Bridged bicyclic aromatic compounds and their use in modulating gene expression of retinoid receptors
AssigneesSRI International, La Jolla Cancer Research Foundation
InventorsMarcia L. Dawson, James F. Cameron, Peter D. Hobbs, Ling Jong, Magnus Pfahl, Xiao-kun Zhang, Jurgen M. Lehmann
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Abstract
Bridged bicyclic aromatic compounds are provided having the structure ##STR1## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 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.
Claims23
A bicyclic aromatic compound having the structural formula ##STR28## wherein:
- R.sup.1 is selected from the group consisting of lower alkyl and adamantyl;
- R.sup.2 is --O--R.sup.13 or --S--R.sup.13 where R.sup.13 is lower alkyl;
- or
- where R.sup.1 is ortho to R.sup.2, R.sup.1 and R.sup.2 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;
- R.sup.3 is selected from the group consisting of carbonyl, ##STR29## in which X.sup.1 and X.sup.2 are both methylene, m is 2 or 3, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are independently hydrogen or lower alkyl, or R.sup.8 and R.sup.9 may be linked together to form a cycloalkylene ring containing 3 to 6 carbon atoms, and * represents the point of attachment of the R.sup.3 substituent to the remainder of the molecule;
- R.sup.4 is selected from the group consisting of ##STR30## in which R.sup.10 is hydrogen or methyl, l is 0 or 1, and ** represents the point of attachment of the R.sup.4 substituent to the remainder of the molecule;
- the R.sup.5 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, R.sup.3 is other than carbonyl, *C.dbd.CH.sub.2 or CH.sub.2 ;
- (b) when n is 0, and R.sup.3 is ##STR31## R.sup.6 and R.sup.7 are not both hydrogen;
- (c) when n is 0, and R.sup.3 is ##STR32## R.sup.8 and R.sup.9 are not both hydrogen;
- and (d) when R.sup.3 is ##STR33## in which one of R.sup.8 and R.sup.9 is hydrogen or lower alkyl and the other is lower alkyl, either (i) R.sup.1 and R.sup.2 are such that they are not linked together to form a cycloalkyl ring, or (ii) R.sup.4 is other than ##STR34## and the pharmaceutically acceptable ester, amides and salts of the compound.
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:
- R.sup.1 is selected from the group consisting of lower alkyl and adamantyl;
- R.sup.2 is --O--R.sup.6 or --S--R.sup.6 where R.sup.6 is lower alkyl;
- or
- where R.sup.1 is ortho to R.sup.2, R.sup.1 and R.sup.2 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;
- R.sup.3 is selected from the group consisting of carbonyl, ##STR53## in which X.sup.1 and X.sup.2 are both methylene, m is 2 or 3, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are independently hydrogen or lower alkyl, or R.sup.8 and R.sup.9 may be linked together to form a cycloalkylene ring containing 3 to 6 carbon atoms, and * represents the point of attachment of the R.sup.3 substituent to the remainder of the molecule;
- R.sup.4 is selected from the group consisting of ##STR54## in which R.sup.10 is hydrogen or methyl, 1 is 0 or 1, and ** represents the point of attachment of the R.sup.4 substituent to the remainder of the molecule;
- the R.sup.5 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, R.sup.3 is other than carbonyl, *C.dbd.CH.sub.2 or CH.sub.2 ;
- (b) when n is 0, and R.sup.3 is ##STR55## R.sup.6 and R.sup.7 are not both hydrogen;
- and (c) when n is 0, and R.sup.3 is ##STR56## R.sup.8 and R.sup.9 are not both hydrogen.
Dependencies are inferred from the claim text.