Heterocyclic compounds as inhibitors of beta-lactamases

• US 7,612,087 B2
• Filed: 07/26/2004
• Issued: 11/03/2009
• Est. Priority Date: 01/28/2002
• Status: Active Grant

• Current Assignee: Allergan Pharmaceuticals International Ltd. (Abbvie Incorporated)
• Original Assignee: Novexel
• Inventors: Fromentin, Claude, Aszodi, Jozsef, Rowlands, David Alan, Lampilas, Maxime
• Primary Examiner(s): Wang; Shengjun
• Application Number:
  US10/898,754
• Publication Number:
  US 20050020572A1
• Time in Patent Office: 1,926 Days
• Field of Search: 514/295, 514/299, 514/300, 514/203
• US Class Current: 514/300
• 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 31/439 the ring forming part of a bridged ring system, e.g. quinuclidine 8-azabicyclo [3.2.1] octanes A61K31/46
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

This invention discloses and claims methods for inhibiting bacterial β-lactamases and treating bacterial infections by inhibiting bacterial β-lactamases in man or an animal comprising administering a therapeutically effective amount to said man or said animal of a compound, or pharmaceutically acceptable salt thereof, of formula (I) either alone or in combination with a β-lactamine antibiotic wherein said combination can be administered separately, together or spaced out over time. Pharmaceutical compositions comprising a compound of formula (I), or a combination of a compound of formula (I) and a therapeutically effective amount of a β-lactamine antibiotic, and a pharmaceutically acceptable carrier are also disclosed and claimed.

Claims

1. A pharmaceutical composition comprising a bacterial β

-lactamase inhibitory amount of a compound, or a pharmaceutically acceptable salt thereof, of formula (I);

2. The pharmaceutical composition of claim 1, wherein said β

-lactamine antibiotic is selected from the group consisting of;

penams, penems, carbapenems, cephems, carbacephems, oxacephems, cephamycims, monobactams, combinations and pharmaceutically acceptable salts thereof.

3. The pharmaceutical composition of claim 1, wherein said compound of Formula (I) comprises trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo-[3.2.1]-octane-2-carboxamide or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical composition of claim 1, wherein said compound of Formula (I) comprises trans-7-oxo-6-(sulphooxy)- 1,6-diazabicyclo-[3.2.1 ]-octane-2-carboxamide or a pharmaceutically acceptable salt thereof and said β

-lactamine antibiotic comprises ceftazidime.

5. A pharmaceutical composition according to claim 1, wherein said β

-lactamine antibiotic comprises a cephalosporin antibiotic 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 or cefditoren pivoxil, cefuroxime, cefuroxime axetil, loracarbacef, latamoxef, combinations and pharmaceutically acceptable salts thereof.

6. A pharmaceutical composition according to claim 1, wherein said β

-lactamine antibiotic comprises ceftazidime.

7. The pharmaceutical composition according to claim 1 wherein n is 1, R₃ is hydrogen, R₁ is hydrogen, COOR or CONR₆R₇ wherein R, R₆ and R₇ are as defined in claim 1, and X is —

C(O)—

B—

herein B is —

O—

(CH₂)_n″

—

or —

NR₈—

(CH₂)_{n ″}

—

wherein n″

is 0 and R₈ is as defined in claim 1.

8. The pharmaceutical composition according to claim 1 wherein R₈ is Y, Y₁ or OY₁, and Y and Y₁ are as defined in claim 1.

9. The pharmaceutical composition according to claim 1 wherein R₂ and R₄ are each hydrogen, and B is —

NR₈—

(CH₂)_n″

—

wherein n″

is 0 and R₈ is OY₁.

10. The pharmaceutical composition according to claim 9 wherein R₃ is hydrogen, and R₁ is hydrogen, COOR or CONR₆R₇.

11. The pharmaceutical composition according to claim 1 wherein the compound of Formula (I) is selected from the group consisting of:

cis-7-oxo-6-oxa-1-azabicyclo[3.2.1]octane-4-propanoic acid,

trans diphenylmethyl 7-oxo-6-oxa-1-azabicyclo[3. 2.1]octan-4-acetate,

cis diphenylmethyl 7-oxo-6-oxa-1-azabicyclo[3.2.1 ]octan-4-acetate,

trans phenylmethyl 3-benzoyl-2-oxo-1,3-diazabicyclo[2.2.1 ]heptane-6-carboxylate,

trans phenylmethyl 2-oxo-3-(sulphooxy)-1,3-diazabicyclo[2.2.1 ]heptane-6-carboxylate,

6-[[(4-methylphenyl)sulphonyl]oxy]-1,6-diazabicyclo[3.2.1]octan-7-one,

6-[(methylsulphonyl)oxy]-1,6-diazabicyclo[3.2.1]octan-7-one,

6-[(4-nitrophenyl)sulphonyl]oxy]-1,6-diazabicyclo[3.2.1]octan-7-one,

trans diphenylmethyl 7-oxo-6-oxa-1-azabicyclo[3.2.1 ]octane-2-carboxylate,

trans (4-nitrophenyl)methyl 7-oxo-6-oxa-1-azabicyclo[3.2.1 ]octane-2-carboxylate,

trans-7-oxo-6-oxa-1-azabicyclo[3.2.1]octane-2 carboxylic acid,

trans phenylmethyl 7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate,

trans phenylmethyl 7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate,

trans phenylmethyl 7-oxo-6-[(phenylsulphonyl)oxy]-1,6-diazabicyclo[3.2.1]octane-2-carboxylate,

trans phenylmethyl 7-oxo-6-[(2-thienylsulphonyl)oxy]-1,6-diazabicyclo[3-.2.1]octane-2-carboxylat

trans-6-benzoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid,

trans methyl 6-benzoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate,

trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

trans-7-oxo-N-(phenylmethyl)-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

trans-7-oxo-N-(2-pyridinylmethyl)-6-(sulphooxy)-1,6-d iazabicyclo[3.2. 1]octane-2-carboxamide,

trans-7-oxo-N-[2-(3-pyridinyl)ethyl]-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

trans-7-oxo-N-[2-(4-pyridinyl)ethyl]-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

trans-7-oxo-N-[2-(2-pyridinyl)ethyl]-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

trans-N-[3-(aminocarbonyl)phenyl]-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.-2.1]octane-2-carboxamide,

trans-N-[4-(dimethylamino)phenyl]-7-oxo-6-(sulphooxy)-1,6-diazabicyclo [3.2.1 ]octane-2-carboxamide,

trans-N-[3-(dimethylamino)phenyl]-7-oxo-6-(sulphooxy)-1,6-diazabicyclo [3.2.1 ]octane-2-carboxamide,

trans-7-oxo-N-[(4-pyridinyl)methyl]-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

trans-7-oxo-N-(3-pyridinyimethyl)-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

trans-N-( 1-amino-1-oxo-3-phenyl-2-propyl)-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1 ]octane-2-carboxamide,

trans-N-(2-amino-2-oxoethyl)-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

trans-N-[3-[(aminocarbonyl)amino]phenyl]-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

trans-N-(2-amino-2-oxo-1-phenylethyl)-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate of 2-amino-2-oxoethyl,

trans 2-(4-pyridinyl)ethyl 7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate,

trans 2-(2-pyridinyl)ethyl 7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate,

6-(sulphooxy)-1,6-diazabicyclo[3.2.1]oct-3-in-7-one, and

3-methoxy-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]oct-3-in-7-one.

12. The pharmaceutical composition of claim 11 comprising said compounds and pharmaceutically acceptable salts of Formula (I) and further comprising said β

-lactamine antibiotic selected from the group consisting of;

penams, penems, carbapenems, cephems, carbacephems, oxacephems, cephamycims, monobactams, combinations and pharmaceutically acceptable salts thereof.

13. The pharmaceutical composition of claim 11 comprising said compounds and pharmaceutically acceptable salts of Formula I and further comprising said β

-lactamine antibiotic selected from the group consisting of;

amoxicillin, ampicillin, azlocillin, mezlocillin, apalcillin, hetacillin, bacampicillin, carbenicillin, sulbenicillin, ticarcillin, piperacillin, azlocillin, mecillinam, pivmecillinam, methicillin, ciclacillin, talampicillin, aspoxicillin, oxacillin, cloxacillin, dicloxacillin, flucloxacillin, nafcillin or pivampicillin, the cephalosporins such as cephalothin, cephaloridine, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cephradine, ceftizoxime, cefoxitin, cephacetrile, cefotiam, cefotaxime, cefsulodin, cefoperazone, ceftizoxime, cefmenoxime, cefmetazole, cephaloglycin, cefonicid, cefodizime, cefpirome, ceftazidime, ceftriaxone, cefpiramide, cefbuperazone, cefozopran, cefepime, cefoselis, cefluprenam, cefuzonam, cefpimizole, cefclidin, cefixime, ceftibuten, cefdinir, cefpodoxime axetil, cefpodoxime proxetil, cefteram pivoxil, cefetamet pivoxil, cefcapene pivoxil or cefditoren pivoxil, cefuroxime, cefuroxime axetil, loracarbacef, latamoxef, the carbapenems such as imipenem, meropenem, biapenem or panipenem and the monobactams such as aztreonam and carumonam, combinations and pharmaceutically acceptable salts thereof.

14. The pharmaceutical composition of claim 11 comprising said compounds and pharmaceutically acceptable salts of Formula I and further comprising said β

-lactamine antibiotic 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 or cefditoren pivoxil, cefuroxime, cefuroxime axetil, loracarbacef, latamoxef, combinations and pharmaceutically acceptable salts thereof.

15. The pharmaceutical composition according to claim 1 wherein said compound of Formula (I) comprises a sodium salt of trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo-[3.2.1]-octane-2-carboxamide.

16. The pharmaceutical composition of claim 1, wherein said compound of Formula (I) comprises a sodium salt of trans-7-oxo-6-(sulphooxy)-1 ,6-diazabicyclo-[3.2.1]-octane-2-carboxamide and said Δ

-lactamine antibiotic comprises ceftazidime.