of claim 1 wherein said compound selectively activates Retinoid X Receptors in preference to Retinoic Acid Receptors. 3. A compound selected from the group consisting of 4-[1-(2-methyl-4-t-butylphenyl)ethenyl]benzoic acid, 4-[1-(2-methyl-4-t-butylphenyl)cyclopropyl]benzoic acid, 4-[(2-methyl-4-t-butylphenyl)carbonyl]benzoic acid oxime, and 4-[1-(2-methyl-4-t-butylphenyl)carbonyl]benzoic acid methyloxime. 4. A pharmaceutical composition comprising in a pharmaceutically acceptable vehicle suitable for enteral, parenteral, or topical administration, one or more compound having the formula: ##STR15## wherein R.sub.1 and R.sub.2, each independently, represent hydrogen or lower alkyl or acyl having 1-4 carbon atoms; R' and R" represent hydrogen, lower alkyl or acyl having 1-4 carbon atoms, OH, alkoxy having 1-4 carbon atoms, thiol or thio ether, or amino, or R' or R" taken together form an oxo (keto), methano, thioketo, HO--N.dbd., NC--N.dbd., (R.sub.7 R.sub.8)N--N.dbd., R.sub.17 O--N=, R.sub.17 N.dbd., epoxy, cyclopropyl, or cycloalkyl group and wherein the epoxy, cyclopropyl, and cycloalkyl groups can be substituted with lower alkyl having 1-4 carbons or halogen; R.sub.6, R.sub.10, R.sub.11, R.sub.12, R.sub.13 each independently represent hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, OR.sub.7, SR.sub.7, NR.sub.7 R.sub.8 or (CF).sub.n CF.sub.3, and exist only if the Z, Z', Z", Z'", or Z"" from which it originates is C, and where one of R.sub.6, R.sub.10, R.sub.11, R.sub.12 or R.sub.13 is X; R.sub.7 represents hydrogen or a lower alkyl having 1-6 carbons; R.sub.8 represents hydrogen or a lower alkyl having 1-6 carbons; R.sub.9 represents a lower alkyl having 1-4 carbons, phenyl, aromatic alkyl, or q-hydroxyphenyl, q-bromophenyl, q-chlorophenyl, q-fluorophenyl, or q-iodophenyl, where q=2-4; R.sub.17 represents hydrogen, lower alkyl having 1-8 carbons, alkenyl (including halogen, acyl, OR.sub.7 and SR.sub.7 substituted alkenes), R.sub.9, alkyl carboxylic acid (including halogen, acyl, OR.sub.7 and SR.sub.7 substituted alkyls), alkenyl carboxylic acid (including halogen, acyl, OR.sub.7 and SR.sub.7 substituted alkenes), alkyl amines (including halogen, acyl, OR.sub.7 and SR.sub.7 substituted alkyls), and alkenyl amines (including halogen, aryl, OR.sub.7 and SR.sub.7 substituted alkenes); R.sub.18 represents hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, OR.sub.7, SR.sub.7, NR.sub.7 R.sub.8, or (CF).sub.n CF.sub.3 ; X is COOH, tetrazole, PO.sub.3 H, SO.sub.3 H, CHO, CH.sub.2 OH, CONH.sub.2, COSH, COOR.sub.9, COSR.sub.9, CONHR.sub.9, or COOW where W is a pharmaceutically acceptable salt, and where X can originate from any C or N on the ring; Z, Z', Z", Z"' and Z"", each independently, represent C, S, O, N, or a pharmaceutically acceptable salt, but is not O or S if attached by a double bond to another such Z or if attached to another such Z which is O or S, and is not N if attached by a single bond to another such Z which is N; and n=0-3. 5. A method for modulating a process mediated by one or more Retinoid X Receptors, said method comprising causing said process to be conducted in the presence of at least one compound having the formula: ##STR16## wherein R.sub.1 and R.sub.2, each independently, represent hydrogen or lower alkyl or acyl having 1-4 carbon atoms; R' and R" represent hydrogen, lower alkyl or acyl having 1-4 carbon atoms, OH, alkoxy having 1-4 carbon atoms, thiol or thio ether, or amino, or R' or R" taken together form an oxo (keto), methano, thioketo, HO--N.dbd., NC--N.dbd., (R.sub.7 R.sub.8)N--N.dbd., R.sub.17 O--N.dbd., R.sub.17 N.dbd., epoxy, cyclopropyl, or cycloalkyl group and wherein the epoxy, cyclopropyl, and cycloalkyl groups can be substituted with lower alkyl having 1-4 carbons or halogen; R.sub.6, R.sub.10, R.sub.11, R.sub.12, R.sub.13 each independently represent hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, OR.sub.7, SR.sub.7, NR.sub.7 R.sub.8 or (CF).sub.n CF.sub.3, and exist only if the Z. Z', Z", Z'", or Z"" from which it originates is C, and where one of R.sub.6, R.sub.10, R.sub.11, R.sub.12 or R.sub.13 is X; R.sub.7 represents hydrogen or a lower alkyl having 1-6 carbons; R.sub.8 represents hydrogen or a lower alkyl having 1-6 carbons; R.sub.9 represents a lower alkyl having 1-4 carbons, phenyl, aromatic alkyl, or q-hydroxyphenyl, q-bromophenyl, q-chlorophenyl, q-fluorophenyl, or q-iodophenyl, where q=2-4; R.sub.17 represents hydrogen, lower alkyl having 1-8 carbons, alkenyl (including halogen, acyl, OR.sub.7 and SR.sub.7 substituted alkenes), R.sub.9, alkyl carboxylic acid (including halogen, acyl, OR.sub.7 and SR.sub.7 substituted alkyls), alkenyl carboxylic acid (including halogen, acyl, OR.sub.7 and SR.sub.7 substituted alkenes), alkyl amines (including halogen, acyl, OR.sub.7 and SR.sub.7 substituted alkyls), and alkenyl amines (including halogen, aryl, OR.sub.7 and SR.sub.7 substituted alkenes); R.sub.18 represents hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, OR.sub.7, SR.sub.7, NR.sub.7 R.sub.8, or (CF).sub.n CF.sub.3 ; X is COOH, tetrazole, PO.sub.3 H, SO.sub.3 H, CHO, CH.sub.2 OH, CONH.sub.2, COSH, COOR.sub.9, COSR.sub.9, CONHR.sub.9, or COOW where W is a pharmaceutically acceptable salt, and where X can originate from any C or N on the ring; Z, Z', Z", Z"' and Z"", each independently, represent C, S, O, N, or a pharmaceutically acceptable salt, but is not O or S if attached by a double bond to another such Z or if attached to another such Z which is O or S, and is not N if attached by a single bond to another such Z which is N; and n=0-3. 6. A method according to claim 5 wherein said process is the in vivo modulation of lipid metabolism, in vivo modulation of skin-related processes, in vivo modulation of malignant cell development, in vivo modulation of premalignant lesions, or in vivo modulation of programmed cell death. 7. A method according to claim 5 wherein said process is in in vivo or in vitro cellular growth and differentiation, or in vivo limb morphogenesis. 8. A method for modulating a process mediated by one or more Retinoid X Receptors, said method comprising administering to a mammalian subject an amount, effective to modulate said process mediated by said one or more Retinoid X Receptors, of one or more compound having the formula: ##STR17## wherein R.sub.1 and R.sub.2, each independently, represent hydrogen or lower alkyl or acyl having 1-4 carbon atoms; R' and R" represent hydrogen, lower alkyl or acyl having 1-4 carbon atoms, OH, alkoxy having 1-4 carbon atoms, thiol or thio ether, or amino, or R' or R" taken together form an oxo (keto), methano, thioketo, HO--N.dbd., NC--N.dbd., (R.sub.7 R.sub.8)N--N.dbd., R.sub.17 O--N.dbd., R.sub.17 N.dbd., epoxy, cyclopropyl, or cycloalkyl group and wherein the epoxy, cyclopropyl, and cycloalkyl groups can be substituted with lower alkyl having 1-4 carbons or halogen; R.sub.6, R.sub.10, R.sub.11, R.sub.12, R.sub.13 each independently represent hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, OR.sub.7, SR.sub.7, NR.sub.7 R.sub.8 or (CF).sub.n CF.sub.3, and exist only if the Z, Z', Z", Z'", or Z"" from which it originates is C, and where one of R.sub.6, R.sub.10, R.sub.11, R.sub.12 or R.sub.13 is X; R.sub.7 represents hydrogen or a lower alkyl having 1-6 carbons; R.sub.8 represents hydrogen or a lower alkyl having 1-6 carbons; R.sub.9 represents a lower alkyl having 1-4 carbons, phenyl, aromatic alkyl, or q-hydroxyphenyl, q-bromophenyl, q-chlorophenyl, q-fluorophenyl, or q-iodophenyl, where q=2-4; R.sub.17 represents hydrogen, lower alkyl having 1-8 carbons, alkenyl (including halogen, acyl, OR.sub.7 and SR.sub.7 substituted alkenes), R.sub.9, alkyl carboxylic acid (including halogen, acyl, OR.sub.7 and SR.sub.7 substituted alkyls), alkenyl carboxylic acid (including halogen, acyl, OR.sub.7 and SR.sub.7 substituted alkenes), alkyl amines (including halogen, acyl, OR.sub.7 and SR.sub.7 substituted alkyls), and alkenyl amines (including halogen, aryl, OR.sub.7 and SR.sub.7 substituted alkenes); R.sub.18 represents hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, OR.sub.7, SR.sub.7, NR.sub.7 R.sub.8, or (CF).sub.n CF.sub.3 ; X is COOH, tetrazole, PO.sub.3 H, SO.sub.3 H, CHO, CH.sub.2 OH, CONH.sub.2, COSH, COOR.sub.9, COSR.sub.9, CONHR.sub.9, or COOW where W is a pharmaceutically acceptable salt, and where X can originate from any C or N on the ring; Z, Z', Z", Z"' and Z"", each independently, represent C, S, O, N, or a pharmaceutically acceptable salt, but is not O or S if attached by a double bond to another such Z or if attached to another such Z which is O or S, and is not N if attached by a single bond to another such Z which is N; and n=0-3. 9. A method for treating a mammalian subject requiring Retinoid X Receptor therapy comprising administering to such subject a pharmaceutically effective amount of one or more compounds having the formula: ##STR18## wherein R.sub.1 and R.sub.2, each independently, represent hydrogen or lower alkyl or acyl having 1-4 carbon atoms; R' and R" represent hydrogen, lower alkyl or acyl having 1-4 carbon atoms, OH, alkoxy having 1-4 carbon atoms, thiol or thio ether, or amino, or R' or R" taken together form an oxo (keto), methano, thioketo, HO--N.dbd., NC--N.dbd., (R.sub.7 R.sub.8)N--N.dbd., R.sub.17 O--N=, R.sub.17 N.dbd., epoxy, cyclopropyl, or cycloalkyl group and wherein the epoxy, cyclopropyl, and cycloalkyl groups can be substituted with lower alkyl having 1-4 carbons or halogen; R.sub.6, R.sub.10, R.sub.11, R.sub.12, R.sub.13 each independently represent hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, OR.sub.7, SR.sub.7, NR.sub.7 R.sub.8 or (CF).sub.n CF.sub.3, and exist only if the Z, Z', Z", Z'", or Z"" from which it originates is C, and where one of R.sub.6, R.sub.10, R.sub.11, R.sub.12 or R.sub.13 is X; R.sub.7 represents hydrogen or a lower alkyl having 1-6 carbons; R.sub.8 represents hydrogen or a lower alkyl having 1-6 carbons; R.sub.9 represents a lower alkyl having 1-4 carbons, phenyl, aromatic alkyl, or q-hydroxyphenyl, q-bromophenyl, q-chlorophenyl, q-fluorophenyl, or q-iodophenyl, where q=2-4; R.sub.17 represents hydrogen, lower alkyl having 1-8 carbons, alkenyl (including halogen, acyl, OR.sub.7 and SR.sub.7 substituted alkenes), R.sub.9, alkyl carboxylic acid (including halogen, acyl, OR.sub.7 and SR.sub.7 substituted alkyls), alkenyl carboxylic acid (including halogen, acyl, OR.sub.7 and SR.sub.7 substituted alkenes), alkyl amines (including halogen, acyl, OR.sub.7 and SR.sub.7 substituted alkyls), and alkenyl amines (including halogen, aryl, OR.sub.7 and SR.sub.7 substituted alkenes); R.sub.18 represents hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, OR.sub.7, SR.sub.7, NR.sub.7 R.sub.8, or (CF).sub.n CF.sub.3 ; X is COOH, tetrazole, PO.sub.3 H, SO.sub.3 H, CHO, CH.sub.2 0H, CONH.sub.2, COSH, COOR.sub.9, COSR.sub.9, CONHR.sub.9, or COOW where W is a pharmaceutically acceptable salt, and where X can originate from any C or N on the ring; Z, Z', Z", Z"' and Z"", each independently, represent C, S, O, N, or a pharmaceutically acceptable salt, but is not O or S if attached by a double bond to another such Z or if attached to another such Z which is O or S, and is not N if attached by a single bond to another such Z which is N; and n =0-3. 10. A method for increasing plasma concentrations of high density lipoprotein in a mammalian subject comprising administering to such subject a pharmaceutically effective amount of one or more compounds having the formula: ##STR19## wherein R.sub.1 and R.sub.2, each independently, represent hydrogen or lower alkyl or acyl having 1-4 carbon atoms; R' and R" represent hydrogen, lower alkyl or acyl having 1-4 carbon atoms, OH, alkoxy having 1-4 carbon atoms, thiol or thio ether, or amino, or R' or R" taken together form an oxo (keto), methano, thioketo, HO--N.dbd., NC--N.dbd., (R.sub.7 R.sub.8)N--N.dbd., R.sub.17 0-N=, R.sub.17 N.dbd., epoxy, cyclopropyl, or cycloalkyl group and wherein the epoxy, cyclopropyl, and cycloalkyl groups can be substituted with lower alkyl having 1-4 carbons or halogen; R.sub.6, R.sub.10, R.sub.11, R.sub.12, Ri.sub.3 each independently represent hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, OR.sub.7, SR.sub.7, NR.sub.7 R.sub.8 or (CF).sub.n CF.sub.3, and exist only if the Z, Z', Z", Z'", or Z"" from which it originates is C, and where one of R.sub.6, R.sub.10, R.sub.11, R.sub.12 or R.sub.13 is X; R.sub.7 represents hydrogen or a lower alkyl having 1-6 carbons; R.sub.8 represents hydrogen or a lower alkyl having 1-6 carbons; R.sub.9 represents a lower alkyl having 1-4 carbons, phenyl, aromatic alkyl, or q-hydroxyphenyl, q-bromophenyl, q-chlorophenyl, q-fluorophenyl, or q-iodophenyl, where q=2-4; R.sub.17 represents hydrogen, lower alkyl having 1-8 carbons, alkenyl (including halogen, acyl, OR.sub.7 and SR.sub.7 substituted alkenes), R.sub.9, alkyl carboxylic acid (including halogen, acyl, OR.sub.7 and SR.sub.7 substituted alkyls), alkenyl carboxylic acid (including halogen, acyl, OR.sub.7 and SR.sub.7 substituted alkenes), alkyl amines (including halogen, acyl, OR.sub.7 and SR.sub.7 substituted alkyls), and alkenyl amines (including halogen, aryl, OR.sub.7 and SR.sub.7 substituted alkenes); R.sub.18 represents hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, OR.sub.7, SR.sub.7, NR.sub.7 R.sub.8, or (CF).sub.n CF.sub.3 ; X is COOH, tetrazole, PO.sub.3 H, SO.sub.3 H, CHO, CH.sub.2 OH, CONH.sub.2, COSH, COOR.sub.9, COSR.sub.9, CONHR.sub.9, or COOW where W is a pharmaceutically acceptable salt, and where X can originate from any C or N on the ring; Z, Z', Z", Z"' and Z"", each independently, represent C, S, O, N, or a pharmaceutically acceptable salt, but is not O or S if attached by a double bond to another such Z or if attached to another such Z which is O or S, and is not N if attached by a single bond to another such Z which is N; and n=0-3. 11. A method for modulating a process mediated by intracellular receptors, said method comprising causing said process to be conducted in the presence of a composition comprising a first compound as set forth below which selectively activates Retinoid X Receptors in preference to Retinoid Acid Receptors, in combination with a second compound which activates one or more intracellular receptors other than Retinoid X Receptors, and wherein the physiological effect in mammals produced by said composition at a given concentration is greater than the additive effect achieved by utilizing each said compound alone at said concentration, said first compound having the formula: ##STR20## wherein R.sub.1 and R.sub.2, each independently, represent hydrogen or lower alkyl or acyl having 1-4 carbon atoms; R' and R" represent hydrogen, lower alkyl or acyl having 1-4 carbon atoms, OH, alkoxy having 1-4 carbon atoms, thiol or thio ether, or amino, or R' or R" taken together form an oxo (keto), methano, thioketo, HO--N.dbd., NC--N.dbd., (R.sub.7 R.sub.8)N--N.dbd., R.sub.17 O--N=, R.sub.17 N.dbd., epoxy, cyclopropyl, or cycloalkyl group and wherein the epoxy, cyclopropyl, and cycloalkyl groups can be substituted with lower alkyl having 1-4 carbons or halogen; R.sub.6, R.sub.10, R.sub.11, R.sub.12, R.sub.13 each independently represent hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, OR.sub.7, SR.sub.7, NR7R.sub.8 or (CF).sub.n CF.sub.3, and exist only if the Z, Z', Z", Z'", or Z"" from which it originates is C, and where one of R.sub.6, R.sub.10, R.sub.11, R.sub.12 or R.sub.13 is X; R.sub.7 represents hydrogen or a lower alkyl having 1-6 carbons; R.sub.8 represents hydrogen or a lower alkyl having 1-6 carbons; R.sub.9 represents a lower alkyl having 1-4 carbons, phenyl, aromatic alkyl, or q-hydroxyphenyl, q-bromophenyl, q-chlorophenyl, q-fluorophenyl, or q-iodophenyl, where q=2-4; R.sub.17 represents hydrogen, lower alkyl having 1-8 carbons, alkenyl (including halogen, acyl, OR.sub.7 and SR.sub.7 substituted alkenes), R.sub.9, alkyl carboxylic acid (including halogen, acyl, OR.sub.7 and SR.sub.7 substituted alkyls), alkenyl carboxylic acid (including halogen, acyl, OR.sub.7 and SR.sub.7 substituted alkenes), alkyl amines (including halogen, acyl, OR.sub.7 and SR.sub.7 substituted alkyls), and alkenyl amines (including halogen, aryl, OR.sub.7 and SR.sub.7 substituted alkenes); R.sub.18 represents hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, OR.sub.7, SR.sub.7, NR.sub.7 R.sub.8, or (CF).sub.n CF.sub.3 ; X is COOH, tetrazole, PO.sub.3 H, SO.sub.3 H, CHO, CH.sub.2 OH, CONH.sub.2, COSH, COOR.sub.9, COSR.sub.9, CONHR.sub.9, or COOW where W is a pharmaceutically acceptable salt, and where X can originate from any C or N on the ring; Z, Z', Z", Z"' and Z"", each independently, represent C, S, O, N, or a pharmaceutically acceptable salt, but is not O or S if attached by a double bond to another such Z or if attached to another such Z which is O or S, and is not N if attached by a single bond to another such Z which is N; and n=0-3. 12. A method for modulating a process selectively mediated by one or more Retinoid X Receptors, said method comprising causing said process to be conducted in the presence of at least one compound which selectively activates a Retinoid X Receptor in preference to all of Retinoic Acid Receptor isoforms .alpha., .beta., and .gamma.. 13. A method for treating a mammalian subject requiring Retinoid X Receptor therapy comprising administering to such subject a pharmaceutically effective amount of one or more compounds which selectively activate a Retinoid X Receptor in preference to all of Retinoic Acid Receptor isoforms .alpha., .beta., and .gamma..