Azabicyclic compounds, preparation thereof and use as medicines, in particular as antibacterial agents

1. A compound of the formula, or one of its salts with a base or an acid:

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

R is selected from the group consisting of alkyl of 1 to 6 carbon atoms optionally substituted by a member selected from the group consisting of pyridyl and carbamoyl,

—CH 2 -alkenyl of 3 to 9 carbon atoms, aryl of 6 to 10 carbon atoms and aralkyl of 7 to 11 carbon atoms, the ring of the aryl or aralkyl being unsubstituted or substituted by a member selected from 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 individually selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl of 1 to 6 carbon atoms and aralkyl of 7 to 11 carbon atoms, unsubstituted or substituted by a member selected from the group consisting of carbamoyl, ureido and dimethylamino, and alkyl of 1 to 6 carbon atoms substituted by pyridyl, unsubstituted or substituted on the phenyl by a member selected from the group consisting of carbamoyl, ureido and dimethylamino, and alkyl of 1 to 6 carbon atoms substituted by pyridyl,

R 2 is hydrogen;

R 3 is hydrogen;

A is

R 4 is hydrogen, or —(CH 2 ) n′1 R 5 , n′ 1 is equal to 1 or 2 and 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 , —NHR, —NHCOH, —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 aralkyl of 7 to 11 carbon atoms, the ring of the aryl or aralkyl unsubstituted or substituted by a member selected from the group consisting of —OH, —NH 2 , —NO 2 , alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or by and at least one halogen,

R 6 and R 7 being as defined above, the dotted line being an optional bond with one or other of the carbon carriers of the substituents R 1 and R 2 ;

n is 1;

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

n′ is equal to 1 or 2,

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 , —NHR, —NHCOH, —NHCOR, —NHSO 2 R, —NH—COOR, —NH—CO—NHR and —NHCONH 2 , R, R 6 and R 7 being as defined above;

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

R 3 is hydrogen or alkyl of 1 to 6 carbon atoms;

A is

 R 4 is hydrogen or —(CH 2 ) n′1 R 5 , n′ 1 and R 5 being as defined above, the dotted line representing an optional bond with one or other of the carbon carriers of —R 1 and R 2 ;

n is 1;

x is —C(O)—B— attached to the nitrogen atom by the carbon atom,

B is —O—(CH 2 ) n″ — attached to the carbonyl by the oxygen, or —NR 8 —(CH 2 ) n″ — or —NR 8 —O— attached to the carbonyl by the nitrogen, n″ is 0 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 , —OCH 2 CH 2 SO m R, OSiRaRbRc and SiR a R b R c , R a , R b and R c are individually alkyl of 1 to 6 carbon atoms or aryl of 6 to 10 carbon atoms, R being as defined above and m being equal to 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 the R, squarate, —NH or —NR tetrazole, —NH or —NR tetrazole substituted by the R, —NHSO 2 R and —NRSO 2 R, R being as defined above;

it being understood that when n is equal to 1 and A is

 in which R 4 is hydrogen and

either X is —C(O)—O—(CH 2 ) n″ in which n″ is 0,

or X is —CO—NR 8 —(CH 2 ) n″ in which n″ is 1 and R 8 is isopropyl,

or X is —CO—NR 8 —(CH 2 ) n″ in which n″ is 0 and R 8 is hydrogen or phenyl,

so all three of R 1 , R 2 and R 3 cannot be hydrogen at the same time.

2. A compound of claim 1 , wherein R 4 is hydrogen.

3. A compound of claim 1 , wherein X is —CO—B in which B is —NR 8 —(CH 2 ) n″ .

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

5. A compound of claim 1 , wherein R 1 is —CONR 6 ,R 7 .

6. A compound of claim 1 , wherein R 2 is H.

7. A compound of claim 1 , wherein R 3 is H.

8. A compound selected from the group consisting of:

trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide and its base salts,

trans-7-oxo-N-(phenylmethyl)-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide and its base salts,

trans-7-oxo-N-(4-pyridinyl methyl)-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide and its base salts,

trans-7-oxo-N-(3-pyridinyl methyl)-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide and its base salts,

trans-7-oxo-N-(2-amino 2-oxo ethyl)-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide and its base salts, and

phenylmethyl trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxylate.

9. A compound of the formula, or one of its salts with a base or an acid:

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

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 aralkyl of 7 to 11 carbon atoms, the ring of the aryl or aralkyl unsubstituted or substituted by a member selected from the group consisting of —OH, —NH 2 , —NO 2 , alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms and by at least one halogen,

R 6 and R 7 individually, are selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl of 6 to 10 carbon atoms and aralkyl of 7 to 11 carbon atoms, unsubstituted or substituted by a member selected from the group consisting of carbamoyl, ureido and dimethylamino, and alkyl of 1 to 6 carbon atoms substituted by pyridyl,

n′ is equal to 1 or 2,

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 , —NHR, —NHCOH, —NHCOR, —NHSO 2 R, —NH—COOR, —NH—CO—NHR and —NHCONH 2 , R, R 6 and R 7 being as defined above;

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

R 3 is hydrogen or alkyl of 1 to 6 carbon atoms;

A is

 R 4 hydrogen or —(CH 2 ) n′1 R 5 , n′ 1 and R 5 being as defined above, the dotted line representing an optional bond with one or other of the carbon carriers of —R 1 and R 2 ;

n is equal to 1;

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

B is —NR 8 —(CH 2 ) n″ — attached to the carbonyl by the nitrogen atom, n″ is equal to 0 or 1 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 , —OCH 2 CH 2 SO m R, —OSiRaRbRc and —SiR a R b R c , R a , R b and R c are individually alkyl of 1 to 6 carbon atoms or aryl of 6 to 10 carbon atoms, R being as defined above and m being equal to 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, R being as defined above;

it being understood that when n is 1 and A is

 in which R 4 is hydrogen and

either X is —C(O)—O—(CH 2 ) n″ in which n″ is 0

or X is —CO—NR 8 —(CH 2 ) n″ in which n″ is 0 and R 8 is hydrogen or phenyl,

so all three of R 1 , R 2 and R 3 cannot represent hydrogen at the same time.

10. A compound of claim 9 , wherein R 4 is hydrogen.

11. A compound of claim 9 , wherein in group B, —R 8 is —Y 1 or —OY 1 , in which —Y 1 is selected from the group consisting of —SO 2 R, —SO 2 NHCOR, —SO 2 NHCOOR, —SO 2 NHCONHR, —SO 3 H wherein R is as defined in claim 9 .

12. A compound of claim 9 , wherein R 1 is —CONR 6 ,R 7 .

13. A compound of claim 9 , wherein R 2 is H.

14. A compound of claim 9 , wherein R 3 is H.

15. A compound of the formula, or one of its salts with a base or an acid:

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 aralkyl of 7 to 11 carbon atoms,

B is —NR 8 —(CH 2 ) n″ attached to the carbonyl by the nitrogen atom, n″ is 0 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 , —OCH 2 CH 2 SO m R, —OSiRaRbRc and SiR a R b R c , R a , R b and R c are individually alkyl of 1 to 6 carbon atoms or aryl of 6 to 10 carbon atoms, R being as defined above and m being equal to 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 the R, squarate, —NH or —NR tetrazole, —NH or —NR tetrazole substituted by the R, —NHSO 2 R and —NRSO 2 R, R being as defined above.

16. A compound of claim 15 , wherein R 4 is hydrogen.

17. A compound of claim 15 , wherein in group B, —R 8 is —Y 1 or —OY 1 , in 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 wherein R is as defined in claim 15 .

18. A pharmaceutical compositions comprising, as active ingredient, at least one product of claim 1 and a pharmaceutical acceptable carrier.

19. A pharmaceutical compositions comprising, as active ingredient, at least one product of claim 8 and a pharmaceutical acceptable carrier.

20. A pharmaceutical compositions comprising, as active ingredient, at least one product of claim 9 and a pharmaceutical acceptable carrier.

21. A pharmaceutical compositions comprising, as active ingredient, at least one product of claim 15 and a pharmaceutical acceptable carrier.

22. A method of treating bacterial infections in warm-blooded animals comprising administering to warm-blooded animals in need thereof a bactericidally effective amount of a compound of claim 1 .