IP Library › Patent Application 12434270

Patent Application

App. No. 12/434,270

HETEROCYCLIC COMPOUNDS AS INHIBITORS OF BETA-LACTAMASES

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Patent No.: US None
App. No.: 12/434,270

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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 (137)

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′ i 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 —C0-NR 8 —(CH 2 ) n″ wherein n″ is 1 and R 8 is isopropyl, or

X is —C0-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-[(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.

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 ;

n′ is 1 or 2;

R 2 is hydrogen or (CH 2 ) n′ 1R 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 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: