NOVEL FUSED BRIDGED BICYCLIC HETEROARYL SUBSTITUTED 6-ALKYLIDENE PENEMS AS POTENT BETA-LACTAMASE INHIBITORS

• US 20110288063A1
• Filed: 05/19/2011
• Published: 11/24/2011
• Est. Priority Date: 05/19/2010
• Status: Abandoned Application

• Current Assignee: Naeja Pharmaceutical Inc.
• Original Assignee: Naeja Pharmaceutical Inc.
• Inventors: Liang, Hong, Ganguli, Biswajeet, Khan, Jehangir, Ling, Rong, Narender Reddy, Andhe V., MAITI, Samarendra N., Yip, Judy, Nguyen, Dai, Gao, Chuanjun
• Application Number:
  US13/111,156
• Publication Number:
  US 20110288063A1
• Time in Patent Office: Days
• US Class Current: 514/193
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/431 containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: C07D 499/08 Modification of a carboxyl radical directly attached in position 2, e.g. esterification

Abstract

A compound of formula (I) or formula (Ia)

Wherein R₁, R_a, R₂, X, R₃, Y₁, Y₂, A, B and C are as defined herein. Also, pharmaceutical compositions comprising such compounds and excipients, methods of treating bacterial infections comprising administering such compounds, methods for making such compounds and hydrates of such compounds.

Claims

1. A compound of formula (I) or formula (Ia)

2. A compound according to claim 1, wherein R₁ can be removed without cleaving β

-lactam ring, and is sufficiently stable under the reaction conditions to permit easy access to the compounds of formula (Ia) by de-esterification.

3. A compound according to claim 1, wherein R₁ is selected from the group consisting of 4-nitrobenzyl and 4-methoxybenzyl.

4. A pharmaceutical composition suitable for the treatment of bacterial infections in mammals comprising at least one compound recited in claim 1 and at least one pharmaceutically acceptable excipient.

5. A pharmaceutical composition according to claim 4, wherein said compound and β

-lactam antibiotic are contained in the range of 1;

20 to 20;

1 weight ratios.

6. A method of treating bacterial infections, comprising administering to a subject in need of such treatment an effective amount of a β

-lactam antibiotic and a compound according to claim 1.

7. A method as recited in claim 5, wherein the β

-lactam antibiotic and the compound according to claim 1 are administered simultaneously.

8. A method as recited in claim 5, wherein the β

-lactam antibiotic and the compound according to claim 1 are administered separately.

9. A method according to claim 5, wherein the β

-lactam antibiotic is selected from the group consisting of amoxicillin, ampicillin, azlocillin, mezlocillin, apalcillin, hetacillin, bacampicillin, carbenicillin, sulbenicillin, ticarcillin, piperacillin, mecillinam, methicillin, ciclacillin, talampicillin, oxacillin, cloxacillin, dicloxacillin, cephalothin, cephaloridine, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cephradine, cephapirin, cefuroxime, cefoxitin, cephacetrile, cefotiam, cefotaxime, cefatriazine, cefsulodin, cefoperazone, ceftizoxime, cefmenoxime, cefmetazole, cephaloglycin, cefonicid, cefodizime, cefpirome, cefepime, ceftazidime, cefpiramide, ceftriaxone, cefbuperazone, cefprozil, cefixime, ceftobiprole, ceftaroline, cefalonium, cefminox, ceforanide, cefuzonam, cefoxitin, cefotetan, loracarbef, cefdinir, cefditoren, cefetamet, cefcapene, cefdaloxime, ceftibuten and cefroxamide.

10. A method for making a compound of formula (I) according to claim 1 comprising:

(a) Providing a compound of formula 1

11. A method of making a compound of formula (Ia) according to claim 1, comprising de-esterifying a compound of formula (I) to obtain a derivative of the formula (Ia) in which R_a is hydrogen.

12. A hydrate of a compound according to claim 1, wherein said hydrate contains variable amounts of water.

13. A hydrate according to claim 11, wherein said variable amounts of water result from lyophilization, crystallization or column purification.

14. A compound according to claim 1, wherein a regio-isomer is included.

15. A compound according to claim 1, wherein a stereoisomer is included.

16. A compound according to claim 1, wherein N-oxide is included.

17. A compound according to claim 1, wherein heterocyclyl means a 5-membered saturated ring containing oxygen.

18. A compound according to claim 1, wherein X is a bridged bicyclic ring system having optionally one or two hetero atoms selected from O and N.

19. A compound according to claim 1, wherein the heterocyclic rings under item (z) include:

20. A compound according to claim 1, wherein the protecting group of item (n) for the optional substituent on the said nitrogen of the bridged bicyclic ring systems containing a NH ring atom is tert-butylcarbonyloxy.

21. A method according to claim 10, wherein reacting the compound of formula 3 to provide a compound of formula 4 comprises reacting the compound of formula 3 with acetic anhydride.