Cephem compounds Number:7,129,232 from the United States Patent and Trademark Office (PTO) owispatent

Title: Cephem compounds

Abstract: The present invention relates to a compound of the formula [I]: ##STR00001## wherein R.sup.1 is lower alkyl, hydroxy(lower)alkyl or halo(lower)alkyl, and R.sup.2 is hydrogen or amino protecting group, or R.sup.1 and R.sup.2 are bonded together and form lower alkylene or lower alkenylene; R.sup.3 is hydrogen or lower alkyl; R.sup.4 is ##STR00002## R.sup.5 is carboxy or protected carboxy; and R.sup.6 is amino or protected amino, or a pharmaceutically acceptable salt thereof, a process for preparing a compound of the formula [I], and a pharmaceutical composition comprising a compound of the formula [I] in admixture with a pharmaceutically acceptable carrier.

Patent Number: 7,129,232 Issued on 10/31/2006 to Ohki,   et al.

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Inventors:	Ohki; Hidenori (Osaka, JP), Okuda; Shinya (Osaka, JP), Yamanaka; Toshio (Osaka, JP), Ohgaki; Masaru (Osaka, JP), Toda; Ayako (Osaka, JP), Kawabata; Kohji (Osaka, JP), Inoue; Satoshi (Takata-gun, JP), Misumi; Keiji (Takata-gun, JP), Itoh; Kenji (Takata-gun, JP), Satoh; Kenji (Takata-gun, JP)
Assignee:	Astellas Pharma Inc. (Tokyo, JP) Wakunaga Pharmaceutical Co., Ltd (Osaka, JP)
Appl. No.:	10/695,895
Filed:	October 30, 2003

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Foreign Application Priority Data

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Oct 30, 2002 [AU]			2002952355
Sep 04, 2003 [AU]			2003904813

Current U.S. Class:	514/202 ; 540/222
Current International Class:	C07D 501/46 (20060101); A61K 31/546 (20060101); A61P 31/04 (20060101); C07D 501/38 (20060101)

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References Cited [Referenced By]

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U.S. Patent Documents

	4927818		May 1990		Takaya et al.
	4952578		August 1990		Sakane et al.
	5109130		April 1992		Sakane et al.
	5173485		December 1992		Sakane et al.
	5187160		February 1993		Sakane et al.
	5194432		March 1993		Takaya et al.
	5210080		May 1993		Takaya et al.
	5215982		June 1993		Sakane et al.
	5663163		September 1997		Takaya et al.
	2004/0248875		December 2004		Ohki et al.
	2005/0004094		January 2005		Yamanaka et al.
	2005/0096306		May 2005		Yamanaka et al.

Foreign Patent Documents

	0 047 977		Mar., 1982		EP
	0 771 803		May., 1997		EP
	1 134 222		Sep., 2001		EP
	WO 97/41128		Nov., 1997		WO
	WO 02/090364		Nov., 2002		WO

Other References

Derwent Publications, AN 1992-387716, JP 04-288086, Oct. 13, 1992. cited by other . R. F. Brown, et al., Journal of Medicinal Chemistry, vol. 33, No. 8, pp. 2114-2121, XP-001084083, "Synthesis and Biological Evaluation of a Series of Parenteral 3'-Quaternary Ammonium Cephalosporins.sup.1", 1990. cited by other . K. Sakagami, et al., Chem. Pharm. Bull, vol. 38, No. 8, pp. 2271-2273, XP-001083825, "Synthetic Cephalosporins. VI..sup.1) Synthesis and Antibacterial Activity of 7-[(Z)-2-(2-Aminothiazol-4-YL)-2-(1-Carboxy-1-Methyl)Ethoxyiminoacetamido- ]-3-(3-Hydroxy-4-Pyridon-1-YL)Methyl-3-Cephem-4-Carboxylic Acid and Related Compounds", 1990. cited by other.

Primary Examiner: Berch; Mark L.
Attorney, Agent or Firm: Oblon, Spivak, McClelland, Maier & Neustadt, P.C.

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Claims

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The invention claimed is:

1. A compound of the formula [I]: ##STR00019## wherein R.sup.1 is lower alkyl, hydroxy(lower)alkyl or halo(lower)alkyl, and R.sup.2 is hydrogen, aryl(lower)alkyl or acyl, or R.sup.1 and R.sup.2 are bonded together and form lower alkylene or lower alkenylene; R.sup.3 is hydrogen or lower alkyl; R.sup.4 is ##STR00020## wherein A is ##STR00021## wherein X is O or NH, R.sup.7 is hydrogen, lower alkyl, aryl(lower)alkyl or acyl, R.sup.8 is hydrogen or hydroxy, R.sup.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.sup.5 is carboxy or an esterfied carboxy; and R.sup.6 is amino, aryl(lower)alkylamino or acylamino, or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein R.sup.1 is lower alkyl or hydroxy(lower)alkyl, and R.sup.2 is hydrogen, aryl(lower)alkyl or acyl, or R.sup.1 and R.sup.2 are bonded together and form lower alkylene; R.sup.3 is hydrogen; A is ##STR00022## wherein X is O or NH; R.sup.7 is hydrogen, aryl(lower)alkyl or acyl; R.sup.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.sup.8 is hydrogen, or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 wherein R.sup.1 is lower alkyl, hydroxy(lower)alkyl or halo(lower)alkyl, and R.sup.2 is hydrogen, aryl(lower)alkyl or acyl, or R.sup.1 and R.sup.2 are bonded together and form lower alkylene or lower alkenylene; R.sup.5 is carboxy or esterified carboxy; R.sup.6 is amino or acylamino; R.sup.7 is hydrogen, lower alkyl or acyl; and R.sup.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.sup.1 is lower alkyl or hydroxy(lower)alkyl, and R.sup.2 is hydrogen, aryl(lower)alkyl or acyl, or R.sup.1 and R.sup.2 are bonded together and form lower alkylene; R.sup.5 is carboxy or esterified carboxy; R.sup.6 is amino or acylamino; R.sup.7 is hydrogen or acyl; and R.sup.9 is amino or acylamino, or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5 wherein R.sup.1 is lower alkyl or hydroxy(lower)alkyl, and R.sup.2 is hydrogen, aryl(lower)alkyl, lower alkanoyl or lower alkoxycarbonyl, or R.sup.1 and R.sup.2 are bonded together and form lower alkylene; R.sup.5 is carboxy or lower alkoxycarbonyl; R.sup.6 is amino, lower alkanoylamino or lower alkoxycarbonylamino; R.sup.7 is hydrogen, lower alkanoyl or lower alkoxycarbonyl; and R.sup.9 is amino, lower alkanoylamino or lower alkoxycarbonylamino, or a pharmaceutically acceptable salt thereof.

7. The compound of claim 6 wherein R.sup.1 is lower alkyl or hydroxy(lower)alkyl, and R.sup.2 is hydrogen, or R.sup.1 and R.sup.2 are bonded together and form lower alkylene; R.sup.5 is carboxy; R.sup.6 is amino; R.sup.7 is hydrogen or lower alkanoyl; and R.sup.9 is amino, or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 wherein R.sup.4 is selected from the group consisting of --NH-A-(NH).sub.m--(CH.sub.2).sub.q--(CH.sub.2).sub.p--R.sup.14, ##STR00023## wherein R.sup.7, A, m, p and q are each as defined in claim 1, R.sup.14 is amino, mono or di(lower)alkylamino, aryl(lower)alkylamino or acylamino, R.sup.15 is guanidino or acyl guanidino, and R.sup.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.sup.4 is selected from the groups consisting of ##STR00024## wherein p is 0, 1 or 2, q is 0 or 1, R.sup.7 is hydrogen, aryl(lower)alkyl or acyl, and R.sup.9 is amino, aryl(lower)alkylamino or acylamino, or a pharmaceutically acceptable salt thereof.

10. The compound of claim 9 wherein R.sup.7 is hydrogen, lower alkanoyl or lower alkoxycarbonyl; and R.sup.9 is amino, lower alkanoylamino or lower alkoxycarbonylamino, or a pharmaceutically acceptable salt thereof.

11. The compound of claim 10 wherein R.sup.7 is hydrogen or lower alkanoyl; and R.sup.9 is amino, or a pharmaceutically acceptable salt thereof.

12. A process for preparing a compound of the formula [I]: ##STR00025## wherein R.sup.1 is lower alkyl, hydroxy(lower)alkyl or halo(lower)alkyl, and R.sup.2 is hydrogen, aryl(lower)alkyl or acyl, or R.sup.1 and R.sup.2 are bonded together and form lower alkylene or lower alkenylene; R.sup.3 is hydrogen or lower alkyl; R.sup.4 is ##STR00026## wherein A is ##STR00027## wherein X is O or NH, R.sup.7 is hydrogen, lower alkyl, aryl(lower)alkyl or acyl, R.sup.8 is hydrogen or hydroxy, R.sup.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.sup.5 is carboxy or an esterfied carboxy; and R.sup.6 is amino, aryl(lower)alkylamino or acylamino, or a salt thereof, which comprises (1) reacting a compound of the formula [II]: ##STR00028## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.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]: ##STR00029## wherein R.sup.5 and R.sup.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]: ##STR00030## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are each as defined above, or a salt thereof, or (2) subjecting a compound of the formula [Ia]: ##STR00031## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, R.sup.7, R.sup.8, A, k, m, n, p and q are each as defined above, and R.sup.9a 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]: ##STR00032## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, R.sup.7, R.sup.8, A, k, m, n, p and q are each as defined above, and R.sup.9b 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]: ##STR00033## wherein R.sup.5 and R.sup.6 are each as defined above, R.sup.10 is an esterfied carboxy, and Y is a leaving group, or a salt thereof with a compound of the formula [VII]: ##STR00034## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each as defined above, or a salt thereof to give a compound of the formula [VIII]: ##STR00035## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.10 are each as defined above, and Z.sup.{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]: ##STR00036## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.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 7.beta.-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethox- yimino)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 7.beta.-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethox- yimino)acetamido]-3-[3-amino-4-(3-aminopropionamido)-2-methyl-1-pyrazolio]- methyl-3-cephem-4-carboxylate.

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

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

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

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Description

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TECHNICAL FIELD

The present invention relates to new cephem compounds and pharmaceutically acceptable salts thereof. More particularly, the present invention relates to new cephem compounds and pharmaceutically acceptable salts thereof, which have antimicrobial activities, to processes for preparation thereof, to pharmaceutical composition comprising the same, and to a method for treating infectious diseases in human being and animals.

DISCLOSURE OF INVENTION

One object of the present invention is to provide novel cephem compounds and pharmaceutically acceptable salts thereof, which are highly active against a number of pathogenic microorganisms.

Another object of the present invention is to provide processes for the preparation of said cephem compounds and salts thereof.

A further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said cephem compounds or their pharmaceutically acceptable salts.

Still further object of the present invention is to provide a method for treating infectious diseases caused by pathogenic microorganisms, which comprises administering said cephem compounds to infected human being or animals.

The object cephem compounds of the present invention are novel and can be represented by the following general formula [I]:

##STR00003## wherein R.sup.1 is lower alkyl, hydroxy(lower)alkyl or halo(lower)alkyl, and R.sup.2 is hydrogen or amino protecting group, or R.sup.1 and R.sup.2 are bonded together and form lower alkylene or lower alkenylene; R.sup.3 is hydrogen or lower alkyl; R.sup.4 is

##STR00004## wherein A is

##STR00005## wherein X is O or NH, R.sup.7 is hydrogen, lower alkyl or amino protecting group, R.sup.8 is hydrogen or hydroxy, R.sup.9 is amino, mono or di(lower)alkylamino, protected amino, guanidino, protected guanidino or saturated 3- to 8-membered heterocyclic group containing 1 to 4 nitrogen atoms optionally substituted by amino or protected amino, k, m, n and q are independently 0 or 1, and p is 0, 1, 2 or 3; R.sup.5 is carboxy or protected carboxy; and R.sup.6 is amino or protected amino.

As to the object compound [I], the following points are to be noted.

That is, the object compound [I] includes syn isomer (Z form), anti isomer (E form) and a mixture thereof. Syn isomer (Z form) means one geometrical isomer having the partial structure represented by the following formula:

##STR00006## wherein R.sup.5 and R.sup.6 are each as defined above, and anti isomer (E form) means the other geometrical isomer having the partial structure represented by the following formula:

##STR00007## wherein R.sup.5 and R.sup.6 are each as defined above, and all of such geometrical isomers and mixture thereof are included within the scope of this invention.

In the present specification and claims, the partial structure of these geometrical isomers and mixture thereof are represented for convenience' sake by the following formula:

##STR00008## wherein R.sup.5 and R.sup.6 are each as defined above.

Another point to be noted is that the pyrazolio moiety of the compound [I] can also exist in the tautomeric form, and such tautomeric equilibrium can be represented by the following formula.

##STR00009## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each as defined above.

Both of the above tautomeric isomers are included within the scope of the present invention, and in the present specification and claims, however, the object compound [I] is represented for convenience' sake by one expression of the pyrazolio group of the formula (A).

The cephem compound [I] of the present invention can be prepared by the following processes as illustrated in the following.

##STR00010##

##STR00011##

##STR00012##

##STR00013## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, A, k, m, n, p and q are each as defined above, R.sup.10 is protected carboxy, Y is a leaving group, Z.sup.{circle around (-)} is an anion, R.sup.1a is protected hydroxy(lower)alkyl, R.sup.1b is hydroxy(lower)alkyl, R.sup.9a is protected amino, protected guanidino or saturated 3- to 8-membered heterocyclic group containing 1 to 4 nitrogen atoms substituted by protected amino, and R.sup.9b is amino, guanidino or saturated 3- to 8-membered heterocyclic group containing 1 to 4 nitrogen atoms substituted by amino.

The starting compounds [II] and [VI] can be prepared by the following processes.

##STR00014##

##STR00015## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.10, Y and Z.sup.{circle around (-)} are each as defined above, R.sup.11 is protected amino, R.sup.12 is protected carboxy, and R.sup.13 is amino protecting group or lower alkyl.

The starting compounds [VII] and [XI] or salts thereof can be prepared by the methods disclosed in the Preparations 3 6, 8 47 and 49 102 described later or similar manners thereto.

In the above and subsequent descriptions of this specification, suitable examples of the various definitions are explained in detail as follows.

The term "lower" is used to mean a group having 1 to 6, preferably 1 to 4, carbon atoms, unless otherwise indicated.

Suitable "lower alkyl" and "lower alkyl" moiety in "hydroxy(lower)alkyl", "protected hydroxy(lower)alkyl", "aryl(lower)alkyl", "halo(lower)alkyl" and "mono or di(lower)alkylamino", include straight or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl and hexyl, in which more preferred one is C.sub.1 C.sub.4 alkyl.

Suitable "hydroxy(lower)alkyl" includes hydroxy(C.sub.1 C.sub.6)alkyl such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl and 6-hydroxyhexyl, in which more preferred one is hydroxy(C.sub.1 C.sub.4)alkyl.

Suitable "halo(lower)alkyl" includes straight or branched alkyl having 1 to 6 carbon atoms substituted by 1 to 5 halogen atoms such as chlorine, bromine, iodine and fluorine. Preferred examples of "halo(lower)alkyl" include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, bromomethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloroethyl, 2,2-dichloroethyl, 2,2,2-trichloroethyl, 3-fluoropropyl and 2,2,3,3,3-pentafluoropropyl, in which more preferred one is halo(C.sub.1 C.sub.4) alkyl.

Suitable "mono or di(lower)alkylamino" includes mono or di(C.sub.1 C.sub.6)alkylamino such as methylamino, dimethylamino, ethylamino, diethylamino, N-ethyl-N-methylamino, propylamino, butylamino and N-ethyl-N-propylamino, in which more preferred one is mono or di(C.sub.1 C.sub.4)alkylamino.

Suitable "lower alkylene" formed by R.sup.1 and R.sup.2 includes straight alkylene having 1 to 6, preferably 2 to 4 carbon atoms, such as methylene, ethylene, trimethylene and tetramethylene, in which more preferred one is straight alkylene having 2 or 3 carbon atoms.

Suitable "lower alkenylene" formed by R.sup.1 and R.sup.2 includes straight alkenylene having 2 to 6, preferably 2 to 4 carbon atoms, such as vinylene and propenylene, in which more preferred one is straight alkenylene having 2 or 3 carbon atoms.

Suitable "saturated 3- to 8-membered heterocyclic group containing 1 to 4 nitrogen atoms" includes azetidinyl (e.g., 1-azetidinyl and 3-azetidinyl), pyrrolidinyl (e.g., 1-pyrrolidinyl and 3-pyrrolidinyl), imidazolidinyl (e.g., 1-imidazolidinyl and 4-imidazolidinyl), piperidinyl (e.g., 1-piperidinyl and 4-piperidinyl) and piperazinyl (e.g., 1-piperazinyl), in which more preferred one is saturated 4- to 6-membered heterocyclic group containing 1 to 4 nitrogen atoms.

The saturated 3- to 8-membered heterocyclic group containing 1 to 4 nitrogen atoms is optionally substituted by amino or protected amino. Suitable examples of "saturated 3- to 8-membered heterocyclic group containing 1 to 4 nitrogen atoms optionally substituted by amino or protected amino" include 1-azetidinyl, 3-amino-1-azetidinyl, 3-tert-butoxycarbonylamino-1-azetidinyl, 3-azetidinyl, 1-pyrrolidinyl, 3-amino-1-pyrrolidinyl, 3-tert-butoxycarbonylamino-1-pyrrolidinyl, 3-pyrrolidinyl, 1-piperidinyl, 4-piperidinyl and 1-piperazinyl.

Suitable "aryl" moiety in "aryl(lower)alkyl" includes C.sub.6 C.sub.12 aryl such as phenyl and naphthyl, in which more preferred one is phenyl.

Suitable "aryl(lower)alkyl" includes mono-, di- or triphenyl(lower)alkyl such as benzyl, phenethyl, benzhydryl and trityl.

Suitable "lower alkanoyl" and "lower alkanoyl" moiety in "lower alkanoylamino" include straight or branched alkanoyl having 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and hexanoyl, in which more preferred one is C.sub.1 C.sub.4 alkanoyl.

Suitable "lower alkoxy" moiety in "lower alkoxycarbonyl" and "lower alkoxycarbonylamino" includes straight or branched alkoxy having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, tert-pentyloxy and hexyloxy, in which more preferred one is C.sub.1 C.sub.4 alkoxy.

Suitable "amino protecting group" in "protected amino" includes an acyl group as mentioned below, substituted or unsubstituted aryl(lower)alkylidene [e.g., benzylidene, hydroxybenzylidene, etc.], aryl(lower)alkyl such as mono-, di- or triphenyl(lower)alkyl [e.g., benzyl, phenethyl, benzhydryl, trityl, etc.], and the like.

Suitable "acyl" includes lower alkanoyl [e.g., formyl, acetyl, propionyl, hexanoyl, pivaloyl, etc.], mono(or di or tri)halo(lower)alkanoyl [e.g., chloroacetyl, trifluoroacetyl, etc.], lower alkoxycarbonyl [e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, tert-pentyloxycarbonyl, hexyloxycarbonyl, etc.], carbamoy, aroyl [e.g., benzoyl, toluoyl, naphthoyl, etc.], aryl(lower)alkanoyl [e.g., phenylacetyl, phenylpropionyl, etc.], aryloxycarbonyl [e.g., phenoxycarbonyl, naphthyloxycarbonyl, etc.], aryloxy(lower)alkanoyl [e.g., phenoxyacetyl, phenoxypropionyl, etc.], arylglyoxyloyl [e.g., phenylglyoxyloyl, naphthylglyoxyloyl, etc.], aryl(lower)alkoxycarbonyl which optionally substituted by suitable substituent(s) [e.g., benzyloxycarbonyl, phenethyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc.], and the like.

Preferable examples of "amino protecting group" include aryl(lower)alkyl and acyl, in which more preferred ones are aryl(lower)alkyl, lower alkanoyl and lower alkoxycarbonyl, and particularly preferred ones are mono-, di- or triphenyl(C.sub.1 C.sub.6)alkyl, C.sub.1 C.sub.6 alkanoyl and (C.sub.1 C.sub.6)alkoxycarbonyl.

Preferable examples of "protected amino" include aryl(lower)alkylamino and acylamino, in which more preferred ones are aryl(lower)alkylamino, lower alkanoylamino and lower alkoxycarbonylamino, and particularly preferred ones are mono-, di- or triphenyl(C.sub.1 C.sub.6)alkylamino, C.sub.1 C.sub.6 alkanoylamino and (C.sub.1 C.sub.6)alkoxycarbonylamino.

Preferable examples of "protected guanidino" include acylguanidino (monoacylguanidino and diacylguanidino) such as 2,3-bis[(lower)alkoxycarbonyl]guanidino [e.g., 2,3-bis(tert-butoxycarbonyl)guanidino], in which more preferred one is 2,3-bis[(C.sub.1 C.sub.6)alkoxycarbonyl]guanidino.

Suitable "protected hydroxy" in the "protected hydroxy(lower)alkyl" includes acyloxy group, aryl(lower)alkyloxy group, and the like. Suitable "acyl" moiety in the "acyloxy" includes lower alkanoyl [e.g., formyl, acetyl, propionyl, hexanoyl, pivaloyl, etc.], mono(or di or tri)halo(lower)alkanoyl, [e.g. chloroacetyl, trifluoroacetyl, etc.], lower alkoxycarbonyl, [e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, tert-pentyloxycarbonyl, hexyloxycarbonyl, etc.], carbamoyl, and the like. Suitable "aryl(lower)alkyl" moiety in the "aryl(lower)alkyloxy" includes mono-, di- or triphenyl(lower)alkyl [e.g., benzyl, phenethyl, benzhydryl, trityl, etc.], and the like.

Suitable "protected carboxy" includes esterified carboxy and the like, and concrete examples of esterified carboxy include lower alkoxycarbonyl [e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, 1-cyclopropylethoxycarbonyl, etc.] which may have suitable substituent(s), for example, lower alkanoyloxy(lower)alkoxycarbonyl [e.g., acetoxymethoxycarbonyl, propionyloxymethoxycarbonyl, butyryloxymethoxycarbonyl, valeryloxymethoxycarbonyl, pivaloyloxymethoxycarbonyl, 1-acetoxyethoxycarbonyl, 1-propionyloxyethoxycarbonyl, 2-propionyloxyethoxycarbonyl, hexanoyloxymethoxycarbonyl, etc.], lower alkanesulfonyl(lower)alkoxycarbonyl, [e.g., 2-mesylethoxycarbonyl, etc.] or mono(or di or tri)halo(lower)alkoxycarbonyl [e.g., 2-iodoethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, etc.]; lower alkenyloxycarbonyl [e.g., vinyloxycarbonyl, allyloxycarbonyl, etc.]; lower alkynyloxycarbonyl [e.g., ethynyloxycarbonyl, propynyloxycarbonyl, etc.]; aryl(lower)alkoxycarbonyl which may have suitable substituent(s) [e.g., benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobezyloxycarbonyl, phenethyloxycarbonyl, trityloxycarbonyl, benzhydryloxycarbonyl, bis(methoxyphenyl)methoxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-hydroxy-3,5-di-tert-butylbenzyloxycarbonyl, etc.]; aryloxycarbonyl which may have suitable substituent(s) [e.g., phenoxycarbonyl, 4-chlorophenoxycarbonyl, tolyloxycarbonyl, 4-tert-butylphenoxycarbonyl, xylyloxycarbonyl, mesityloxycarbonyl, cumenyloxycarbonyl, etc.]; and the like.

Preferable examples of "protected carboxy" include lower alkoxycarbonyl and aryl(lower)alkoxycarbonyl which may have suitable substituent(s), in which more preferred one is (C.sub.1 C.sub.6)alkoxycarbonyl.

Suitable "leaving group" includes halogen [e.g., chlorine, bromine, iodine, etc.] or acyloxy such as arylsulfonyloxy [e.g., benzenesulfonyloxy, tosyloxy, etc.], lower alkylsulfonyloxy [e.g., mesyloxy, etc.], lower alkanoyloxy [e.g., acetyloxy, propionyloxy, etc.], and the like.

Suitable "anion" includes formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, chloride, bromide, iodide, sulfate, hydrogen sulfate, phosphate, and the like.

Suitable pharmaceutically acceptable salts of the object compound [I] are conventional non-toxic salts and include, for example, a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt [e.g., sodium salt, potassium salt, etc.], an alkaline earth metal salt [e.g., calcium salt, magnesium salt, etc.], an ammonium salt; a salt with an organic base, for example, an organic amine salt [e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.]; an inorganic acid addition salt [e.g., hydrochloride, hydrobromide, sulfate, hydrogen sulfate, phosphate, etc.]; an organic carboxylic or sulfonic acid addition salt [e.g., formate, acetate, trifluoroacetate, maleate, tartrate, citrate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.]; and a salt with a basic or acidic amino acid [e.g., arginine, aspartic acid, glutamic acid, etc.].

The preferred embodiments of the cephem compound of the present invention represented by the general formula [I] are as follows. (1) The compound of the formula [I] wherein R.sup.1 is lower alkyl or hydroxy(lower)alkyl, and R.sup.2 is hydrogen or amino protecting group, or R.sup.1 and R.sup.2 are bonded together and form lower alkylene; R.sup.3 is hydrogen; A is

##STR00016## wherein X is O or NH; R.sup.7 is hydrogen or amino protecting group; R.sup.9 is amino or protected amino; and p is 0, 1 or 2, or a pharmaceutically acceptable salt thereof. (2) The compound of (1) above wherein R.sup.8 is hydrogen, or a pharmaceutically acceptable salt thereof. (3) The compound of the formula [I] wherein R.sup.1 is lower alkyl, hydroxy(lower)alkyl or halo(lower)alkyl, and R.sup.2 is hydrogen, aryl(lower)alkyl or acyl, or R.sup.1 and R.sup.2 are bonded together and form lower alkylene or lower alkenylene; R.sup.5 is carboxy or esterified carboxy; R.sup.6 is amino or acylamino; R.sup.7 is hydrogen, lower alkyl or acyl; and R.sup.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. (4) The compound of (3) above wherein R.sup.1 is lower alkyl or hydroxy(lower)alkyl, and R.sup.2 is hydrogen, aryl(lower)alkyl or acyl, or R.sup.1 and R.sup.2 are bonded together and form lower alkylene; R.sup.5 is carboxy or esterified carboxy; R.sup.6 is amino or acylamino; R.sup.7 is hydrogen or acyl; and R.sup.9 is amino or acylamino, or a pharmaceutically acceptable salt thereof. (5) The compound of (4) above wherein R.sup.1 is lower alkyl or hydroxy(lower)alkyl, and R.sup.2 is hydrogen, aryl(lower)alkyl, lower alkanoyl or lower alkoxycarbonyl, or R.sup.1 and R.sup.2 are bonded together and form lower alkylene; R.sup.5 is carboxy or lower alkoxycarbonyl; R.sup.6 is amino, lower alkanoylamino or lower alkoxycarbonylamino; R.sup.7 is hydrogen, lower alkanoyl or lower alkoxycarbonyl; and R.sup.9 is amino, lower alkanoylamino or lower alkoxycarbonylamino, or a pharmaceutically acceptable salt thereof. (6) The compound of (5) above wherein R.sup.1 is C.sub.1 C.sub.6 alkyl or hydroxy(C.sub.1 C.sub.6)alkyl, and R.sup.2 is hydrogen, mono-, di- or triphenyl(C.sub.1 C.sub.6)alkyl, C.sub.1 C.sub.6 alkanoyl or (C.sub.1 C.sub.6)alkoxycarbonyl, or R.sup.1 and R.sup.2 are bonded together and form C.sub.1 C.sub.6 alkylene; R.sup.5 is carboxy or (C.sub.1 C.sub.6)alkoxycarbonyl; R.sup.6 is amino, C.sub.1 C.sub.6 alkanoylamino or (C.sub.1 C.sub.6)alkoxycarbonylamino; R.sup.7 is hydrogen, C.sub.1 C.sub.6 alkanoyl or (C.sub.1 C.sub.6)alkoxycarbonyl; and R.sup.9 is amino, C.sub.1 C.sub.6 alkanoylamino or (C.sub.1 C.sub.6)alkoxycarbonylamino, or a pharmaceutically acceptable salt thereof. (7) The compound of (5) above wherein R.sup.1 is lower alkyl or hydroxy(lower)alkyl, and R.sup.2 is hydrogen, or R.sup.1 and R.sup.2 are bonded together and form lower alkylene; R.sup.5 is carboxy; R.sup.6 is amino; R.sup.7 is hydrogen or lower alkanoyl; and R.sup.9 is amino, or a pharmaceutically acceptable salt thereof. (8) The compound of (7) above wherein R.sup.1 is C.sub.1 C.sub.6 alkyl or hydroxy(C.sub.1 C.sub.6)alkyl, and R.sup.2 is hydrogen, or R.sup.1 and R.sup.2 are bonded together and form C.sub.1 C.sub.6 alkylene; R.sup.5 is carboxy; R.sup.6 is amino; R.sup.7 is hydrogen or C.sub.1 C.sub.6 alkanoyl; and R.sup.9 is amino, or a pharmaceutically acceptable salt thereof. (9) The compound of the formula [I] wherein R.sup.4 is selected from the group consisting of --NH-A-(NH).sub.m--(CH.sub.2).sub.q--(CH.sub.2).sub.p--R.sup.14,

##STR00017## wherein R.sup.7, A, m, p and q are each as defined above in the formula [I], R.sup.14 is amino, mono or di(lower)alkylamino or protected amino, R.sup.15 is guanidino or protected guanidino, and R.sup.16 is saturated 3- to 8-membered heterocyclic group containing 1 to 4 nitrogen atoms optionally substituted by amino or protected amino, or a pharmaceutically acceptable salt thereof. (10) The compound of the formula [I] wherein R.sup.4 is selected from the group consisting of

##STR00018## wherein p is 0, 1 or 2, q is 0 or 1, R.sup.7 is hydrogen or amino protecting group, and R.sup.9 is amino or protected amino, or a pharmaceutically acceptable salt thereof. (11) The compound of (10) above wherein R.sup.7 is hydrogen, lower alkanoyl or lower alkoxycarbonyl; and R.sup.9 is amino, lower alkanoylamino or lower alkoxy carbonylamino, or a pharmaceutically acceptable salt thereof. (12) The compound of (11) above wherein R.sup.7 is hydrogen, C.sub.1 C.sub.6 alkanoyl or (C.sub.1 C.sub.6 alkoxycarbonyl; and R.sup.9 is amino, C.sub.1 C.sub.6 alkanoylamino or (C.sub.1 C.sub.6)alkoxycarbonylamino, or a pharmaceutically acceptable salt thereof. (13) The compound of (11) above wherein R.sup.7 is hydrogen or lower alkanoyl; and R.sup.9 is amino, or a pharmaceutically acceptable salt thereof. (14) The compound of (13) above wherein R.sup.7 is hydrogen or C.sub.1 C.sub.6 alkanoyl; and R.sup.9 is amino, or a pharmaceutically acceptable salt thereof.

The processes for preparing the object compound of the present invention are explained in detail in the following.

Process 1

The compound [I] or a salt thereof can be prepared by reacting the compound [II] or its reactive derivative at the amino group, or a salt thereof with the compound [III] or its reactive derivative at the carboxy group, or a salt thereof.

Suitable reactive derivative at the amino group of the compound [II] includes Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound [II] with a carbonyl compound such as aldehyde, ketone and the like; a silyl derivative formed by the reaction of the compound [II] with a silyl compound such as bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide [e.g., N-(trimethylsilyl)acetamide], bis(trimethylsilyl)urea and the like; a derivative formed by the reaction of the compound [II] with phosphorus trichloride or phosgene.

Suitable salts of the compound [II] and its reactive derivative can be referred to the ones as exemplified for the compound [I].

Suitable reactive derivative at the carboxy group of the compound [III] includes an acid halide, an acid anhydride, an activated amide, and an activated ester. A suitable example of the reactive derivatives may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid [e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.], dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, alkanesulfonic acid [e.g., methanesulfonic acid, etc.], aliphatic carboxylic acid [e.g., acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.] and aromatic carboxylic acid [e.g., benzoic acid, etc.]; a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; an activated ester [e.g., cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH.sub.3).sub.2N.sup.+.dbd.CH--] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.]; or an ester with an N-hydroxy compound [e.g., N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxy-1H-benzotriazole, etc.]. These reactive derivatives can optionally be selected from them according to the kind of the compound [III] to be used.

Suitable salts of the compound [III] and its reactive derivative can be referred to the ones as exemplified for the compound [I].

The reaction is usually carried out in a conventional solvent such as water, alcohol [e.g., methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely affect the reaction. These conventional solvents may also be used in a mixture with water.

In this reaction, when the compound [III] is used in free acid form or its salt form, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide; N,N'-diethylcarbodiimide; N,N'-diisopropylcarbodiimide; N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide; N,N'-carbonyl-bis-(2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; thionyl chloride; oxalyl chloride; lower alkyl haloformate [e.g., ethyl chloroformate, isopropyl chloroformate, etc.], triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, etc.; and the like.

The reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, and the like.

The reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.

Process 2

The compound [Ib] or a salt thereof can be prepared by subjecting the compound [Ia] or a salt thereof to elimination reaction of the amino protecting group.

Elimination reaction is carried out in accordance with a conventional method such as hydrolysis and the like.

The hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.

Suitable base includes an inorganic base and an organic base such as an alkali metal [e.g., sodium, potassium, etc.], an alkaline earth metal [e.g., magnesium, calcium, etc.], the hydroxide or carbonate or hydrogencarbonate thereof, trialkylamine [e.g., trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, and the like.

Suitable acid includes an organic acid [e.g., formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.], and an inorganic acid [e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.].

The elimination using Lewis acid such as trihaloacetic acid [e.g., trichloroacetic acid, trifluoroacetic acid, etc.], and the like is preferably carried out in the presence of cation trapping agents [e.g., anisole, phenol, etc.].

The reaction is usually carried out in a solvent such as water, alcohol [e.g., methanol, ethanol, etc.], methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction. A liquid base or acid can be also used as a solvent.

The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.

Process 3-(i)

The compound [VIII] or a salt thereof can be prepared by reacting the compound [VI] or a salt thereof with the compound [VII] or a salt thereof.

Suitable salt of the compounds [VI], [VII] and [VIII] can be referred to the ones as exemplified for the compound [I].

The present reaction may be carried out in a solvent such as water, phosphate buffer, acetone, chloroform, acetonitrile nitrobenzene, methylene chloride, ethylene chloride, formamide, N,N-dimethylformamide, methanol, ethanol, diethyl ether, tetrahydrofuran, dimethyl sulfoxide, or any other organic solvent which does not adversely affect the reaction, preferably in ones having strong polarities. Among the solvents, hydrophilic solvents may be used in a mixture with water. When the compound [VII] is liquid, it can also be used as a solvent.

The reaction is preferably conducted in the presence of a base, for example, an inorganic base such as alkali metal hydroxide, alkali metal carbonate, alkali metal hydrogencarbonate, an organic base such as trialkylamine, and the like.

The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature, under warming or under heating. The present reaction is preferably carried out in the presence of alkali metal halide [e.g., sodium iodide, potassium iodide, etc.], alkali metal thiocyanate [e.g., sodium thiocyanate, potassium thiocyanate, etc.], and the like.

Anion Z.sup.{circle around (-)} may be one derived from a leaving group Y, and it may be converted to other anion by a conventional method.

Process 3-(ii)

The compound [I] or a salt thereof can be prepared by subjecting the compound [VIII] or a salt thereof to elimination reaction of the carboxy protecting group.

Elimination reaction is carried out in similar manner to the reaction in the aforementioned Process 2, and therefore the reagents to be used and reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of Process 2.

Process 4

The compound [Id] or a salt thereof can be prepared by subjecting the compound [Ic] or a salt thereof to elimination reaction of the hydroxy protecting group.

Suitable method of this elimination reaction includes conventional one such as hydrolysis, reduction and the like.

(i) For Hydrolysis

The hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.

Suitable base includes an inorganic base and an organic base such as an alkali metal [e.g., sodium, potassium, etc.], an alkaline earth metal [e.g., magnesium, calcium, etc.], the hydroxide or carbonate or hydrogencarbonate thereof, trialkylamine [e.g., trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, and the like.

Suitable acid includes an organic acid [e.g., formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.], and an inorganic acid [e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.].

The elimination using Lewis acid such as trihaloacetic acid [e.g., trichloroacetic acid, trifluoroacetic acid, etc.] and the like is preferably carried out in the presence of cation trapping agents [e.g., anisole, phenol, etc.].

The reaction is usually carried out in a solvent such as water, alcohol [e.g., methanol, ethanol, etc.], methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction. A liquid base or acid can be also used as a solvent.

The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.

(ii) For Reduction

Reduction is carried out in a conventional manner, including chemical reduction and catalytic reduction.

Suitable reducing reagents to be used in chemical reduction are a combination of a metal [e.g., tin, zinc, iron, etc.] or metallic compound [e.g., chromium chloride, chromium acetate, etc.] and an organic acid or inorganic acid [e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.].

Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts [e.g., platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.], palladium catalysts [e.g., spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.], nickel catalysts [e.g., reduced nickel, nickel oxide, Raney nickel, etc.], cobalt catalysts [e.g., reduced cobalt, Raney cobalt, etc.], iron catalysts [e.g., reduced iron, Raney iron, etc.], copper catalysts [e.g., reduced copper, Raney copper, Ullman copper, etc.] and the like.

The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, N,N-dimethylformamide or a mixture thereof.

Additionally, in case that the above-mentioned acids to be used in chemical reduction are liquid, they can also be used as a solvent.

Further, a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent, and other conventional solvent such as diethyl ether, dioxane, tetrahydrofuran, etc., or a mixture thereof.

The reaction temperature of this reduction is not critical and the reaction is usually carried but under cooling to warming.

When R.sup.6 is protected amino, the amino protecting group in R.sup.6 can be eliminated by a conventional method such as hydrolysis.

Processes A and B for the preparation of the starting compounds are explained in detail in the following.

Process A-(i)

The compound [XII] or a salt thereof can be prepared by reacting the compound [X] or a salt thereof with the compound [XI] or a salt thereof.

This reaction can be carried out in a similar manner to the reaction in the aforementioned Process 3-(i), and therefore the reagents to be used and reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of Process 3-(i).

Process A-(ii)

The compound [II] or a salt thereof can be prepared by subjecting the compound [XII] or a salt thereof to elimination reaction of the amino protecting groups in R.sup.11 and R.sup.13 and the carboxy protecting group in R.sup.12.

This reaction can be carried out in a similar manner to the reaction in the aforementioned Process 2, and therefore the reagents to be used and reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of Process 2.

Process B

The compound [VI] or a salt thereof can be prepared by reacting the compound [XIII] or its reactive derivative at the amino group, or a salt thereof with the compound [XIV] or its reactive derivative at the carboxy group, or a salt thereof.

This reaction can be carried out in a similar manner to the reaction in the aforementioned Process 1, and therefore the reagents to be used and reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of Process 1.

The compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitatipon, and the like.

It is to be noted that the compound [I] and other compounds may include one or more stereoisomer(s) such as optical isomer(s) and geometrical isomer(s) due to asymmetric carbon atom(s) and double bond(s), and all of such isomers and mixtures thereof are included within the scope of this invention.

The object compounds [I] and pharmaceutically acceptable salts thereof include solvates [e.g., enclosure compounds (e.g., hydrate, etc.)].

The object compound [I] and pharmaceutically acceptable salts thereof are novel and exhibit high antimicrobial activity, inhibiting the growth of a wide variety of pathogenic microorganisms including Gram-positive and Gram-negative microorganisms and are useful as antimicrobial agents.

Now in order to show the utility of the object compound [I], the test data on MIC (minimal inhibitory concentration) of a representative compound of this invention are shown in the following.

Test Method

In vitro antibacterial activity was determined by the two-fold agar-plate dilution method as described below.

One loopful of an overnight culture of each test strain in Trypticase-soy broth (10.sup.6 viable cells per ml) was streaked on heart infusion agar (HI-agar) containing graded concentrations of representative test compound, and the minimal inhibitory concentration (MIC) was expressed in .mu.g/ml after incubation at 37.degree. C. for 20 hours.

Test Compound

Compound (a): 7.beta.-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethox- yimino)acetamido]-3-[7-(3-aminopropionamido)-2,3-dihydro-5-(1H-imidazo[1,2- -b]pyrazolio)]methyl-3-cephem-4-carboxylate (Example 3) Compound (b): 7.beta.-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethox- yimino)acetamido]-3-[3-amino-4-(3-aminopropionamido)-2-methyl-1-pyrazolio]- methyl-3-cephem-4-carboxylate (Example 4) Compound (c): 7.beta.-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethox- yimino)acetamido]-3-[3-amino-4-(aminoacetyl)amino-2-methyl-1-pyrazolio]met- hyl-3-cephem-4-carboxylic acid hydrogen sulfate (Example 6) Compound (d): 7.beta.-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethox- yimino)acetamido]-3-{3-amino-4-[3-(2-aminoethyl)ureido]-2-methyl-1-pyrazol- io}methyl-3-cephem-4-carboxylic acid hydrogen sulfate (Example 7) Compound (e): 7.beta.-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methyl- ethoxyimino)acetamido]-3-(3-amino-4-guanidino-2-methyl-1-pyrazolio)methyl-- 3-cephem-4-carboxylic acid hydrogen sulfate (Example 11) Ceftazidime Test Results

TABLE-US-00001 TABLE 1 Test strain Test compound MIC (.mu.g/ml) Pseudomonas (a) 2 aeruginosa (b) 1 FP 1380 (c) 2 (d) 2 (e) 1 Ceftazidime 128

For therapeutic administration, the object compound [I] and pharmaceutically acceptable salts thereof of the present invention are used in the form of a conventional pharmaceutical preparation which contains said compound as an active ingredient, in admixture with pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral or external administration. The pharmaceutical preparations may be in a solid form such as tablet, granule, powder, capsule, or in a liquid form such as solution, suspension, syrup, emulsion, lemonade and the like.

If needed, there may be included in the above preparations auxiliary substances, stabilizing agents, wetting agents and other commonly used additives such as lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, and the like.

While the dosage of the compound [I] may vary from and also depend upon the age, conditions of the patient, a kind of diseases, a kind of the compound [I] to be applied, etc. In general amounts between 1 mg and 4,000 mg or even more per day may be administered to a patient. An average single dose of about 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg or 2000 mg of the object compounds [I] of the present invention may be used in treating diseases infected by pathogenic microorganisms.

The following Preparations and Examples are given for the purpose of illustrating the present invention in more detail.

Preparation 1

To a solution of (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)[(2-tert-butoxy-1,1-dimethyl-2-oxoet- hoxy)imino]ethanoic acid (5 g) in a mixture of tetrahydrofuran (80 ml) and N,N-dimethylformamide (20 ml) was added a solution of sodium bis(trimethylsilyl)amide (8.33 g) in tetrahydrofuran (12 ml), and the mixture was stirred for 15 minutes. To the reaction mixture was added a solution of di-tert-butyl dicarbonate (3.3 g) in tetrahydrofuran (20 ml) under ice-cooling, and the mixture was stirred under ice-cooling for 3 hours. To the reaction mixture was added ethyl acetate, and the mixture was washed with 10% aqueous potassium hydrogen sulfate solution, and then washed with a phosphate buffer (pH 6.86). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with diisopropyl ether and dried in vacuo to give (Z)-2-{5-[(tert-butoxycarbonyl)amino]-1,2,4-thiadiazol-3-yl}[(2-tert-buto- xy-1,1-dimethyl-2-oxoethoxy)imino]ethanoic acid (3.10 g).

IR(KBr) 3191.6, 2981.4, 1714.4, 1550.5, 1153.2, 1000.9 cm.sup.-1

.sup.1H-NMR(DMSO-d.sub.6) .delta. 1.37 (9H, s), 1.45 (6H, s), 1.50 (9H, s), 12.7 (1H, s)

ESI-MS: m/z=429(M-H)

Preparation 2

A mixture of N,N-dimethylformamide (0.648 ml) and phosphoryl chloride (0.781 ml) was stirred at room temperature for 30 minutes. To the mixture were added tetrahydrofuran (4 ml) and (Z)-2-{5-[(tert-butoxycarbonyl)amino]-1,2,4-thiadiazol-3-yl}[(2-tert-buto- xy-1,1-dimethyl-2-oxoethoxy)imino]ethanoic acid (3 g) at 4.degree. C., and the reaction mixture was stirred at room temperature for 1 hour. Meanwhile, a mixture of benzhydryl 7.beta.-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride (3 g) and N-(trimethylsilyl)acetamide (8.72 g) in tetrahydrofuran (15 ml) was warmed to make a clear solution. The solution was then cooled to -20.degree. C. and added to the activated acid solution obtained above. The reaction mixture was stirred at a temperature of -10.degree. C. to 0.degree. C. for 1 hour and poured into a mixture of ethyl acetate and water. The aqueous layer was separated, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo and purified by column chromatography on silica gel eluting with hexane/ethyl acetate (3:2) to give benzhydryl 7.beta.-[(Z)-2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-(1-te- rt-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephem-4- -carboxylate (4.79 g).

IR(KBr) 2981.4, 1793.5, 1720.2, 1524.8, 1371.1, 1247.7, 1151.3 cm.sup.-1

.sup.1H-NMR(DMSO-d.sub.6) .delta. 1.39 (6H, s), 1.48 (3H, s), 1.50 (6H, s), 3.58 (1H, d, J=18.3 Hz), 3.76 (1H, d, J=18.3 Hz), 4.44 (2H, s), 5.29 (1H, d, J=5.0 Hz), 6.01 (1H, dd, J=8.6, 5.0 Hz), 6.97 (1H, s), 7.2 7.6 (10H, m), 9.65 (1H, d, J=5.0 Hz), 12.7 (1H, s)

ESI-MS: m/z=849(M+Na)

Preparation 3

To a solution of 5-amino-1-methylpyrazole (5 g) in ethanol (50 ml) was added isoamyl nitrite (6.92 ml), and then 20% hydrochloric acid (5 drops) was added at 4.degree. C. The reaction mixture was refluxed for 2 hours and cooled to room temperature. To the reaction mixture was added diisopropyl ether (50 ml), and the mixture was stirred for 0.5 hour. The resulting precipitate was collected by filtration and dried in vacuo to give 5-amino-1-methyl-4-nitrosopyrazole (3.53 g).

.sup.1H-NMR(DMSO-d.sub.6) .delta. 3.51 (3H, s), 8.07 (2H, brs), 8.51 (1H, s)

APCI-MS: m/z=127(M+H)

Preparation 4

To a solution of 5-amino-1-methyl-4-nitrosopyrazole (1 g) in water (40 ml) were added concentrated sulfuric acid (0.423 ml) and palladium on carbon (0.3 g) under a hydrogen atmosphere. The mixture was stirred overnight. The reaction mixture was filtered, and the filtrate was evaporated in vacuo. To the residue was added isopropyl alcohol, and the resulting precipitate was collected by filtration to give 4,5-diamino-1-methylpyrazole sulfuric acid salt (1.71 g).

.sup.1H-NMR(DMSO-d.sub.6) .delta. 3.54 (3H, s), 7.19 (1H, s)

ESI-MS: m/z=113(M+H)

Preparation 5

To a suspension of 1,1'-carbonyldiimidazole (9.73 g) in dehydrated chloroform (72 ml) was added tert-butyl N-(2-aminethyl)carbamate (9.61 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added N-ethyldiisopropylamine (14.22 g) and 4,5-diamino-1-methylpyrazole sulfuric acid salt (10.51 g), and the mixture was stirred at 50.degree. C. for 15 hours. The insoluble materials were removed by filtration. To the filtrate were added chloroform (200 ml) and 5% aqueous sodium hydrogen carbonate solution (100 ml). The organic layer was separated, and the aqueous layer was extracted with a mixed solvent of chloroform and methanol (4:1). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with ethyl acetate and dried in vacuo to give 5-amino-4-(3-{2-[(tert-butoxycarbonyl)amino]ethyl}ureido)-1-methylpyrazol- e (14.0 g) as a solid.

.sup.1H-NMR(DMSO-d.sub.6) .delta. 1.38 (9H, s), 2.96 2.98 (2H, m), 3.03 3.07 (2H, m), 3.50 (3H, s), 4.81 (2H, br), 5.92 (1H, br), 6.80 (1H, br), 6.96 (1H, s), 7.18 (1H, br)

EXAMPLE 1

To a solution of benzhydryl 7.beta.-[(Z)-2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-(1-te- rt-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephem-4- -carboxylate (500 mg) in N,N-dimethylformamide (1.0 ml) was added sodium iodide (100 mg), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added a solution of 5-amino-4-(3-{2-[(tert-butoxycarbonyl)amino]ethyl}ureido)-1-methylpyrazol- e (216 mg) in N,N-dimethylformamide (1.0 ml). The whole mixture was stirred at 32.degree. C. for 4 hours. To the resulting reaction mixture were added ethyl acetate (50 ml) and water (50 ml). The aqueous layer was separated, and the organic layer was washed with 10% aqueous sodium trifluoroacetate solution and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to about 5 ml in vacuo. The concentrate was poured into diisopropyl ether (75 ml), and the resulting precipitate was collected by filtration and dried in vacuo. To a solution of the resulting solid in methylene chloride (1.8 ml) were added anisole (0.6 ml) and trifluoroacetic acid (1.2 ml). The resulting solution was stirred at room temperature for 4 hours and poured into diisopropyl ether (80 ml). The resulting precipitate was collected by filtration and dried in vacuo to give a crude product (380 mg), which was purified by preparative high-performance liquid chromatography (HPLC) utilizing ODS column. The eluate containing a desired product was concentrated to about 30 ml in vacuo. The concentrate was adjusted to about pH 3 with concentrated hydrochloric acid and chromatographed on Diaion.RTM. HP-20 (Mitsubishi Chemical Corporation) eluting with 30% aqueous