7-OXO-1,6-diazabicyclo[3.2.1]octane derivatives and their use as antibacterial agents

Patent metadata

Field	Value
Publication number	US-9657022-B2
Application number	US-201515106305-A
Country	US
Kind code	B2
Filing date	Jan 21, 2015
Priority date	Jan 21, 2014
Publication date	May 23, 2017
Grant date	May 23, 2017

Abstract

Compounds of Formula (I), their preparation, and use in preventing or treating a bacterial infection are disclosed.

First claim

The invention claimed is:

1. A compound wherein said compound is selected from:
(2S,5R)-sulfuric acid mono-{2-[N′-(2-(S)-pyrrolidin-2-yl-acetyl)-hydrazinocarbonyl]-7-oxo-1,6-diaza-bicyclo[3.2.1]oct-6-yl}ester;
(2S,5R)-sulfuric acid mono-{2-[N′-(2-azetidin-3-yl-acetyl)-hydrazinocarbonyl]-7-oxo-1,6-diaza-bicyclo[3.2.1]oct-6-yl}ester;
(2S,5R)-sulfuric acid mono-{2-[N′-(2-(S)-piperidin-2-yl-acetyl)-hydrazinocarbonyl]-7-oxo-1,6-diaza-bicyclo[3.2.1]oct-6-yl}ester;
(2S,5R)-sulfuric acid mono-{2-[N′-(2-(R)-piperidin-2-yl-acetyl)-hydrazinocarbonyl]-7-oxo-1,6-diaza-bicyclo[3.2.1]oct-6-yl}ester;
(2S,5R)-sulfuric acid mono-{2-[N′-(2-(S)-piperidin-3-yl-acetyl)-hydrazinocarbonyl]-7-oxo-1,6-diaza-bicyclo[3.2.1]oct-6-yl}ester;
(2S,5R)-sulfuric acid mono-{2-[N′-(2-(RS)-piperazin-2-yl-acetyl)-hydrazinocarbonyl]-7-oxo-1,6-diaza-bicyclo[3.2.1]oct-6-yl}ester;
or a stereoisomer or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising the compound according to claim 1 .

3. The pharmaceutical composition according to claim 2 , wherein the compound is (2S,5R)-sulfuric acid mono-{2-[N′-(2-(S)-pyrrolidin-2-yl-acetyl)-hydrazinocarbonyl]-7-oxo-1,6-diaza-bicyclo[3.2.1]oct-6-yl}ester or a stereoisomer or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical composition according to claim 2 , further comprising at least one beta-lactamase inhibitor, or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical composition according to claim 4 , wherein the beta-lactamase inhibitor is selected from the group consisting of sulbactam, tazobactam, clavulanic acid, avibactam, and a pharmaceutically acceptable salt thereof.

6. The pharmaceutical composition according to claim 2 , further comprising at least one antibacterial agent or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition according to claim 6 , wherein the antibacterial agent is selected from a group consisting of aminoglycosides, ansamycins, carbacephems, cephalosporins, cephamycins, lincosamides, lipopeptides, macrolides, monobactams, nitrofurans, penicillins, penems, carbapenems, polypeptides, quinolones, sulfonamides, tetracyclines, oxazolidinones, and beta-lactam antibacterial agents.

8. The pharmaceutical composition according to claim 6 , wherein the antibacterial agent is a cephalosporin antibiotic, wherein the cephalosporin antibiotic is selected from the group consisting of cephalotin, cephaloridine, cefaclor, cefadroxil, cefamandole, cefazolin, cefalexin, cefradine, ceftizoxime, cefoxitin, cephacetrile, cefotiam, cefotaxime, cefsulodin, cefoperazone, cefmenoxime, cefmetazole, cepfaloglycin, cefonicid, cefodizime, cefpirome, ceftazidime, ceftriaxone, cefpiramide, cefbuperazone, cefozopran, cefepime, cefoselis, cefluprenam, cefuzonam, cefpimizole, cefclidin, cefixime, ceftibuten, cefdinir, cefpodoxime auxetil, cefpodoxime proxetil, cefteram pivoxil, cefetamet pivoxil, cefcapene pivoxil, cefditoren pivoxel, cefuroxime, cefuroxime auxetil, loracarbacef, ceftaroline, ceftolozane, and latamoxef.

9. The pharmaceutical composition according to claim 4 , comprising (a) (2S,5R)-sulfuric acid mono-{2-[N′-(2-(S)-pyrrolidin-2-yl-acetyl)-hydrazinocarbonyl]-7-oxo-1,6-diaza-bicyclo[3.2.1]oct-6-yl}ester, or a stereoisomer, or a pharmaceutically acceptable salt thereof, and (b) sulbactam, or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical composition according to claim 6 , comprising: (a) (2S,5R)-sulfuric acid mono-{2-[N′-(2-(S)-pyrrolidin-2-yl-acetyl)-hydrazinocarbonyl]-7-oxo-1,6-diaza-bicyclo[3.2.1]oct-6-yl}ester, and (b) at least one antibacterial agent selected from cefepime, cefpirome, ceftaroline, ceftazidime, ceftalozane, or a pharmaceutically acceptable salt thereof.

11. A method for treating a bacterial infection in a subject, the method comprising administering to the subject the compound according to claim 1 .

12. A method for treating a bacterial infection in a subject, the method comprising administering to the subject: (a) the compound according to claim 1 , and (b) at least one beta-lactamase inhibitor or a pharmaceutically acceptable salt thereof.

13. A method for treating a bacterial infection in a subject, the method comprising administering to the subject: (a) the compound according to claim 1 , and (b) at least one antibacterial agent or a pharmaceutically acceptable salt thereof.

14. The method for treating a bacterial infection in a subject according to claim 11 , wherein the method comprises administering to the subject (2S,5R)-sulfuric acid mono-{2-[N′-(2-(S)-pyrrolidin-2-yl-acetyl)-hydrazinocarbonyl]-7-oxo-1,6-diaza-bicyclo[3.2.1]oct-6-yl}ester, or a stereoisomer or a pharmaceutically acceptable salt thereof.

15. The method for treating a bacterial infection in a subject according to claim 12 , wherein the method comprises administering to the subject: (a) (2S,5R)-sulfuric acid mono-{2-[N′-(2-(S)-pyrrolidin-2-yl-acetyl)-hydrazinocarbonyl]-7-oxo-1,6-diaza-bicyclo[3.2.1]oct-6-yl}ester, or a stereoisomer, or a pharmaceutically acceptable salt thereof, and (b) sulbactam, or a pharmaceutically acceptable salt thereof.

16. The method for treating a bacterial infection in a subject according to claim 13 , wherein the method comprises administering to said subject: (a) (2S,5R)-sulfuric acid mono-{2-[N′-(2-(S)-pyrrolidin-2-yl-acetyl)-hydrazinocarbonyl]-7-oxo-1,6-diaza-bicyclo[3.2.1]oct-6-yl}ester, or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one antibacterial agent selected from cefepime, cefpirome, ceftaroline, ceftazidime, ceftalozane, or a pharmaceutically acceptable salt thereof.

17. A process for the preparation of a compound of Formula (I),

wherein,
R 1 is:
(a) cycloalkyl optionally substituted with one or more substituents independently
selected from C 1 -C 6 alkyl, halogen, CN, OR 3 , NR 3 R 4 , or CONR 3 R 4 , or

(b) heterocycloalkyl optionally substituted with one or more substituents independently
selected from C 1 -C 6 alkyl, halogen, CN, OR 3 , NR 3 R 4 , or CONR 3 R 4 ;

R 2 is —SO 3 M,
R 3 and R 4 are each independently:
(a) hydrogen, or
(b) C 1 -C 6 alkyl optionally substituted with one or more substitutents independently selected from halogen, CN, OH, O(C 1 -C 6 alkyl), NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , CONH(C 1 -C 6 alkyl), CON(C 1 -C 6 alkyl) 2 , cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

M is hydrogen or a cation;

said process comprising:
(a) reacting a compound of Formula (Ia) with R1CH2CONHNH2 (Ib), in presence of a coupling agent, to obtain a compound of Formula (Ic);

(b) hydrogenolysis of a compound of Formula (Ic) to obtain a compound of Formula (Id);

(c) sulfonating a compound of Formula (Id), followed by the treatment with tetrabutyl ammonium sulfate, to obtain a compound of Formula (Ie) and
(d) converting a compound of Formula (Ie) to obtain a compound of Formula (I).

18. The process according to claim 17 , wherein the coupling agent in step (a) is selected from 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-hydroxybenzotriazole, dicyclohexyl carbodiimde or pivalyl chloride.

Assignees

• Wockhardt Ltd

Inventors

• Raikar Sanjay
• Dabhade Sanjay Kisan
• Pavase Laxmikant
• Bhagwat Sachin
• Yeole Ravindra Dattatraya
• Patel Mahesh Vithalbhai

Classifications

• A61P31/00

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

• A61P43/00

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

• A61P31/04

  Antibacterial agents · CPC title

• C07F7/1804

  Compounds having Si-O-C linkages (Si-O-acyl linkages C07F7/1896) · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title