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

US5877207A · kind A · utility

Assignee

• ALLERGAN SALES, LLC · US

Inventors

• Elliott S. Klein · Santa Monica, US
• Alan T. Johnson · Rancho Santa Margarita, US
• Andrew M. Standeven · Ventura, US
• Richard L. Beard · Newport Beach, US
• Samuel J. Gillett · Albany, US
• Tien T. Duong · Irvine, US
• Sunil Nagpal · Lake Forest, US
• Vidyasagar Vuligonda · Irvine, US
• Min Teng · Aliso Viejo, US
• Roshantha A. Chandraratna · معلمی نژاد, US

Key dates

• Filing date: Jun 24, 1997
• Grant date: Mar 2, 1999
• Expiry date: Jun 24, 2017

Classification

• Technology area (CPC C): Chemistry; Metallurgy
• CPC primary: C07C2602/28
• WIPO field: Organic fine chemistry
• WIPO sector: Chemistry

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.