Nitrogen containing heterocyclic compounds

Patent metadata

Field	Value
Publication number	US-9499544-B2
Application number	US-201514808804-A
Country	US
Kind code	B2
Filing date	Jul 24, 2015
Priority date	Aug 30, 2011
Publication date	Nov 22, 2016
Grant date	Nov 22, 2016

Abstract

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

First claim

The invention claimed is:

1. A pharmaceutical composition comprising: (a) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof; and (b) a compound of Formula (I)

or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:
Q is a heteroaryl selected from oxadiazole, thiadiazole and tetrazole;
R 1 is:
(a) hydrogen,
(b) (CO) n —R 3 , or
(c) COOR 4 ,

n is 0 or 1;
R 2 is:
(a) SO 3 M

M is hydrogen or a cation;
R 3 is:
(a) hydrogen,
(b) C 1 -C 6 alkyl optionally substituted with one or more substituents independently selected from halogen, OR 5 , CN, COOR 5 , CONR 5 R 7 , NR 6 R 7 , NR 5 COR 8 , NR 5 CONR 6 R 7 , heterocyclyl, heteroaryl, cycloalkyl and aryl,
(c) NR 6 R 7 ,
(d) CONR 6 R 7 ,
(e) aryl optionally substituted with one or more substituents independently selected from C 1 -C 6 alkyl, OR 5 , NR 6 R 7 , halogen, CN, CONR 6 R 7 , SO 2 -alkyl, SO 2 -aryl, OSO 2 -alkyl, OSO 2 -aryl, and NHCONR 6 R 7 ,
(f) heterocyclyl optionally substituted with one or more substituents independently selected from C 1 -C 6 alkyl, OR 5 , NR 6 R 7 , halogen, CN, CONR 6 R 7 , SO 2 -alkyl, SO 2 -aryl, OSO 2 -alkyl, OSO 2 -aryl, and NHCONR 6 R 7 ,
(g) heteroaryl optionally substituted with one or more substituents independently selected from C 1 -C 6 alkyl, OR 5 , NR 6 R 7 , halogen, CN, CONR 6 R 7 , SO 2 -alkyl, SO 2 -aryl, OSO 2 -alkyl, OSO 2 -aryl, and NHCONR 6 R 7 , or
(h) OR 8 ;

R 4 is:
(a) hydrogen, or
(b) C 1 -C 6 alkyl optionally substituted with one or more substituents independently selected from halogen, OR 5 , CN, COOR 5 , CONR 6 R 7 , NR 6 R 7 , NR 5 COR 8 , heterocyclyl, heteroaryl, cycloalkyl and aryl;

R 5 and R 8 are each independently:
(a) hydrogen, or
(b) C 1 -C 6 alkyl optionally substituted with one or more substituents independently selected from halogen, CN, CONR 6 R 7 , NR 6 R 7 , heterocyclyl, heteroaryl, cycloalkyl and aryl;

R 6 and R 7 are each independently:
(a) hydrogen, or
(b) C 1 -C 6 alkyl optionally substituted with one or more substituents independently selected from halogen, OR 5 , CN, COOR 5 , CONR 5 R 8 , NR 5 R 8 , NR 5 COR 8 , heterocyclyl, heteroaryl, cycloalkyl and aryl.

2. The pharmaceutical composition according to claim 1 , wherein the compound of Formula (I) is selected from:
trans-sulfuric acid mono-[2-(5-aminomethyl-[1,3,4]-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1]-octan-6-yl]ester;
trans-sulfuric acid mono-[2-(5-((S)-1-amino-ethyl)-[1,3,4]-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1]-octan-6-yl]ester;
trans-sulfuric acid mono-[2-(5-((R)-1-amino-ethyl)-[1,3,4]-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1]-octan-6-yl]ester;
trans-sulfuric acid mono-[2-(5-(piperidin-4-yl)-[1,3,4]-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1]-octan-6-yl]ester;
trans-sulfuric acid mono-[2-(5-((S)-pyrrolidin-2-yl)-[1,3,4]-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1]-octan-6-yl]ester;
trans-sulfuric acid mono-[2-(5-(piperazin-1-yl-methyl)-[1,3,4]-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1]-octan-6-yl]ester;
trans-sulfuric acid mono-[2-(5-((RS)-1-amino-1-phenyl-methyl)-[1,3,4]-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1]-octan-6-yl]ester;
trans-sulfuric acid mono-[2-(5-(piperidin-4-yl)-[1,2,4]-oxadiazol-3-yl)-7-oxo-1,6-diazabicyclo[3.2.1]-octane;
trans-sulfuric acid mono-[2-(5-((R)-piperidin-3-yl)-[1,3,4]-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1]-octane;
and stereoisomers and a pharmaceutically acceptable salts thereof.

3. The pharmaceutical composition according to claim 1 , wherein the compound of Formula (I) is selected from:
Sodium salt of trans-6-(sulphooxy)-2-(5-methyl-[1,3,4]-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(5-ethyl-[1,3,4]-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(5-trifluoromethyl-[1,3,4]-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(5-carboxamido-[1,3,4]-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(5-(isooxazol-3-yl)-[1,3,4]-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(5-(furan-2-yl)-[1,3,4]-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(5-phenyl-[1,3,4]-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(5-(pyridin-2-yl)-[1,3,4]-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(5-(6-carboxamido-pyridin-2-yl)-[1,3,4]-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(5-(5,6-dihydro-8H-imidazo[2,1-c][1,4]-oxazin-2-yl)-[1,3,4]-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(5-(morpholino-4-methyl)-[1,3,4]-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1]-octane;
Sodium salt of trans-sulfuric acid mono-[2-(5-(morpholin-4-yl-carbonyl)-[1,3,4]-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1]-octan-6-yl]ester;
Sodium salt of trans-6-(sulphooxy)-2-(5-methy-[1,3,4]-thiadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(5-methyl-[1,2,4]-oxadiazol-3-yl)-7-oxo-1,6-diazabicyclo[3.2.1]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(5-ethoxycarbonyl-[1,2,4]-oxadiazol-3-yl)-7-oxo-1,6-diazabicyclo[3.2.1]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(2-methyl-2H-[1,2,3,4]-tetrazol-5-yl)-7-oxo-1,6-diazabicyclo[3.2.1]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(1-methyl-1H-[1,2,3,4]-tetrazol-5-yl)-7-oxo-1,6-diazabicyclo[3.2.1]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(3-ethoxycarbonyl-[1,2,4]-oxadiazol-5-yl)-7-oxo-1,6-diazabicyclo[3.2.1]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(5-carboxamido-[1,2,4]-oxadiazol-3-yl)-7-oxo-1,6-diazabicyclo[3.2.1]-octane;
and stereoisomers thereof.

4. A pharmaceutical composition comprising: (a) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, and pharmaceutically acceptable derivatives thereof; and (b) the compound of Formula (I) according to any one of claims 1 to 3 .

5. The pharmaceutical composition according to claim 1 , further comprising at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, and pharmaceutically acceptable derivatives thereof.

6. The pharmaceutical composition according to claim 1 , wherein the antibacterial agent is selected from the group consisting of aminoglycosides, ansamycins, carbacephems, cephalosporins, cephamycins, lincosamides, lipopeptides, macrolides, monobactams, nitrofurans, penicillins, polypeptides, quinolones, penems, carbapenems, sulfonamides, tetracyclines, and oxazolidinone antibacterial agents.

7. The pharmaceutical composition according to claim 1 , wherein the antibacterial agent is selected from the group consisting of cephalothin, cephaloridine, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cephradine, ceftizoxime, cefoxitin, cephacetrile, cefotiam, cefotaxime, cefsulodin, cefoperazone, ceftizoxime, cefmenoxime, cefmetazole, cephaloglycin, cefonicid, cefodizime, cefpirome, ceftazidime, ceifriaxone, cefpiramide, cefbuperazone, cefozopran, cefepime, cefoselis, cefluprenam, cefuzonam, cefpimizole, cefclidin, cefixime, ceftibuten, cefdinir, cefpodoxime axetil, cefpodoxime proxetil, cefteram pivoxil, cefetamet pivoxil, cefcapene pivoxil, cefditoren pivoxil, cefuroxime, cefuroxime axetil, loracarbacef, ceftaroline, ceftolozane, piperacillin, doripenem, meropenem, imipenem and latamoxef.

8. A method for treating bacterial infection in a subj

Assignees

• Wockhardt Ltd

Inventors

• Bhagwat Sachin
• Deshpande Prasad Keshav
• Bhawsar Satish
• Patil Vijaykumar Jagdishwar
• Tadiparthi Ravikumar
• Pawar Shivaji Sampatrao
• Jadhav Sunil Bhaginath
• Dabhade Sanjay Kisan
• Deshmukh Vikas Vitthalrao
• Dhond Bharat
• Birajdar Satish
• Shaikh Mohammad Usman
• Dekhane Deepak
• Patel Piyush Ambalal

Classifications

• A61K31/43

  Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula [IMAGE cpc-sch-A61K-0952.gif], e.g. penicillins, penems · CPC title

• A61P31/00

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

• A61K31/431

  containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title

• A61K31/424

  condensed with heterocyclic ring systems, e.g. clavulanic acid · CPC title