Retinoid-like activity is exhibited by compounds of formula (I) where X is S, O, or NR' where R' is hydrogen or lower alkyl; R is hydrogen or lower alkyl; A is pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl or pyrazinyl; n is 0-4; and B is H, -COOH or a pharmaceutically acceptable salt, ester or amide thereof, -CH2OH or an ether or ester derivative, or -CHO or an acetal derivative, or -COR1 or a ketal derivative where R1 is -(CH2)mCH3 where m is 0-4, or a pharmaceutically acceptable salt thereof.

Disubstituted acetylenes bearing heteroaromatic and heterobicyclic groups having retinoid-like activity

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.

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

Compounds of the formula Y 3 (R 4 )—X—Y 1 (R 1 R 2 )—Z—Y 2 (R 2 )—A—B where the symbols have the meaning defined in the specification, have retinoid, retinoid antagonist or retinoid inverse agonist type biological activity.

Substituted diaryl or diheteroaryl methans, ethers and amines having retinoid agonist, antagonist or inverse agonist type biological activity

Process of treatment of mammals, including humans to treat diseases or conditions of the type which are normally treated with retinoid-like compounds is disclosed, with pharmaceutical compositions containing an active compound which is a selective agonist of the RXR retinoid receptor sites in preference to the RAR retinoid receptor sites. A compound is defined to be a selective agonist of the RXR receptor site if the compound is at least approximately ten times more effective as an agonist in the RXR receptor sites than in the RAR receptor sites.

Method of treatment with compounds having selective agonist-like activity on RXR retinoid receptors

Retinoid-like compounds which act as agonists of the RXR retinoid receptor sites induce apoptosis of tumor cells in cell cultures, and are used as drugs to treat tumors in mammals including humans. Compounds which are specific agonists of RXR receptors and also compounds which are agonists of both RAR and RXR agonist (pan-agonists) induce apoptosis, although the RXR agonist compounds are preferred as drugs to avoid undesirable side effects associated with RAR agonist activity. The RXR agonists compounds are administered to mammals afflicted with tumors in pharmaceutical compositions adapted for systemic topical or for intralesional administration. The range of concentration of the active ingredient RXR agonist compound in the pharmaceutical compositions is approximately between 0.001 and 5 percent by weight, and such that the composition delivers approximately 0.1 mg to 100 mg of the active ingredient per kg body weight of the patient, per day of treatment.

Treatment of mammals afflicted with tumors with compounds having RXR retinoid receptor agonist activity

Retinoid-like activity is exhibited by compounds of the formula ##STR1## where X is S, O or NR 1 where R 1 is hydrogen or lower alkyl; n is 0-5; R is H or lower alkyl and A is H, --COOH or a pharmaceutically acceptable salt, ester or amide thereof, --CH 2 OH or an ether or ester derivative thereof, or --CHO or an acetal derivative thereof, or --COR 2 or a ketal derivative thereof where R 2 is --(CH 2 ) m CH 3 where m is 0-4; or a pharmaceutically acceptable salt.

Chandraratna Roshantha A S

Papers

Acetylenes disubstituted with a phenyl group and a heterobicyclic group having retinoid-like activity

Process for preparing acetylenes disubstituted with phenyl group and heterobicyclic group having retinoid like activity