Heterocyclic compounds, their preparation and their use as medicaments, in particular as anti-bacterial agents

1. A process for the production of a compound of the formula

wherein

R 1 is —CONR 6 R 7 , R 6 and R 7 , are individually selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl of 6 to 10 carbon atoms and aryl alkyl of 7 to 11 carbon atoms optionally substituted by carbamoyl, ureido or dimethylamino, and alkyl of 1 to 6 carbon atoms substituted by pyridyl,

R 2 is hydrogen,

R 3 is hydrogen,

A is

R 4 , R 4 is hydrogen,

n′ 1 is 1 or 2, R 5 is selected from the group consisting of —COOH, —CN, —OH, —NH 2 , —CONR 6 R 7 , —COOR, —OR, —OCOH, —OCOR, —OCOOR, —OCONHR, —OCONH 2 , —NHR, —NHCOH, —NHCOR, —NHSO 2 R, —NH—COOR, —NH—CO—NHR and —NHCONH 2 ,

R is selected from the group consisting of alkyl of 1 to 6 carbon atoms optionally substituted by pyridyl or carbamoyl, —CH 2 -alkenyl of 3 to 9 carbon atoms, aryl of 6 to 10 carbon atoms and aryl alkyl of 7 to 11 carbon atoms, with the aryl ring optionally substituted by a 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 6 and R 7 are defined as above, the dotted line is an optional bond,

n is 1,

X is —(CO)—B—, B is —NR 8 —(CH 2 ) n″ — attached to the carbonyl by the nitrogen,

n″ is 0 or 1,

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 , R a , Rb, and Rc are alkyl of 1 to 6 carbon atoms or aryl of 6 to 10 carbon atoms, R is defined as above,

m is 0 or 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 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) and

Y 3 is selected from the group consisting of tetrazole, squarate, —NH, —NHSO 2 R and —NRSO 2 R and a salt with a base or an acid comprising at least the next two following steps:

a) reacting a compound of the formula

R 1 is defined as above,

R 2 is defined as above, A is defined as above,

HZ is HNR′ 8 —(CH 2 ) n″ —,

R′ 8 is selected from the group consisting of hydrogen, protected —OH, —R′, OR′, —Y′, —OY′, Y′ 1 , OY′ 1 , Y′ 2 , OY′ 2 , Y′ 3 ,

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 SO 2 R′, —CH 2 PO(OR′) 2 , —CH 2 SO 3 , —CH 2 PO(OR′)OH, —CH 2 PO(R′)OH, —CH 2 PO(OH) 2 , the carboxylic acid, hydroxyl and hydroxylamine groups of which being respectively protected in the form of i) alkyl, allyl, benzyl, benzhydryl and p-nitrobenzyl sters, ii) ethers, esters and carbonates, and iii) benzyl and allyl esters,

Y′ 1 is selected from the group consisting of —SO 2 R′, —SO 2 NHCOH, —SO 2 NHCOR′, —SO 2 NHCOOR′, —SO 2 NHCONH 2 , —SO 2 NHCONHR′ and —SO 3 H, protected by branched alkyl of 3 to 6 carbon atoms,

Y′ 2 is selected from the group consisting of —PO(OH) 2 , —PO(OH)(OR′), —PO(OH)(R′), and —PO(OR′) 2 , the Hydroxy groups of which being protected in the form of esters,

Y′ 3 is selected from the group consisting of —NH or —NR tetrazole substituted by R′, —NHSO 2 R′ and —NR′SO 2 R′,

n″ is defined as above,

with a carbonylation agent selected from the group of phosgene, diphosgene, triphosgene, aryl chloroformates, aralkyl chloroformates, alkyl chloroformates, alkenyl chloroformates, alkyl dicarbonates, carbonyl-diimidazole and mixtures thereof optionally in the presence of a base, to obtain a compound of the formula

wherein either X 1 is hydrogen and X 2 is ZCOX 3 , X 3 is the remainder of the carbonyl, or X 1 is —COX 3 and X 2 is —ZH and X 3 is as above, and

b) cyclizing the compound of formula III in the presence of a base.

2. The process of claim 1 wherein the carbonylation is effected in the presence of a base.

3. The process of claim 2 wherein the base in an amine.

4. The process of claim 1 wherein in step b), the base is selected from the group consisting of amines, hydrides, alcoholates, amides and carbonates of alkali metal or alkaline earth metals.

5. The process of claim 1 for the production of a compound of formula (I) wherein Y 1 is —SO 3 H and its salts further comprising a sulfatation step and optionally a salification step.

6. The process of claim 5 wherein the sulfatation is effected with —SO 3 -amine complex or —SO 3 -dimethylformamide in the presence of pyridine.

7. The process of claim 5 wherein salification is effected with an alkali metal salt, a quaternary ammonium salt or an amine salt.