Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9649310-B2
Application number	US-201615042964-A
Country	US
Kind code	B2
Filing date	Feb 12, 2016
Priority date	Jul 28, 2011
Publication date	May 16, 2017
Grant date	May 16, 2017

Abstract

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.

First claim

What is claimed:

1. A method of treating Huntington's disease, Alzheimer's disease, Parkinson's disease, olivoponto cerebellar atrophy, non-Alzheimer's dementia, cerebral amyotrophic lateral sclerosis, cerebral ischemia, cerebral hypoxia, and epilepsy in a subject in need of such a treatment which method comprises administering to the subject a therapeutically effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof wherein:
R 1 is optionally substituted aryl or optionally substituted heteroaryl;
R 2 is tetrazolyl;
R 3 is hydrogen or optionally substituted lower alkyl; and
R 4 is hydrogen, halo, optionally substituted lower alkyl, hydroxyl, optionally substituted lower alkoxy, or optionally substituted amino, or
R 1 and R 4 taken together with intervening atoms, form a bicyclic ring of the formula

which is optionally substituted where m is 0 or 1 and n is 0 or 1, provided that at least one of m and n is 1,
provided that when R 3 and R 4 are hydrogen, then R 1 is not 5-chloropyridin-3-yl, 3,5-dichlorophenyl, or

where R 21 is halo and R 22 is hydrogen, halo, trifluoromethoxy, methyl, or isopropoxy.

2. The method of claim 1 , wherein said condition or disorder is Huntington's disease.

3. The method of claim 1 , wherein R 1 is phenyl optionally substituted with one, two, or three groups chosen from heteroaryl, heterocycloalkyl, cycloalkyl, optionally substituted cycloalkoxy, optionally substituted amino, halo, optionally substituted lower alkyl, optionally substituted lower alkoxy, and hydroxy.

4. The method of claim 1 , wherein R 1 is phenyl optionally substituted with one, two, or three groups chosen from heteroaryl, heterocycloalkyl, cycloalkyl, cycloalkoxy optionally substituted with lower alkyl, lower alkoxy, or lower alkyl substituted with halo, optionally substituted amino, halo, lower alkyl optionally substituted with amino, alkylamino, dialkylamino, or heterocycloalkyl, trifluoromethyl, trifluoromethoxy, lower alkoxy, and hydroxy.

5. The method of claim 1 , wherein R 1 is phenyl optionally substituted with one, two, or three groups chosen from furan-2-yl, 1H-pyrrol-2-yl, pyrrolidin-3-yl, pyrrolidin-1-yl, oxetan-3-yl optionally substituted with lower alkyl, halo, lower alkyl, cyclopropyl optionally substituted with lower alkyl, lower alkoxy, or lower alkyl substituted with halo, optionally substituted amino, lower alkyl optionally substituted with amino, alkylamino, dialkylamino, or heterocycloalkyl, trifluoromethoxy, cyclopropoxy optionally substituted with lower alkoxy, lower alkoxy, or lower alkyl substituted with halo, and trifluoromethyl.

6. The method of claim 1 , wherein R 1 is 3-chloro-4-cyclopropoxyphenyl, 4-tert-butyl-3-chlorophenyl, 3-chloro-4-(furan-2-yl)phenyl, 3-chloro-4-(1H-pyrrol-2-yl)phenyl, 3-chloro-4-(1H-imidazol-2-yl)phenyl, 3-chloro-4-(pyrrolidin-3-yl)phenyl, 3-chloro-4-(pyrrolidin-1-yl)phenyl, 3-chloro-4-(3-methyloxetan-3-yl)phenyl, 3-chloro-4-[1-(trifluoromethyl)cyclopropyl]phenyl, 3-chloro-4-cyclopropylphenyl, 3-chloro-4-(1-methylcyclopropyl)phenyl, 3-chloro-4-(1-methoxycyclopropyl)phenyl, 3-chloro-4-[cyclopropyl(methyl)amino]phenyl, 3-chloro-4-(cyclopropylamino)phenyl, 3-chloro-4-[(dimethylamino)methyl]phenyl, 4-(aziridin-1-ylmethyl)-3-chlorophenyl, 3-chloro-4-trifluoromethoxyphenyl, 3-chloro-4-methylphenyl, 3-fluoro-4-methylphenyl, 3-chloro-4-fluorophenyl, 3-chloro-4-isopropoxyphenyl, 3,4-difluorophenyl, 2-trifluoromethylphenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 4-chlorophenyl, or 3,5-dichlorophenyl.

7. The method of claim 1 , wherein R 2 is 1H-tetrazol-5-yl, 2H-tetrazol-5-yl, or tetrazol-1-yl.

8. The method of claim 1 , wherein R 4 is hydrogen, methyl, fluoro, methoxy, methoxymethyl, hydroxyl, or amino.

9. The method of claim 1 , wherein R 4 is hydrogen.

10. The method of claim 1 , wherein R 3 is hydrogen.

11. A method of treating Huntington's disease, Alzheimer's disease, Parkinson's disease, olivoponto cerebellar atrophy, non-Alzheimer's dementia, cerebral amyotrophic lateral sclerosis, cerebral ischemia, cerebral hypoxia, and epilepsy in a subject in need of such a treatment which method comprises administering to the subject a therapeutically effective amount of a compound selected from:
4-(6-(3-chloro-4-isopropoxyphenyl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid,
4-(3,4-dichlorophenyl)-6-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyrimidine,
4-(6-(3,4-dichlorophenyl)pyrimidin-4-yl)piperazine-2-carboxylic acid,
(R)-1-(6-(3,4-dichlorophenyl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid,
(S)-1-(6-(3,4-dichlorophenyl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid,
1-(6-(3,4-dichlorophenyl)pyrimidin-4-yl)pyrrolidine-3-carboxylic acid,
2-(6-(3-chloro-4-cyclopropoxyphenyl)pyrimidin-4-yl)oxazole,
1-(6-(3,4-dichlorophenyl)pyrimidin-4-yl)piperazine-2-carboxylic acid,
5-(6-(3-chloro-4-cyclopropoxyphenyl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid,
4-(3-chloro-4-cyclopropoxyphenyl)-6-(1H-1,2,3,4-tetrazol-5-yl)pyrimidine,
3-[6-(3-chloro-4-cyclopropoxyphenyl)pyrimidin-4-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one,
4-[3-chloro-4-(oxetan-3-yloxy)phenyl]-6-(2H-1,2,3,4-tetrazol-5-yl)pyrimidine,
3-{6-[3-chloro-4-(oxetan-3-yloxy)phenyl]pyrimidin-4-yl}-4,5-dihydro-1,2,4-oxadiazol-5-one,
4-[3-chloro-4-(cyclopropylmethoxy)phenyl]-6-(2H-1,2,3,4-tetrazol-5-yl)pyrimidine,
3-{6-[3-chloro-4-(cyclopropylmethoxy)phenyl]pyrimidin-4-yl}-4,5-dihydro-1,2,4-oxadiazol-5-one,
4-[3-chloro-4-(cyclopropoxymethyl)phenyl]-6-(2H-1,2,3,4-tetrazol-5-yl)pyrimidine,
3-{6-[3-chloro-4-(cyclopropoxymethyl)phenyl]pyrimidin-4-yl}-4,5-dihydro-1,2,4-oxadiazol-5-one,
4-[3-chloro-4-(cyclopropylmethyl)phenyl]-6-(2H-1,2,3,4-tetrazol-5-yl)pyrimidine,
3-{6-[3-chloro-4-(cyclopropylmethyl)phenyl]pyrimidin-4-yl}-4,5-dihydro-1,2,4-oxadiazol-5-one,
4-[3-chloro-4-(cyclopropylsulfanyl)phenyl]-6-(2H-1,2,3,4-tetrazol-5-yl)pyrimidine,
3-{6-[3-chloro-4-(cyclopropylsulfanyl)phenyl]pyrimidin-4-yl}-4,5-dihydro-1,2,4-oxadiazol-5-one,
4-[3-chloro-4-(cyclopropanesulfinyl)phenyl]-6-(2H-1,2,3,4-tetrazol-5-yl)pyrimidine,
3-{6-[3-chloro-4-(cyclopropanesulfinyl)phenyl]pyrimidin-4-yl}-4,5-dihydro-1,2,4-oxadiazol-5-one,
4-[3-chloro-4-(cyclopropanesulfonyl)phenyl]-6-(2H-1,2,3,4-tetrazol-5-yl)pyrimidine,
3-{6-[3-chloro-4-(cyclopropanesulfonyl)phenyl]pyrimidin-4-yl}-4,5-dihydro-1,2,4-oxadiazol-5-one,
{2-chloro-4-[6-(2H-1,2,3,4-tetrazol-5-yl)pyrimidin-4-yl]phenyl}(cyclopropyl)methanol,
3-{6-[3-chloro-4-(1-cyclopropoxyethyl)phenyl]pyrimidin-4-yl}-4,5-dihydro-1,2,4-oxadiazol-5-one,
4-(3-chloro-4-cyclopropanecarbonylphenyl)-6-(2H-1,2,3,4-tetrazol-5-yl)pyrimidine,
3-[6-(3-chloro-4-cyclopropanecarbonylphenyl)pyrimidin-4-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one,
4-(3-chloro-4-cyclopropylphenyl)-6-(2H-1,2,3,4-tetrazol-5-yl)pyrimidine,
3-[6-(3-chloro-4-cyclopropylphenyl)pyrimidin-4-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one,
4-[4-(aziridin-1-ylmethyl)-3-chlorophenyl]-6-(2H-1,2,3,4-tetrazol-5-yl)pyrimidine,
3-{6-[4-(aziridin-1-ylmethyl)-3-chlorophenyl]pyrimidin-4-yl}-4,5-dihydro-1,2,4-oxadiazol-5-one,
({2-chloro-4-[6-(2H-1,2,3,4-tetrazol-5-yl)pyrimidin-4-yl]phenyl}methyl)dimethylamine,
3-(6-{3-chloro-4-[(dimethylamino)methyl]phenyl}pyrimidin-4-yl)-4,5-dihydro-1,2,4-oxadiazol-5-one,
4-(7-chloro-1-benzofuran-5-yl)-6-(2H-1,2,3,4-tetrazol-5-yl)pyrimidine,
3-[6-(7-chloro-1-benzofuran-5-yl)pyrimi

Assignees

• Chdi Foundation Inc

Inventors

• Dominguez Celia
• Toledo-Sherman Leticia M
• Courtney Stephen Martin
• Prime Michael
• Mitchell William
• Brown Christopher John
• De Aguiar Pena Paula C
• Johnson Peter

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title