β-lactamase inhibitor and process for preparing the same

Patent metadata

Field	Value
Publication number	US-9708320-B2
Application number	US-201514872988-A
Country	US
Kind code	B2
Filing date	Oct 1, 2015
Priority date	May 30, 2012
Publication date	Jul 18, 2017
Grant date	Jul 18, 2017

Abstract

A diazabicyclooctane compound, which is a beta-lactame inhibitor, represented by the following formula (I):

wherein A represents Ra(Rb)N— or RcO—; B represents NH or NC 1-6 alkyl; C represents benzyl, H or SO 3 M, wherein M represents H, an inorganic or an organic cation; Ra and Rb represent H, C 1-6 alkyl or acyl; Rc represents C 1-6 alkyl or a heterocyclyl; A is unsubstituted or substituted with 0 to 4 substituents Fn1, wherein Fn1 represents C 1-6 alkyl, O═, or Rg-(CH 2 ) 0-3 —, wherein Rg represents a heterocyclyl, phenyl, heteroaryl, acyl, RdO 2 S—, Re(Rf)N—, Re(Rf)NCO—, ReO—, ReOCO— or a protective group, wherein Rd represents C 1-6 alkyl or MO—; Re and Rf represent H or C 1-6 alkyl, and a heterocycle having at least one nitrogen atom may be formed between Ra and Rb, between Rc and B, or between Re and Rf.

First claim

The invention claimed is:

1. A diazabicyclooctane compound represented by the following formula (I):

wherein A represents RcO—; B represents NH or NC 1-6 alkyl; C represents a benzyl group, H or SO 3 M, wherein M represents H, an inorganic cation or an organic cation; Rc represents a C 1-6 alkyl group; A is substituted with one substituent Fn1, wherein Fn1 represents an azetidine group; or a pharmaceutically acceptable salt thereof, or a solvate thereof.

2. The compound of claim 1 , which further comprises a protecting group P 1 and a protecting group P 3 and which is represented by a formula selected from the group consisting of

wherein P 2 represents tert-butoxycarbonyl, benzyloxycarbonyl or H; P 3 represents benzyl, H or SO 3 M; wherein M represents H, sodium, pyridinium or tetrabutylammonium; or a pharmaceutically acceptable salt thereof, or a solvate thereof.

3. The compound of claim 1 , which is selected from the group consisting of
(2S,5R)-N-[(2S)-azetidin-2-ylmethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide and
(2S,5R)-N-(azetidin-3-ylmethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; or a pharmaceutically acceptable salt thereof, or a solvate thereof.

4. A pharmaceutical composition comprising a pharmaceutically effective amount of the diazabicyclooctane compound represented by the formula (I) of claim 1 ; or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.

5. A pharmaceutical composition comprising the compound of claim 1 and a β-lactam antibiotic, in a combined pharmaceutically effective amount, and optionally a pharmaceutically acceptable carrier.

6. A method for treating a bacterial infection comprising administering to a patient a pharmaceutically effective amount of the compound of claim 1 .

7. The pharmaceutical composition of claim 5 , wherein the β-lactam antibiotic is selected from the group consisting of ampicillin, amoxicillin, piperacillin, ticarcillin, flomoxef, cefotaxim, ceftriaxone, ceftazidime, cefepime, ceftaroline, ceftolozane, imipenem, meropenem, biapenem, doripenem, ertapenem and aztreonam.

8. A method for treating a bacterial infection comprising administering to a patient in combination or separately at the same time, the compound of claim 1 and a β-lactam antibiotic, in a pharmaceutically effective amount.

9. The method for treating a bacterial infection of claim 8 , wherein the β-lactam antibiotic is selected from the group consisting of ampicillin, amoxicillin, piperacillin, ticarcillin, flomoxef, cefotaxim, ceftriaxone, ceftazidime, cefepime, ceftaroline, ceftolozane, imipenem, meropenem, biapenem, doripenem, ertapenem and aztreonam.

10. The diazabicyclooctane compound of claim 1 , wherein the compound is (2S,5R)-N-[(2S)-azetidin-2-ylmethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide.

11. The diazabicyclooctane compound of claim 1 , wherein the compound is (2S,5R)-N-[azetidin-3-ylmethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide.

Assignees

• Meiji Seika Pharma Co Ltd

Inventors

• Abe Takao
• Furuuchi Takeshi
• Sakamaki Yoshiaki
• Inamura Seiichi
• Morinaka Akihiro

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

• A61K31/546

  containing further heterocyclic rings, e.g. cephalothin · CPC title

• C07D471/08 Primary

  Bridged systems · CPC title