Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
Certain chemical entities are provided herein. Also provided are pharmaceutical compositions comprising at least one chemical entity and one or more pharmaceutically acceptable vehicle. Methods of treating patients suffering from certain diseases and disorders responsive to the inhibition of KMO activity are described, which comprise administering to such patients an amount of at least one chemical entity effective to reduce signs or symptoms of the disease or disorder are disclosed. These diseases include neurodegenerative disorders such as Huntington's disease. Also described are methods of treatment include administering at least one chemical entity as a single active agent or administering at least one chemical entity in combination with one or more other therapeutic agents. Also provided are methods for screening compounds capable of inhibiting KMO activity.
1. A method of treatment of a condition or disorder mediated by Kynurenine 3-monooxygenase activity wherein the condition or disorder is Huntington's disease, Alzheimer's disease, or Parkinson's disease in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of Formula I
or a pharmaceutically acceptable salt thereof wherein:
X and Y are N;
R 1 is chosen from aryl and heteroaryl, each of which is optionally substituted with one, two, or three groups chosen from halo, optionally substituted lower alkyl, lower alkoxy, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and hydroxy;
L is —C(O)O—;
R 2 is hydrogen;
R 4 is chosen from hydrogen and optionally substituted lower alkyl; and
R 5 is chosen from hydrogen and fluoro.
2. The method of claim 1 wherein R 1 is phenyl optionally substituted with one, two, or three groups chosen from halo, optionally substituted lower alkyl, optionally substituted lower alkoxy, and hydroxy.
3. The method of claim 2 wherein R 1 is phenyl optionally substituted with one, two, or three groups chosen from halo, lower alkyl, trifluoromethyl, lower alkoxy, and hydroxy.
4. The method of claim 3 wherein R 1 is phenyl optionally substituted with one, two, or three groups chosen from halo, lower alkyl, and trifluoromethyl.
5. The method of claim 4 wherein R 1 is chosen from 2-trifluoromethylphenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 4-chlorophenyl, and 3,5-dichlorophenyl.
6. The method of claim 1 wherein R 4 is hydrogen.
7. The method of claim 1 wherein R 5 is hydrogen.
8. A method of treatment of a condition or disorder mediated by Kynurenine 3-monooxygenase activity, wherein the condition or disorder is Huntington's disease, Alzheimer's disease, or Parkinson's disease, in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound chosen from:
6-(2-Trifluoromethyl-phenyl)-pyrimidine-4-carboxylic acid;
6-(3-Chloro-phenyl)-pyrimidine-4-carboxylic acid;
6-(3,4-Dichloro-phenyl)-pyrimidine-4-carboxylic acid;
6-(3,5-Dichloro-phenyl)-pyrimidine-4-carboxylic acid;
6-(3,4-Dichloro -phenyl)-2-methyl-pyrimidine-4-carboxylic acid;
6-(4-Fluoro-3-trifluoromethyl-phenyl)-pyrimidine-4-carboxylic acid;
6-(3-Trifluoromethyl-phenyl)-pyrimidine-4-carboxylic acid;
6-(5-Fluoro-pyridin-3-yl)-pyrimidine-4-carboxylic acid;
6-(3-Fluoro-5-trifluoromethyl-phenyl)-pyrimidine-4-carboxylic acid;
6-(5-Chloro-pyridin-3-yl)-pyrimidine-4-carboxylic acid;
6-Phenyl-pyrimidine-4-carboxylic acid;
6-(2-Fluoro-5-trifluoromethyl-phenyl)-pyrimidine-4-carboxylic acid;
6-(2,4-Difluoro-phenyl)-pyrimidine-4-carboxylic acid;
6-(3-Chloro-2-fluoro-phenyl)-pyrimidine-4-carboxylic acid;
6-(3-Chloro-phenyl)-2-methyl-pyrimidine-4-carboxylic acid;
6-(3-Methoxy-phenyl)-pyrimidine-4-carboxylic acid;
6-m-Tolyl-pyrimidine-4-carboxylic acid;
6-(4-Methoxy-phenyl)-pyrimidine-4-carboxylic acid;
6-(3-Fluoro-phenyl)-pyrimidine-4-carboxylic acid;
6-(3-Chloro-4-trifluoromethyl-phenyl)-pyrimidine-4-carboxylic acid;
6-(3,4-Difluoro-phenyl)-pyrimidine-4-carboxylic acid;
6-(5-Chloro-2-fluoro-phenyl)-pyrimidine-4-carboxylic acid;
6-(3-Chloro-4-methoxy-phenyl)-pyrimidine-4-carboxylic acid;
6-(3-Chloro-4-fluoro-phenyl)-pyrimidine-4-carboxylic acid;
6-(3,4-Dichloro-phenyl}-5-fluoro-pyrimidine-4-carboxylic acid;
6-(3-Chloro-4-methyl-phenyl)-pyrimidine-4-carboxylic acid;
and
6-(3,4-Dichloro-phenyl)-5-fluoro-pyrimidine-4-carboxylic acid;
or a thereof.
9. The method according to claim 1 wherein the condition or disorder mediated by Kynurenine 3-monooxygenase activity is Huntington's disease.