Methods of treatment with compounds having RAR.sub..alpha. receptor specific or selective activity
AssigneeAllergan Sales, Inc.
InventorsMin Teng, Tien T. Duong, Roshantha A. Chandraratna
Life of this patent
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Abstract
Retinoid compounds which act specifically or selectively on RAR.sub..alpha. receptor subtypes in preference over RAR.sub..beta. and RAR.sub..gamma. receptor subtypes, posses desirable pharmaceutical properties associated with retinoids, and are particularly suitable for treatment of tumors, such as acute monocytic leukemia, cervical carcinoma, myeloma, ovarian carcinomas and head and neck carcinomas, without having one or more undesirable side effects of retinoids, such as inducement of weight loss, mucocutaneous toxicity, skin irritation and teratogenecity.
Claims2
A process of administering to a mammal in need thereof an effective amount of a retinoid compound which binds specifically or selectively to a RAR.sub..alpha. retinoid receptors in preference over RAR.sub..beta. and RAR.sub..gamma. retinoid receptors, for the purpose of treating or preventing a malignant tumor or leukemic disease or condition, the retinoid compound being specific or selective for RAR.sub..alpha. retinoid receptors in preference over RAR.sub..beta. and RAR.sub..gamma. retinoid receptors where in a binding assay the K.sub.d value of binding to RAR.sub..alpha. receptors is approximately 500 times smaller than the K.sub.d value for binding to RAR.sub..beta. and RAR.sub..gamma. retinoid receptors, where the compound is 2-fluoro-4-[2',2',4',4'-tetramethyl-8'-trifluoromethylchroman-6'-yl)carbam oyl benzoic acid, and said compound is administered to treat acute monocytic leukemia.
A process of administering to a mammal in need thereof an effective amount of a retinoid compound which binds specifically or selectively to a RAR.sub..alpha. retinoid receptors in preference over RAR.sub..beta. and RAR.sub..gamma. retinoid receptors, for the purpose of treating or preventing a malignant tumor or leukemic disease or condition, the retinoid compound being specific or selective for RAR.sub..alpha. retinoid receptors in preference over RAR.sub..beta. and RAR.sub..gamma. retinoid receptors when in a binding assay the K.sub.d value of binding to RAR.sub..alpha. receptors is approximately 500 times smaller than the K.sub.d value for binding to RAR.sub..beta. and RAR.sub..gamma. retinoid receptors, the retinoid compound having the formula ##STR13## where X.sub.1 is O;
- R.sub.1 is independently H or alkyl of 1 to 6 carbons;
- R.sub.2 is independently hydrogen, or lower alkyl of 1 to 6 carbons;
- R.sub.3 is hydrogen, lower alkyl of 1 to 6 carbons or F;
- m is an integer having the value of 0-5;
- o is an integer having the value of 0-4;
- p is an integer having the value of 0-2;
- r is an integer having the value 0-2;
- Y is a phenyl or naphthyl group optionally substituted with one or two R.sub.2 groups;
- W.sub.1 is a substituent selected independently from the group consisting of F, Br, Cl, I, fluoro substituted C.sub.1-6 alkyl, NO.sub.2, N.sub.3 and OH, with the provisos that:
- when Z is O then the sum of p and r is at least 1, and
- when Z is O and the sum of p and r is 1 then W.sub.1 is not a Cl group in the 8 position of a chroman ring;
- W.sub.2 is a substituent selected independently from the group consisting of F, Br, Cl, I, fluoro substituted C.sub.1-6 alkyl, NO.sub.2, and OH;
- L is --(C=Z)--NH-- or --NH--(C=Z)--;
- Z is O or S, and
- B is COOH or a pharmaceutically acceptable salt thereof, COOR.sub.8, where 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, where the disease or condition is selected from acute monocytic leukemia, cervical carcinoma, myeloma, ovarian carcinomas, and head and neck carcinomas.
Dependencies are inferred from the claim text.