SecA inhibitors and methods of making and using thereof

Patent metadata

Field	Value
Publication number	US-9957247-B2
Application number	US-201314406085-A
Country	US
Kind code	B2
Filing date	Jun 5, 2013
Priority date	Jun 7, 2012
Publication date	May 1, 2018
Grant date	May 1, 2018

Abstract

Inhibitors of SecA, and methods of making and using thereof, are described herein. The compounds described herein can be used to treat or prevent microbial infections, such as bacterial infections.

First claim

We claim:

1. A pharmaceutical composition comprising one or more compounds of the following formula:

wherein
X and Y are N;
D and G are independently NR 7 or O;
A, B, E, and F are N;
L and M are independently S;
J is S; and
R 1 and R 4 are independently selected from hydrogen, substituted or unsubstituted, linear, branched, hetero C 1 -C 30 alkyl, C 3 -C 30 cyclic alkyl, C 2 -C 30 alkenyl, or C 2 -C 30 alkynyl, substituted or unsubstituted aryl or heteroaryl, halogen, substituted or unsubstituted alkoxy, hydroxy, cyano, formyl, acyl, —COOH, —COO − , —CONH 2 , —CONHR 17 , —CONR 17 R 17 , —OCONHR 17 , —NHCOOR 17 , —OCONR 17 R 17 , —NR 14 COOR 17 , —NHCONHR 17 , —NR 17 CONHR 17 , —NHCONR 17 R 17 , —NR 17 CONR 17 R 17 , —CH 2 OH, —CHR 17 OH, —CR 17 R 17 OH, —COOR 17 , —SH, —NH 2 , —NHR 17 , —NR 17 R 17 , —SR 17 , —SOR 17 , and —SOOR 17 ;
R 5 and R 6 are substituted or unsubstituted aryl or heteroaryl groups;
R 7 and R 17 are independently selected from hydrogen, substituted or unsubstituted, linear, branched, hetero C 1 -C 30 alkyl, C 3 -C 30 cyclic alkyl, C 2 -C 30 alkenyl, C 3 -C 30 cyclic alkenyl, C 2 -C 30 alkynyl groups, C 3 -C 30 cyclic alkynyl, or aryl group;
wherein substituents of the substituted groups are selected from the group consisting of linear or branched C 1 -C 30 alkyl, C 1 -C 30 heteroalkyl, C 3 -C 30 cyclic alkyl, C 2 -C 30 alkenyl, C 2 -C 30 alkynyl, phenyl, aryl, heteroaryl, halo, hydroxyl, alkoxy, phenoxy, aroxy, alkylthio, phenylthio, arylthio, cyano, isocyano, carbonyl, carboxyl, amino, amido, sulfonyl, sulfonic acid, phosphoryl, phosphonyl, and polyaryl groups; and wherein the C 1 -C 30 alkyl, the C 1 -C 30 heteroalkyl, the C 3 -C 30 cyclic alkyl, the C 2 -C 30 alkenyl, the C 2 -C 30 alkynyl, the phenyl, the aryl, the heteroaryl, the alkoxy, the phenoxy, the aroxy, the alkylthio, the phenylthio, the arylthio, the carbonyl, the carboxyl, the amino, the amido, the sulfonyl, the phosphoryl, the phosphonyl, or the polyaryl groups are optionally substituted with one or more halogens or hydroxyl groups;
or pharmaceutically acceptable salts thereof;
wherein the one or more compounds are present in an effective amount to inhibit SecA.

2. A pharmaceutical composition comprising one or more compounds of the following formula:

wherein
Z and W are S;
X and Y are N;
Cy is substituted or unsubstituted triazole or an oxadiazole group;
R 2 is a halogen;
R 1 and R 3 are independently selected from hydrogen, substituted or unsubstituted, linear, branched, hetero C 1 -C 30 alkyl, C 2 -C 30 alkenyl, or C 2 -C 30 alkynyl, substituted or unsubstituted aryl, halogen, substituted or unsubstituted alkoxy, hydroxy, cyano, formyl, acyl, —COOH, —COO − , —CONH 2 , —CONHR 11 , —CONR 11 R 11 , —OCONHR 11 , —NHCOOR 11 , —OCONR 11 R 11 , —NR 14 COOR 11 , —NHCONHR 11 , —NR 11 CONHR 11 , —NHCONR 11 R 11 , —NR 14 CONR 11 R 11 , —CH 2 OH, —CHR 11 OH, —CR 11 R 11 OH, —COOR 11 , —SH, —NH 2 , —NHR 11 , —NR 11 R 11 , —SR 11 , —SOR 11 , and —SOOR 11 ;
R 4 is a substituted or unsubstituted aryl or heteroaryl group;
R 5 and R 11 are independently selected from hydrogen, substituted or unsubstituted, linear, branched, or hetero C 1 -C 30 alkyl, C 3 -C 30 cyclic alkyl, C 2 -C 30 alkenyl, C 3 -C 30 cyclic alkenyl, C 2 -C 30 alkynyl groups, C 3 -C 30 cyclic alkynyl, or aryl group;
wherein substituents of the substituted groups are selected from the group consisting of C 1 -C 30 alkyl, C 1 -C 30 heteroalkyl, C 3 -C 30 cyclic alkyl, C 2 -C 30 alkenyl, C 2 -C 30 alkynyl, phenyl, aryl, heteroaryl, halo, hydroxyl, alkoxy, phenoxy, aroxy, alkylthio, phenylthio, arylthio, cyano, isocyano, carbonyl, carboxyl, amino, amido, sulfonyl, sulfonic acid, phosphoryl, phosphonyl, and polyaryl groups; and wherein the C 1 -C 30 alkyl, the C 1 -C 30 heteroalkyl, the C 3 -C 30 cyclic alkyl, the C 2 -C 30 alkenyl, the C 2 -C 30 alkynyl, the phenyl, the aryl, the heteroaryl, the alkoxy, the phenoxy, the aroxy, the alkylthio, the phenylthio, the arylthio, the carbonyl, the carboxyl, the amino, the amido, the sulfonyl, the phosphoryl, the phosphonyl, or the polyaryl groups are optionally substituted with one or more halogens or hydroxyl groups;
or pharmaceutically acceptable salts thereof;
wherein the one or more compounds are present in an effective amount to inhibit SecA.

3. The pharmaceutical composition of claim 2 , comprising one or more pharmaceutically acceptable carriers.

4. A method of treating a bacterial infection comprising administering the pharmaceutical composition of claim 2 .

5. The method according to claim 4 , wherein the pharmaceutical composition is administered by one or more routes selected from the group consisting of buccal, sublingual, intravenous, subcutaneous, intradermal, transdermal, intraperitoneal, oral, eye drops, parenteral and topical administration.

6. The pharmaceutical composition of claim 1 , wherein the one or more compounds are selected from the group consisting of:

end pharmaceutically acceptable salts thereof.

7. The pharmaceutical composition of claim 2 , wherein the one or more compounds are selected from the group consisting of:

8. The pharmaceutical composition of claim 2 , wherein the compound is:

9. The pharmaceutical composition of claim 2 , wherein the compound is:

10. The pharmaceutical composition of claim 1 , wherein R 7 is hydrogen or a C 1 -C 30 alkyl.

11. The pharmaceutical composition of claim 1 , wherein R 1 is a C 1 -C 30 alkyl.

12. The pharmaceutical composition of claim 1 , wherein R 5 and R 6 are substituted or unsubstituted aryl groups.

13. The pharmaceutical composition of claim 2 , wherein Cy is a triazole ring, and R 4 is a substituted or unsubstituted aryl group.

14. The pharmaceutical composition of claim 2 , wherein R 4 is a substituted or unsubstituted aryl and R 1 is an aryl group.

15. The pharmaceutical composition of claim 1 , comprising one or more pharmaceutically acceptable carriers.

16. A method of treating a bacterial infection comprising administering the pharmaceutical composition of claim 1 .

17. The method according to claim 16 , wherein the pharmaceutical composition is administered by one or more routes selected from the group consisting of buccal, sublingual, intravenous, subcutaneous, intradermal, transdermal, intraperitoneal, oral, eye drops, parenteral and topical administration.

Assignees

• Univ Georgia State Res Found

Inventors

• Wang Binghe
• Tai Phang-Cheng
• Jin Jinshan
• Hsieh Yinghsin
• Ritter Ying-Ju
• Cui Jianmei
• Chaudhary Arpana S
• Dai Chaofeng
• Damera Krishna
• Chen Weixuan

Classifications

• A61P31/12

  Antivirals · CPC title

• A61P31/10

  Antimycotics · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title