Inha inhibitors and methods of use thereof

• US 6,372,752 B1
• Filed: 02/07/2000
• Issued: 04/16/2002
• Est. Priority Date: 02/07/2000
• Status: Expired due to Fees

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Genzyme Corporation (Sanofi )
• Inventors: Yee, Christopher, Staveski, Mark M., Sneddon, Scott F., Janjigian, Andrew
• Primary Examiner(s): CHANG, CELIA C
• Application Number:
  US09/499,183
• Time in Patent Office: 799 Days
• Field of Search: 514/249, 514/256, 514/273, 544/331, 544/333, 544/353
• US Class Current: 514/273
• CPC Class Codes: C07C 233/11 with carbon atoms of carboxamide groups bound to carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 233/13 with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
• CPC Class Codes: C07C 233/22 having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 233/65 having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
• CPC Class Codes: C07C 2601/16 the ring being unsaturated
• CPC Class Codes: C07D 209/08 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 209/18 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 295/192 from aromatic carboxylic acids
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links

Abstract

The invention relates to compounds which inhibit the Mycobacterial enoyl-ACP reductase required for cell wall biosynthesis. The invention also relates to pharmaceutical compositions comprising these compounds and to methods of use of these compounds for treating a bacterial infection in a patient.

Claims

1. A compound of Formula III,

or a salt thereof with a pharmaceutically acceptable acid, wherein

R_e is a substituted or unsubstituted phenyl group or a substituted or unsubstituted heteroaryl group;

and

R_l represents one or more substituents independently selected from the group consisting of alkoxy, cyano, nitro and trifluoromethyl, provided that the compound is not 2-[4-(2-nitro-4-chlorophenyl)-pyrazol-1-yl]-4-trifluoromethyl pyrimidine.

2. The compound of claim 1 wherein R_e is a substituted or unsubstituted pyrimidyl, pyrazyl, pyridyl, quinolyl, quinoxalyl or benzimidazolyl group.

3. The compound of claim 2 wherein R_e is 2-quinoxalyl, 4-pyrimidyl, 2-benzimidazolyl;

2-, 3- or 4-pyridyl, 2-quinolyl, 4-quinolyl and 2-pyrazyl.

4. A compound of Formula III,

or a salt thereof with a pharmaceutically acceptable acid, wherein

R_e is a phenyl group which is substituted with one or more substituents independently selected from the group consisting of nitro, alkoxy, and alkylsulfonyl;

and

R_l represents one or more substituents independently selected from the group consisting of alkoxy, cyano, nitro and trifluoromethyl.

5. The compound of claim 4 wherein R_e is selected from the group consisting of 5-methoxy-2-nitrophenyl, 2-nitrophenyl, 4-methylsulfonyl-2-nitrophenyl and 4-methoxyphenyl.

6. A compound of Formula III,

or a salt thereof with a pharmaceutically acceptable acid, wherein

R_e is a substituted phenyl group, wherein the phenyl group is substituted with one or more substituents wherein at least one substituent is selected from the group consisting of nitro and alkylsulfonyl;

a substituted heteroaryl group;

or an unsubstituted heteroaryl group, wherein the unsubstituted heteroaryl group is not pyridyl; and

R_l represents one or more substituents independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, cyano, nitro and trifluoromethyl, provided that the compound is not 2-[4-(2-nitro-4-chlorophenyl)-pyrazol-1-yl]-4-trifluoromethyl pyrimidine.

7. A compound of Formula III,

or a salt thereof with a pharmaceutically acceptable acid, wherein

R_e is a substituted or unsubstituted phenyl group or a substituted or unsubstituted heteroaryl group;

and

R_l represents trifluoromethyl.

8. A compound represented by the following structural formula:

9. A method of treating a Mycobacterial infection in a patient, comprising the step of administering to the patient a therapeutically effective amount of one or more compounds of Formula III,

or a salt thereof with a pharmaceutically acceptable acid, wherein

R_e is a substituted phenyl group, wherein the phenyl group is substituted with one or more substituents wherein at least one substituent is selected from the group consisting of nitro and alkylsulfonyl;

a substituted heteroaryl group;

or an unsubstituted heteroaryl group, wherein the unsubstituted heteroaryl group is not pyridyl; and

R_l represents one or more substituents independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, cyano, nitro and trifluoromethyl, provided that the compound is not 2-[4-(2-nitro-4-chlorophenyl)-pyrazol-1-yl]-4-trifluoromethyl pyrimidine.

10. The method of claim 9 wherein the Mycobacterial infection is an infection by a Mycobacterial species selected from the group consisting of Mycobacterium tuberculosis, Mycobacterium avian-intracellulare, Mycobacterium kansasii, Mycobacterium bovis, Mycobacterium africanum, Mycobacterium genavense, Mycobacterium leprae, Mycobacterium xenopi, Mycobacterium simiae, Mycobacterium scrofulaceum, Mycobacterium malmoense, Mycobacterium celatum, Mycobacterium abscessus, Mycobacterium chelonae, Mycobacterium szulgai, Mycobacterium gordonae, Mycobacterium haemophilum, Mycobacterium fortuni and Mycobacterium marinum.

11. The method of claim 9 wherein the the Mycobacterial infection is an infection by Mycobacterium tuberculosis.

12. The method of claim 10 wherein the infection by Mycobacterium tuberculosis is a dormant infection.

13. The method of claim 10 wherein the patient has active tuberculosis.

14. The method of claim 9 wherein R_l represents a substituent bonded to carbon-4 of the pyrimidine ring, wherein said substituent is selected from the group consisting of fluorine, chlorine, bromine, iodine and trifluoromethyl.

15. The method of claim 9 wherein R_e is selected from the group consisting of 5-methoxy-2-nitrophenyl, 2-nitrophenyl, 4-methylsulfonyl-2-nitrophenyl and 4-methoxyphenyl.

16. The method of claim 9 wherein R_e is a substituted or unsubstituted pyrimidyl, pyrazyl, pyridyl, quinolyl, quinoxalyl or benzimidazolyl group.

17. The method of claim 16 wherein R_e is 2-quinoxalyl, 4-pyrimidyl, 2-benzimidazolyl;

2-, 3- or 4-pyridyl, 2-quinolyl, 4-quinolyl and 2-pyrazyl.

18. A method of treating a bacterial infection in a patient, comprising the step of administering to the patient a therapeutically effective amount of one or more compounds of Formula III,

or a salt thereof with a pharmaceutically acceptable acid, wherein

R_e is a substituted or unsubstituted phenyl group or a substituted or unsubstituted heteroaryl group;

and

R_l represents one or more substituents independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, cyano, nitro and trifluoromethyl, provided that the compound is not 2-[4-(2-nitro-4-chlorophenyl)-pyrazol-1-yl]-4-trifluoromethyl pyrimidine.

19. The method of claim 18 wherein the bacterial infection is an infection by a Gram-negative bacterial species.

20. A method of treating a bacterial infection in a patient, comprising the step of administering to the patient a therapeutically effective amount of a compound represented by the following structural formula: