Heterocyclic compounds as inhibitors of beta-lactamases

1. A pharmaceutical composition comprising a bacterial β-lactamase inhibitory amount of a compound, or a pharmaceutically acceptable salt thereof, of formula (I):

wherein R 1 is hydrogen, COOH, CN, COOR, CONR 6 R 7 , (CH 2 ) n′ R 5 or C(═NR 6 )NHR 7 ;

R is selected from the group consisting of alkyl containing 1 to 6 carbon atoms optionally substituted by a pyridyl or carbamoyl radical, —CH 2 -alkenyl containing 3 to 9 carbon atoms, aryl containing 6 to 10 carbon atoms and aralkyl containing 7 to 11 carbon atoms, wherein the nucleus of said aryl or aralkyl is optionally substituted by OH, NH 2 , NO 2 , alkyl containing 1 to 6 carbon atoms, alkoxy containing 1 to 6 carbon atoms or by one or more halogen atoms;

R 6 and R 7 are identical or different and are independently selected from the group consisting of hydrogen, alkyl containing 1 to 6 carbon atoms, aryl containing 6 to 10 carbon atoms and aralkyl containing 7 to 11 carbon atoms optionally substituted by a carbamoyl, ureido or dimethylamino radical, and alkyl containing 1 to 6 carbon atoms substituted by a pyridyl radical;

n′ is 1 or 2;

R 5 is selected from the group consisting of COOH, CN, OH, NH 2 , CO-NR 6 R 7 , COOR, OR, OCHO, OCOR, OCOOR, OCONHR, OCONH 2 , NHR, NHCOH, NHCOR, NHSO 2 R, NH—COOR, NH—CO—NHR and NHCONH 2 wherein R, R 6 and R 7 are as defined above;

R 2 is hydrogen or (CH 2 ) n′1 R 5 wherein n′ 1 is 0, 1 or 2, and R 5 is as defined above;

R 3 is hydrogen or alkyl containing 1 to 6 carbon atoms;

A is a

 group wherein R 4 is hydrogen or (CH 2 ) n′1 R 5 and n′ 1 and R 5 are as defined above, and the dotted line is an optional bond with one of the two carbons which carry R 1 and R 2 ;

n is 1;

X is a divalent —C(O)—B— group linked to the nitrogen atom by the carbon atom wherein B is a divalent —O—(CH 2 ) n″ — group linked to the carbonyl by the oxygen atom, a divalent —NR 8 —(CH 2 ) n″ — or —NR 8 —O— group linked to the carbonyl by the nitrogen atom, n″ is 0, and wherein B is —NR 8 —(CH 2 ) n″ —, R 8 is selected from the group consisting of hydrogen, OH, R, OR, Y, OY, Y 1 , OY 1 , Y 2 , OY 2 , Y 3 , OCH 2 CH 2 SO m R, OSiR a R b R c and SiR a R b R c and wherein B is —NR 8 —O—, R 8 is selected from the group consisting of hydrogen, R, Y, Y 1 , Y 2 , Y 3 and SiR a R b R c , wherein R a , R b and R c is each independently a linear or branched alkyl containing 1 to 6 carbon atoms or aryl containing 6 to 10 carbon atoms, R is as defined above and m is 0, 1 or 2;

Y is selected from the group consisting of COH, COR, COOR, CONH 2 , CONHR, CONHOH, CONHSO 2 R, CH 2 COOH, CH 2 COOR, CH 2 CONHOH, CH 2 CONHCN, CH 2 tetrazole, protected CH 2 tetrazole, CH 2 SO 3 H, CH 2 SO 2 R, CH 2 PO(OR) 2 , CH 2 PO(OR)(OH), CH 2 PO(R)(OH) and CH 2 PO(OH) 2 ;

Y 1 is selected from the group consisting of SO 2 R, SO 2 NHCOH, SO 2 NHCOR, SO 2 NHCOOR, SO 2 NHCONHR, SO 2 NHCONH 2 and SO 3 H;

Y 2 is selected from the group consisting of PO(OH) 2 , PO(OR) 2 , PO(OH)(OR) and PO(OH)(R);

Y 3 is selected from the group consisting of tetrazole, tetrazole substituted by R, squarate, NH or NR-tetrazole, NH or NR-tetrazole substituted by R, NHSO 2 R and NRSO 2 R wherein R is as defined above; and

R 1 , R 2 and R 3 are not simultaneously hydrogen when n is 1,

R 4 is hydrogen and

X is —C(O)—O—(CH 2 ) n″ wherein n″ is 0, or

, or

X is —CO—NR 8 —(CH 2 ) n″ wherein n″ is 0 and R 8 is hydrogen or phenyl; and a therapeutically effective amount of a β-lactamine antibiotic.

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, R 3 is hydrogen, R 1 is hydrogen, COOR or CONR 6 R 7 wherein R, R 6 and R 7 are as defined in claim 1 , and X is —C(O)—B—herein B is —O—(CH 2 ) n″ —or —NR 8 —(CH 2 ) n ″ — wherein n″ is 0 and R 8 is as defined in claim 1 .

8. The pharmaceutical composition according to claim 1 wherein R 8 is Y, Y 1 or OY 1 , and Y and Y 1 are as defined in claim 1 .

9. The pharmaceutical composition according to claim 1 wherein R 2 and R 4 are each hydrogen, and B is —NR 8 —(CH 2 ) n″ — wherein n″ is 0 and R 8 is OY 1 .

10. The pharmaceutical composition according to claim 9 wherein R 3 is hydrogen, and R 1 is hydrogen, COOR or CONR 6 R 7 .

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.