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 . A method for inhibiting bacterial β-lactamases in man or an animal comprising administering to said man or said animal a therapeutically effective 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 bond between the two carbons which carry R 1  and R 2 , 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 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″ — 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. 
 
     
     
         2 . The method 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— wherein B is —O—(CH 2 ) n″ — or —NR 8 —(CH 2 ) n″ — wherein n″ is O and R 8  is as defined in  claim 1 . 
 
     
     
         3 . The method according to  claim 2  wherein R 8  is Y, Y 1  or OY 1 , and Y and Y 1  are as defined in  claim 1 . 
     
     
         4 . The method according to  claim 1  wherein A is 
       
         
           
           
               
               
           
         
       
       R 2  and R 4  are each hydrogen, and B is —NR 8 —(CH 2 ) n″ — wherein n″ is O and R 8  is OY 1 . 
     
     
         5 . The method according to  claim 4  wherein
 n is 1, R 3  is hydrogen, and R 1  is hydrogen, COOR or CONR 6 R 7  wherein R, R 6  and R 7  are as defined in  claim 1 . 
 
     
     
         6 . The method 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-carboxylate, 
 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. 
 
     
     
         7 . The method according to  claim 1  further comprising administering a combination of a compound of formula (I) and a therapeutically effective amount of a β-lactamine antibiotic. 
     
     
         8 . The method according to  claim 7  wherein the combination is administered separately, together or spread over time. 
     
     
         9 . A method for the treatment of bacterial infection in man or an animal comprising inhibiting bacterial β-lactamases by administering to said man or said animal a therapeutically effective 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 bond between the two carbons which carry R 1  and R 2  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 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″ — 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. 
 
     
     
         10 . The method according to  claim 9  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 9 , and X is —C(O)—B— wherein B is —O—(CH 2 ) n″ — or —NR 8 —(CH 2 ) n″  wherein n″ is O and R 8  is as defined in  claim 9 . 
 
     
     
         11 . The method according to  claim 10  wherein R 8  is Y, Y 1  or OY 1 , and Y and Y 1  are as defined in  claim 9 . 
     
     
         12 . The method according to  claim 9  wherein A is 
       
         
           
           
               
               
           
         
       
       R 2  and R 4  are each hydrogen, and B is —NR 8 —(CH 2 ) n″ — wherein n″ is O and R 8  is OY 1 . 
     
     
         13 . The method according to  claim 12  wherein
 n is 1, R 3  is hydrogen, and R 1  is hydrogen, COOR or CONR 6 R 7  wherein R, R 6  and R 7  are as defined in  claim 9 . 
 
     
     
         14 . The method according to  claim 9  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-carboxylate, 
 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. 
 
     
     
         15 . The method according to  claim 9  further comprising administering a combination of a compound of formula (I) and a therapeutically effective amount of a β-lactamine antibiotic. 
     
     
         16 . The method according to  claim 15  wherein the combination is administered separately, together or spread over time. 
     
     
         17 . A pharmaceutical composition comprising 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 bond between the two carbons which carry R 1  and R 2 , 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 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″ — 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″ —, or 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. 
 
     
     
         18 . The pharmaceutical composition of  claim 17  further comprising the combination of a compound of formula (I) and a therapeutically effective amount of a β-lactamine antibiotic.