Heterocyclic compounds, method for preparing same and use thereof as medicines, in particular as antibacterial agents

1. A compound selected from the group consisting of a compound the formula:

wherein:

a) either R 1 is selected from the group consisting of hydrogen, —COOH, —CN, —COOR, —(CH 2 )n′R 5 , —CONR 6 R 7 and

R is selected from the group consisting of alkyl of 1 to 6 carbon atoms, optionally substituted by pyridyl, a —CH 2 -alkenyl of 3 to 9 carbon atoms, (poly)alkoxyalkyl of 1 to 4 oxygen atoms and 3 to 10 carbon atoms, aryl of 6 to 10 carbon atoms, aralkyl of 7 to 11 carbon atoms, the ring of the aryl or aralkyl optionally substituted by at least one member of the group consisting of —OH, —NH 2 , —NO 2 , alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms and at least one halogen,

R 5 is selected from the group consisting of —COOH, —CN, —OH, —NH 2 , —CO—NR 6 R 7 , —COOR, —OR, —OCOH, —OCOR, —OCOOR, —OCONHR, —OCONH 2 , —OSO2R, —NHR, —NHCOR, —NHCOH, —NHSO 2 R, —NH—COOR, —NH—CO—NHR, —NH—CO—NH 2 and N 3 , R being defined as above,

R 6 and R 7 are individually selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl 6 to 10 carbon atoms and aralkyl of 7 to 11 carbon atoms and alkyl of 1 to 6 carbon atoms substituted by pyridyl,

n′ is 1 or 2,

R 3 and R 4 together form a phenyl or a heterocycle of aromatic character with 5 or 6 vertices containing 1 to 4 heteroatoms chosen from nitrogen, oxygen and sulfur, and optionally substituted by at least one R′, R′ being selected from the group consisting of hydrogen, and the alkyl of 1 to 6 carbon atoms, optionally substituted by at least one member of the group consisting of hydroxy, oxo, halogen, cyano, nitro, alkenyl of 2 to 6 carbon atoms, halogen, amino, —OH, protected —OH, —OR, —NHCOH, —NHCOR, —NHCOOR, —COOH, —COOR, —C(C 6 H 5 ) 3 and —CH 2 —CH 2 —S(O)m-R, R being as defined previously and m being 0, 1 or 2, or

b) R 4 is hydrogen or —(CH 2 ) n′1 R 5 , n′1 being 0, 1 or 2 and R 5 being as defined above,

and R 1 and R 3 together form a phenyl or an optionally substituted heterocycle, as defined above,

in both case a) and b)

R 2 is selected from the group consisting of hydrogen, halogen, R, —S(O) m R, —OR, —NHCOR, —NHCOOR and —NHSO 2 R, m and R being as defined previously,

X is —C(O)—B— linked to the nitrogen atom by the carbon atom,

B is —NR 8 linked with the carbonyl by the nitrogen and 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 , —O—CH 2 —CH 2 —S(O)m-R, —SiRaRbRc and —OSiRaRbRc, Ra, Rb and Rc are individually alkyl of 1 to 6 carbon atoms or aryl 6 to 10 carbon atoms and R and m are as defined previously,

Y is selected from the group consisting of —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 fro 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, R being defined as above,

n is 1 or 2 and its pharmaceutically acceptable salts with a base or acid.

2. A compound of claim 1 wherein R 2 is hydrogen.

3. A compound of claim 1 wherein R 3 and R 4 together form a phenyl or heterocycle, optionally substituted, as defined in claim 1 .

4. A compound of claim 1 wherein R 3 and R 4 together form phenyl or heterocycle selected from the group consisting of thienyl, furyl, pyrazolyl and triazolyl, optionally substituted.

5. A compound of claim 1 wherein R 1 is selected from the group consisting of hydrogen, —COOCH 3 , —COOC 2 H 5 , —CONH 2 , —CONHCH 3 , —CONHCH 2 -phenyl and —CONHCH 2 -pyridyl.

6. A compound of claim 1 wherein R 8 is —Y 1 or —OY 1 which Y 1 is selected from the group consisting of —SO 2 R, —SO 2 NHCOR, —SO 2 NHCOOR, —SO 2 NHCONHR and —SO 3 H and R is as defined in claim 1 .

7. A compound of claim 1 wherein R 8 is selected from the group consisting of hydrogen, hydroxyl, —CO-phenyl, —O-allyl, —OCH 2 COOH and —O-benzyl.

8. A compound selected from the group consisting of:

the sodium salt of trans-3-oxo-4-(sulphooxy)-2,3,4,5-tetrahydro-2,5-methano-1H-2,4-benzodiazepine-1-carboxamide;

the sodium salt of 3-methyl-5-(sulphooxy)-5,6,7,8-tetrahydro-4,7-methano-4H-[1,2,3]-triazolo[4,5-e][1,3]diazepine-6 (3H)-one;

the sodium salt of trans-1-methyl-6-oxo-5-(sulphooxy)-4,5,6,8-tetrahydro-4,7-methano-1H-pyrazolo[3,4-e][1,3]diazepine-8(7H)-carboxamide;

the sodium salt of trans-N-methyl-3-oxo-4-(sulphooxy)-2,3,4,5-tetrahydro-2,5-methano-1H-2,4-benzodiazepine-1-carboxamide;

the sodium salt of 5-(sulphooxy)-5,6,7,8-tetrahydro-4,7-methano-4H-furo[2,3-e][1,3]diazepine-6-one;

the pyridinium salt of 1-propyl-5-(sulphooxy)-4,5,7,8-tetrahydro-4,7-methano-imidazo[4,5-e][1,3]diazepine-6(1H)-one;

the sodium salt of trans methyl 6-oxo-5-(sulphooxy)-5,6,7,8-tetrahydro-4,7-methano-4H-furo[2,3-e][1,3]diazepine-8-carboxylate;

the sodium salt of 1-methyl-5-(sulphooxy)-5,6,7,8-tetrahydro-4,7-methano-4H-pyrazolo[3,4-e][1,3]diazepine-6(1H)-one;

the sodium salt of trans-3-oxo-N-(4-pyridinylmethyl)-4-(sulphooxy)-2,3,4,5-tetrahydro-2,5-methano-1H-2,4-benzodiazepine-1-carboxamide;

the sodium salt of trans-6-oxo-5-(sulphooxy)-5,6,7,8-tetrahydro-4,7-methano-4H-thieno[2,3-e][1,3]diazepine-8-carboxamide;

the sodium salt of trans-6-oxo-5-(sulphooxy)-5,6,7,8-tetrahydro-4,7-methano-4H-furo[2,3-e][1,3]diazepine-8-carboxamide;

the sodium salt of trans-1,2,3,5-tetrahydro-8-hydroxy-3-oxo-2-(sulphooxy)-1,4-methano-4H-2,4-benzodiazepine-5-carboxamide;

the sodium salt of trans-7-(acetylamino)-1,2,3,5-tetrahydro-8-hydroxy-3-oxo-2-(sulphooxy)-1,4-methano-4H-2,4-benzodiazepine-5-carboxamide;

the sodium salt of trans-1,5-dihydro-5-(hydroxymethyl)-2-(sulphooxy)-1,4-methano-4H-2,4-benzodiazepin-3(2H)-one;

the sodium salt of trans-4,5,6,8-tetrahydro-N-methyl-6-oxo-5-(sulphooxy)-4,7-methano-7H-thieno[2,3-e][1,3]diazepine-8-carboxamide;

the sodium salt of 7,8-dihydro-7-(sulphooxy)-5,8-methano-5H-thieno[2,3-e][1,3]diazepin-6(4H)-one and

the triethylammonium salt of trans-2-bromo-4,5,6,8-tetrahydro-6-oxo-5-(sulphooxy)-4,7-methano-7H-thieno[2,3-e][1,3]diazepine-8-carboxamide.

9. An antibacterial composition comprising an antibacterial amount of a compound of claim 1 and a pharmaceutical carrier.

10. A method of combating bacterial infections in warm-blooded animals comprising administering to warm-blooded animals in need thereof an antibacterially effective amount of a compound of claim 1 .