Claims for Patent: 5,466,861

Summary for Patent: 5,466,861

Title:	Bridged bicyclic aromatic compounds and their use in modulating gene expression of retinoid receptors
Abstract:	Bridged bicyclic aromatic compounds are provided having the structure ##STR1## wherein R1, R2, R3, R4, R5 and n are as defined herein. The novel compounds are useful for modulating gene expression of retinoic acid receptors, vitamin D receptors and thyroid receptors. Pharmaceutical compositions and methods for modulating gene expression are provided as well.
Inventor(s):	Marcia L. Dawson, James F. Cameron, Peter D. Hobbs, Ling Jong, Magnus Pfahl, Xiao-kun Zhang, Jurgen M. Lehmann
Assignee:	Ligand Pharmaceuticals Inc
Application Number:	US07/982,305
Patent Claims:	1. A bicyclic aromatic compound having the structural formula ##STR28## wherein: R1 is selected from the group consisting of lower alkyl and adamantyl;R2 is --O--R13 or --S--R13 where R13 is lower alkyl; or where R1 is ortho to R2, R1 and R2 may be linked together to form a 5- or 6-membered cycloalkylene ring, either unsubstituted or substituted with 1 to 4 lower alkyl groups, and optionally containing 1 or 2 heterocyclic atoms selected from the group consisting of O, S and NR where R is hydrogen or lower alkyl; R3 is selected from the group consisting of carbonyl, ##STR29## in which X1 and X2 are both methylene, m is 2 or 3, R6, R7, R8 and R9 are independently hydrogen or lower alkyl, or R8 and R9 may be linked together to form a cycloalkylene ring containing 3 to 6 carbon atoms, and * represents the point of attachment of the R3 substituent to the remainder of the molecule; R4 is selected from the group consisting of ##STR30## in which R10 is hydrogen or methyl, l is 0 or 1, and ** represents the point of attachment of the R4 substituent to the remainder of the molecule; the R5 are independently selected from the group consisting of lower alkyl and lower alkoxy; and n is 0, 1, 2 or 3, with the provisos that: (a) when n is 0, R3 is other than carbonyl, *C═CH2 or CH2 ; (b) when n is 0, and R3 is ##STR31## R6 and R7 are not both hydrogen; (c) when n is 0, and R3 is ##STR32## R8 and R9 are not both hydrogen; and (d) when R3 is ##STR33## in which one of R8 and R9 is hydrogen or lower alkyl and the other is lower alkyl, either (i) R1 and R2 are such that they are not linked together to form a cycloalkyl ring, or (ii) R4 is other than ##STR34## and the pharmaceutically acceptable ester, amides and salts of the compound. 2. A pharmaceutical composition for control of cellular processes regulated by retinoic acid, vitamin D, or thyroid hormone, comprising an effective regulating amount of the compound of claim 1 in combination with a pharmaceutically acceptable carrier. 3. The compound of claim 1, having a structure selected from the group consisting of ##STR35## where R11 is selected from the group consisting of O, S, (CH3)2 C and CH2, and R12 is hydrogen or methyl. 4. The compound of claim 3, having the structural formula (II). 5. The compound of claim 4, wherein R3 has the structural formula ##STR36## 6. The compound of claim 4, wherein R3 has the structural formula ##STR37## 7. The compound of claim 4, wherein R3 has the structural formula ##STR38## 8. The compound of claim 4, having the structural formula ##STR39## 9. The compound of claim 4, having the structural formula ##STR40## 10. The compound of claim 4, having the structural formula ##STR41## 11. The compound of claim 4, having the structural formula ##STR42## 12. The compound of claim 4, having the structural formula ##STR43## 13. The compound of claim 4, having the structural formula ##STR44## 14. The compound of claim 4, having the structural formula ##STR45## 15. A pharmaceutical composition for control of cellular processes regulated by retinoic acid, vitamin D, or thyroid hormone, comprising an effective regulating amount of the compound of claim 4 in combination with a pharmaceutically acceptable carrier. 16. The compound of claim 4, wherein n is 0. 17. The compound of claim 16, wherein R3 has the structural formula ##STR46## 18. The compound of claim 17, wherein R3 is selected from the group consisting of ##STR47## 19. The compound of claim 16, wherein R4 is ##STR48## 20. The compound of claim 16, wherein R3 has the structural formula ##STR49## 21. The compound of claim 20, wherein R3 is selected from the group consisting of ##STR50## 22. The compound of claim 16, wherein R3 has the structural formula ##STR51## 23. A pharmaceutical composition for control of cellular processes regulated by retinoic acid, vitamin D, or thyroid hormone, comprising an effective regulating amount of a bicyclic aromatic compound, or a pharmaceutically acceptable ester, amide or salt thereof, in combination with a pharmaceutically acceptable carrier, wherein the bicyclic aromatic compound has the structural formula (I) ##STR52## in which: R1 is selected from the group consisting of lower alkyl and adamantyl;R2 is --O--R6 or --S--R6 where R6 is lower alkyl; or where R1 is ortho to R2, R1 and R2 may be linked together to form a 5- or 6-membered cycloalkylene ring, either unsubstituted or substituted with 1 to 4 lower alkyl groups, and optionally containing 1 or 2 heterocyclic atoms selected from the group consisting of O, S and NR where R is hydrogen or lower alkyl; R3 is selected from the group consisting of carbonyl, ##STR53## in which X1 and X2 are both methylene, m is 2 or 3, R6, R7, R8 and R9 are independently hydrogen or lower alkyl, or R8 and R9 may be linked together to form a cycloalkylene ring containing 3 to 6 carbon atoms, and * represents the point of attachment of the R3 substituent to the remainder of the molecule; R4 is selected from the group consisting of ##STR54## in which R10 is hydrogen or methyl, 1 is 0 or 1, and ** represents the point of attachment of the R4 substituent to the remainder of the molecule; the R5 are independently selected from the group consisting of lower alkyl and lower alkoxy; and n is 0, 1, 2 or 3, with the provisos that: (a) when n is 0, R3 is other than carbonyl, *C═CH2 or CH2 ; (b) when n is 0, and R3 is ##STR55## R6 and R7 are not both hydrogen; and (c) when n is 0, and R3 is ##STR56## R8 and R9 are not both hydrogen.