US 5,877,207 A · Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities

Abstract

Aryl-substituted and aryl and (3-oxo-1-propenly)-substituted benzopyran, benzothiopyran, 1,2-dihydroquinoline, and 5,6-dihydronaphthalene derivatives have retinoid negative hormone and/or antagonist-like biological activities. The invented RAR antagonists can be administered to mammals, including humans, for the purpose of preventing or diminishing action of RAR agonists on the bound receptor sites. Specifically, the RAR agonists are administered or coadministered with retinoid drugs to prevent or ameliorate toxicity or side effects caused by retinoids or vitamin A or vitamin A precursors. The retinoid negative hormones can be used to potentiate the activities of other retinoids and nuclear receptor agonists. For example, the retinoid negative hormone called AGN 193109 effectively increased the effectiveness of other retinoids and steroid hormones in in vitro transactivation assays. Additionally, transactivation assays can be used to identify compounds having negative hormone activity. These assays are based on the ability of negative hormones to down-regulate the activity of chimeric retinoid receptors engineered to possess a constitutive transcription activator domain.

Claims34

Dependent claims

A compound of the formula ##STR19## wherein X is C(R.sub.1).sub.2 or O;

R.sub.1 is H or alkyl of 1 to 6 carbons;
R.sub.2 is lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF.sub.3, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
m is an integer having the value of 0-3;
R.sub.3 is lower alkyl of 1 to 6 carbons or F;
o is an integer having the value of 0-3;
s is an integer having the value of 1-3;
R.sub.8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R.sub.8 is phenyl or lower alkylphenyl;
R.sub.15 is independently H, F, Cl, Br, I, NO.sub.2, N(R.sub.8).sub.2, COR.sub.8, NR.sub.8 CON(R.sub.8).sub.2, OCOR.sub.8, OR.sub.8, CN, an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a trialkylsilyl or trialkylsilyloxy group where the alkyl groups independently have 1 to 6 carbons;
r is an integer having the values of 0-5, and
the CONH group is in the 6 or 7 position of the benzopyran, and in the 2 or 3 position of the dihydronaphthalene ring, or a pharmaceutically acceptable salt of said compound.

7 more elements

Dependencies are inferred from the claim text.

Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities

Life of this patent

Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities

Life of this patent

Abstract

Claims34