Methods of treatment with compounds having RARα receptor specific or selective activity
AssigneeAllergan, 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 RARα receptor subtypes in preference over RARβ and RARΓ 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.
Claims4
A process of administering to a mammal in need thereof a retinoid compound which binds specifically or selectively to a RARα retinoid receptors in preference over RARβ and RARγ retinoid receptors, for the purpose of treating or preventing a disease or condition selected from acute monolytic leukemia, cervical carcinoma, myeloma, ovarian carcinomas, head and neck carcinomas, proliferative vitreoretinopathy (PVR) and age related macular degeneration (AMD) where the RARα, specific or selective retinoid compound has the formula (ii)
- where
- R2 is independently hydrogen, or lower alkyl of 1 to 6 carbons;
- m is an integer having the value of 0-5;
- p is an integer having the value of 0-2.;
- r is an integer having the value 0-2;
- X2 is N or CH;
- V is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl, or naphthyl and heteroaryl groups being optionally substituted with one or two R2 groups;
- W2 is a substituent selected independently from the group consisting of F, Br, Cl, I, fluoro substituted C1-6 alkyl, NO2, and OH;
- W3 is a substituent selected independently from the group consisting of F, Br, Cl, I, C1-6alkyl, fluoro substituted C1-6 alkyl, NO2, and OH with the proviso that when X2 is CH and r is 0 then p is not 0 and at least one W3 group is not alkyl;
- L is —(C═Z)—NH— or —NH—(C═Z)—
- Z is O or S, and
- B is COOH or a pharmaceutically acceptable salt thereof, or COOR8, where CONR9R10, —CH2OH, CH2OR11, CH2 OCOR11, CHO, CH(OR12)2, CHOR13O, —COR7, CR7(OR12), CR7OR13O, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 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 R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons.
A process in accordance with claim 6 where in the formula of the RARα specific or selective retinoid compound Y is phenyl.
A process of administering to a mammal in need thereof a retinoid compound which binds specifically or selectively to a RARα retinoid receptors in preference over RARβ and RARΓ retinoid receptors, for the purpose of treating or preventing a disease or condition selected from acute monocytic leukemia, cervical carcinoma, myeloma, ovarian carcinomas, head and neck carcinomas, proliferative vitreoretinopathy (PVR) and age related macular degeneration (AM/D) the retinoid compound being specific or selective for RARα retinoid receptors in preference over RARβ and RARΓ retinoid receptors when in a binding assay the Kd value of binding to RARα receptors is approximately 500 times smaller than the Kd value for binding to RARβ and RARΓ retinoid receptors, the retinoid compound having the formula (ii)
- where R2 is independently hydrogen, or lower alkyl of 1 to 6 carbons;
- m is an integer having the value of 0-5;
- p is an integer having the value of 0-2;
- r is an integer having the value 0-2;
- X2 is N or CR;
- Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl, naphthyl and heteroaryl groups being optionally substituted with one or two R2 groups;
- W2 is a substituent selected independently from the group consisting of F, Br, Cl, I, fluoro substituted C1-6 alkyl, NO2, and OH;
- W3 is a substituent selected independently from the group consisting of F, Br, Cl, I, C1-6alkyl, fluoro substituted C1-6alkyl, NO2, and OH with the proviso that when X2 is CH and r is 0 then p is not 0 and at least one W3 group is not alkyl;
- L is —(C═Z)—NH— or —NH—(C═Z)—
- Z is O or S, and
- B is COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, —CH2 OH, CH2 OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, —COR7, CR7(OR12)2, CR7OR13O, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 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 R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons.
A process in accordance with claim 18 where the RARα specific or selective retinoid compound is:
- ethyl 2-fluoro-4-[2′6′-di-tert-butylpyrid-4′-yl)carbamoyl]benzoate, or
- 2-fluoro-4-[2′6′-di-t-butylpyrid-4′-yl)carbamoyl]benzoic acid.
Dependencies are inferred from the claim text.