CA1112237A - Cephem compounds and processes for preparation thereof - Google Patents

Abstract

ABSTRACT

New 7-substituted-3-cephem-4-carboxylic acid derivatives are provided of the formula:

Description

Q~

NEW CEPHEM COMPOUNDS AND
PROCESSES FOR PREPARATI ON THEREOF

This invention relates to new cephem compoundO
More particularly, it relates to new 7-substituted~3-cephem-4-carboxylic acid, its pharmaceu~ically accep~a-ble salt and pharmaceutically acceptable bioprecursor thereof, which have antimicrobial activities and are lS a].so useful as intermediates for preparing other highly potent antimicrobial cephem compounds, and processes for preparation thereof, ~nd to pharmaceutical composi-tlon comprising the same and methods of using the same prophylactically and therapeutically for treatment of infectious diseases in human being and animals.
Accordingly, the objects of this invention are to provide~
new 7-substituted-3-cephem-4-carboxylic acid, its pharmaceutically acceptable salt and pharmaceutically ~5 acceptable bioprecursor thereof9 which exhibit excel-lent antimicrobial activi~ies against a wide variety of ~athogeni~ microorganisms including Gram negative and Gram positive bacteria, processes for preparation of the same9 .30 pharmaceutical composition comprising one of the same as an active ingredient9 and a method of using the same prophylactically and therapeutically for treatment of infectious diseases caused by pathogenic microorganisms in human being and animals.

.

. .
.

'~
, . .

The cephem compounds provided by this invention include the ones represented by the formula N
Rl ~ ~ A-CONH ~ ,S ~ (I) 0~

O ~3 wherein Rl is amino or protected amino, A is lower alkylene which may be substituted with oxo, hydroxy, amino, prot~cted h~dxoxy or protected amino, R is hydrogen, halogen or hydroxy, and R3 is carboxy or functionally modified carboxy, and pharmaceutically acceptable salts and bioprecursors thereof It is to be noted *hat the cephem compounds (I) as illustrated above include a compound useful as an anti-microbial agent and also a compound useful as an inter-; mediate for preparing the other antimicrobial agent, ~o particularly as illustrated below.
The terms and definitions desrribed in this spe-cification are illustrated as follows.
As being wéll known, the 2-amino- or 2-pro*ected amino- thiazolyl group lies in tautomeric relation with the corresponding 2-imino- or 2-protected imino-thiazolinyl group. The tautomerism between the said ~hiazolyl and thiazolinyl groups can be illustrated by the following equilibrium :
N ~ r--- Rl ~ S ~

wherein Rl is amino or protected amino~ and Rl is imino or protected imino.
Accordingly, it is to be understood that both of the said groups are substantially the same, and the ~ . .

" ,: ~

, '7 tautomers consisting of such groups are regardecl as the same compounds, especially in the manufac~uring chemis~ry. Therefore, both of the ~automeric ~orms of the compounds having such groups in ~heir molecule are included in the scope of this invention and de-signated inclusively with one expression ~'2-amn~no-or protected amino- thiazolyl" and represented by the formula: Rl~ ~ (wherein Rl is as defined above) for the S convenient sake throughout this specification.
And further, it is well kno~n that the 3-hydroxy-3-cephem compound having the partial structure of the formula:

~ ~ ~ OH
' R
lies in a tautomeric rèlation with the 3-oxo-cephem compound of the formula:
~0 - S
0~

each of which is referred to as the enol- or keto-tautomer, and that the enol-tautomer,is usually the stabilized one.
Accordingly~ both of the compounds having such tautomeric structures are included within ~he same scope of the compound, and thereore, the structure and nomenclature of such tautomers are expressed inclusively with one expression of ~he stabilized anol tautomer, i.e. "3-hydroxy-3-cephem" compound, ~hroughout this speciication.
In the abo~e and subsequent descriptions of ~his .
.

., , . , . ,: ,.",, , ., ,.,:, i;. .. i." . , ; : -.

: . . , , ' ., . .

specifi.cation, suitable examples and illustratlon of the various definitions which this invention intends to include within the scope thereof are explained in detail as follows.
"Lower alkylene" for A may be straight or branched bivalent hydrocarbon residue such as methylene, ethylene, trimethylene, propylene, ethylethylene, tetramethylene, pentamethylene, l-methylpentamethylene,

2-methylpentamethylene, 3-methylpentamethylene, hexamethylene and the like and more preferable one may be alkylene of 1 ~o 4 carbon atoms and the most pre-ferable one is methylene.
"Lower alkylene substituted with oxo" for A may be referred to as "oxo(lower)alkylene", and particularly it may be oxome~hylene~ oxoethylene, l-oxotrimethylene, 2-oxotrimethylene, 2-oxo*etramethylene, 3-oxopenta-methylene, and the like, and more preferabiy the one having 1 to 4 carbon atoms and the most preferably oxomethylene (namely, carbonyl).
"Lower alkylene substituted with hydroxy" for A may be referred to as "hydroxy(lower)alkylene", and particularly it may be hydroxymethylene, hydroxyethy-lene,;;l-hydroxytrimethylene, 2-hydroxy~rimethylene~ 2-hydroxytetramethylene, 3-hydroxypentamethylene, and the like, more prefsrably the one having 1 to 4 carbon atoms and the most preferably hydToxymethylene.
"Lower alkylene substituted with amino" for A may be referred to as "amino(lower~alkylene", and particu-larly it may be aminomethylene, aminoethylene, 1-aminotrimethylsne, 2-aminotrimethylene, I-amino-3-methyltrimethylene, 2-aminotetramethylene, 3-amino-pentamethylene and the like, more preferably the one having 1 to 4 carbon atoms and the most preferably aminomethylene.
Suitable "protected hydroxy" group in the . .

definition for A may include an acyloxy and hydroxy substituted with a conventional protective group other than khe acyl group (e.g. benzyl, tetrahydropyranyl, etc.). And, suitable acyl moiety in the "acyloxy" as mentioned above can be referred to the same examples of ~'acyl" as illustraked hereinafter for that of "acylamino" for Rl, and preferabie examples of "acyloxy" may be substituted or unsubstituted lower alkanoyloxy, substituted or unsubs~ituted lower alkoxy-carbonyloxy, substituted or unsubs~ituted ar~lower~-- alkanoyloxy, heterocycle~lower)alkanoyloxy and the like.
Suitable "protected amino" group in the defini-tion for A includes the same ones as the "protected amino" for Rl as illustrated in the following.
"Protective group" in the "protected amino" for may be the conventional N-pro~ec~ive group such as substituted or unsubstituted artlower)alkyl (e.g. b~nzyl, benzhydryl, trityl, 4-methoxybenzyl, 3,4-dimethoxybenzy~
etc.), halo(lower~alkyl te.g. trichloromethyl, tri-chloroethyl J tri1uoromethyl, etc.), tetrahydropyranyl 9 substituted phenylthio, substituted alkylidene~ sub-stituted aralkylidene, substi~u~ed cycloalkylidene, acyl J or the like.
Suitable acyl for the protective group may be sub-stituted or unsubstituted lower alkanoyl (e.g. formyl, acetyl, chloroacetyl~ trifluoroacetyl, etc.j, substi-tuted or unsubstituted ar(lower)alkanoyl (e.g. phenyl-acetyl, phenylpropionyl, etc.~, substituted or unsub-- stituted lower alkoxycarbonyl (e.g. me~hoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, l-cyclopropylethoxy~
carbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl, trichloroethoxycarbonyl, 2-pyridyl-methoxycarbonyl J etc.), substituted or unsubstituted ar(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, , .
.

- : .

:; :

- 6 ~ 3 ~

ben~hydryloxycarbonyl, 4-nitrobenzyloxyoarbonyl, etc.), lower cycloalkoxycarbonyl ~e.g. cyclo~e~tyloxycarbonyl, cyclohexyloxyca~bonyl, etc.), 8-quinolyloxycarbonyl, succinyl, phthaloyl, or the like.
And further, the reaction product ~f a silan~
boron-,aluminium-or phosphorus-compound with the amino group may also be included in the protective group.
Suitable examples of such compounds may be trlmethyl-silyl chloride, trimethoxysilyl chloride, boron tri-chloride, butoxyboron dichloride, aluminum trichloride, diethoxy aluminum chloride, phosphorus dibromide, phenylphosphorus dibromide, or ~he like.
"Halogen" for R2 may be chlorine, bromine, iodine or fluorine, and preferred one is chlorine or bromine.
"Functionally modified carboxy" for R3 may be an ester amide or ~he like, and preferably an ester.
Suitable examples of the ester may be alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester) t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester~ heptyl ester, octyl ester, l-cyclopropyl-ethyl ester, etc.); alkenyl ester (e.g. vinyl ester, allyl ester, etc.~; alkynyl es~er (e.g. ethynyl ester, propynyl ester, etc.); alkoxyalkyl ester (e.g.
methoxym~hyl ester, ethoxymethyl ester, isopropoxy-methyl ester, l-methoxyethyl esb~r, l-ethoxyethyl ester, etc.); alkylthioalkyl ester (e.g. methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl es~er, isopropylthiomethyl ester, e~c.); haloalkyl ester (e.g. 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.); alkanoyloxyalkyl ester ~e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, palmitoyloxymethyl ester,et~

. -- - - . .
:. :
:

': ~ ' : ' :
: , - 7 ~ Z~l~

alkanesulfonylalkyl ester (e.g. mesylmethyl ester3 2-mesylethyl ester, etc.); substituted or unsubstituted aralkyl ester ~e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl es~er, 4-hydroxy-3,5-di-t-butylbenzyl ester, etc.); substituted or unsubstituted aryl es~er (e.g. phenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesi~yl ester~ cumenyl ester, salicyl ester, etc.); an ester with a silyl compound such as trialXylsilyl compound, dialkylalkoxysilyl compound or trialkoxysilyl compound, for example, trialkylsilyl ester (e.g. trimethylsilyl ester, triethylsilyl ester, etc.), dialkylalkoxysilyl ester (e.g. dimethylmethoxy-silyl ester, dimethylethoxysilyl ester, diethylmethoxy-silyl ester, etc.) or trialkoxysilyl ester (e.g.
trimethoxysilyl ester, triethoxysilyl ester~ étc.) sr ~he like.
With regard to the terms "protected hydroxy", 'Iprotected amino" and "functionally modified carboxy"
in the above, it is to be understood that these groups bear the meaning not only in synthetic manufacture of the object compound by chemical process(es), but also in physiological and pharmaceutical properties of the object compound per se. That is, in khe meaning of the synth~tiG manufacture, free hydroxy group, free àmino group and/or free carboxy group may be trans-formed into the 'tpr~te~t~d hydro~y", "protected amino"
and/or 'tfunctionally modified carboxy" as mentioned

3~ above before conducting the process~es) for prevent-ing any possible undesired side reaction(s), and the "protected hydroxy", "protected amino" and/or "func-tionally modified carboxy" group in the resultant compound may be transformed into free hydroxy, amino 35 and/or carboYy group after the eac-ion is conducted.

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This will be apparent from the explanation of the processes in the following.
OrL the other hand, in the meaning of the physio-logical and pharmaceutical properties of the object S compound, the compound bearing the "protected hydroxy", "protected amino" and/or "functionally modified carboxy" group is optionally used for improving the properties such as solubility, stability, absorbability, toxicity of the particularly active object compound bearing the free hydroxy, free amino and/or carboxy group.
. Suitable "pharmaceutically acceptable salt" of the object compound ~I) may be co~ventional non-~oxic sal~, and may include a salt with an inorganic base or acid, for example~ a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium sal~, etc.), ammonium salt9 an inorganir acid salt (e.g. hydrochloride, hydrobromide, sulfa~e, phosphate, carbonate, bicarbonate, etc.), a salt with an organic base or acid, for example, an amine salt (e.g. tri-methylamine salt, triethylamine salt, pyridine salt, -procaine salt, picoline salt, dicyclohexylamine salt, - N,N'-idibenzylethylenediamine salt, N-methylglucamine salt, diethanolamine salt, ~riethanolamine salt, tris-~hydroxymethylamino)methane salt, phenethylbenzylamine salt, etc.), an organic carboxylic or sulfonic acid salt (e.g. acetate, maleate, lac~ate, tartrate, mesyl~
ate, benzenesulfonateJ tosylate, etc.~, a basic or acidic amino acid salt (e.g. arginine saIt, aspartic acid salt7 glutamic acid salt, lysine salt, serine sal~
etc.) and the like.
It is well known in the pharmaceutical field that the active drug, when it has any undesired physio-logical and~or pharmaceutical property such as , ,.

- ~ :, , ~. - ~ , ~' `

g ~ 7~i7 solubility, stability, absorbability, etc., is con-verted into modified derivative'thereof for improving such'undesired properties, and then said derivative, upon administration to a patient, exhibits ~he active efficacy by being converted to the parent drug in the body. In this meaning, the term "pharmaceutically acceptable bioprecursor" used thPoughout this specifi-cation is intended to fundamentally mean all of the modified derivatives, which have structural formulae different from ~hose of the active compounds of this invention, but are converted in the body to the a~tive ' comppunds of this invention upon administra~ion, and also to mean the derivatives which are sometimes derived physiologically from the compounds of this invention in the body and exhibit antimicrobial efficacy.
The compound (I) of this' invention can be prepared by processes as shown in the following scheme.

Process A : N-Acylation ,N
H2 ~ S~ R ~S~ (m) 1 ~ ~ A-CON ~ S~
C~ N ~ R _________~ S ~ ~ N ~ ~' . R3 (II) .
Process B: Thiazole ring formation 'X-CH2CO-Al-CON ~ S Rl-e-30~ N ~ R2 I
n3 o~ ~
., (~ .
- Rl ~ ~ ~ R2 (Ib) ' , ~ .

;

Process C: Reductive ormation o-f amino(lower)alkylene R ~ ~ A2-oONH~ 2 .. ~ Rl~ ~ A3-~ ]-~ ~ 2 . R R
~ (Ic~

P~rocess D: Reductive formation of hydroxy(lower)-alkylene Rl ~ A -CONH ~ ~ ~2 agent g Rl~ ~ A -CON ~ 2 R
(Id',) . (Id) Process E: Elimination of amino protective group Rl ~A CONH~ R2 H2N~A-CONH~R2 ) R

Process F: Carboxy formation .
R ~ A CONH ~ ~ R2 - ~ R ~ ~A-CONE ~ ' ~ 2 tIf') (If) wherein Rl, R2, R3 and A are each as defined above, - . ' ':

O X is halogeng Rl is protec*ed amino, R3 is functionally modified car~oxy, A~ is lower alkylene which may be substituted with hyd~oxy amino, protested hydroxy or protected amino, A2 is Iower alkylene substituted with a group of the formula: = N - oR4 wherein R4 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl or cycloalkyl 7 A3 is amino(lower)alkylene, A4 is oxo(lower)alkylene, and A5 is hydroxy~lower)alkylene Process A N-Acylation A compound (I) and i~s salt can be prepared by reacting a 7-amino-3-cephem compound ~II), its reactive derivative at the amino or a salt thereof wi~h a carboxylic acid (III), its reactive deriva~ive at the carboxy or a salt thereof according to a conventional manner of so-called N-acylation reaction well known in ~-lactam chemistry.
Suita~le reactive derivative at the amino group of the compound (II) may include a conventional react-ive derivative as used in a wide variety of amidation ~eaction, for example, isocyanato, isothiocyanato, a derivative formed by the reac*ion of a compound (II~
with a silyl compound (e;g. trimethylsilylacetamidel ~30 bis(trimethylsilyl)acetamide, etc.), with an aldehyde compound (e.g. acetaldehyde, isopentaldehyde, benzalde-hyde, salicylaldehyde7 phenylacetaldehyde, p-nitIo-benzaldehyde, m-chlorobenzaldehyde, p-chlorobenzalde-hyde, hydroxynaphthoaldehyde, furfural, thiophene-3~ carboaldehyde; etc.7 OT the corresponding hydrate, : .. ~ , . .
.::
, . .. . .
-: ' ' ~ , ' .
,:
:
, .

acetal, hemiacetal or enolate thereof), with a ketone~

compound ~e.g. acetone, methyl ethyl keton~, rnethyl isobutyl ketone, acetylacetone, ethyl acetoacetate, etc., or the cor-responding ket~, hemiketal or enolate thereof), wi~h phosphorus compound ~e~g. phosphorus oxychloride~ phospho ~ chloride, etc.), or with a sulfur compound ~e.g. thionyl chloride, etc.) and the like.
Suitable salt of the compound ~II) may be refer-red to the one as exemplified for the compound ~I).
Suitable reactive derivative at the carboxy group of the compound ~III) may include, for example, an acid halide, an acid anhydride, an activated amide9 an activated ester, and the like, and preferably acid halide such as acid chloride or acid bromide; a mixed acid anhydride with an acid such as substituted phos-lS phoric acid (e.g. dialkylphosphoric acid, phenylphos-phoric acid, diphenylphasphoric acid, dibenzylphos-phoric acid, halogenated phosphoric acid, etc.), dialkylphosphorus acid, sulfurous acid, thios~lfuric acid, sul~uric acid, alkylcarbonic acid, aliphakic carboxylic acid (e.g. pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.), aromatic carboxylic acid (e.g. benzoic acid, etc.); a symmetrical acid anhydride; an activated acid amide with imidazole, 4-substituted imidazole, dimethylpyr~zole, triazole or tetrazole; an ac~ivated ester (e.g. cyanomethyl ester, methoxymethyl ester~
dimethylaminomethyl ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, tTichloro-phenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxy-methyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, an es~er with a N-hydroxy compound such as N,N-dimethylhydroxylamine, 1-hydroxy-2-~lH)-pyridone, N~hydroxysuccinimide, ,, .
, . ' , ~ ~'"' ;' , .
:: ' -- 13 ~ ~ ~r N hydroxyph~halimide~ l-hydroxybenzo~riazole, 1~
hydroxy-6-chIorobenzo~riazole, ~tc.~, and ~he like.
~ Suitable salt of the compound (III) may include a salt with an inorganic base such as alkali metal salt te.g. sodium sal~, potassium salt, 0tc.) and an alkaline earth metal salt (e.g. calcium salt~ magnesium salt, etc.), a salt with an organic base such as tertiary amine salt (e.g~ trimethylamine salt, tri-ethylamine salt, N~N-dime~hylaniline salt, pyridine salt, etc.), a salt with an inorganic acid ~e.g.
hydrochloride, hydrobromide, etc.) and the like.
The suitable reactive derivatives of the com~
pounds (II) and (III) can optionally be selec~ed from the above according to th~ kind of the compounds (II) and ~III) to be used practically, and to the reaction conditions.
The reaction is usually carried out in a conven-~ional solvent such as water, acetone, dioxane, acetonitrile, chloro~orm, benzene9 methylene chloride, ~O ethylene chloride, tetrahydrouran, ethyl acetate, N9N-dimethylformamide9 pyridine or any other solvent which does not adversely influence the reaction~ or an opti~nal mixture thereo~
When the acylating agent (III) is used in a form of free acid or salt in this reaction, the reaction is preferably carried out in the presence of a con-densing agent such as a carbodiimide compound (e.g.
N,NI-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide, N,N'-diethyl-carbodiimide, N,N'-diisopropylcarbodiimide, N-ethyl-N'-(3-di.methylaminopropy]3carbodiimide, etc.);
a bisimidazolide compound (e.g. N,N'-carbonylbis(2-- methylimidazole~, etc.), an imine compound (e.g.
pentamethyleneketene-N-cyclohexylimine, ,.; . , ,, , ~ .

- 14 - ~ 2~

diphenylketene-N-cyclohexylimine, ~tc.), an olefinic or acetylenic ether compound (e.g. e~hoxyacetylene, ~-- chIorovinylethyl ether, etc.~, 1-(4-chlorobenzenesul-fonyloxy)-6-chloro-lH-benzotriazole, N-ethylbenzis-oxazolium salt, N-e~hyl-5-phenylisoxazolium-3'-sulfonate, a phosphorus compound (e.g. polyphosphoric acid, ~rialkyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride, phosphorus trichloride, diethylchlorophosphite, orthophenylene chlorophosphite, etc.), thionyl chloride, oxalyl chloride, Vilsmeier reagent prepared by the reaction o dimethylformamide with a halogen compoun~ such as thionyl chloride 9 phosphorus oxychloride, phosgene or the like.
The protective group in the protected amino, and protected hydroxy group of the compound (III) and the functionally modified carboxy group of the compound (II) may occasionally be transformed into free amino, hydroxy and carboxy group respectively in the course of the reaction or post-treatment in this pTocessJ and these cases are included within the scope of this invention.
The object compound (I) and salt thereqf are useful as an antimicrobial agent, and a part thereof can also be used as a s~arting material in the following pro~
cesses.

Process B : Thiazole ring formation The starting compound (IV) and its salt to be used in this - process can be prepared by reacting a compound (II), its reactive derivative at the amino group or a salt thereof with a compound (III'), its reactive deriva~i-ve at the carboxy group or reaction equivalent thereof, as illustrated in the following scheme.

~ r ~ R~

(II) . -. D 1 X- CH2CO-Al - COOH ~I I I t X- CH2CO-Al- CONH~L
o (IV) wherein R2, R3 and X are each as defined above.
Suitable 7'halogen" f~r X may be chlorine, bromine, iodine, and suitable reactive equivalent of the compound (III') may be a combina~ion of diketene and halogen such as chlorine or bromine. The reaction of a compound tII) with a compou~d (III') can be con-ducted substan~ially in the same manner as thP above Process A.
A compound ~Ib) and its salt can be prepared by reacting a compound (IV) or its salt wi~h a ~hiourea sompound (V).
The reaction is usually conducted in a solvent such as water, alcohol (e.g. methanol, ethanol, etc.~, benzene) dimethylformamide, te~rahydrofuran or any other solvent which does not adversely influence the reaction, within a tempera~ure range of an ambien~
temperature to heating.

Process C : Reduc~ire forma~ion of amino~lower)~
_ alkylene .

. , .
- "
:: ,, :, . . ,: , . . .
,. . , ~.
,, " ' '; , A compound (Ic) and its salt can be prepared by reducing a compound (VI) or its sal~, which can be prepared by reacting a compound ~ s reactive derivative at the amino group or a salt thereof with a S compound of the formula:

wherein Rl and A2 are each as de-fined above, its react-ive derivative at the carboxy group or a salt thereof, - in the same manner as the above Process A.
. .The ~eduction in this process may be conducted by a conventional method, for example, catalytic reduction using a conventional catalyst (e.g. Raney nickel) platinum oxide, palladium on carbon, ruthenium on car-bon, rhodium on alumina, copper chromium oxide, etcO);
chemical reduction using a combination of an acid (e.
g. hydrochloric acid, sulfuric acid, formic acid, acetic acid, etc.) and a metal or a metal salt (e.g.
iron, zinc, tin, chromium chloride, chromium acetate, etc.), a combination of a metal or a~ amalgam (e.g.
- sodium, zinc amalgam, sodium amalgam~ aluminum amalgam, etc.) and a solvent (e g. water, methanol, ethanol, etc.), or a reducing agent such as a complex of metal hydride (e.g. sodium borohydride, alkyl-tin-hydride, lithium aluminum hydride, diethyl aluminum hydride 9 etc.); electrolytic reduction or the like. The react-îon conditions such as temperature, pressure, time and solvent can be selec~ed according to the kinds of the starting compound (VI) and the reduction method to be applied.

Process D : Reductive ~ormation of hydroxy(lower)-= .
alkylene A compound (Id) and its sal~ can be prepared by ..
- ~ ;

- 17 ~

reducing a compound (Id') or its salt, which can be preparea by the abo've'Proces's A.
The reduc'tion method of this process may be a conventional one which can be applied for the reduction of oxo group into hydroxy group, and particular of which is substantially the same as t~ose explained in the above Process C.

Process E : Elimina~ion of amino-protective group 10A compound (Ie) and i.ts salt can be prepared by subjecting a compound (Ie') or its salt to elimination reaction of the amino-protective group in the pro-tected amino group for Ra.
The starting compound (Ie') can be prepared, for example, by the above Process A.
The elimination reaction may be çonducted in accordance with a conventional method such as hydro-lysis, reduction (reductive elimination) or the like.
These methods may be selected according to the kind of the amino-protective group ~o be eliminated.
The hydrolysis may include a method using an acid tacidic hydrolysis), a base (basic hydrolysis) or hydrazine, and the like.
Among these methods, hydrolysis using an acid is one of the common and preferable methods or eliminat-ing the amino-protective group such as an acyl group, ~or example, substituted or unsubstituted.lower alkanoyl, substituted or unsubstituted lower alkoxy-carbonyl, substituted or unsubstituted ar(lower)-- 30 alkoxycarbonyl, lower cycloalkoxycarbonyl, substituted phenylthio J .substituted alkylidene, substituted In I
aralkylideneJ substituted cycloalkylidene or the like.
Suitable acid to be used in this acidic hydrolysis may include an organic or inorganic acid such as formic acid, trifluoroacetic acid, benzenesulfonic acid, , ... . .

p-toluenesulfonic acidJ hydrochloric acid, cation-ex`change resin, and the like. Prefera~le acid is the one which can easily be separated out from the react-ion product by a conventional manner such as neutrali-zation or distîllation under reduced pressure, forexample, formic acid, trifluoroacetic acid, hydrochloric acid or the like. The acid suitable for the reaction can be selected in consideratîon of the chemical pro-perty of the starting compound and the product as well as the kind of the pro~ec~ive group to be eliminated.
The acidic hydrolysis can be conducted in the presence or absence of a solvent. Suitable solvent may be a conventional organic solvent, water or a mixture thereof, which does not adversely influence this react-ion. Particularly, when the hydrolysis is conductedwith trifluoroacetic acid, the reaction may be acoele-rated by addition of anisole.
The hydrolysis using a base can be applied for eliminating the protective group such as an acyl group, preferably, for example, haloalkanoyl (e.g. trifluoro-acetyl, etc.) and the like. Suitable base may include, or example, an inorganic base such as alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.),~alkaline earth metal hydroxide (e g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbonate, etc.~, alkali metal bicarbonate ~e.g. sodium bicarbonate, potassium bicarbonate, etc.), alkaline earth metal phosphate (e.g. magnesium phosphate, calcium phosphate, etc.~, alkali metal hydrogen phosphate (e.g. disodium hydro-gen phosphate, dipotassium hydrogen phosphate, etc.), or the like, and an organic base such as alkali metal acetate (e~g. sodium acetate, potassium acetate, etc.), .

~ . ~
- -, .

' - 1 9 ~ ~
trialkylamine ~e.g. trimethylamine, triethylamine, etc.), picoline, N-methylpyrrolidine, N:methylmorpholine~ 1,5-- diazabicyclo~4,3,0]-5-nonene, 1,4-diazabicyclo[2,2,2]-octane, 1,5-diazabicyclo[5,4,0~-7-undeceneanion-exchange resin or the like. The hydrolysis using a base is often carried out in water or a conventional organic solvent or a mixture thereof.
The hydrolysis using hydrazine can be applied for eliminating the protective group such as dibasic acyl, for example, succinyl, phthaloyl or the like.
The reductive elimination can be applied for eli-minating the protective group such as acyl, for example, halo~lower)alkoxycarbonyl ~e~g. trichloroethoxycarbonyl, etc.), substituted or unsubstituted ar(lower)alkoxy-carbonyl (e.g. benzyloxycarbonyl, p-nitrobenzyloxy-carbonyl, etc.), 2-pyridylmethoxycarbonyl, etc., aralkyl ~e.g. benzyl~ benzhydryl 9 trityl, etc.~ and the like. Suitable reduction may include, for example, reduction using an alkali metal borohydride (e.g.
sodium borohydride, etc.~, conventional catalytic hyd~ogenolysis and the like.
And further, the protective group such as halo-tlower)alkoxycarbonyl or 8-quinolyloxycarbonyl can be eliminated by treatment with a heavy metal such as copper, zinc or the like.
The reaction temperature is not critical and may optionally be selected in consideration o-f the chemical property of the starting compound and reaction product as well as the kind of the N-protective group and the method to be applied, and the reaction is preferably carried out under a mild condition such as under cool-ing~ at ambient temperature or slightly elevated tem-perature.
The process includes in its scope the cases that t~e functionally modified carboxy for R3 is .. .. . .. .... . .. . .

, .. . ..
, ;. , .
,; . , - 20 - ~L~

simultaneously txans~ormed into ~he free carboxy group in the course of the above reaction or in ~he post-treatment.
As to this process, it is to be understood that the purpose of this process lies in providing the generally more active compound (Ie) having an amino-thiazolyl group by eliminating the protective group in the protected amino group of the compound (Ie') pre-pared by the other processes as mentioned ab~ve or below.

Process F : Carboxy formation .
This process is to provide a free carboxy compound ~If) or its salt, which generally exhibits higher anti-microbial activity as compared with the corresponding functîonally modified carboxy compound (If').
Accordingly, the meaning of the unc~ionally modified carboxy in the compound (If') lies în mainly synthetic manufacture by chemical process(es) as ~0 illustrated hereinabove.
This process is conducted by transforming the unctionally modified carboxy group of the star~ing compound (I~) into free carboxy group, and the prefer-red functionally modified earboxy for Ra in the eom-pound (If') may be an esterified carboxy group as exem-plified for R3 of the compound (I).
The method to be applied to this process includes conventional ones such as hydrolysis, reduction and the like.
.The method of hydrolysis includes a conventional one using an acid~ base, enzyme or enzymatic preparat-ion, and the like.
Suitable examples of the acid and base are to be ~eferred to those as exemplified ;n the above Process E, and the acidic or basic hydrolysis can be carried , ' , :
, ..

;

- 21 ~ `7 out in a similar manner to that of the Process E.
Suitable enzyme includes an esterase and esterase preparation which exhibits an esterase activity such as a cultured broth of microorganism or processed materials of microorganism, the preparation of animal or plant tissues, or the like, and prefeT-ably a cultured broth of microorganism or processed material thereof.
An esterase to be used in the e~zymatic hydro-lysis may be used not only in a purified state, butalso in a crude state.
. The compound obtained in accordance with the processes as explained above can be isola*ed and purified in a conventional manner.
In case that th0 object compound (I) has free caTboxy and/or ree amino, it may be transformed into its pharmaceutically acceptable salt by a conven-~ional method.
The object compound (I), its pharmaceutically acceptable salt and bioprecursor thersof exhibit high antimicrobial activities inhibiting the growth of a wide variety of pathogenic microorganisms including Gram-positive and Gram-negative bacteria and are useful as antimicrobial agents.
In order to show the utility of the compound (I), the test data of some representative compounds (I) are shown in the following.

In vitro antibacterial activity:
Test Method In vitro antibact0rial activity w s determined by the two-fold agar-pla~e dilution method as descri-bed below.
One loopful of an overnight culture of each test strain in Trypticase-soy broth (lO8 viable cells per 1.
.
.~ ~

- I , .

~ '7 ml.) was streaked on heart infusion agar (HI-agar) con-taining graded concentrations of antibiotics, and the minimal inhibitory concentration ~MIC) was express~d in terms of ~g/ml. after incubation at 37C for 20 hours.

Test_com~ounds No. 1 H N~

COOH

N CH2CONH~S ~
No. 2 H2NIl~ o~LN~oOH

N--CHCONH S
No. 3 H2 J~ SJJ NH2 ~00 HCOOH salt 2 5 No . ~ N CHC011H~ S~ .
H2NI~bH o~ N~J .
COOH .;~

.

..
:, f3;~J

Test ~esults ~IC (~g/mQ) 5 ¦ Compound No. 1 Z 3 4 Salmonella enteritidis 1.56 1.56 3 f 133.13 _. .. _ _ .. .. ._ ! Escherichia coli 3~ 1.56 1.56 0.78 1.56 ..... - - _ .- ~
Klebsiella aerogenes 417 0.1 0.2 0.39 0.78 Proteus mirabilis 520 0.78 0.3g 0.78. 1.56 _ Proteus .
vulgaris 616 12.5 6.25 1.56 12.5 .
For prophylactic and/or therapeutic administrat-ion, the active compound (I) of the present invention is used in the orm 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 pharma-ceutical preparations may be in solid form such as capsule, tablet, dragee, ointment or suppository, or in liquid form such as solution, suspension7 or emul-sion. If needed, there may be included in the above preparations auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and the other commonly used additives.
While the dosage of the compounds may vary from : ,, - '. -: , t ;

,:" ' ; ' :: :: : :

and also depe~d upon the age and conditions of the patient, a kind of disease and a degreé o~ the in-fection, and further a kind of the active compound (I) to be applied, etc., an average single dose of about 50 mg. 9 100 mg., 250 mg. and 500 mg. of the active compound tI) ;s sufficient for treating infectious diseases caused by pathogenic bacteria. In general, the active compound (I) can be adminis~ered in an amount between 1 mg/kg and 100 mg/kg, pref~rably 5 mg/kg and 50 mg/kg.
And urther, it is ~o be noted tha~, among the objeGt compound (I) 5 the compound (Id') and its salt are us~ful as an intermediate or preparing the more active cephalosporin compound o the formula (VI), its nontoxic, pharmaceutically acceptable salt or a bioprecursor thereof.
A compound (VI) and its salt can be prepared by ~eacting a compound (Id') or i~s salt with a compound ~VII) or its salk as illustrated by the ollowing schema:
Rl~ ~ A4-coNH ~ ~ 2 (Id'~

.r R4 - ONH2 ~VII) Rl~ ~ A2-CONH ~ ~ ~VI~

h i Rl R2 R3 R4 A2 ~nd A4 are each as defined above.

.

. . ;. "

22.~7 1~

o The suitable example of the compound (VII) may be hydroxylamine, lower alkoxyamine (e.g. methoxyamine, ethoxyamine, propoxyamine, butoxyamine, etc.), lower alkenyloxyamine (e.g. vinyloxyamine, allyloxyamine, propenyloxyamine, butenyloxyamine, etc.), lower alkynyloxyamine (e.g. ethynyloxyamine, propynyloxy-amine, butynyloxyamine, etc.) or cycloalkoxyamine (e~g. cyclobutoxyamine, cyclopentyloxyamine, cyclo-hexyloxyamine, etc.).
The salt of the compound (VII) may be acid salt such as hydrochloride, hydrobromide, sulfate or the like.
This reaction is usually conducted in a solvent such as water, alcohol or any other solvent which does not adversely influence the reaction~ within a tem-perature range from cooling to heating.
When a salt of the compound (VII) is used, the reaction is preferably conducted in the presence of a base as exemplified in the Process E.
Still further, it is to be noted that, among the object compounds (I), the compounds (Ic) and (Id) and their salts are also useful as intermediates ~or pre-paring the other cephalosporin compounds, which may be prepared by acylating the amino group in the symbol A of the compound (Ic) oresterifying the hydroxy group in the symbol A5 of the compound ~Id), respec-tively. .
The partial structure of the formula~ -CO-of the compound (VI) is intended to mean N
both of the geometric ormula: o-R4 -c- co- -c-co-~-o-R4 R4-~-~

(5) (A) I

, The geomet~y of the form~la (S) is referrea to as "syn"
and another formula (A) is referred to as "anti".
From the view point of struc~ure-activity reIationship, i~ is to be noted that the syn isomer of the compound (VI) tends to be of much higher antimicrobial ac~ivity than the corresponding anti isomer,.and accordingly the syn isomer of the compound (VI) is more preferable antimicrobial agent than the corresponding ~nti isomer in the prophylactic and therapeutic value.
1~ Following examples are given only for explaining this invention in more detail.

.

~ . .

:' : , ~ 30 , ~ 35 , . . .. . .

'' . : ' ., ;

Example l (1) 4-Nitrobenzyl 7-amino-3-cephem-4-carboxylate hydrochloride ~9 g), ~rimethylsilylacetamide (24.81 g3 and bis(trimethylsilyl)acetamide (9 ml) were added to dry ethyl acetate (100 ml) and stirred at 45C for an hour.
On the other hand, phosphoryl chloride (8.4 ml;
was added dropwise to a stirred mixture of dimethyl-formamide ~4.0 ml) and dry ethyl acetate (16.0 ml) under ice cooling, and stirred for a while. To the solution were added ethyl ace~ate (240 ml) and 2-(2-formamido-4-thiazolyl)glyoxylic acid ~5.35 g) gradual-ly at -3C~ and ~he mixture was stirred at the same temperature for 15 minutes. The solution was added dropwise to the solution containing the cephalosporin compound prepared above at -15C and stirred at ~he same temperature for 30 minutes. Water (50 ml) was added to the resultant solution, and the precipitates wsre collected by filtration, washed with water and ~20 dried over phosphorus pentoxide under reduced pressure to give 4-nitrobenzyl 7-E2-formamido-4-thiazolyl)-glyoxyloylaminoJ-3-cephem-4-carboxyla~e ~7.124 g).
The ethyl acetate layer was separated from the filt-rate, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate9 and concentrated under reduced pressure to give the same object compound as abov~ ~1.03 g). Total yield 8.154 I.R. ~mU~oi . 1775, 1725, 1650 cm 1 N.M.R. ~(DMSO-d6, ppm) : 3.66 ~2H, m), 5.17 (lH, d, J=5.2Hz), 5.42 ~2H, s), 5~90 (lH, dd, J=5 2Hz, 7.8Hz), 6.66 (lH, t, J=
5.0Hz), 7.67 (2H, d, J-9Hz), 8.22 (2H, d~ J=9Hz), 8.39 (lH, s), 8.55 (lH, s), .

de ~7 q y k .

, 9.87 (1H, d7 J-7.8Hz) (2) A mixture of 4-nitrobellzyl 7-~2-(2-formamido-~-thiazolyl)glyoxyloylamino]-3-cephem-4-carboxyla~e (3.0 g) methanol (60 ml) and tetrahydrofuran (gQ ml) was 5added to a mixture of 10% palladium-carbon (1.5 g), ace~ic acid ~10 ml) a~d methanol (10 ml) in an a~mos-phere of nitrogen gas, and then subjected to ca~alytic reduction at room temperature under ordinary pressure for 4 hours. Th~ resultant mixture was filtered, and 10the ~iltrate was concentrated under reduced pressure.
The precipitates were collected by filtration, washed with~diisopropyl ether (50 ml) and dried to give powder (I.34 g). A mixture of water (100 ml) and ethyl acetate (100 ml) was added to the powder adjusted to pH 6.0 with 15sodium bicarbonate and the aqueous layer was separated, washed with ethyl acetate and diethyl ether. The re-maining ether was removed of-~ by bubbling with nitrogen gas, and the aqueous solu~ion was adjusted to pH 2.0 with 10% hydrochloric acid. The resultant precipi~ates r 20were collected by filtration and dried over phosphorus pentoxide ~o give 7-[2-(2-formamido-4-thiazolyl)glyoxy-loylamino]-3-cephem~4-carboxylic acid (0.47 g~. The above filtrate was concentrated under reduced pressure, and the residue was pulverized with a mixture of diethyl ~5ether and pekroleum ether. The precipitates were col-lected by filtrationa washed with diethyl ether and petroleum ether and dried under reduced pressure to give the same objective compound tl.l g). Total yi~ld 1.57 g.
I.R. v mUa~ol : 1780, 1670 cm 1 N.M.R- ~(DMS0-d6, ppm) : 3.63 (2H, m, J=4Hz), 5.17 (lH, d, J=5.2Hz), 5.87 (lH, dd9 J=5.2Hz, 8.2Hz)~ 6.53 ~lH, t, J=4Hz), 8.42 (lH, s), 8.59 (lH, s), 9.83 (lH, ., ~. , . . '- .
, . ' ' .

d, J=8.2Hz) ~3) A mixture of conc.hydrochloric ac;d (2.44 g~ and - methanol ~10 ml) was added to a mixture of 7-[~-(2-formamido-4-thiazolyl)glyoxyloylamino]-3-cephem-4-S carboxylic acid (2,44 g) in methanol (40 ml) under ice-cooling, stirred at 20 to 22C for 5 hours and fil-tered, The filtrate was concentra~ed under reduced pressure, and water (100 ml) was added to the residue adjusted to pH 6.5 with sodium bicarbonate with stirring and filtered. The filtrate was washed with ethylacetate) and adjusted to pH 3.5 with 10% hydrochloric acid. The resultant precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 7-[2-(Z-amino-

4-thiazolyl)glyoxyloylamino]-3-cephem-4-carboxylic acid (0.492 g). The filtrate and wash~ngs were subjected to column chromatography on macroporous, non-ionic adsorp-tion resin "Diaion HP-20" tTrademar~, manufactured by Mitsubishi Chemical Industries Ltd.3, washed with water 2Q and eluted with 15~ isopropyl alcohol. The isopropyl alcohol was distilled o~f under reduced pressure and ~he remaining solutio~ was lyophilized to gl~e the same object compound (1.561 g). Total yield 2.053 g.

I.R. v NUa~ol : 1780, 1668 cm 1 N.M.R. ~(D~O, ppm) : 3.57 (2H, m), 5.17 (lH, d, J=4.8Hz), 5.78 ~lH,d, J=4.8Hz), 6.33 (lH, m), 8.26 (lH, s) Example 2 (1) Phosphoryl chloride (0.7 g~ was added to N~N-dimethylformamide (10 ml) at 20C and stirred at 40C
for 30 minutes. 2-(2-Formamidothiazol-4-yl)glyoxylic acid ~0.4 g) was added to the solution at 0 to 5C and stirred for 40 minutes. The solution was added to a solution of 4-nitrobenzyl 7-amino-3-hydroxy-3-cephem--': , ", ,.
, .. , ~ ' ' :

4-carboxyla~e ~0.7 g), trimethylsilylace~amid~ (1.85 g) and bis(trimethylsilyl)acetamide (1.62 g) in ethyl acetate (20 ml) at -20C and stirred at -Z0C for an hour. After adding water (20 ml) to the resultant solution~ the ethyl acetate layer was separated, washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulfate and concentTated in vacuo.
The residue was triturated with diethyl ether to give 4-nitrobenzyl-7-~2-~2-formamidothiazol-4-yl~glyoxyloyl-amino]-3-hydroxy-3-cephem-4-carboxylate ~0.85 g).
I.R. v NaU~ol : 3150, 1770, 1660, 1600 cm l N.M.R. ~(DMSO-d6, ppm) : 3;;58 (2H~As-q, J=18Hz),

5.48 (2H, s), 5.25-5.83 (3H, m), 7.75 ;
(2H, d, J=9Hz), 8.32 (2H, d, ~=9Hz~, 8.58 (lH, s~, 8.63 (lH, s), 9.92 (lH, t, J=8Hz) (2) A mixture o-f 4-nitrobenzyl 7-[2-(2-formamido-thiazol-4-yl)glyoxyloylamino]-3-hydroxy-3-cephem-4-carboxylate (0.7 g) and conc.hydrochloric acid (0.23 g) in methanol (10 ml~ was stirred at room temperature for 3 hours. The sol~ent was evapora~ed in vacuo and the residue was triturated with diisopropyl e~her.
The precipitates wer~ collected by filtra~ion and washed with diisopropyl ether to give 4-nitrobenzyl 1-[2-(2-aminothiazol-4-yl)glyoxyloylamino]-3-hydroxy-3-cephem-4-carboxylate hydrochloride (0.6 g).

I.R. VmaJl : 3300, 1770, 1660, 1630, 1600, 1510 cm ;
N.M.R. ~(DMS0-d6, ppm) : 3.52 (2H, broad s), 5.40 (2H, s), 5.18-5.57 (3H, m), 7.70 (2H,- d, J=9Hz), 8.25 (2H, d, J=9Hz), 8.27 (lH, s), 9.97 (lH, t, J=9Hz) . ~ , . . .
~;

, .~
'1 .

s~3~ 1~
i 31 l Example 3 I
N,N-Dimethylformamide (88 mg) and phosphorus oxy-chloride (184 mg) were mixed to prepare Vilsmeier re- I
agent in a conventional manner, and the resul~ant Vilsmeier reagent was suspended in dry tetrahydrofuran ~10 ml). To the suspension was added 2-(2-formamido-thiazol-4-yl)glyoxylic acid (0.2 g) under ice-cooling with stirring, and the solution was stirred at the .
same temperature for 30 minutes. to prepare the acti- .
vated acid solution. 4-Nitrobenzyl 7-amino-3-chloro- .
3-cephem-4-carboxylate (0.4 g) was dissolved in a solution of trimethylsilylacetamide (1.0 g) in ethyl acetate (100 ml). To the solution was added the : activated acid solution obtained above all at once at -20~C, and the solution was stirred a~ -20 to. -5C for , 1.5 hours. After water and ethyl acetate (50 ml~ were .
`` . added to the resuitan~ solu~ion at -20C, the insoluble 1substance was separated by filtration, washed with !
water and acetone in turn and then dried to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)glyoxyloyl-` amino]-3-chloro-3-cephem-4-carboxylate (0.1 g).

I R v Nu~ol : 3350, 1780, 1730, 1650, 16009 1520 cm N.M.R. ~(~MS0-d6~ ppm) : 3.96 (2H, q, J=18Hz), 5.50 ~2H, s), 5.92 (lH, dd, J=5.8Hz), 7.74 (2H, d, J=9Hz), 8.28 ~2H, d, J=9Hz), 8.48 (lH, s)~ 8.~0 (lH, s), 10.00 (lH, :
d, J=8Hz), 12.63 (lH, broad s) -30 Example 4 (l~ 7-Amino-3-cephem-4-carboxylic acid (2.54 g) was dissolved in a solution of trimethylsilylace~amide (11.7 g) and bis(trimethylsilyl)acetamide (15 ml) in dried ethyl acetate (50 ml). A solu$ion of bromine ~2.43 g) in dried methylene chloride (10 ml) was added .. . .. . .
.
.. .. . .

:.
...

- 32 '~ '7 dropwise to a solution of dike~ene (1.28 g) ;n dried methylene chloride (25 ml~ at -30C over 10 minutes and stirred at the same tempera~ure for 1.5 hours. The solution was added to the above solution containing 7-amino-3-cephem-4-carboxylic acid at -15C over 10 minu- .
tes, and stirred at -15 to-10C for 1.5 hours.
Water (50 ml) was added to the resultant solution. The ethyl acetate layer was separated, and extracted with aqueous solution o sodium bicarbonate. The aqueous extract was adjusted to pH 2.0 wi~h 10% hydrochloric acid and extracted with ethyl acetate. The etbyl acetate extract was washed with water, dried o~er mag-nesium sulfate and concentrated under reduced pressure to give 7-[2-(2-bromoacetyl)acetamido]-3-cephem-4-carboxylic acid ~2.82 g).

I.R. v NaUJol : 17~0, 1660 cm 1 N.M.R. ~(DMSO-d6, ppm) : 3.58 (2H, d, J=4H~), 3.65 t2H, s)~ 4.40 (2H, s), 5.06 (lH, d, J=5Hz), 5.73 (lH, dd, J=8Hz, 5Hz~,

6.50 (lH, t, J~4Hz), 9.08 (lH, d, J=8Hz) ~2) Thiourea (663 mg), sodium bicarbonate (732 mg) and water (20 ml) were added to a stirred solution of

7-[2-(2-bromoacetyl)acetamido]-3-cephem-4-carboxylic acid (2.11 g) in tetrahydrofuran (20 ml) under ice-cooling and stirred at the same temperature for an hour.
Af~er ~he resultant solution was adjusted to pH 400 with dilute hydrochloric acid, the precipita~es were 30 . collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give ~?-[2-(2-amino-4-thiazolyl~acetamido]-3-cephem-4-carboxylic acid (1.01 g). .

I.R, v mUJl : 3550, 3330, 1750, 1670, 16~0 cm 1 N.M.R. ~(DMS0-d6, ppm) : 3.42 ~2H, s), 3.60 (2H, d, J=4Hz), 5.08 (lH, d, J=5Hz), 5.77 ~1 dd, J=8Hzf 5Hz), 6.30 (lH, s), 6.52 (lH, t, J-4Hz), 8.87 (lH, d, J=8Hz~
Example 5 .
(l) 4-Nitrobenzyl 7-amino-3-cephem-4-carboxylate (5 g) was dissolved in a solution of trimethylsilyl- , acetamide (13.8 g) and bis(~rimethylsilyl)acetamide .
(10 ml~ in dry ethyl acetate (50 ml) and stirred at 45C for l.S hours. A solution of bromine (2.88 g~ in .
methylene chloride (7 ml) was added dropwise to a solu-tion of diketene (1.5 g) in methylene chloride (7 ml~
at -40C over 20 minutes and stirred at -30C for 1 hour. The solution obtained thus was added to drop-wi~ to the above solu~ion of 4-ni~robenzyl 7-amino-3-cephem-4-carboxyla~e under cooling at -15~C and then stirred at the same temperature for 30 minutes. Water (50 ml~ was added to ~he resultant solution and ex-tracted with ethyl ace~a~e. The ethyl acetate extract .
was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give oily 4-nitrobenzyl 7-[2-(2-bromoacetyl)acetamido]-3-cephem-4-carboxylate ~6.15 g).

. I.R. v NUaJol : 17~09 1740, 1630 cm 1 N.M.R. ~(DMS0-d6, ppm) : 3.62 (2H, broad s),.
4,37 (2H, s), 5.08 ~lH, d, J=5Hz), 5.40 (2H, s), 5.77-6.05 (m), 6.67 (lH, t, J-5Hz), 7.68, 8.04 (4H, m), J=9Hz)~
9.07 (lH, d, Jz8Hz) (2) Thiourea tl.l3 g), sodium bicarbonate (1.24 g~
,. I

,:

, ` ' ~ ` ' `

` !

and water ~20 ml) were added to a solukion o 4-nitrobenzyl 7-~2-(2-bromoacetyl)acetamido~-'3-'cephem-4-carboxylate ~6.15 g) in te~rahydrofuran (60 ml~ ~ and stirred at room tempcrature for an hour. After con-centratin~ the resultant solution under reduced pres-sure~ the residue was extracted with ethyl ace~ate.
The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The oily residue was subjected to column chromatography on sili'ca gel, and eluted with benzene, a mixture of benzene (1 part) and ethyl acetate (1 part) and then ethyl acetate in turn. The ethyl acetate fractions were collected and concentrated under reduced pressure to give 4-nitrobenzyl 7-[2-~2-amino-4-thiazolyl)-acetamido]-3-cephem-4-carboxylate (1.5 g).

I.R. ~ NuJol : 3350, 1780, 1740, 16809 1610 cm 1 N.M.R. ~(DMSO-d6, ppm) : 3.40 (2H, broad s), ~0 3.6~ (ZH, broad s), 5.12 (lH, d, J=5Hz), 5,43 (2H, s), 5.84 (lH, dd, J=8Hz, 5Hz)~
6.30 (lH, s), 6.70 (lH, broad s), 7.72 (2H, d, J=9Hz), 8.27 (2H, d, J=9Hz),

8.93 (lH, d, J=8Hz) (3) A solution of 4-nitrobenzyl 7-[2-(2-amino-4-thiazolyl)acetamido]-3-cephem-~-carboxylate (1.4 g) in a mixture of methanol ~25 m1) and tetrahydrofuran (60 l ml) was added to a mixture of 10% palladium -on-carbon ¦
(1.7 g), glacial acetic acid (7 ml) and methanol (20 ¦
'30 ml) in an atmosphere of nitrogen. Hydrogen gas was introduced into the mixture and shaken for 8.5 hours at room temperature. After removing the insoluble substance by filtratio~, the iltrate was concen~rated under reduced pressure. The residue was pulverized with diethyl ether, and the resultant substance was .
. .

, dissolved in an aqueous solu~ion of sodium bicarbonate, washed with ethyl acetate and diethyl ether in turn and then the remaining ether was removed by bubbling with nitrogen gas. The resultant solution was adjusted to ! 5 pH 4.5 with dilute hydrochloric acid, subjected to column chromatography on macroporous non-ionic adsorpt-ion resin "Diaion HP-20" (Trademark, manufactured by Mitsubishi Chemical Industries Ltd.), and eluted with 2Q~ isopropyl aicohol. Isopropyl alcohol was distilled of under reduced pressure and the r~maining solu~ion was lyophilized to give 7-[2-(2-amino-4-thiazolyl) acetamido]-3-cephem-4-carboxylic acid (lB5 mg).

I.R. ~Na~l : 3550, 3330, 1750, 1670, 1620 cm 1 N.M.R. l~DMSO-d6, ppm) 3.42 (2H, s), 3.60 ~2H, d, J=4Hz), 5.Q8 (lH, d, J=5Hz), 5.77 (lH, dd, J-8Hz, 5Hz), 6.30 ~lH, s), 6.52 (lH, t, J=4Hz), 8.87 (lH, d, J=8Hz) Example 6 ~1) 7-Amino-3-cephem-4-carboxylic acid (1.7 g) and sodium bicarbonate (2.84 g) were dissolved in a mixture of water (35 ml) and acetone (35 ml). On the other handJ phosphorus oxychloride (1.95 ml) was added drop~
wise to a suspension of 2-~Z-amino-4-thiazolyl)-2-methoxyiminoacetic acid (syn-isomer: 3.42 g) in dry 3thyl acetate (34 ml) over lD minutes at 0 to 6C, and the mixture was stirred at the same temperature for 30 minutes. To the solution was added dropwise a solution of trimethylsilylacetamide (2.39 g) in ethyl aceta~e (5 ml) at 0 to 6C over 20 minutes, and the mixture was stirred for 20 minutes. After phosphorus oxychloride (1.95 ml) was added dropwise to ~he mixture at the above temperature over 10 minutes, the mixture obtained thus was stirred for 30 minutes. And further, - 36 - I .-I
dimethylformamide (1.2~ ml) was added dropwise *o the mixture over 10 minutes at the same temperature and stirred for one hour to gi~e a clear solution. The solution was added dropwise to the solution of 7-amino-3-cephem-4-carboxylic acid at -S to 5C, over 30 i minutes, at pH 6.5 to 7.5, and the reaction mixture i was stirred for one hour a~ the same temperature.
~thyl acetate ~200 ml) was added to the resultan~
solution, and the aqueous layer was separated, washed with methylene chloride, bubbled with nitrogen gas and adjusted topH 4 with acetic acid. The solution was sub-jected to column chromatography on macroporous, non-ionic adsorption resin "Diaion HP-20" (Trade mark:
manufactured by Mitsubishi Chemical Industries Ltd.) and eluted wi~h 20~ aqueous solution of isopropyl alcohol. The eluate was concentrated under reduced pressure and lyophilized to give 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer: 2.0 g) I. R. ~ maxl : 3470, 3280, 3200, 17809 1695 1655, 1622 cm 1 N.M.R. ~(DMSO-d6, ppm) : 3.60 (2H, broad s), 3.84 (3H, s), 5.12 (lH, dd, J=5Hz), 5.84 (lH, dd, J=5.8Hz), 6.52 (lH, broad t), 6.76 (lH, s), 7.26 (2Hj broad s),

9.65 (lH, d, J=8Hz) (2) Zinc powder (4.5 g) was added to a`stirred solution of 7-[2-(2-amino-4-thiazolyl~-2-methoxyimino-acetamido]-3-cephem-4~carboxylic acid (syn isomer :
3 g) in 90~ formic acid ~150 ml) under ice-cooling over 5 minutes, and stirred at the same temperature for 15 minutes. Af~er the resul~an~ solu~ion was filtered and washed with formic acidJ the filtrate . .

, ~, ' ~ , , . .

Z~

and the washings were combined and concentrated under reduced pressure ~o a volume of about 20 ml. The concentrate w~s dissolved in water ~150 ml) and bubbled with hydrogen sulfide gas for 20 minutes under ice-S cooling. The precipitating zinc sulfide was filtered off, and ~he filtra~e was treated with activated - charcoal and lyophilized to give 7-~2-(2-amino-4-thiazolyl)glycinamido]-3-cephem-4-carboxylic acid formate t2.9 g), pale yellow powdera mp~240C.
I.R. v mUaxol : 3330, 32009 3100, 1770, 1690 cm 1 N.M.R. ~(D20; ppm) : 3.42-3.61 (2H, m), 5.03-5.16 (lH, m), 5.19 (lH, s), 5.60 (1/2H, d, J=5Hz), 5.79 (1~2H, d, J=SHz), 6.36 -6.50 tlH, m), 8.32 (lH, s) Example 7 To a stirred solution of 7-E2-(2-amino-4-thiazolyl)glyoxyloylamino]-3-cephem-4-carboxylic aacid (520 mg) in methanol (15 ml) was added sodium boro hydride (100 mg) under ice-cooling, and stirred at the same temperature for 3 hours. Methanol was distilled off under reduced pressu~e from the reaction mixture, and the residue was dissolved in water (3 ml) and adjusted to pH 3 with 6N-hydrochloric acid. The pre-cipitates were collected by iltration, washed with water and dried over phosphorus pentoxide to give 7-~2-(2-amino-4-thiazolyl)-2-hydroxyaretamido~-3-cephem-4-carboxylic acid (290 mg).
I. R. v NmUJol : 1775, 1630 cm 1 N.M.R. ~ (D~O+DMS0-d6, ppm) : 5.03 (lH, s), 5.07 .
~lH, d, J=4.6Hz~, 5.72 (lH, d, J-4.6Hz), 6.49 ~lH, m, J=3.2Hz), 6.67 ~lH, s) .~ .

, .
- :

~ 3~ - ;
:

A solution of 7-L2-~-amino-4-~hiazolyl)glyoxyloyl-amino]-3-cephem-4-carboxylic acid hydrochIoride (I.78 g) in water ~100 ml) was adjusted to pH 6.0 with sodium bicarbonate under ice-cooling with stirring. Sodium acetatc (0.38 g) and methoxylamine hydrochloride (1.37 g) were added to the solution adjusted to pH 7.0 with sQdium bicarbonate and then stirred at 48C for an hour.
The resultant solution was washed with ethyl acetate (200 ml) and diethyl ether ~100 ml) in turn, and then nitrogen gas was bubbled into the solution to remove diethyl ether. The aqueous solution was adjusted to pH 3.5 with 10% hydrochloric acid under ice-cooling with stirring. The precipitates were collected by fil-tration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid ~syn isomer, 120 mg). The mQth~r liquor was subjected to column chromatography on macroporous, nonionic adsorption resin"Diaion HP-20"
(Trademark: manufactured by Mitsubishi Chemical Indust-ries Ltd.) and eluted with 40% aqueous acetone. The eluate was concentrated under reduced pressure, lyo-philized, and then dried over phosphorus pentoxide to give the same object compound (950 mg). Total ~eld 1070 mg.

I R ~ Nu~ol : 3460, 3290, 3150, 17809 1655 1623 cm~l 3Q N.M.R. ~(DMSO-d6, ppm) : 3.60 (2H, broad s), 3.84 (3H, s), 5.12 (lH, d, J=5Hz), 5.84 (lH,d,d, J=5~z`~ 8Hz), 6.52 ~lH, t~, 6.76 (lH, s), 7.26 (2H, broad s), 9.65 ~lH, d~ J=8Hz) .

, ~ .

Example 9 The following compounds may be prepared .in a similar manner to that of Example 8.
(1) 7-[2-~2-a.minothiazol-4-yl~-2-hydroxyimino-5 acetamido]-3-cephem-4-carboxylic acid (syn isomer) I. R~ v NUx~l : 3350-3200; 1770, 1670, 1630 cm 1 N.M.R. ~(DMS0-d6, ppm3 : 3,60 (2H, broad s), 5.10 (lH, d, J=5Hz), 5.83 (lH, dd, J=5Hz, 8Hz)g 6.47 tlH, t, J=4Hz), 6.67 (lH, s), 9.47 (lH, d, J=8Hz) ~2) 7-[2-(2-aminothiazol-4-yl)-2-ethoxyiminoacet-.
amido]-3-cephem-4-carboxylic acid (syn isomer) I. R. v Naxl : 3500, 3300, 3200, 1785, 1625, 1600 cm~
N.M.~. ~(DMS0-d6, ppm) : 1.20 (3H9 t, J=7Hz).
3 57 t2H, m), 4.08 (2H, q, J=7Hz), 5.08 (lH, d, J=5Hz), 5.83. (lH, dd9 J-5Hz, 8Hz), 6.47 (lH, m), 6.73 (lH, s), 7.20 (2H9 m), 9.58 (lH, d, J=8Hz~
(3) 7-[2-(2-aminothiazol-4-yl)-2-propoxyimino-acetamido]-3-cephem-4-carboxylic aeid (syn isomer) ~5 I. R. v NUxl : 3250, 1770, 1650, 1660, 1620 cm 1 N.M.R. ~ (DMS0-d6~ ppm) : 0.93 (3H, t, J~7Hz), 1.67 (2H, sextet, J=7Hz), 3.60 ~2H, m), 4.03 (2H5 t, J-7Hz), 5.13 (lH, diJ~J=5Hz), 5.83 (lH, dd, J-5Hz, 8Hz), 6.48 (2H, t, J=4Hz), 6.70 (lH, s), 7.18 (2H, m), ~.53 ~lH, d, J=8Hz) (4) 7-[2-(2-aminothiazol-4~yl)-2-butoxyiminoacet-35 amido~-3-cephem-4-carboxylic acid (syn isomer) :
.,. . , :

. , . ~
:: .

~ 40 ~

I R ~ NU]ol 3320, 1775~ 1660 cm 1 N.M.R. ~ (DMSO-d6, ppm) ; 0.8~ (3H, ~, J-7Hz), 1.1-1.9 (4H, m~, 3.58 (2H, broad s), 4 05 ~2H, t, J=7Hz), 5.08 (lH, d, J=5Hz), 5.80 (lH, dd, J=5Hz~ 8Hz), 6.44 (lH, o broad s) 7 7.1~ (2H, s), 9 51 (lH, d, J=8Hz) ~5) 7-[2-(2-aminothiazol-4-yl)-2-pentyloxyimino-acetamido]-3-cephem-4-caTboxylic acid (syn isomer).

I. R. v NU]l : 3300, 1775, 1650~ 1540 cm 1 N.M.R. ~ (DMSO-d6, ppm) : 0.6-2.0 (9H9 m), 3.56 (2H, d, J-2Hz), 4.03 (2H, t, J=6Hz), 5.08 ~lH, d, J=5Hz), 5.81 (lH, dd, J35Hz, 8Hz~, 6.46 (lH, t, J=4Hz~, 6069 (lH, s~, 7.20 (2H, s), 9.1S (lH~
d, J=8Hz) (6) 7-[2-(2-aminoakhiazol-4~yl)-2-hexyloxyimino-acetamido~-3-cephem-4-carboxylic acid (syn isomer).

I. R. v Na~l : 32S0, 1760, 1640, 1600 cm 1 N.M.R.~(DMSO-d6, ppm) : 1.88 (3H, m), 1.1 -1.9 (8H, m), 3.60 (2H, m), 4.06 (2H, t, J=6Hz), 5.10 (lH, t, J=5Hz), 5.82 (lH, dd, J=SHz, 8Hz~, 6.46 (lH7 m), 6.70 (lH, s), 7.25 (2H, m), 9.56 tlH, d, J=8Hz) ~7~ 7-~2-(2-aminothiazol-4-yl~-2-allyloxyimino-acetamid~-3-ceph~m-4-carboxylic acid (syn isomer).

I R v NUJol 3300, 17~0, 1660, 1630 cm N.M.R. ~(DMSO-d6, ppm) : 3.67 (2H, d, J=4Hz), .

.
' ~ ' ' ' , " .

4.67 (2H, m), 5.17,(lH~ d, J=5Hz~, 5.25 (lH, m), 5.50 ~lH, m)~ 5.90 ~lH, dd, J-SHz, 8Hz), 6.G3 (lH, m)~ 6,55 (lH9 m), 6.80 (lH, s), 7.50 (2H, m), 9.68 (lH, d, J=8Hz) t8) 0 7-[2-(2-aminothiazol-4-yl)-2-propargyloxyimino-acetamido]-3-cephem-4-carboxylic acid (syn isomer). :

I. R. v Nu~ol 3500, 3300, 1780, 1720, 1660, 1630 cm~l N.M.R. ~(DMSO-d6, ppm) : 3.48 (lH, m)g 3.67 (2H, m), 4.80 (2H, d, J=2Hz), 5.17 (lH9 d, J=5Hz), 5.88 (lH, dd, J=5Hz, 8Hz), 6.55 ~lH, m), 6.~5 (lH, s), 7.33 (2H, m), 9.73 (lH, d, J=8Hz) ~9) 7- ~2- (2-aminothiazol-4-yl~ - 2-cyclohexyloxyimino-acetamido]-3-cephem-4-carboxylic acid (syn isomer) I. R. ~ Na~l : 335-0, 1775~ 1665, 1620, 1540 cm 1 N.M.R. ~ (DMSO-d6, ppm) : 0.8-2.2 (lOH9 m), 3.60 ;(2H, broad s~, 4.04 (lH, m), 5.09 (lH, .
d, J=SHz), 5.83 (lH, dd, J=5Hz, 9Hz), 6.45 (lH, t, J=4Hz), 6.67 (lH, s), 7.19 (2H, s), 9.48 (lH, d, J=9Hz) .
In this disclosure the expression 'such as' is to be understood as meaning 'for example'.
.

.

, , , . ~ ,

Claims (72)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing a compound of the formula:

(I) or a tautomer thereof, wherein R1 is amino or protected amino, A is lower alkylene which may be substituted with oxo, hydroxy, amino, protected amino or protected hydroxy, R2 is hydrogen, halogen or hydroxy, and R3 is carboxy or functionally modified carboxy, provided that when R2 is halogen, then A is lower alkylene which is substituted with oxo, or a pharmaceutically acceptable salt or a pharmaceutically acceptable bioprecursor thereof, which comprises (1) reacting a 7-amino-3-cephem compound of the formula :

(II) wherein R2 and R3 are each as defined above, its reactive derivative at the amino group or its salt, with a carboxylic acid of the formula :

(III) wherein R1 and A are each as defined above, to provide the compound of the formula (I), (2) reacting a compound of the formula :

(IV) wherein R3 is as defined above, A1 is lower alkylene which may be substituted with hydroxy, amino, protected hydroxy or protected amino, R2'is hydrogen or hydroxy, and X is halogen, or its salt with a thiourea compound of the formula:

(V) wherein R1 is as defined above, to provide a compound of the formula:

(Ib) wherein R1, R2', R3 and A1 are each as defined above, or its salt, (3) reacting a compound of the formula :

(VI) wherein R1, R2' and R3 are each as defined above, and A2 is lower alkylene substituted with a group of the formula : =N-O-R4 wherein R4 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl or cycloalkyl, or its salt, with a reducing agent effective to reduce the group of the formula:=N-O-R4 wherein R4 is as defined above to an amino group, to provide a compound of the formula:

(Ic) wherein R1, R2' and R3 are each as defined above, and A3 is lower alkylene substituted with amino, or its salt, (4) reacting a compound of the formula :

(Id') wherein R1, R2' and R3 are each as defined above, and A4 is lower alkylene substituted with oxo, or its salt, with a reducing agent effective to reduce the oxo group to a hydroxy group, to provide a compound of the formula:

(Id) wherein R1, R2' and R3 are each as defined above, and A5 is lower alkylene substituted with hydroxy, or its salt, (5) subjecting a compound of the formula :

(Ie') wherein R2, R3 and A are each as defined above, and R? is protected amino, or its salt, to elimination reaction of the protective group in the protected amino group for R?, by hydrolysis or reduction, to provide a compound of the formula:

(Ie) wherein R2, R3 and A are each as defined above, or its salt, or (6) subjecting a compound of the formula:

(If') wherein R1, R2 and A are each as defined above, and R? is functionally modified carboxy, or its salt, to hydrolysis or reduction, to provide a compound of the formula:

(If) wherein R1, R2 and A are each as defined above, or its salt, and if desired, converting the resulting compound to a pharmaceutically acceptable salt or a pharmaceutically acceptable bioprecursor thereof.

2. A process for preparing the compound of the formula:

(I) wherein R1 is amino or protected amino, A is lower alkylene which may be substituted with oxo, hydroxy, amino, protected hydroxy or protected amino, R2 is hydrogen, halogen or hydroxy, and R3 is carboxy or functionally modified carboxy, provided that when R2 is halogen, the A is lower alkylene which is substituted with oxo, or a pharmaceutically acceptable salt thereof which comprises reacting a compound of the Formula :

(II) wherein R2 and R3 are each as defined above, its reactive derivative at the amino group or its salt, with a compound of the formula :

(III) wherein R1 and A are each as defined above, or its salt, its reactive derivative at the carboxy group or a salt thereof, and if desired converting a free acid or base of formula (I) obtained to a corresponding pharma-ceutically acceptable salt thereof.

3. A process of claim 2, wherein R2 is hydrogen.

4. A process of claim 3, wherein R1 is acylamino, A is lower alkylene substituted with oxo, and R3 is esterified carboxy.

5. A process of claim 4, wherein R1 is formamido, A is carbonyl, in the 4-position of the thiazole ring, and R3 is 4-nitrobenzyloxycarbonyl.

6. A process of claim 2, wherein R2 is halogen.

7. A process of claim 6, wherein R1 is acylamino, A is lower alkylene substituted with oxo, and R3 is esterified carboxy.

8. A process of claim 7, wherein R1 is formamido, A is carbonyl in the 4-position of the thiazole ring, R2 is chlorine, and R3 is 4-nitrobenzyloxycarbonyl.

9. A process of claim 2, wherein R2 is hydroxy.

10. A process of claim 9, wherein R1 is acylamino, A is lower alkylene substituted with oxo, and R3 is esterified carboxy.

11. A process of claim 10, wherein R1 is formamido, A is carbonyl in the 4-position of the thiazole ring and R3 is 4-nitrobenzyloxycarbonyl.

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

(Ib) wherein R1 is amino or protected amino, A1 is lower alkylene which may be substituted with hydroxy, amino, protected hydroxy or protected amino, R2'is hydrogen or hydroxy, and R3 is carboxy or functionally modified carboxy, or a pharmaceutically acceptable salt thereof which comprises reacting a compound of the formula:

(IV) wherein R2', R3 and A1 are each as defined above, and X is halogen, or its salt, with a thiourea compound of the formula:
(V) wherein R1 is as defined above, and when desired con-verting a free acid or base obtained, of formula (Ib) to a corresponding pharmaceutically acceptable salt thereof.

13. A process of claim 12, wherein R2' is hydrogen.

14. A process of claim 13, wherein R1 is amino, A1 is lower alkylene, and R3 is carboxy or esterified carboxy.

15. A process of claim 14, wherein A1 is methylene, R3 is carboxy, and X is bromine.

16. A process of claim 14, wherein A1 is methylene, R3 is 4-nitrobenzyloxycarbonyl, and X is bromine.

17. A process for preparing a compound of the formula:

(Ic) wherein R1 is amino or protected amino, A3 is lower alkylene substituted with amino, R2'is hydrogen or hydroxy, and R3 is carboxy or functionally modified carboxy, or a pharmaceutically acceptable salt thereof which comprises reacting a compound of the formula:

(VI) wherein R1, R2'and R3 are each as defined above, and A2 is lower alkylene substituted with a group of the formula:=N-O-R4 wherein R4 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl or cycloalkyl, or its salt, with a reducing agent effective to reduce the group of the formula:=N-O-R4 wherein R4 is as defined above to an amino group, and, if desired, converting a free acid or base of formula (Ic) obtained to a corresponding pharmaceutically acceptable salt thereof.

18. A process of claim 17, wherein R2' is hydrogen.

19. A process of claim 18, wherein R1 is amino, R3 is carboxy, and R4 is lower alkyl.

20. A process of claim 19, wherein A2 is methoxyiminomethylene in the 4-position of the thiazole ring and A3 is aminomethylene.

21. A process for preparing a compound of the formula:

(Id) wherein R1 is amino or protected amino, A5 is lower alkylene substituted with hydroxy, and R2'is hydrogen or hydroxy, and R3 is carboxy or functionally modified carboxy, or a pharmaceutically acceptable salt thereof which comprises reacting a compound of the formula:

(Id') wherein R1, R2' and R3 are each as defined above, and A4 is lower alkylene substituted with oxo, or its salt, with a reducing agent effective to reduce the oxo group to a hydroxy group, and when desired con-verting a free acid or base obtained of formula (Id) to a corresponding pharmaceutically acceptable salt thereof.

22. A process of claim 21, wherein R2'is hydrogen.

23. A process of claim 22, wherein R1 is amino, and R3 is carboxy.

24. A process of claim 23, wherein A4 is carbonyl in the 4-position of the thiazole ring and A5 is hydroxymethylene.

25. A process for preparing a compound of the formula:

(Ie) wherein A is lower alkylene which may be substituted with oxo, hydroxy, amino, protected hydroxy or protected amino, R2 is hydrogen, halogen or hydroxy, and R3 is carboxy or functionally modified carboxy, provided that when R2 is halogen, then A is lower alkylene substituted with oxo, or a pharmaceutically acceptable salt thereof which comprises subjecting a compound of the formula:

(Ie') wherein R2, R3 and A are each as defined above, and R? is protected amino, or its salt, to elimination reaction of the protective group in the protected amino group for R?, by hydrolysis or reduction.
and when desired converting a free acid or base of ?
formula (Ie) obtained, to a corresponding pharma-ceutically acceptable salt thereof.

26. A process of claim 25, wherein R2 is hydrogen.

27. A process of claim 26, wherein R? is acylamino, A is lower alkylene substituted with oxo, and R3 is carboxy.

28. A process of claim 27, wherein R? is formamido, and A is carbonylin the 4-position of the thiazole ring.

29. A process of claim 25, wherein R2 is hydroxy.

30. A process of claim 29, wherein R? is acylamino, A is lower alkylene substituted with oxo, and R3 is esterified carboxy.

31. A process of claim 30, wherein R? is formamido, A is carbonyl in the 4-position of the thiazole ring and R3 is 4-nitrobenzyloxycarbonyl.

32. A process for preparing a compound of the formula:
(If) wherein R1 is amino or protected amino, A is lower alkylene which may be substituted with oxo, hydroxy, amino, protected hydroxy or protected amino, and R2 is hydrogen, halogen or hydroxy, provided that when R2 is halogen, then A is lower alkylene substituted with oxo, or a pharmaceutically acceptable salt thereof which comprises subjecting a compound of the formula:

(If') wherein R1, R2, and A are each as defined above, and R? is functionally modified carboxy, or its salt, to hydrolysis or reduction; and when desired converting a free acid or base of formula (If) obtained, to a corresponding pharmacuetically acceptable salt thereof.

33. A process of claim 32, wherein R2 is hydrogen.

34. A process of claim 33, wherein R1 is amino or acylamino, A is lower alkylene which may be substituted with oxo, and R? is esterified carboxy.

35. A process of claim 34, wherein R1 is amino, A is methylene in the 4-position of the thiazole ring and R? is 4-nitrobenzyloxycarbonyl.

36. A process of claim 34, wherein R1 is formamido, A is carbonyl in the 4-position of the thiazole ring and R? is 4-nitrobenzyloxycarbonyl.

37. A compound of the formula:

(I) or a tautomer thereof wherein R1, A, R2 and R3 are each as defined in claim 1, or a pharmaceutically acceptable salt or a pharmaceutically acceptable bioprecursor thereof whenever prepared by the process of claim 1, or by an obvious chemical equivalent thereof.

38. A compound of the formula (I), as defined in claim 2, wherein R1, A, R2 and R3 are each as defined in claim 2, or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 2, or by an obvious chemical equivalent thereof.

39. A compound of the formula (I), as defined in claim 2, wherein R1, A, R2 and R3 are each as defined in claim 3, or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 3, or by an obvious chemical equivalent thereof.

40. A compound of the formula (I), as defined in claim 2, wherein R1, A, R2 and R3 are each as defined in claim 4, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 4, or by an obvious chemical equivalent thereof.

41. 4-Nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-glyoxyloylamino]-3-cephem-4-carboxylate, or a pharma-ceutically acceptable salt thereof, whenever prepared by the process of claim 5, or by an obvious chemical equivalent thereof.

42. A compound of the formula (I), as defined in claim 2, wherein R1, A, R2 and R3 are each as defined in claim 6, or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 6, or by an obvious chemical equivalent thereof.

43. A compound of the formula (I), as defined in claim 2, wherein R1, A, R2 and R3 are each as defined in claim 7, or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 7, or by an obvious chemical equivalent thereof.

44. 4-Nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-glyoxyloylamino]-3-chloro-3-cephem-4-carboxylate, or a pharmaceutically acceptable salt thereof, whenever pre-pared by the process of claim 8, or by an obvious chemical equivalent thereof.

45. A compound of the formula (I), as defined in claim 2, wherein R1, A, R2 and R3 are each as defined in claim 9, or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 9, or by an obvious chemical equivalent thereof.

46. A compound of the formula (I), as defined in claim 2, wherein R1, A, R2 and R3 are each as defined in claim 10, or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 10, or by an obvious chemical equivalent thereof.

47. 4-Nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-glyoxyloylamino]-3-hydroxy-3-cephem-4-carboxylate, or a pharmaceutically acceptable salt thereof whenever pre-pared by the process of claim 11, or by an obvious chemical equivalent thereof.

48. A compound of the formula:

(Ib) wherein R1, A1, R2 and R3 are each as defined in claim 12, or a pharmaceutically acceptable salt thereof when-ever prepared by the process of claim 12, or by an obvious chemical equivalent thereof.

49. A compound of the formula (Ib), as defined in claim 12, wherein R1, A1, R2 and R3 are each as defined in claim 13, or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 13, or by an obvious chemical equivalent thereof.

50. A compound of the formula (Ib) as defined in claim 12, wherein R1, A1, R2' and R3 are each as defined in claim 14, or a pharmaceutically acceptable salt there-of whenever prepared by the process of claim 14, or by an obvious chemical equivalent thereof.

51. 7-[2-(2-Aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 15, or by an obvious chemical equivalent thereof.

52. 4-Nitrobenzyl 7-[2-(2-aminothiazol-4-yl)acet-amido]-3-cephem-4-carboxylate, or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 16, or by an obvious chemical equivalent thereof.

53. A compound of the formula:

(IC) wherein R1, A3, R2' and R3 are each as defined in claim 17, or a pharmaceutically acceptable salt thereof when-ever prepared by the process of claim 17, or by an obvious chemical equivalent thereof.

54. A compound of the formula (Ic) as defined in claim 17, wherein R1, A3, R2 and R3 are each as defined in claim 18, or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 18, or by an obvious chemical equivalent thereof.

55. A compound of the formula (Ic) as defined in claim 17, wherein R1, A3, R2' and R3 are each as defined in claim 19, or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 19, or by an obvious chemical equivalent thereof.

56. 7-[2-(2-Aminothiazol-4-yl)glycinamido]-3-cephem-4-carboxylic acid, or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 20, or by an obvious chemical equivalent thereof.

57. A compound of the formula:

(Id) wherein R1, A5, R2' and R3 are each as defined in claim 21, or a pharmaceutically acceptable salt thereof when-ever prepared by the process of claim 21, or by an obvious chemical equivalent thereof.

58. A compound of the formula (Id) as defined in claim 21, wherein R1, A5, R2' and R3 are each as defined in claim 22, or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 22, or by an obvious chemical equivalent thereof.

59. A compound of the formula (Id) as defined in claim 21, wherein R1, A5, R2' and R3 are each as defined in claim 23, or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 23, or by an obvious chemical equivalent thereof.

60. 7-[2-(2-Aminothiazol-4-yl)-2-hydroxyacetamido]-3-cephem-4-carboxylic acid, or a pharmaceutically accept-able salt thereof whenever prepared by the process of claim 24, or by an obvious chemical equivalent thereof.

61. A compound of the formula:

(Ie) wherein A, R2 and R3 are each as defined in claim 25, or a pharmaceutically acceptable salt thereof whenever pre-pared by the process of claim 25, or by an obvious chemical equivalent thereof.

62. A compound of the formula (Ie) as defined in claim 25, wherein A, R2 and R3 are each as defined in claim 26, or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 26, or by an obvious chemical equivalent thereof.

63. A compound of the formula (Ie) as defined in claim 25, wherein A, R2 and R are each as defined in claim 27, or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 27, or by an obvious chemical equivalent thereof.

64. 7-[2-(2-Aminothiazol-4-yl)glyoxyloylamino]-3-cephem-4-carboxylic acid, or a pharmaceutically accept-able salt thereof whenever prepared by the process of claim 28, or by an obvious chemical equivalent thereof.

65. A compound of the formula (Ie) as defined in claim 25, wherein A, R2 and R3 are each as defined in claim 29, or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 29, or by an obvious chemical equivalent thereof.

66. A compound of the formula (Ie) as defined in claim 25, wherein A, R2 and R3 are each as defined in claim 30, or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 30, or by an obvious chemical equivalent thereof.

67. 4-Nitrobenzyl 7-[2-(2-aminothiazol-4-yl)glyoxyloyl amino]-3-hydroxy-3-cephem-4-carboxylate, or a pharma-cuetically acceptable salt thereof whenever prepared by the process of claim 31, or by an obvious chemical equivalent thereof.

68. A compound of the formula:

(If) wherein R1, A and R2 are each as defined in claim 32, or a pharmaceutically acceptable salt thereof whenever pre-pared by the process of claim 32, or by an obvious chemical equivalent thereof.

69. A compound of the formula (If), as defined in claim 32, wherein R1, A and R2 are each as defined in claim 33, or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 33, or by an obvious chemical equivalent thereof.

70. A compound of the formula (If), as defined in claim 32, wherein R1, A and R2 are each as defined in claim 34, or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 34, or by an obvious chemical equivalent thereof.

71. 7 [2-(2-Aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, or a pharmaceutically accept-able salt thereof whenever prepared by the process of claim 35, or by an obvious chemical equivalent thereof.

72. 7-[2-(2-Formamidothiazol-4-yl)glyoxyloylamino]-3-cephem-4-carboxylic acid, or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 36, or by an obvious chemical equivalent thereof.