Cephem compounds

1. A compound of the formula [I]:

wherein

R 1 is lower alkyl, hydroxy(lower)alkyl or halo(lower)alkyl, and

R 2 is hydrogen, aryl(lower)alkyl or acyl, or

R 1 and R 2 are bonded together and form lower alkylene or lower alkenylene;

R 3 is hydrogen or lower alkyl;

R 4 is

wherein

A is

 wherein X is O or NH,

R 7 is hydrogen, lower alkyl, aryl(lower)alkyl or acyl,

R 8 is hydrogen or hydroxy,

R 9 is amino, mono or di(lower)alkylamino, aryl(lower)alkylamino, acyl amino, guanidino, acyl guanidino or saturated 3- to 8-membered heterocyclic group containing 1 to 4 nitrogen atoms optionally substituted by amino, aryl(lower)alkylamino or acylaminio,

k, m, n and q are independently 0 or 1, and

p is 0, 1, 2 or 3;

R 5 is carboxy or an esterfied carboxy; and

R 6 is amino, aryl(lower)alkylamino or acylamino,

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein

R 1 is lower alkyl or hydroxy(lower)alkyl, and

R 2 is hydrogen, aryl(lower)alkyl or acyl, or

R 1 and R 2 are bonded together and form lower alkylene;

R 3 is hydrogen;

A is

 wherein X is O or NH;

R 7 is hydrogen, aryl(lower)alkyl or acyl;

R 9 is amino, aryl(lower)alkylamino or acylamino; and

p is 0, 1 or 2,

or a pharmaceutically, acceptable salt thereof.

3. The compound of claim 2 wherein R 8 is hydrogen, or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 wherein

R 1 is lower alkyl, hydroxy(lower)alkyl or halo(lower)alkyl, and

R 2 is hydrogen, aryl(lower)alkyl or acyl, or

R 1 and R 2 are bonded together and form lower alkylene or lower alkenylene;

R 5 is carboxy or esterified carboxy;

R 6 is amino or acylamino;

R 7 is hydrogen, lower alkyl or acyl; and

R 9 is amino, mono or di(lower)alkylamino, acylamino, guanidino, acylguanidino or saturated 3- to 8-membered heterocyclic group containing 1 to 4 nitrogen atoms optionally substituted by amino or acylamino,

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4 wherein

R 1 is lower alkyl or hydroxy(lower)alkyl, and

R 2 is hydrogen, aryl(lower)alkyl or acyl, or

R 1 and R 2 are bonded together and form lower alkylene;

R 5 is carboxy or esterified carboxy;

R 6 is amino or acylamino;

R 7 is hydrogen or acyl; and

R 9 is amino or acylamino,

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5 wherein

R 1 is lower alkyl or hydroxy(lower)alkyl, and

R 2 is hydrogen, aryl(lower)alkyl, lower alkanoyl or lower alkoxycarbonyl, or

R 1 and R 2 are bonded together and form lower alkylene;

R 5 is carboxy or lower alkoxycarbonyl;

R 6 is amino, lower alkanoylamino or lower alkoxycarbonylamino;

R 7 is hydrogen, lower alkanoyl or lower alkoxycarbonyl; and

R 9 is amino, lower alkanoylamino or lower alkoxycarbonylamino,

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 6 wherein

R 1 is lower alkyl or hydroxy(lower)alkyl, and

R 2 is hydrogen, or

R 1 and R 2 are bonded together and form lower alkylene;

R 5 is carboxy;

R 6 is amino;

R 7 is hydrogen or lower alkanoyl; and

R 9 is amino,

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 wherein

R 4 is selected from the group consisting of

—NH-A-(NH) m —(CH 2 ) q —(CH 2 ) p —R 14 ,

wherein R 7 , A, m, p and q are each as defined in claim 1 ,

R 14 is amino, mono or di(lower)alkylamino, aryl(lower)alkylamino or acylamino,

R 15 is guanidino or acyl guanidino, and

R 16 is saturated 3- to 8-membered heterocyclic group containing 1 to 4 nitrogen atoms optionally substituted by amino, aryl(lower)alkylamino or acylamino,

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 wherein

R 4 is selected from the groups consisting of

wherein

p is 0, 1 or 2,

q is 0 or 1,

R 7 is hydrogen, aryl(lower)alkyl or acyl, and

R 9 is amino, aryl(lower)alkylamino or acylamino,

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 9 wherein

R 7 is hydrogen, lower alkanoyl or lower alkoxycarbonyl; and

R 9 is amino, lower alkanoylamino or lower alkoxycarbonylamino,

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 10 wherein

R 7 is hydrogen or lower alkanoyl; and

R 9 is amino,

or a pharmaceutically acceptable salt thereof.

12. A process for preparing a compound of the formula [I]:

wherein

R 1 is lower alkyl, hydroxy(lower)alkyl or halo(lower)alkyl, and

R 2 is hydrogen, aryl(lower)alkyl or acyl, or

R 1 and R 2 are bonded together and form lower alkylene or lower alkenylene;

R 3 is hydrogen or lower alkyl;

R 4 is

wherein

A is

 wherein X is O or NH,

R 7 is hydrogen, lower alkyl, aryl(lower)alkyl or acyl,

R 8 is hydrogen or hydroxy,

R 9 is amino, mono or di(lower)alkylamino, aryl(lower)alkylamino, acyl amino, guanidino, acyl guanidino or saturated 3- to 8-membered heterocyclic group containing 1 to 4 nitrogen atoms optionally substituted by amino, aryl(lower)alkylamino or acylamino,

k, m, n and q are independently 0 or 1, and

p is 0, 1, 2 or 3;

R 5 is carboxy or an esterfied carboxy; and

R 6 is amino, aryl(lower)alkylamino or acylamino,

or a salt thereof, which comprises

(1) reacting a compound of the formula [II]:

wherein R 1 , R 2 , R 3 and R 4 are each as defined above, or its reactive derivative at the amino group, or a salt thereof with a compound of the formula [III]:

wherein R 5 and R 6 are each as defined above, or its reactive derivative at the carboxy group, or a salt thereof to give a compound of the formula [I]:

wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each as defined above, or a salt thereof, or

(2) subjecting a compound of the formula [Ia]:

wherein R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , A, k, m, n, p and q are each as defined above, and R 9 a is, aryl(lower)alkylamino or acylamino, acylguanidino or saturated 3- to 8-membered heterocyclic group containing 1 to 4 nitrogen atoms substituted by aryl(lower)alkylamino or acylamino, or a salt thereof to elimination reaction of a protecting group on the amino to give a compound of the formula [Ib]:

wherein R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , A, k, m, n, p and q are each as defined above, and R 9 b is amino, guanidino or saturated 3- to 8-membered heterocyclic group containing 1 to 4 nitrogen atoms substituted by amino, or a salt thereof, or

(3) reacting a compound of the formula [VI]:

wherein R 5 and R 6 are each as defined above, R 10 is an esterfied carboxy, and Y is a leaving group, or a salt thereof with a compound of the formula [VII]:

wherein R 1 , R 2 , R 3 and R 4 are each as defined above, or a salt thereof to give a compound of the formula [VIII]:

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 10 are each as defined above, and Z {circle around (−)} is an anion, or a salt thereof, and subjecting the compound of the formula [VIII] or a salt thereof to elimination reaction of the group protecting the esterfied carboxy, to give a compound of the formula [I]:

wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each as defined above, or a salt thereof.

13. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier.

14. A method for treating a bacterial infection comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to human or animals.

15. The compound of claim 1 , which is 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[7-(3-aminopropionamido)-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate.

16. The compound of claim 1 , which is 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[3-amino-4-(3-aminopropionamido)-2-methyl-1-pyrazolio]methyl-3-cephem-4-carboxylate.

17. The compound of claim 1 , which is 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[3-amino-4-(aminoacetyl)amino-2-methyl-1-pyrazolio]methyl-3-cephem-4-carboxylic acid hydrogen sulfate.

18. The compound of claim 1 , which is 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-{3-amino-4-[3-(2-aminoethyl)ureido]-2-methyl-1-pyrazolio}methyl-3-cephem-4-carboxylic acid hydrogen sulfate.

19. The compound of claim 1 , which is 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(3-amino-4-guanidino-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylic acid hydrogen sulfate.