Heterocyclic compounds as inhibitors of beta-lactamases

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.

1 - 18 . (canceled) 
     
     
         19 . A pharmaceutical composition comprising
 (a) 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—COORU, 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 bond between the two carbons which carry R 1  and R 2 , 
 
       
         
           
           
               
               
           
         
         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 or 2; 
         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′1 — or —NR 8 —O— group linked to the carbonyl by the nitrogen atom, n″ is 0 or 1, 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, A is 
       
       
         
           
           
               
               
           
         
         wherein R 4  is hydrogen and
 X is —C(O)—O—(CH 2 ) n″  wherein n″ is 0 or 1, or 
 X is —CO—NR 8 —(CH 2 ) n″  wherein n″ is 1 and R 8  is isopropyl, or 
 X is —CO—NR 8 —(CH 2 ) n″  wherein n″ is 0 and R 8  is hydrogen or phenyl; and 
 
         (b) a therapeutically effective amount of a β-lactamine antibiotic. 
       
     
     
         20 . A pharmaceutical composition according to  claim 19 , wherein said β-lactamine antibiotic comprises an antibiotic selected from the group consisting of: penams, penems, carbapenems, cephems, carbacephems, oxacephems, cephamycims, monobactams, and combinations and pharmaceutically acceptable salts thereof. 
     
     
         21 . A pharmaceutical composition according to  claim 19 , 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, ceftriaxone, 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, latamoxef, and combinations and pharmaceutically acceptable salts thereof. 
     
     
         22 . A pharmaceutical composition according to  claim 21 , wherein said β-lactamine antibiotic comprises ceftazidime. 
     
     
         23 . The pharmaceutical composition according to  claim 19 , 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 19 , and X is —C(O)-B- wherein B is —O—(CH 2 ) n″ —or —NR 8 —(CH 2 ) n″ — wherein n″ is 0 and R 8  is as defined in  claim 19 . 
     
     
         24 . The pharmaceutical composition according to  claim 19 , wherein R 8  is Y, Y 1  or OY 1 . 
     
     
         25 . The pharmaceutical composition according to  claim 19 , 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 . 
     
     
         26 . The pharmaceutical composition according to  claim 25 , wherein R 3  is hydrogen, and R 1  is hydrogen, COOR or CONR 6 R 7 . 
     
     
         27 . The pharmaceutical composition according to  claim 19 , 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-diaza-bicyclo[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-diazabicyclo[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-pyridinylmethyl)-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.   
     
     
         28 . The pharmaceutical composition of  claim 27 , wherein said β-lactamine antibiotic is selected from the group consisting of: penams, penems, carbapenems, cephems, carbacephems, oxacephems, cephamycims, monobactams, and combinations and pharmaceutically acceptable salts thereof. 
     
     
         29 . The pharmaceutical composition of  claim 27 , wherein said β-lactamine antibiotic is 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, pivampicillin, 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, cefditoren pivoxil, cefuroxime, cefuroxime axetil, loracarbacef, latamoxef, imipenem, meropenem, biapenem, panipenem, aztreonam, carumonam, and combinations and pharmaceutically acceptable salts thereof. 
     
     
         30 . The pharmaceutical composition of  claim 27 , wherein said β-lactamine antibiotic 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, ceftriaxone, 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, latamoxef, and combinations and pharmaceutically acceptable salts thereof. 
     
     
         31 . The pharmaceutical composition according to  claim 19 , 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. 
     
     
         32 . The pharmaceutical composition according to  claim 19 , 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. 
     
     
         33 . The pharmaceutical composition of  claim 19 , 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. 
     
     
         34 . The pharmaceutical composition of  claim 19 , 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 β-lactamine antibiotic comprises ceftazidime.