Claims for Patent: 7,612,087

Summary for Patent: 7,612,087

Title:	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.
Inventor(s):	Jozsef Aszodi, Claude Fromentin, Maxime Lampilas, David Alan Rowlands
Assignee:	Allergan Pharmaceuticals International Ltd
Application Number:	US10/898,754
Patent Claims:	1. A pharmaceutical composition comprising a bacterial β-lactamase inhibitory amount of a compound, or a pharmaceutically acceptable salt thereof, of formula (I): wherein R1 is hydrogen, COOH, CN, COOR, CONR6R7, (CH2)n′R5 or C(═NR6)NHR7; R is selected from the group consisting of alkyl containing 1 to 6 carbon atoms optionally substituted by a pyridyl or carbamoyl radical, —CH2-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, NH2, NO2, alkyl containing 1 to 6 carbon atoms, alkoxy containing 1 to 6 carbon atoms or by one or more halogen atoms; R6 and R7 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; R5 is selected from the group consisting of COOH, CN, OH, NH2, CO-NR6R7, COOR, OR, OCHO, OCOR, OCOOR, OCONHR, OCONH2, NHR, NHCOH, NHCOR, NHSO2R, NH—COOR, NH—CO—NHR and NHCONH2 wherein R, R6 and R7 are as defined above; R2 is hydrogen or (CH2)n′1R5 wherein n′1 is 0, 1 or 2, and R5 is as defined above; R3 is hydrogen or alkyl containing 1 to 6 carbon atoms; A is a group wherein R4 is hydrogen or (CH2)n′1R5 and n′1 and R5 are as defined above, and the dotted line is an optional bond with one of the two carbons which carry R1 and R2; 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—(CH2)n″— group linked to the carbonyl by the oxygen atom, a divalent —NR8—(CH2)n″— or —NR8—O— group linked to the carbonyl by the nitrogen atom, n″ is 0, and wherein B is —NR8—(CH2)n″—, R8 is selected from the group consisting of hydrogen, OH, R, OR, Y, OY, Y1, OY1, Y2, OY2, Y3, OCH2CH2SOmR, OSiRaRbRc and SiRaRbRc and wherein B is —NR8—O—, R8 is selected from the group consisting of hydrogen, R, Y, Y1, Y2, Y3 and SiRaRbRc, wherein Ra, Rb and Rc 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, CONH2, CONHR, CONHOH, CONHSO2R, CH2COOH, CH2COOR, CH2CONHOH, CH2CONHCN, CH2tetrazole, protected CH2tetrazole, CH2SO3H, CH2SO2R, CH2PO(OR)2, CH2PO(OR)(OH), CH2PO(R)(OH) and CH2PO(OH)2; Y1 is selected from the group consisting of SO2R, SO2NHCOH, SO2NHCOR, SO2NHCOOR, SO2NHCONHR, SO2NHCONH2 and SO3H; Y2 is selected from the group consisting of PO(OH)2, PO(OR)2, PO(OH)(OR) and PO(OH)(R); Y3 is selected from the group consisting of tetrazole, tetrazole substituted by R, squarate, NH or NR-tetrazole, NH or NR-tetrazole substituted by R, NHSO2R and NRSO2R wherein R is as defined above; and R1, R2 and R3 are not simultaneously hydrogen when n is 1, R4 is hydrogen and X is —C(O)—O—(CH2)n″ wherein n″ is 0, or , or X is —CO—NR8—(CH2)n″ wherein n″ is 0 and R8 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, 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.