Nitrogen-containing heterocyclic compounds, their preparation and their use as antibacterial drugs

1. A compound of formula (I), isomers, diasteroisomers, or combinations thereof, the compound comprising:

wherein:

R 1 represents a (CH 2 ) n —NH 2 radical, n being equal to 1 or 2;

R 2 represents a hydrogen atom;

R 3 and R 4 form together a nitrogen-containing heterocycle with aromaticity with 5 apices containing 1, 2 or 3 nitrogen atoms, substituted on this nitrogen atom or on one of these nitrogen atoms with a (CH 2 ) m —(C(O)) p —R 5 group, m being equal to 0, 1, 2 or 3, p being equal to 0 or 1 and R5 representing a hydroxy group, in which case p is equal to 1, or an amino, (C 1 -C 6 )alkyl of di-(C 1 -C 6 )alkyl amino group, or a nitrogen-containing heterocycle with aromaticity with 5 or 6 apices containing 1 or 2 nitrogen atoms and, if necessary, an oxygen or sulfur atom;

wherein when the sub-group (C(O)) p —R5 forms a carboxy, amino, (C1-C6)alkyl or di(C1-C6)alkyl amino group, m is different from 0 or 1;

wherein the compound is in a free form and/or as zwitterions and salts with pharmaceutically acceptable mineral or organic bases and acids.

2. The compound of general formula (I) according to claim 1 , wherein R 3 and R 4 form together a substituted pyrazolyl radical.

3. The compound of general formula (I) according to claim 1 , wherein R 1 is a (CH 2 ) n —NH 2 group, n being equal to 1, and the heterocycle formed by R 3 and R 4 is substituted with a (CH 2 ) m —(C(O)) p —R 5 group as defined in claim 1 .

4. The compound of general formula (I) according to claim 1 , wherein R 5 represents an amino, (C 1 -C 6 )alkyl or di-(C 1 -C 6 )alkyl amino group.

5. The compounds of general formula (I) according to claim 1 selected from the group consisting of:

trans 8-(aminomethyl)-2-carbamoyle-4,8-dihydro-5-(sulfo-oxy)-4,7-methano-7H-pyrazolo[3,4-e][1,3]diazepin-6(5H)-one,

trans 8-(aminomethyl)-2-dimethylcarbamoyle-4,8-dihydro-5-(sulfooxy)-4,7-methano-7H-pyrazolo[3,4-e][1,3]diazepin-6(5H)-one,

trans 8-(aminomethyl)-2-methylcarbamoyle-4,8-dihydro-5-(sulfooxy)-4,7-methano-7H-pyrazolo[3,4-e][1,3]diazepin-6(5H)-one,

trans 8-(aminomethyl)-1-(2-aminoethyl)-4,8-dihydro-5-(sulfooxy)-4,7-methano-7H-pyrazolo[3,4-e][1,3]diazepin-6(5H)-one,

trans 8-(aminomethyl)-2-(2-aminoethyl)-4,8-dihydro-5-(sulfooxy)-4,7-methano-7H-pyrazolo[3,4-e][1,3]diazepin-6(5H)-one,

trans 8-(aminomethyl)-2-(2-pyridinyl)-4,8-dihydro-5-(sulfo-oxy)-4,7-methano-7H-pyrazolo[3,4-e][1,3]diazepin-6(5H)-one,

trans 8-(aminomethyl)-5,6-dihydro-6-oxo-5-(sulfooxy)-4H-4,7-methanopyrazolo[3,4-e][1,3]diazepin-2(8H)-acetic acid,

trans 8-(aminomethyl)-5,6-dihydro-6-oxo-5-(sulfooxy)-4H-4,7-methanopyrazolo[3,4-e][1,3]diazepin-2(8H)-acetamide, and combinations thereof;

in free form and/or as zwitterions and/or salts with pharmaceutically acceptable mineral or organic bases and acids, isomers, diasteroisomers, and combinations thereof.

6. A medicament composition comprising a compound according to claim 1 .

7. A pharmaceutical composition comprising an active ingredient comprising a compound according to claim 1 .

8. A method for preparing a compound of formula (I), isomers, diasteroisomers, or combinations thereof, represented by:

wherein:

R 1 represents a (CH 2 ) n —NH 2 radical, n being equal to 1 or 2;

R 2 represents a hydrogen atom;

R 3 and R 4 form together a nitrogen-containing heterocycle with aromaticity with 5 apices containing 1, 2 or 3 nitrogen atoms, substituted on this nitrogen atom or on one of these nitrogen atoms with a (CH 2 ) m —(C(O)) p —R 5 group, m being equal to 0, 1, 2 or 3, p being equal to 0 or 1 and R 5 representing a hydroxy group, in which case p is equal to 1, or an amino, (C 1 -C 6 )alkyl of di-(C 1 -C 6 )alkyl amino group, or a nitrogen-containing heterocycle with aromaticity with 5 or 6 apices containing 1 or 2 nitrogen atoms and, if necessary, an oxygen or sulfur atom;

wherein when the sub-group (C(O)) p —R5 forms a carboxy, amino, (C1-C6)alkyl or di(C1-C6)alkyl amino group, m is different from 0 or 1; wherein the compound is in a free form or as zwitterions and salts with pharmaceutically acceptable mineral or organic bases and acids;

the method comprising treating a compound of formula (II) represented by:

wherein R′ 1 represents a (CH 2 ) n —NH 2 radical, n being equal to 1 or 2, wherein the nitrogen atom is protected, R 2 represents a hydrogen atom, R′ 3 and R′ 4 form together a nitrogen-containing heterocycle with aromaticity with 5 apices containing 1, 2 or 3 nitrogen atoms and P represents a group protecting the hydroxy radical, in the presence of a base, with a compound of formula (III):

X—(CH 2 ) m —(C(O)) p —R′ 5   (III)

wherein X represents a halogen atom or a OH group which may be activated, m is equal to 0, 1, 2 or 3, and p is equal to 0 or 1, and R′ 5 represents a radical R 5 wherein the reactive amino or carboxy group is if necessary protected, in order to obtain a compound of formula (IV):

wherein R′ 1 , R 2 and P are as defined above and R″ 3 and R″ 4 form together a nitrogen-containing heterocycle with aromaticity with 5 apices as defined above for R 3 and R 4 , substituted with a (CH 2 ) n —(C(O)) p —R′ 5 group, m, p and R′ 5 being as defined above,

deprotecting the hydroxyl radical, wherein the obtained compound is submitted to sulfatation reaction by action of complexed SO 3 ,

wherein the process optionally further comprises subjecting the compound obtained to one or more of the following reactions, in a suitable order:

deprotection of the aminated function(s) and if necessary of the carboxy functions present,

salification,

ion exchange,

resolution or separation of diastereoisomers.

9. A method for preparing a compound of formula (I), isomers, diasteroisomers, or combinations thereof, represented by:

wherein:

R 1 represents a (CH 2 ) n —NH 2 radical, n being equal to 1 or 2;

R 2 represents a hydrogen atom;

R 3 and R 4 form together a nitrogen-containing heterocycle with aromaticity with 5 apices containing 1, 2 or 3 nitrogen atoms, substituted on this nitrogen atom or on one of these nitrogen atoms with a (CH 2 ) m —(C(O)) p —R 5 group, m is equal to 0, p is equal to 1 and R 5 represents an amino, (C 1 -C 6 )alkyl or di-(C 1 -C 6 )alkyl amino group; wherein the compound is in a free form or as zwitterions and salts with pharmaceutically acceptable mineral or organic bases and acids;

the method comprising treating a compound of formula (II) represented by:

wherein R′ 1 represents a (CH 2 ) n —NH 2 radical, n being equal to 1 or 2, wherein the nitrogen atom is protected, R 2 represents a hydrogen atom, R′ 3 and R′ 4 form together a nitrogen-containing heterocycle with aromaticity with 5 apices containing 1, 2 or 3 nitrogen atoms and P represents a group protecting the hydroxy radical; in the presence of a base, with diphosgene, and then with an amine of formula

H—R″ 5

wherein R″ 5 represents an amino, (C 1 -C 6 ) alkyl or di(C 1 -C 6 ) alkyl amino,

in order to obtain a compound of formula (IV′):

wherein R 3 and R 4 form together a nitrogen-containing heterocycle with aromaticity with 5 apices, substituted with a —C(O)—R″ 5 group;

deprotecting the hydroxyl radical, wherein the obtained compound is submitted to a sulfatation reaction by action of complexed SO 3 ;

wherein the process optionally further comprises subjecting the compound obtained to one or more of the following reactions, in a suitable order:

deprotection of the aminated function(s) and if necessary of the carboxy functions present,

salification,

ion exchange, or

resolution or separation of diastereoisomers.

10. A compound of formula (I), isomers, diasteroisomers, or combinations thereof, the compound comprising:

wherein:

R 1 represents a (CH 2 ) n —NH 2 radical, n being equal to 1;

R 2 represents a hydrogen atom;

R 3 and R 4 form together a nitrogen-containing heterocycle with aromaticity with 5 apices containing 1, 2 or 3 nitrogen atoms, substituted on this nitrogen atom or on one of these nitrogen atoms with a (CH 2 ) m —(C(O)) p —R 5 group, m being equal to 0, 1, 2 or 3, p being equal to 0 or 1 and R 5 representing a hydroxy group, in which case p is equal to 1, or an amino, (C 1 -C 6 )alkyl of di-(C 1 -C 6 )alkyl amino group, or a nitrogen-containing heterocycle with aromaticity with 5 or 6 apices containing 1 or 2 nitrogen atoms and, if necessary, an oxygen or sulfur atom;

wherein when the sub-group (C(O)) p —R5 forms a carboxy, amino, (C1-C6)alkyl or di(C1-C6)alkyl amino group, m is different from 0 or 1;

wherein the compound is in a free form and/or as zwitterions and salts with pharmaceutically acceptable mineral or organic bases and acids.

11. A compound of formula (I), isomers, diasteroisomers, or combinations thereof, the compound comprising:

wherein:

R 1 represents a (CH 2 ) n —NH 2 radical, n being equal to 1;

R 2 represents a hydrogen atom;

R 3 and R 4 form together a nitrogen-containing heterocycle with aromaticity with 5 apices containing 1, 2 or 3 nitrogen atoms, substituted on this nitrogen atom or on one of these nitrogen atoms with a (CH 2 ) m —(C(O)) p —R 5 group, m being equal to 0, 1, 2 or 3, p being equal to 0 or 1, wherein R 5 represents an amino, (C 1 -C 6 )alkyl or di-(C 1 -C 6 )alkyl amino group and the sub-group (C(O)) p —R 5 forms an amino, (C1-C6)alkyl or di(C1-C6)alkyl amino group, m is different from 0 or 1;

wherein the compound is in a free form or as zwitterions and salts with pharmaceutically acceptable mineral or organic bases and acids.