Methods of providing and using compounds having activity as inhibitors of cytochrome P450RAI
AssigneeAllergan Sales, Inc.
InventorsJayasree Vasudevan, Alan T. Johnson, Liming Wang, Dehua Huang, Roshantha A. Chandraratna
Life of this patent
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Abstract
Novel compounds having the Formulas 1 through 8, wherein the symbols have the meaning defined in the specification, and certain previously known compounds have been discovered to act as inhibitors of the cytochrome P450RAI (retinoic acid inducible) enzyme, and are used for treating diseases responsive to treatment by retinoids. The compound can also be used in co-treatment with retinoids.
Claims6
A method of inhibiting the enzyme cytochrome P450RAI in a mammal by administering to said mammal an effective dose of a pharmaceutical composition comprising a compound of the formula
- wherein A is heteroaryl selected from a group consisting of pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said heteroaryl groups being optionally substituted with one or two R2 groups;
- X is O, or S;
- Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, or I;
- Z is
- —C≡C—,
- —(CR1═CR1)n,
- where n′ is an integer having the value 1-5,
- —CO—NR1—,
- NR1—CO—;
- —CO—O—,
- —O—CO—,
- —CS—NR1—,
- NR1—CS—,
- —CO—S—,
- —S—CO—,
- —N═N—;
- R1 is independently H or alkyl of 1 to 6 carbons;
- p is an integer having the values of 0 to 4;
- R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
- R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
- m is an integer having the values 0 to 2;
- R4 is independently H, alkyl of 1 to 6 carbons, or F;
- fluorosubstituted alkyl of 1 to 6 carbons, or halogen;
- o is an integer having the values of 0 to 2;
- n is an integer having the values of 0 to 4, and
- R8 is H, alkyl of 1 to 6 carbons, —CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
A method of inhibiting the enzyme cytochrome P450RAI in a mammal by administering to said mammal an effective dose of a pharmaceutical composition comprising a compound of the formula
- wherein A is heteroaryl selected from a group consisting of pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said heteroaryl groups being optionally substituted with one or two R2 groups;
- X3is S or O;
- Y1 is H, lower alkyl of 1 to 3 carbons, cycloalkyl of 3 to 6 carbons, benzyl, lower alkyl substituted cycloalkyl of 3 to 6 carbons;
- Z is
- —C≡C—,
- —(CR1═CR1)n, where n′ is an integer having the value 1-5,
- —CO—NR1—,
- NR1—CO—,
- —CO—O—,
- —O—CO—,
- —CS—NR1—,
- NR1—CS—,
- —CO—S—,
- —S—CO—,
- —N═N—;
- R1 is independently H or alkyl of 1 to 6 carbons;
- R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
- R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
- m is an integer having the values 0 to 2;
- R4 is independently H, alkyl of 1 to 6 carbons, or F;
- fluorosubstituted alkyl of 1 to 6 carbons, or halogen;
- o is an integer having the values of 0 to 4;
- n is an integer having the values of 0 to 4, and
- R8 is H, alkyl of 1 to 6 carbons, —CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base, with the proviso that:
- Y1 is cycloalkyl,
- when Y1 is not cycloalkyl then n is 1.
A method of inhibiting the enzyme cytochrome P450RAI in a mammal by administering to said mammal an effective dose of a pharmaceutical composition comprising a compound wherein the variables are defined as follows with reference to the formula below:
- X5 is S, X6 is N, n is 0 and R8 is H, alkyl of 1 to 6 carbons, —CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
A method of inhibiting the enzyme cytochrome P450RAI in a mammal by administering to said mammal an effective dose of a pharmaceutical composition comprising a compound wherein the variables are defined as follows with reference to the formula below:
- R10 is CH3, R11 is Cl, R12 is F, X6 is N and R8 is H, alkyl of 1 to 6 carbons, —CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
Dependencies are inferred from the claim text.