Cephem compounds

A compound of the formula: ##STR1## wherein R.sup.1 is amino or protected amino; R.sup.2 is hydrogen, lower alkyl or hydroxy protective group; R.sup.3 is carboxy or protected carboxy; R.sup.4 is an unsubstituted 5, 6 or 7-membered heteromonocyclic group containing two nitrogen atoms as heteroatoms, and which optionally further contains one oxygen or sulfur atom; or R.sup.4 is said 5, 6 or 7-membered heteromonocyclic group substituted by 1 to 4 groups selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, lower alkylamino, cyclo(lower)alkyl, cyclo(lower)alkenyl, halogen, amino, protected amino, protected hydroxy, cyano, nitro, carboxy, hydroxy(lower)alkyl, amino(lower)alkyl, and carbamoyloxy; and n is 1 or 2.

What we claim is:

1. A compound of the formula: ##STR10##

wherein R.sup.1 is amino or protected amino;

R.sup.2 is hydrogen, lower alkyl or hydroxy protective group;

R.sup.3 is carboxy or protected carboxy;

R.sup.4 is an unsubstituted 5, 6 or 7-membered heteromonocyclic group containing two nitrogen atoms as heteroatoms, and which optionally further contains one oxygen or sulfur atom; or R.sup.4 is said 5, 6 or 7-membered heteromonocyclic group substituted by 1 to 4 groups selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, lower alkylamino, cyclo(lower)alkyl, cyclo(lower)alkenyl, halogen, amino, protected amino, protected hydroxy, cyano, nitro, carboxy, hydroxy(lower)alkyl, amino(lower)alkyl, and carbamoyloxy; and

n is 1 or 2;

or a pharmaceutically acceptable salt thereof, including all geometrical isomers, stereoisomers, solvates or hydrates thereof.

2. The compound of claim 1, wherein

R.sup.4 is said unsubstituted or substituted 5, 6 or 7-membered heteromonocyclic group containing two nitrogen atoms as heteroatoms, which contains one oxygen or sulfur atom, and which is bonded to the adjacent --(CH.sub.2).sub.n group by a carbon atom in the ring.

3. The compound of claim 1, wherein R.sup.4 is said unsubstituted or substituted 5, 6 or 7-membered unsaturated heteromonocyclic ring containing two nitrogen atoms as heteroatoms, which ring is selected from the group consisting of pyrazole, pyrazoline, imidazole, imidazoline, pyrimidine, and a partially hydrogenated compound thereof, pyridazine, and a partially hydrogenated compound thereof, and pyrazine, and a partially hydrogenated compound thereof.

4. The compound of claim 1, wherein R.sup.4 is selected from the group consisting of 1,2,5-thiadiazole, 1,2,4-thiadiazole, 1,2,3-thiadiazole, 6H-1,2,5-thiadiazine and hydrogenated compounds thereof.

5. The compound of claim 1, wherein R.sup.4 is selected from the group consisting of 1,2,3-oxadiazole, 1,2,5-oxadiazole, 1,2,4-oxadiazole, 6H-1,2,5-oxadiazine and hydrogenated compounds thereof.

6. The compound of claim 1, wherein R.sup.4 is selected from the group consisting of pyrazolidine, imidazolidine, piperazine, 1,3-diazacyclohexane and 1,2-diazacyclohexane.

7. The compound of claim 1, wherein R.sup.4 is selected from the group consisting of 4-methyl-1,2,3-thiadiazol-5-yl, pyrazol-4-yl, 1-methylpyrazol-4-yl, 1,2,5-thiadiazol-3-yl, 2-methyl-1,3,4-thiadiazol-5-yl, 3-methyl-1,2,4-thiadiazol-5-yl-imidazol-2-yl, 2-methyl-1,3,4-oxadiazol-5-yl, pyradin-2-yl, pyrimidin-4-yl, pyridazin-3-yl, 1,2,3-thiadiazol-4-yl and 1,2,3-thiadiazol-5-yl.

8. The compound of claim 1, wherein in R.sup.4, said 5,6 or 7-membered heteromonocyclic group is substituted by one to four groups selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, methylamino, ethylamino, cyclopentyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, halogen, amino, protected amino, protected hydroxy, cyano, nitro, carboxy, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, and carbamoyloxy.

9. The compound of claim 1, which is

7.beta.-[2-(2-aminothiazol-4-yl)-2-(Z)-(hydroxyimino)acetamido]-3-[(pyrazol -4-yl)methylthio]-3-cephem-4-carboxylic acid or a pharmaceutically acceptable salt thereof.

10. A process for preparing a compound of the formula: ##STR11##

wherein R.sup.1 is amino or protected amino;

R.sup.2 is hydrogen, lower alkyl or hydroxy protective group;

R.sup.3 is carboxy or protected carboxy;

R.sup.4 is optionally substituted 5, 6 or 7-membered heteromonocyclic group containing two nitrogen atoms as heteroatoms, and which optionally further contains one oxygen or sulfur atom; and

n is 1 or 2,

or pharmaceutically acceptable salt thereof, which comprises

(1) reacting a compound of the formula (II): ##STR12##

wherein R.sup.3, R.sup.4 and n are each defined above, or a reactive compound thereof at the amino group, or a salt thereof with a compound of the formula (III): ##STR13##

wherein R.sup.1 and R.sup.2 are each as defined above, or a reactive compound thereof at the carboxy group, or a salt thereof to give a compound of the formula (I): ##STR14##

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

11. The process of claim 10, wherein said reaction of said compound (II) with said compound (III) is conducted in the presence of a solvent.

12. The process of claim 10, wherein said reactive compound at the amino group of the compound (II) comprises a Schiff's base imino or enamine thereof, a silyl compound thereof or a compound formed by reaction of the compound (II) with phosgene or phosphorus trichloride.

13. The process of claim 10, wherein said reactive compound at the carboxy group of the compound (III) comprises an acid halide, acid anhydride, ester, amide or azide thereof.

14. The process of claim 1, wherein said solvent comprises water, methanol, ethanol, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, pyridine or N,N-dimethylformamide.

15. The process of claim 11, wherein the compound (III) is in free acid form or the salt form thereof, and said reaction is effected in the presence of a condensing agent.

16. A pharmaceutical composition which comprises, as an active ingredient, a compound of claim 1, or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically-acceptable carrier.

17. A method for treating a disease caused by a pathogenic microorganism, which comprises administering an effective amount of one or more compounds of claim 1, or a pharmaceutically acceptable salt thereof to a mammal in need thereof.

18. The method of claim 17, wherein said mammal is human.

19. The method of claim 17, wherein said disease is caused by Gram-negative or Gram-positive bacteria.

20. The method of claim 17, wherein said disease is caused by S. aureus, E. coli or H. influenzae.