Pyridone derivatives and uses thereof in the treatment of tuberculosis

Patent metadata

Field	Value
Publication number	US-2015291526-A1
Application number	US-201314648217-A
Country	US
Kind code	A1
Filing date	Dec 12, 2013
Priority date	Dec 13, 2012
Publication date	Oct 15, 2015
Grant date	—

Abstract

A compound of Formula (I) is provided that has been shown to be useful for treating a disease, disorder or syndrome that is mediated by the inhibition of mycolic acid biosynthesis through inhibition of M. tuberculosis Enoyl Acyl Carrier Protein Reductase enzyme (InhA):

wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined herein.

First claim

1 . A compound of Formula (I)

wherein
R 1 is H, methyl or ethyl;
R 2 is phenyl, pyrrole or pyrazole, wherein said phenyl is optionally substituted with one or more substituents independently selected from fluoro or chloro; provided that when said substituent is chloro, said chloro is on the meta or ortho position of said phenyl and the number of chloro substituent is not more than one;
R 3 is a structural formula selected from the group consisting of

where R 100 and R 200 are each independently selected from the group consisting of H, (C 1 -C 6 )alkyl, cycloalkyl, an organic cation and an inorganic cation;
R 4 is H or —C(═O)NH 2 ;
R 5 is selected from the group consisting of (C 1 -C 6 )alkyl, cycloalkyl, phenyl, heterocycle and heteroaryl, optionally substituted with one or more independent R 300 substituents; and
R 300 is selected from the group consisting of H, (C 1 -C 6 )alkyl, cycloalkyl, hydroxy, amino and F;

or a pharmaceutically acceptable salt thereof.

2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is H.

3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is phenyl.

4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is (Ia).

5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is (Ic), and R 100 and R 200 are both H.

6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is H.

7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is (C 1 -C 6 )alkyl, phenyl, tetrahydro-2H-pyran or pyridine.

8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is cycloalkyl.

9 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is cyclohexane.

10 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is cyclohexane which is substituted with one or more substituents independently selected from (C 1 -C 6 )alkyl, cycloalkyl or F.

11 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is cyclohexane which is substituted with one or more substituents independently selected from methyl, cyclopropane or F.

12 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is cyclohexane which is substituted with two methyl substitutents.

13 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

14 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound has the following structure

15 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound has the following structure

16 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound has the following structure

17 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

18 . The pharmaceutical composition of claim 17 further comprising at least one additional pharmaceutical agent.

19 . The pharmaceutical composition of claim 18 wherein said at least one additional pharmaceutical agent is an antituberculosis agent.

20 . The pharmaceutical composition of claim 19 wherein said antituberculosis agent is selected from the group consisting of isoniazid, rifampicin, pyrazinamide, ethambutol, streptomycin, kanamycin, amikacin, capreomycin, ofloxacin, levofloxacin, moxifloxacin, cycloserine, para-aminosalicylic acid, ethioamide, prothionamide, thioacetazone clofazimine, amoxicilin with clavulanate, imipenem, linezolid, clarithromycin, and thioridazine.

21 . A method for treating a disease, disorder or syndrome mediated by the inhibition of mycolic acid biosynthesis through inhibition of M. tuberculosis Enoyl Acyl Carrier Protein Reductase enzyme (InhA) comprising the step of administering to a patient in need thereof a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

22 . The method of claim 21 wherein said patient is human.

23 . The method of claim 21 wherein said disease, disorder or syndrome is tuberculosis.

24 . The method of claims 22 wherein said human has (i) a sputum smear-positive, sputum smear-negative, or extrapulmonary tuberculosis; (ii) tuberculosis caused by drug resistant Mycobacterium tuberculosis complex ( M. tuberculosis ) organisms; or (iii) tuberculosis combined with human immunodeficiency virus (HIV) infection.

25 . A method of treating tuberculosis comprising the step of administering to a patient in need thereof a pharmaceutical composition of claim 17 .

26 . The method of claim 25 wherein said patient is human.

27 . The method of claim 26 wherein said human has (i) a sputum smear-positive, sputum smear-negative, or extrapulmonary tuberculosis; (ii) tuberculosis caused by drug resistant Mycobacterium tuberculosis complex ( M. tuberculosis ) organisms; or (iii) tuberculosis combined with human immunodeficiency virus (HIV) infection.

28 - 29 . (canceled)

30 . A method for treating a disease, disorder or syndrome mediated by the inhibition of mycolic acid biosynthesis through inhibition of M. tuberculosis Enoyl Acyl Carrier Protein Reductase enzyme (InhA) comprising the step of administering to a patient in need thereof
(i) a first composition comprising any one of the compounds according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient; and (ii) a second composition comprising at least one additional pharmaceutical agent and a pharmaceutically acceptable carrier or excipient.

31 . The method of claim 30 wherein said patient is human.

32 . The method of claim 31 wherein said human has (i) a sputum smear-positive, sputum smear-negative, or extrapulmonary tuberculosis; (ii) tuberculosis caused by drug resistant Mycobacterium tuberculosis complex ( M. tuberculosis ) organ

Assignees

• Kondreddi Ravinder Reddy
• Manjunatha Ujjini H
• Ma Ngai Ling
• Peukert Stefan
• Rao Srinivasa Ps
• Novartis Ag

Inventors

• Kondreddi Ravinder Reddy
• Ma Ngai Ling
• Peukert Stefan
• Rao Srinivasa P S
• Ujjini Manjunatha

Classifications

• A61K31/4433

  containing a six-membered ring with oxygen as a ring hetero atom · CPC title

• C07D405/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title

• A61K31/675

  having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate · CPC title