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

Patent metadata

Field	Value
Publication number	US-9822058-B2
Application number	US-201314390190-A
Country	US
Kind code	B2
Filing date	Mar 13, 2013
Priority date	Apr 5, 2012
Publication date	Nov 21, 2017
Grant date	Nov 21, 2017

Abstract

Certain compounds, or pharmaceutically acceptable salts or prodrugs thereof, are provided herein. Also provided are pharmaceutical compositions comprising at least one compound, or pharmaceutically acceptable salt or prodrug thereof, described herein 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 compound, or pharmaceutically acceptable salt or prodrug thereof, described herein 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 compound, or pharmaceutically acceptable salt or prodrug thereof, described herein as a single active agent or administering at least one compound, or pharmaceutically acceptable salt or prodrug thereof, described herein 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 compound of Formula I:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R 1 is

R 11 is chloro and R 12 is Z—R 20 , wherein:
Z is —O—, —S—, —S(O)—, —S(O) 2 —, or —CR 21 R 22 —,
R 21 and R 22 are independently selected from hydrogen, lower alkyl, hydroxyl, and lower alkoxy, or R 21 and R 22 , taken together with the carbon to which they are attached, form an optionally substituted 3- to 7-membered cycloalkyl or heterocycloalkyl, and
R 20 is optionally substituted C 1 -C 6 alkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl;

R 13 is hydrogen or halo;
X is —CR 2 R 3 —;
R 2 and R 3 are independently selected from hydrogen, optionally substituted amino, hydroxyl, lower alkoxy, and optionally substituted lower alkyl, or R 2 and R 3 , taken together with the carbon to which they are attached, form an optionally substituted 5- to 7-membered cycloalkyl or optionally substituted 5- to 7-membered heterocycloalkyl;
L is —C(O)O—;
R 5 is hydrogen; and
R 6 and R 7 are independently selected from hydrogen, halo, optionally substituted amino, hydroxyl, lower alkoxy, and optionally substituted lower alkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt or prodrug thereof, wherein R 2 is hydrogen, hydroxyl, lower alkoxy, amino optionally substituted with one or more alkyl groups, or lower alkyl optionally substituted with one or more groups independently selected from halo, hydroxyl, lower alkoxy, and amino optionally substituted with one or more alkyl groups.

3. The compound of claim 2 , or a pharmaceutically acceptable salt or prodrug thereof, wherein R 2 is hydrogen, amino, methylamino, dimethylamino, hydroxyl, methyl, methoxy, difluoromethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, aminomethyl, (methylamino)methyl, or (dimethylamino)methyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt or prodrug thereof, wherein R 3 is hydrogen or lower alkyl.

5. The compound of claim 4 , or a pharmaceutically acceptable salt or prodrug thereof, wherein R 3 is hydrogen or methyl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt or prodrug thereof, wherein R 2 and R 3 are hydrogen.

7. The compound of claim 1 , or a pharmaceutically acceptable salt or prodrug thereof, wherein R 2 is methyl and R 3 is hydrogen.

8. The compound of claim 1 , or a pharmaceutically acceptable salt or prodrug thereof, wherein R 2 and R 3 are methyl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt or prodrug thereof, wherein R 2 and R 3 , taken together with the carbon to which they are attached form an optionally substituted 5- or 6-membered cycloalkyl or optionally substituted 5- or 6-membered heterocycloalkyl.

10. The compound of claim 9 , or a pharmaceutically acceptable salt or prodrug thereof, wherein R 2 and R 3 , taken together with the carbon to which they are attached, form an optionally substituted cyclopentyl or optionally substituted pyrrolidin-3-yl.

11. The compound of claim 10 , or a pharmaceutically acceptable salt or prodrug thereof, wherein R 2 and R 3 , taken together with the carbon to which they are attached, form a cyclopentyl or pyrrolidin-3-yl.

12. The compound of claim 1 , or a pharmaceutically acceptable salt or prodrug thereof, wherein Z is —O—.

13. The compound of claim 1 , or a pharmaceutically acceptable salt or prodrug thereof, wherein Z is —S—.

14. The compound of claim 1 , or a pharmaceutically acceptable salt or prodrug thereof, wherein Z is —S(O) 2 —.

15. The compound of claim 1 , or a pharmaceutically acceptable salt or prodrug thereof, wherein Z is —CR 21 R 22 —.

16. The compound of claim 1 , or a pharmaceutically acceptable salt or prodrug thereof, wherein R 20 is methyl, difluoromethyl, trifluoromethyl, ethyl, 2,2,2-trifluoro-1-methyl-ethyl, (2R)-butan-2-yl, (2S)-butan-2-yl, cyclopropyl, cyclobutyl, cyclopentyl, isopropyl, or oxetan-3-yl.

17. The compound of claim 1 , or a pharmaceutically acceptable salt or prodrug thereof, wherein R 1 is 3-chloro-4-(cyclopropanesulfinyl)phenyl, 3-chloro-4-(cyclopropanesulfonyl)phenyl, 3-chloro-4-cyclopropoxy-phenyl, 3-chloro-4-(cyclopropylsulfanyl)phenyl, 3-chloro-4-isopropoxy-phenyl, 3-chloro-4-(oxetan-3-yloxy)phenyl, 3-chloro-4-(trifluoromethoxy)phenyl, 3-chloro-4-cyclopropoxyphenyl, 4-(aziridin-1-ylmethyl)-3-chlorophenyl, 4-[(2R)butan-2-yloxy]-3-chlorophenyl, or 4-[(2S)-butan-2-yloxy]-3-chlorophenyl.

18. The compound of claim 1 , or a pharmaceutically acceptable salt or prodrug thereof, wherein R 7 is hydrogen, aminomethyl, methoxymethyl, methyl, 1-aminoethyl, 1-methoxy-ethyl, methoxy, or halo.

19. The compound of claim 18 , or a pharmaceutically acceptable salt or prodrug thereof, wherein R 7 is methyl.

20. The compound of claim 18 , or a pharmaceutically acceptable salt or prodrug thereof, wherein R 7 is hydrogen.

21. A compound of formula:

or a pharmaceutically acceptable salt or prodrug thereof.

22. A pharmaceutical composition comprising at least one compound of claim 1 , or a pharmaceutically acceptable salt or prodrug thereof, and at least one pharmaceutically acceptable excipient.

23. A method of treating a condition or disorder mediated by Kynurenine 3-mono-oxygenase activity in a subject in need of such a treatment which method comprises administering to the subject a therapeutically effective amount of at least one compound of claim 1 , or a pharmaceutically acceptable salt or prodrug thereof.

24. The method of claim 23 wherein said condition or disorder involves a neurodegenerative pathology.

Assignees

• Chdi Foundation Inc

Inventors

• Toledo-Sherman Leticia M
• Dominguez Celia
• Prime Michael
• Mitchell William Leonard
• Johnson Peter
• Went Naomi

Classifications

• A61P43/00

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

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07C229/46

  having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title