CH643266A5 - 3,7-Disubstituted 3-cephem-4-carboxylic acids and esters thereof, processes for their preparation and pharmaceuticals containing them - Google Patents

Description

The invention relates to new 3,7-disubstituted 3-cephem-4-carboxylic acids and esters and their salts, in particular their pharmaceutically acceptable salts which have antibacterial activities, processes for their preparation and pharmaceutical compositions containing them for the treatment of infectious diseases in humans and animals.

The 3,7-disubstituted 3-cephem-4-carboxylic acid compounds forming a subject of the invention are new and are represented by the general formula:

r4

l3 (I)

20th

in which mean:

R1 amino, acylamino or aryl (lower) alkylamino, R3 carboxy or esterified carboxy,

R2 isobutyl and R4 acetoxy or

R2 cyclo (lower) alkyl or lower alkynyl and R4 lower alkanoyloxy or

R2 lower alkyl and R4 (Cs-C6) alkanoyloxy or R2 (C2-C6) alkyl, lower alkenyl, cyclo (lower) alkyl or lower alkynyl and R4 is hydrogen, carbamoyloxy, thiadiazolylthio, which can be substituted by a lower alkyl, or triazolylthio or

R2 (C2-Cô) alkyl, cyclo (lower) alkyl or lower alkynyl and R4 tetrazolylthio substituted by a methyl radical, or

R2 lower alkyl, lower alkenyl; Cyclo (lower) alkyI or lower alkynyl and R4 aroyloxy, which may be substituted by nitro or amino, cyclo (lower) alkanecarbonyloxy, carbamoyloxy, substituted by an aryl radical, which in turn may be substituted by halogen, aryl (lower) alkanoyloxy , Aryloxy (lower) alkanoyloxy with lower alkoxy, thenoyloxy, tetrazolylthio with a (C3-Co) alkyl, or benzothiazolylthio.

The compounds of formula (I) are prepared by methods 1 to 4 described below.

Procedure 1

+ R ^ Xx-COOH R ^^ Ç-CONH- »^

lo v-Zll \ g 'N *

ÌR2 °

IN-

Procedure 2

S "N

L2

Nn ^ ~ CH2-R

(XI)

(DI)

(X)

or certain reactive or a derivative at the reactive

Amino group or a salt functional derivative or a salt thereof thereof on the

Carboxy group or a salt thereof r1 ¥> s-co®rr \ 4

In 20 \

R

Elimination of the amino protection group>

(la)

or a salt of it

Ho

(Ib)

or a salt of it

643 266

8th

Procedure 3

> T \ c ts /

con h de)

ri / -V, _CÛNH-

ch - r

2 elimination of carboxy protection

flEüfiRS v jj r

$ 2 0

OR

COOH

or a salt of it

Procedure 4

CV

ri € ^ (rcoa, TTs

N A Y N

l 2a 0 ^ NY ^ "ÔR2 fS

"egg

or a salt of it

CHjR

4a

reduction

^> r "Tß-

(! £)

or a salt thereof ch „-r

S n N * <j <w2 "

OR ^ a 0 I,

R

Where R1, R2, R3 and R4 each have the meanings given above,

4b Rla acylamino,

R3a esterified carboxy,

R2a lower alkyl, lower alkenyl, cyclo (lower) alkyl 45 or lower alkynyl,

R4a is aroyloxy with one or more nitro groups and R4b aroyloxy with one or more amino groups.

Among the starting compounds, some of the compound 5o fertilizers (III) are new, and they can be prepared by methods represented by the following reaction scheme:

CD

au-co-c-z> ch3-co-c-z

*!,

5 i_2

OH OR halogenation ^

(iv) CV)

Y-CH0CO-C-Z * • il N

1 2 OR

(VI)

H ~ N-C-NH 2 n 2 S

H

N TT-C-Z

V N

1 OR2

(VII)

643 266

C-COOH

Amino preservatives

(Illa)

(Illa1)

(2)

M

COCOOH

R O-NHo ox) 1

or a salt of it

^ rì ^ -c-cooh

Ór2

(VIII)

where R1, Rla and R2 each have the meanings given above,

Z is protected carboxy and Y is halogen.

(HI)

Some of the other starting compounds (II) are also new and can be prepared by methods which are explained below:

(1)

C6H13NH2

CS.

^ C6H13NHCS-SH

R ° - Y '

CXI)

(X)

or a salt of it

643 266

10th

X-n.

c6h13nhcs-sr

5 uni)

(XII)

C6H13

(2)

or a salt of it

"TO-

ch2-r ° +

HS

N-N

■ N

r *

'7

R

(XIV)

CXV)

or a salt thereof or a salt thereof

H2N-

'3

f «

ch2-s—

r

(Ha)

or a salt of it

(3)

rla-i

r3

ch2oh

ch20r

4c

R

(XVI)

(XVII)

643 266

oxidation

R

la

J \ ^ - CH2-0-R4c reduction ^

0

R3

(XVIII)

CH2-0-R '

4c

Elimination of

Amino protection

group

">

H2NT ~ r 1 4c y n ^ -ch2-O-R4c o T

R '

(XIX)

(IIb)

in which Rla and R3 each have the meanings given above,

Y 'an acid residue,

R5 lower alkyl,

X is an alkali metal,

R6 is a group which can be substituted by a group of the formula

N-N

• N

^ 7 R

R "(Ci-Csjalkyl and

R4c is carbamoyl with an aryl which can be substituted by halogen, aryloxy (lower) alkanoyl with lower alkoxy, thenoyl, cyclo (lower) alkane carbonyl or aroyl with nitro.

With regard to the compounds of the formulas (I), (Ib), (Id) and (If) according to the invention and the starting compounds of the formulas (la), (le), (Ie), (III), (Illa), (Illa ') , (VII) and (VIII) applies that these compounds according to the invention and these starting compounds also include the tautomeric isomers with respect to their thiazole groups. That is, if the group of the formula

(in which R1 has the meanings given above) in the formula of these compounds according to the invention and of these starting compounds the formula (A) given below

N "3,

i J1 T

R1 \

where R1 has the meanings given above), 30 this group of the formula

VT

35

alternatively also by their tautomeric formula (B)

40

Rib ^ y

(where Rlb represents imino or protected imino). This means that both group (A) and group (B) are in the equilibrium state as so-called 45 tautomeric forms, which can be represented by the following reaction equilibrium:

JCf

R. S (A)

H / N3X-

(B)

55

(wherein R1 and Rlb each have the meanings given above).

These types of tautomerism between 2-aminothiazole compounds and 2-iminothiazoline compounds, as indicated above 60, are known per se in the literature and it will be readily apparent to those skilled in the art that both tautomeric isomers are in equilibrium with one another are present and are easily mutually convertible, and it is therefore self-evident that these isomers also fall into the same category of the compound itself. Both tautomeric forms of the compounds according to the invention and of the starting compounds are therefore clearly within the scope of the present invention.

643 266

For simplification, the compounds according to the invention and the starting compounds which comprise the group of these tautomeric isomers are represented here by using only one of the two expressions therefor, i.e. of the formula

"ï ~ & -"

Rr ^ sT (A)

For the compounds (I), (Ib), (Id) and (IQ) according to the invention and the starting compounds (la), (le), (Ie), (III), (Illa), (Illa ') and (IV) to (VII) furthermore applies that these compounds according to the invention and these starting compounds also comprise the syn isomer, anti isomer and a mixture thereof. For example, in the compound (I) according to the invention the syn isomer can be represented by the partial structure of the formula in their molecule, while the corresponding anti isomer through the partial structure of the formula

Ri-ft -y c-co.

s 11

r2o-n can be represented in its molecule, and if it is expedient for the explanation of the invention to express both the syn isomer and the anti isomer by a general formula, this is represented by the partial structure of the formula

With regard to the other compounds and starting compounds according to the invention mentioned above, the syn isomer and the anti isomer can also be based on the same geometric isomers as have been explained for the compound (I).

Suitable salts, in particular pharmaceutically acceptable salts, of the 3,7-disubstituted-3-cephem-4-carboxylic acid compounds (I) according to the invention are conventional salts, in particular conventional non-toxic salts, and these may include inorganic salts, such as metal salts, for example alkali metal salts ( such as sodium, potassium salt and the like) and alkaline earth metal salts (such as calcium, magnesium salt and the like), ammonium salts and the like, organic salts, e.g. organic amine salts (such as trimethylamine, triethylamine, ethanolamine, diethanolamine, pyridine, picoline, dicyclohexylamine, N, N'-dibenzylethylenediamine salt and the like) and the like, organic acid salts (e.g. acetate, maleate, tartrate, methanesulfonate , Benzenesulfonate, toluenesulfonate and the like), inorganic acid salts (e.g. hydrochloride, hydrobromide, sulfate, phosphate and the like) or salts with an amino acid (such as arginine, aspartic acid, glutamic acid and the like) and the like.

12

In the foregoing and subsequent description of the invention, suitable examples and explanations for the various definitions encompassed by the present invention are as follows:

5 Unless otherwise stated, the expression “low” or “low” stands for radicals or groups which contain 1 to 6 carbon atoms.

The expression “(Ca-Cb)” means that the following group a to b contains carbon atoms, for example, “-10” means “(C2-C6) alkyl” alkyl having 2 to 6 carbon atoms.

Examples of the aryl (lower) alkyl group in the symbol Ri are benzyl, trityl and the like.

A suitable acyl group in the terms "acylamino", "acylimino" and "acyloxy" may include carbamoyl, an aliphatic acyl group and an acyl group containing an aromatic or heterocyclic ring. Suitable examples of the acyl may be its lower alkanoyl (such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovale-20 ryl, oxalyl, succinyl, pivaloyl, hexanoyl and the like); Cyclo (lower) alkanecarbonyl having 4 to 7 carbon atoms (e.g. cyclopropanecarbonyl, cyclohexanecarbonyl and the like), preferably one having 6 to 7 carbon atoms; lower alkoxycarbonyl of 2 to 7 carbon atoms 25 (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl and the like); lower alkanesulfonyl (e.g. mesyl, ethanesulfonyl, propanesulfonyl, iso-30 propanesulfonyl, butanesulfonyl and the like); Arenesulfonyl (e.g. benzenesulfonyl, tosyl and the like); Aroyl (e.g. benzoyl, toluoyl, naphthoyl, phthaloyl, indancarbonyl and the like); Ar (lower) alkanoyl (e.g. phenylacetyl, phenyl-propionyl and the like); Ar (lower) alkoxycarbonyl (e.g. 35 benzyloxycarbonyl, phenethyloxycarbonyl and the like); Aryloxy (lower) alkanoyl (e.g. phenoxyacetyl, phenoxypropionyl, phenoxyhexanoyl and the like); heterocyclic carbonyl (e.g. Thenoyl, Furoyl, Nicotinoyl and the like); and the same.

40 The above acyl group may have 1 to 3 suitable sub-substituents, e.g. Halogen (such as chlorine, bromine, iodine or fluorine), hydroxy, cyano, nitro, amino, lower alkoxy (such as methoxy, ethoxy, propoxy, isopropoxy and the like), preferably one with 1 to 2 carbon atoms, lower alkyl ( e.g. methyl, ethyl, propyl, isopropyl, butyl and the like), lower alkenyl (e.g. vinyl, allyl and the like), aryl (e.g. phenyl, tolyl and the like) which may be substituted by halogen, or the like.

Preferred examples of acyl with one or more of these substituents can be halogen (lower) alkanoyl (in particular trihalogen (lower) alkanoyl), N-aryl- or N-halogen-substituted arylcarbamoyl, aryloxy (lower) alkanoyl with lower alkoxy or aroyl Nitro or amino.

55 Preferred examples of acylamino can be lower alkanoylamino, Ar (lower) alkanoylamino (especially phenyl (lower) alkanoylamino) or halogen (lower) alkano-oylamino (especially trihalogen (lower) alkanoylamino).

The carboxy group can be in the form of the following esters: 60 lower alkyl esters (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, t-penthl, hexyl -, 1-Cyclopropyläthylester and the like), wherein the lower alkyl radical may preferably be one having 1 to 4 carbon atoms; a lower alkenyl ester (such as vinyl ester, 65 allyl ester and the like); a lower alkynyl ester (such as ethynyl, propynyl ester and the like); a mono (or di or tri) halogen (lower) alkyl ester (such as 2-iodoethyl, 2,2,2-trichloroethyl ester and the like); a lower alkane

13

643 266

oyloxy (lower) alkyl esters (such as acetoxymethyl, propionyloxy methyl, butyryloxymethyl, valeryloxymethyl, pivaloyloxy methyl, hexanoyloxymethyl, 2-acetoxyethyl, 2-propionyloxy ethyl and the like); a lower alkanesulfon-yl (lower) alkyl ester (such as mesylmethyl, 2-mesylethyl ester and the like); an Ar (lower) alkyl ester, e.g. a mono- or di- or triphenyl (lower) alkyl ester which may have one or more suitable substituents (for example a benzyl, 4-methoxybenzyl, 4-nitrobenzyl, phenethyl, trit-yl, benzhydryl, bis ( methoxyphenyl) methyl, 3,4-dimethoxy-benzyl, 4-hydroxy-3,5-di-tert-butylbenzyl ester and the like); an aryl ester, which may have one or more suitable substituents (such as a phenyl, tolyl, tert-butylphenyl, xylyl, mesityl, cumenyl ester and the like) and the like.

Preferred examples of the esterified carboxy group are lower alkoxycarbonyl (such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl and the like) having 2 to 7 carbon atoms, preferably one having 2 to 7 carbon atoms

5 carbon atoms; lower alkanoyloxy (lower) alkoxy-carbonyl having 3 to 13 carbon atoms (such as acetoxy-methoxycarbonyl, pivaloyloxymethoxycarbonyl, hexanoyloxy-methoxycarbonyl and the like), preferably one having 6 to 8 carbon atoms; or Ar (lower) alkoxycarbonyl having 8 to 20 carbon atoms (such as benzyloxycarbonyl, phenethyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl and the like), preferably one having 12 to 14 carbon atoms.

A suitable cyclo (lower) alkyl is one with 3 to

6 carbon atoms, and may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, and preferably one having 5 to 6 carbon atoms.

A suitable lower alkynyl is one having 2 to 6 carbon atoms and may include ethynyl, 2-propynyl, 2-butynyl, 3-pentynyl, 3-hexynyl and the like, and preferably one having 2 to 4 carbon atoms, especially one those with 2 to 3 carbon atoms.

A suitable lower alkanoyloxy is one having a lower alkanoyl group as mentioned above, and may include, for example, formyloxy, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, succinyloxy, pivaloyloxy, hexanoyloxy and the like, preferably one having 2 to 6 Carbon atoms.

Suitable lower alkyl may include one that may be branched, e.g. Methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like.

Suitable lower alkenyl is one having 2 to 6 carbon atoms, and may include, for example, vinyl, allyl, isopropenyl, 1-propenyl, 2-butenyl, 3-pentenyl and the like, and preferably one having 2 to 4 carbon atoms.

Suitable thiadiazolylthio may include, for example, 1,2,4-thiadiazolylthio, 1,3,4-thiadiazolylthio, 1,2,5-thiadiazolylthio and the like. This thiadiazolyl-thio group may have a lower alkyl group as mentioned above.

Suitable triazolylthio may include, for example, 4H-l, 2,4-triazolylthio, 1H-l, 2,3-triazolylthio, 2H-1,2,3-triazolylthio and the like.

A suitable tetrazoylthio may include 1H-tetrazo-lylthio or 2H-tetrazolylthio.

Suitable aroyloxy may include, for example, benzoyloxy, toluoyloxy, naphthoyloxy, phthaloyloxy, indancarbonyloxy and the like, which may have 1 to 3 nitro groups or amino groups.

A suitable cyclo (lower) alkanecarbonyloxy is one having 4 to 7 carbon atoms and may include, for example, cyclopropanecarbonyloxy, cyclohexanecarbonyloxy and the like, preferably one having 6 to 7 carbon atoms.

Suitable aryl which is the substituent of carbamoyloxy may include phenyl, tolyl and the like, which may be substituted by 1 to 3 halogen atoms (e.g. chlorine, bromine and the like).

Suitable Ar (lower) alkanoyloxy may preferably be phenyl (lower) alkanoyloxy, and may include phenyl acetoxy, phenylpropionyloxy and the like.

A suitable arylox (lower) alkanoyloxy may preferably be phenoxy (lower) alkanoyloxy, and may include phenoxyacetoxy, phenoxypropionyloxy, phenoxyhexanoyloxy, and the like, which contain 1 to 3 lower alkoxy (such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy , t-butoxy, pentyloxy, hexyloxy and the like), preferably one having 1 to 3 carbon atoms.

Suitable halogen can include chlorine, bromine, fluorine and iodine.

A suitable acid residue may include the above-mentioned halogen, lower alkanesulfonyloxy (e.g. mesyloxy, ethanesulfonyloxy and the like), arenesulfonyloxy (e.g. benzenesulfonyloxy, p-toluenesulfonyloxy and the like) and the like.

A suitable alkali metal can include sodium, potassium and the like.

A suitable group which may be substituted by a group of formula n-n may include azido, the above halogen, acyloxy (preferably lower alkanoyloxy) and the like.

Suitable carbamoyl with an aryl which may be substituted with halogen, aryloxy (lower) alkanoyl with lower alkoxy, cyclo (lower) alkanecarbonyl and aroyl with nitro can be one as exemplified above for acyl.

Among the suitable examples of each of the groups of the compounds of the present invention as explained and explained above, the preferred examples thereof are as follows:

The preferred example of R1 can be amino or acylamino (especially lower alkanoylamino or halogen (lower) alkanoylamino); and the preferred example of R3 can be carboxy or Ar (lower) alkoxycarbonyl (especially diphenyl (lower) alkoxycarbonyl).

The processes for the preparation of the compounds according to the invention are explained in more detail below.

Procedure 1

The compound (I) of the present invention or a salt thereof can be prepared by reacting the compound (II) or a reactive derivative on the amino group or a salt thereof with the compound (III) or a reactive derivative on the carboxy group or a salt thereof .

A suitable reactive derivative on the amino group of the compound (II) may be a Schiff base type imino isomer or its tautomeric enamine type isomer, which is prepared by reacting the compound (II) with a carbonyl compound such as e.g. Acetic Acetic Acid or the like; a silyl derivative that made

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

643 266

is by reacting the compound (II) with a silyl compound such as trimethylsilylacetamide, bis (trimethylsilyl) acetamide or the like; a derivative prepared by reacting the compound (II) with phosphorus trichloride or phosphine and the like.

A suitable salt of compounds (II) and (III) may include an acid addition salt such as e.g. an organic acid salt (such as an acetate, maleate, tartrate, benzenesulfonate, toliolsulfonate and the like), or an inorganic acid salt (such as a hydrochloride, hydrobromide, sulfate, phosphate and the like); a metal salt (e.g. a sodium, potassium, calcium, magnesium salt and the like); an ammonium salt; an organic amine salt (e.g. a triethylamine, dicyclohexylamine salt and the like) and the like.

A suitable reactive derivative on the carboxy group of the compound (III) may include an acid halide, an acid anhydride, an activated amide, an activated ester and the like. The suitable example may be an acid chloride, an acid azide; a mixed acid anhydride with an acid, e.g. a substituted phosphoric acid (such as dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid and the like), dialkylphosphoric acid, sulphurous acid, thiosulphuric acid, sulfuric acid, alkylcarbonic acid, an aliphatic carbonic acid, pentanoic acid, teric acid or trichloroacetic acid and the like) or an aromatic carboxylic acid (such as benzoic acid and the like); a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester (e.g. a cyanomethyl, methoxymethyl, dimethyliminomethyl [(CH3) 2N + = CH -] -, vinyl, propargyl, p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl, , Mesylphenyl, phenylazophenyl, phenylthio, p-nitrophenylthio, p-cresylthio, carboxymethylthio, pyranyl, pyrid-yl, piperidyl, 8-quinolylthioesters and the like) or an ester with an N-hydroxy compound (such as N, N-dimethyl-hydroxylamine, 1-hydroxy-2- (1H) pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-6-chloro-1H-benzotriazole and the like) and the like. These reactive derivatives can be selected as desired depending on the type of compound (III) used.

The reaction is usually carried out in a conventional solvent, for example in water, 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, carried out. These conventional solvents can also be used in the form of a mixture thereof.

When the compound (III) is used in the form of the free acid or its salt in the reaction, 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-carbon- ylbis (2-methylimidazole), pentamethylene ketene-N-cyclohexylimine, diphenyl ketene-N-cyclohexylimine, ethoxyacetylene, 1-alkoxy-l-chloroethylene, trialkyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride, phosphoryl chloride, phosphoryl chloride, phosphoryl chloride, phosphoryl chloride, phosphoryl chloride, phosphoryl chloride, phosphoryl chloride, phosphoryl chloride, phosphoryl chloride, phosphoryl chloride, phosphoryl chloride, phosphoryl chloride, phosphoryl trichloride, -Ethyl-7-hydroxybenzisoxazolium salt, the intramolecular 2-ethyl-5- (n-sulfophenyl) isoxazolium hydroxide -

14

Salt, l- (p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotri-azole, the so-called Vilsmeier reagent, which is prepared by reacting dimethylformamide with thionylchloride, phosgene, phosphorus oxychloride and the like, or the like .

The reaction can also be carried out in the presence of an inorganic or organic base, e.g. an alkali metal bicarbonate, a tri (lower) alkylamine, pyridine, N- (lower) alkylmorpholine, N, N-di (lower) alkylbenzylamine 10 or the like. The reaction temperature is not critical and the reaction is usually carried out under cooling or at ambient temperature.

In the reaction according to the invention, a syn isomer of the compound (I) according to the invention can be preferred

15 can be obtained by carrying out the reaction of the compound (II) with the corresponding syn isomer of the starting compound (III), for example in the presence of a Vilsmeier reagent, as mentioned above, and under approximately neutral conditions.

20th

Procedure 2

The compound (Ib) of the present invention or a salt thereof can be prepared by subjecting the compound (Ia) or a salt thereof to a reaction to eliminate the acyl group.

A suitable salt of the compound (Ia) may include a metal salt, an ammonium salt, an organic amine salt and the like as mentioned above.

The elimination reaction according to the invention is carried out using a hydrolysis, a reduction or a process in which the compound (Ia) is reacted with an imino-halogenating agent and then with an imino etherifying agent and the compound obtained is subjected to hydrolysis.

35 Hydrolysis can be a method using an acid or a base or hydrazine and the like. These methods can be selected depending on the type of protecting groups to be eliminated.

Among these methods, hydrolysis, which is carried out using an acid, is one of the most common and preferred methods for eliminating protecting groups, e.g. substituted or unsubstituted alkoxycarbonyl (such as t-pentyloxycarbonyl and the like), 45 alkanoyl (such as formyl and the like), cycloalkoxycarbonyl, substituted or unsubstituted aralkoxycarbonyl (such as benzyloxycarbonyl, substituted benzyloxycarbonyl and the like) or the like. A suitable acid may include an organic or an inorganic acid, e.g. Formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid and the like, and a preferred acid is, for example, formic acid, trifluoroacetic acid, hydrochloric acid and the like. The acid suitable for the reaction can be selected depending on the type of protective group to be eliminated. If the elimination reaction is carried out with the acid, it can be carried out in the presence or absence of a solvent. Suitable solvents can be an organic solvent, water or a mixture thereof. If trifluoroacetic acid is used, the elimination reaction can preferably be carried out in the presence of anisole.

The hydrolysis, which is carried out using hydrazine 65, is typically used to eliminate a protective group, e.g. Succinyl or phthaloyl.

When the hydrolysis is carried out with a base, it is preferred to eliminate an acyl group

15

643 266

for example, of haloalkanoyl (such as trifluoroacetyl and the like) and the like. Suitable bases can include an inorganic base or an organic base. The hydrolysis, which is carried out using a base, is often carried out in water or in a hydrophilic organic solvent or in a mixture thereof.

Among the protecting groups, the acyl group can generally be eliminated by hydrolysis as mentioned above or by using other conventional hydrolysis. If the acyl group is halogen-substituted alkoxycarbonyl or 8-quinoiloxycarbonyl, it can be eliminated by treatment with a heavy metal such as copper, zinc or the like.

Reductive elimination is generally used to eliminate a protecting group such as haloalkoxycarbonyl (e.g. trichloroethoxycarbonyl and the like), substituted or unsubstituted aralkoxycarbonyl (e.g. benzyloxycarbonyl, substituted benzyloxycarbonyl and the like), 2-pyridylmethoxycarbonyl and the like. Suitable reduction may include, for example, reduction with an alkali metal borohydride (such as sodium borohydride and the like) and the like.

Among the protecting groups, the acyl group can be eliminated by treatment with an imino halogenating agent (such as phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride and the like) and an imino etherifying agent such as e.g. a lower alkanol (such as methanol, ethanol and the like), followed by hydrolysis if necessary. The reaction temperature is not critical and it can be conveniently selected depending on the nature of the amino protecting group and the elimination method used, as described above, and the reaction according to the invention is preferably carried out under mild conditions, for example under cooling, at ambient temperature or at a slightly elevated temperature carried out.

The present invention also includes the case that the protected carboxy group is converted into the free carboxy group under the reaction conditions in the course of the reaction or in the after-treatment.

Procedure 3

The compound (Id) according to the invention or a salt thereof can be prepared by subjecting the compound (Ic) to hydrolysis to split the ester group.

The hydrolysis can be a method using an acid or a base and the like. These methods can be selected depending on the type of ester groups to be split.

Hydrolysis performed using an acid is one of the most common and preferred methods for eliminating protecting groups, e.g. Ar (lower) alkyl [such as mono (or di or tri) phenyl (lower) alkyl, substituted phenyl (lower) alkyl and the like], lower alkyl, substituted lower alkyl or the like. A suitable acid can be, for example, an inorganic or organic acid such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid and the like. The reaction according to the invention can be carried out in the presence of anisole. The acid suitable for the reaction can be selected depending on the protecting group to be eliminated and other factors.

The hydrolysis carried out using an acid can be carried out in the presence of a solvent, for example an organic solvent, water or a

Mixture of them can be performed. The reaction temperature is not critical and can be selected appropriately depending on the nature of the protecting group and the elimination process used, and the reaction according to the invention is preferably carried out under mild conditions, for example under cooling, at ambient temperature or with gentle heating.

The present invention also includes the case that the protected amino group is converted into the free amino group during the reaction or aftertreatment in the process according to the invention.

Procedure 4

The compound (If) according to the invention or a salt thereof can be prepared by subjecting the compound (le) or a salt thereof to a reduction.

A suitable salt of the compound (Ie) may be one as exemplified above for the compound (Ia). The reduction according to the invention is carried out using a conventional method, for example by catalytic reduction or the like. Suitable catalysts can include platinum (IV) oxide, palladium on activated carbon and the like. Suitable solvents can include an alcohol (such as methanol, ethanol and the like), tetrahydrofuran or any other solvent which does not adversely affect the reaction. The reaction temperature is not critical and the reaction is usually carried out under cooling, at ambient temperature or under heating.

The processes for the preparation of the starting compound (IIb) are explained in more detail below.

1. The compound (XVII) can be prepared by reacting the compound (XVI) with an acylating agent.

Suitable acylating agents may include a compound of the formula R4d-OH (XXI), wherein R4d represents aryloxy (envious) alkanoyl, which may include lower alkoxy, thenoyl, cyclo (lower) alkane carbonyl or aroyl with nitro, or a reactive derivative thereof, and a compound of the formula

RS — N = C = 0 (XXII)

wherein R8 represents aryl which may be substituted by halogen.

Suitable reactive derivatives of the compound (XXI) include those as exemplified above for the compound (III).

A suitable aryl for R8 can be phenyl, tolyl, xylyl, mesityl, cumenyl, naphthyl and the like, where the aryl group can be substituted by 1 to 3 halogen atoms (e.g. chlorine, bromine, iodine or fluorine).

The reaction is carried out in a manner similar to that indicated in Process 1.

In the formula of the compound (XVII), the structure of the following formula means a mixture of 3- and 2-cephem compounds.

2. The compound (XVIII) can be prepared by oxidizing the compound (XVII).

Suitable oxidizing agents may include conventional oxidizing agents such as those used to oxidize the sulfur atom in the first position of cephalosporin compounds, such as e.g. a peracid (like

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Perbenzoic acid, 3-chloroperbenzoic acid), hydrogen peroxide / sodium tungstate or the like.

The reaction is usually carried out in a solvent such as ethyl acetate, tetrahydrofuran or any other solvent which does not adversely affect the reaction, and is usually carried out under cooling or at ambient temperature.

3. The compound (XIX) can be prepared by reducing the compound (XVIII).

Suitable reducing agents can include conventional reducing agents used for the reduction of S-oxide, e.g. a phosphorus halide (such as phosphorus trichloride, phosphorus tribromide and the like)

or similar.

The reaction is preferably carried out in a solvent such as dimethylformamide or the like, and is preferably carried out under cooling or at ambient temperature.

4. The compound (IIb) can be prepared by subjecting the compound (XIX) to a reaction to eliminate the amino protecting group.

The elimination reaction is carried out in a manner similar to that indicated in Method 2.

In the reactions mentioned above and / or in the aftertreatment of the reactions according to the invention, the tautomeric isomers mentioned can occasionally be converted into the other tautomeric isomers, and this case is also within the scope of the present invention.

If the compound (I) according to the invention is obtained in the free acid form in the 4-position and / or if the compound (I) according to the invention has a free amino group, it can be converted into a salt, preferably a pharmaceutically acceptable salt, using a conventional method of which, as stated above, are transferred.

The compound (I) according to the invention and its salts, in particular its pharmaceutically acceptable salts, are all new compounds which have a high antibacterial activity (activity), inhibit or prevent the growth of a large number of pathogenic microorganisms including gram-positive and gram-negative bacteria and represent valuable antibacterial agents.

To demonstrate the usefulness or advantageous properties of the compound (17) according to the invention, the data for some representative compounds are given below, which were obtained in tests for determining the antibacterial in vitro activity.

Test connections

(1) 7- [2- (2-Propynyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] cephalosporanic acid (syn isomer).

(2) 7- [2- (2-Propynyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem4-carboxylic acid (syn isomer).

(3) 7- [2- (2-propynyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1 H-1,2,3-triazol-5-yl) thiomethyl- 3-cephem-4-car-bonic acid (syn isomer).

(4) 7- [2-ethoxyimino-2- (2-aminothiazol-4-yl) acetamido-3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-car- bonic acid (syn isomer).

(5) 7- [2- (2-Propynyloxyimino) -2- (2-aminothiazol4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4 -car-bonic acid (syn isomer).

(6) 7- [2-Allyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomeres).

(7) 7- [2-Hexyloxyimino-2- (2-aminothiazole-

4-yl) acetamido] 3- (1-methyl-1 H-tetrazol-5-yl) thiomethyl

3-cephem-4-carboxylic acid (syn isomer).

(8) 7- [2-isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (l-hexyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-

4-carboxylic acid (syn isomer).

Test procedure

In vitro antibacterial activity was determined using the dual agar plate dilution method described below.

A loop fill of an overnight culture of each test strain in trypticase soy broth (10® living cells per ml) was streaked on a cardiac infusion agar (HI agar) containing graded concentrations of the test compounds and the minimum inhibitory concentration (MIC) expressed in jxg / ml, determined after 20 hours of incubation at 37 ° C.

Test results

Test bacteria

MIC (µg / ml) test compounds (1) '(2) (3)

Pr. Vulgaris 1

0.78

0.20

0.39

Test bacteria MIC (µg / ml) test compounds (4) '(5) (6) (7)

(8th)

B. subtilis

ATCC 6633 0.78 0.39

0.78 0.78

0.78

For therapeutic administration, the compounds (I) according to the invention and / or their pharmaceutically acceptable salts in the form of conventional pharmaceutical preparations (medicaments) are used, which are a further subject of the invention and which, as the active ingredient (active component), comprise at least one of these compounds, if appropriate in mixture with a pharmaceutically acceptable carrier, such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external administration.

The pharmaceutical preparations can be in solid form, for example in the form of capsules, tablets, dragées, ointments or suppositories, or in liquid form for injection, e.g. in the form of solutions, suspensions or emulsions. If necessary, the above-mentioned preparations can also contain auxiliary substances, stabilizing agents, wetting agents or emulsifying agents, buffers and other customarily used additives.

Although the dosage of the compounds may vary and also depends on the age, condition of the patient, the type of disease, the type of compound (I) administered and the like, the average single dose has been approximately 10, 50, 100, 250, 500 and 1000 mg has been shown to be effective in the treatment of infectious diseases caused by pathogenic bacteria. In general, a daily dose between 1 and about 6000 mg "per body or more can be administered to a patient.

The invention is explained in more detail by the production examples and examples described below, but without being restricted thereto.

Production Example 1

1. 71.2 g of ethyl 2- (2-propynyloxyimino) -3-oxobutyrate (syn isomer) was obtained by reacting 56.7 g

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643 266

Ethyl 2-hydroxyimino-3-oxobutyrate with 43 g of 2-propynyl bro-mid in the presence of 72.3 g of potassium carbonate and 280 ml of N, -N-dimethylformamide.

I.R. (Film): 3280, 3220, 2120, 1735, 1670 cm- '.

2.61.6 g of ethyl 2- (2-propynyloxyimino) -3-oxo-4-chlorobutyrate (syn isomer) was obtained by reacting 71.2 g of ethyl 2- (2-propynyloxyimino) -3-oxobutyrate (syn isomer) with 50.2 g of sulfuryl chloride in 81 ml of acetic acid.

I.R. (Film): 3300.2130, 1745, 1720, 1675 cm-1.

3. 35.6 g of ethyl 2- (2-propynyloxyimino) -2- (2-aminothia-zol4-yl) acetate (syn isomer) was obtained by reacting 61 g of ethyl 2- (2-propynyloxyimino) -3-oxo-4-chlorobutyrate with 20 g of thiourea in the presence of 35.8 g of sodium acetate trihydrate, 150 ml of water and 180 ml of ethanol.

I.R. (Nujol): 3290, 2220, 1729 cm- '.

4. 1.924 g of 2- (2-propynyloxyimino) -2- (2-aminothiazol-4-yl) acetic acid (syn isomer) was obtained by hydrolysis of 2.8 g of ethyl-2- (2-propynyloxyimino) -2 - (2-aminothiazol-4-yl) acetate (syn-isomer) in the presence of 22.17 ml of an aqueous 1N sodium hydroxide solution, 23 ml of methanol and 20 ml of tetrahydrofuran.

I.R. (Nujol): 2190, 1740 cm-1.

Production Example 2

107 g of formic acid was added to 239 g of acetic anhydride while cooling with ice, and the mixture was stirred at 50 ° C for 1 hour and then cooled to 20 ° C. To the mixture was added 135 g of 2- (2-propynyloxyimino) - 2- (2-aminothiazol-4-yl) acetic acid (syn isomer) and the mixture was stirred at ambient temperature for 3 hours. 400 ml of diisopropyl ether were added to the mixture, and then the precipitated crystals were collected by filtration, washed with diisopropyl ether and then dried, giving 118.4 g of 2- (2-propynyloxyimino) -2- (2-formamidothiazol-4-yl ) acetic acid (syn isomer) was obtained.

I.R. (Nujol): 3250.2130.1685, 1600, 1560 cm-1.

N.M.R. (dô-DMSO, 5): 3.53 (IH, m), 4.87 (2H, d, J = 2Hz), 7.63 (IH, s), 8.61 (IH, s), 12.7 (IH, broad s).

Production Example 3

To a solution of 30 g of 2- (2-formamidothiazol-4-yl) glyoxylic acid and 12.6 g of sodium bicarbonate in 1300 ml of water was added 19.8 g of allyloxyamine hydrochloride and the mixture was stirred at ambient temperature at pH 6 for 7 hours . 500 ml of ethyl acetate was added to the reaction mixture. After the mixture was adjusted to pH 1.9 with 10% hydrochloric acid, the ethyl acetate layer was separated. The ethyl acetate layer was washed with an aqueous sodium chloride solution, dried over magnesium sulfate, and then the solvent was distilled off. The residue was pulverized in diisopropyl ether, collected by filtration, and then dried to obtain 25.3 g of 2-allyloxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer).

I.R. (Nujol): 3110, 1730, 1660, 1540 cm- '.

N.M.R. (dô-DMSO, 6): 4.70 (2H, m), 5.13-5.60 (2H, m), 5.73-6.27 (IH, m), 7.57 (IH, s), 8.35 (IH, s).

Production Example 4

1.35.2 g of sulfuryl chloride were added all at once to a stirred solution of 48.9 g of ethyl 2-ethoxyimino-3-oxobutyrate (syn isomer) in 49 ml of acetic acid at room temperature, and stirring was carried out at the same temperature 1 Continued for an hour. After the solution thus obtained was added to 200 ml of water, the solution was extracted with methylene chloride. The extract was washed with a saturated aqueous sodium chloride solution, neutralized with an aqueous sodium bicarbonate solution and washed with water. The solution was dried over magnesium sulfate and concentrated under reduced pressure to obtain 53.8 g of ethyl 2-ethoxyimino-3-oxo-4-chlorobutyrate (syn isomer) in the form of a pale yellow oil.

2. A mixture of 38.7 g of ethyl 2-ethoxyimino-3-oxo4-chlorobutyrate, 13.2 g of thiourea, 14.3 g of sodium acetate, 95 ml of methanol and 95 ml of water was at 40 ° C for 40 minutes touched. After the resulting solution was adjusted to pH 6.5 with an aqueous sodium bicarbonate solution, the precipitates which occurred were collected by filtration and washed with diisopropyl ether, whereby 14.7 g of ethyl 2-ethoxyimino-2- (2-aminot-hiazole -4-yl) acetate (syn-isomer), mp 130 to 131 ° C, was obtained.

I.R. (Nujol): 3450, 3275, 3125, 1715, 1620 cm- '.

3. 5 g of ethyl 2-ethoxyimino-2- (2-aminothiazol-4-yl) acetate (syn isomer) was added to a mixture of 45.9 ml of 1N sodium hydroxide and 30 ml of ethanol and it was 5 hours long at room temperature. After the ethanol had been removed from the resulting solution under reduced pressure, the residue was dissolved in 60 ml of water and adjusted to pH 2.0 with 10% hydrochloric acid. The solution was subjected to salting-out, and the precipitates were collected by filtration and dried to obtain 2.9 g of 2-athoxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer).

I.R. (Nujol): 3625, 3225 (shoulder), 3100, 1650, 1615 cm- '.

N.M.R. (dó-DMSO, 5): 1.20 (3H, t, J = 7Hz), 4.09 (2H, q, J = 7Hz), 6.82 (1 H, s), 7.24 (2H, broad s).

4. 100 g of 2-ethoxyimino-2- (2-aminothiazoI-4-yl) acetic acid (syn isomer), 85.5 g of formic acid and 190.1 g of acetic anhydride were treated in the same manner as in Preparation Example 2, with 99.1 g of 2-ethoxy-mino2- (2-formamidothiazol-4-yl) acetic acid (syn isomer) were obtained.

I.R. (Nujol): 3200, 3140, 3050, 1700 cm- '.

N.M.R. (dâ-DMSO, 5): 1.18 (3H, t, J = 6Hz). 4.22 (2H, q, J = 6Hz), 7.56 (1 H, s), 8.56 (1 H, s), 12.62 (1H, broad s).

Production Example 5

The following compounds were prepared in a manner similar to that in Preparation Examples 1 to 4:

(1) 2-Isopropoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer), mp 168-169 ° C (dec.).

(2) 2-Butoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer).

I.R. (Nujol): 3350, 3160, 3050, 1700, 1680, 1570 cm- '.

(3) 2-Hexyloxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer), mp 115-M6 ° C (dec.).

I.R. (Nujol): 3170, 3070, 1720, 1700, 1660 cm-1

N.M.R. (ds-DMSO, S): 0.6-2.1 (11H, m), 4.15 (2H, t, J = 6Hz), 7.53 (1H, s), 8.56 (1 H, s), 12.69 (1H, s)

(4) 2-Pentyloxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer), mp 176 ° C (dec.).

I.R. (Nujol): 3160, 1655, 1620, 1460 cm "1

N.M.R. (dô-DMSO, S): 7.20 (2H, s), 6.82 (IH, s), 4.07 (2H, t, J = 6Hz), 0.6-2.2 (9H, m)

(5) 2-Propoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer), mp 164 ° C (dec.).

I.R. (Nujol): 3200.3120.3050, 1700, 1550 cm- '.

(6) 2-Pentyloxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer), mp 125 ° C (dec.).

I.R. (Nujol): 3200, 3140, 1700, 1565 cm- '.

(7) 2-Allyloxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer), mp 187 ° C (dec.).

I.R. (Nujol): 3350, 1630; 1580, 1460 cm- '.

(8) 2-Hexy! Oxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer), mp 174 ° C (dec.).

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643 266

I.R. (Nujol): 1660, 1625, 1425 cm-1.

(9) 2-Isopropoxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer), mp 151 ° C (dec.).

(10) 2-Isobutoxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer), mp 122-124 ° C.

(11) 2-Cyclohexyloxyimino-2- (2 * aminothiazol-4-yl) acetic acid (syn isomer), mp 148 ° C (dec.).

(12) 2-Propoxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer), mp 161 ° C (dec.).

(13) 2-Isobutoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer), mp 163 ° C (dec.).

Production Example 6

1. 500 ml of water was added to 490.0 g of hexylamine and a solution of 193.6 g of sodium hydroxide in 700 ml of water was added with ice cooling and stirring. 367.8 g of carbon disulfide were added dropwise at 2 to 10 ° C. over a period of 2 hours, and 687.3 g of methyl iodide were then added dropwise at 0 to 5 ° C. over a period of 1 hour. The resulting mixture was stirred at the same temperature for 30 minutes and at ambient temperature for 2 hours. The reaction mixture was extracted with 1.5 l of diethyl ether. The extract was washed with 300 ml of a saturated sodium chloride aqueous solution, dried over magnesium sulfate and concentrated to give 825.5 g of methyl N-hexyldithiocarbamate in the form of an oil.

1st row (Film): 3225, 2960, 2935, 2860 cm "1

N.M.R. (CDCh, 8): 0.86 (3H, t, J = 5.0Hz), 1.10-1.90 (8H, m), 2.58 (3H, s), 3.72 (2H, m)

2. 155.9 g of sodium azide and 0.8 l of water were added with stirring to a solution of 430 g of methyl N-hexyldithiocarbamate in 1.71 ethanol, and the resulting mixture was stirred at 90 ° for 3.5 hours C heated under reflux. The ethanol was distilled off from the reaction mixture, and the residue was washed with 11 diethyl ether, adjusted to pH 2.0 with concentrated hydrochloric acid and extracted with 11 diethyl ether. The extract was washed with water, dried over magnesium sulfate and concentrated to give 431.3 g of 1-hexyl-1H-tetrazole-5-thiol in the form of an oil.

I.R. (Film): 3110.2960.2930.2860 cm ~ '

N.M.R. (CDCh, 5): 0.91 (3H, t, J = 5.0Hz), 1.10-1.65 (6H, m), 1.97 (2H, m), 4.33 (2H, t, J = 7.0Hz).

3. To 150.0 g of 7-aminocephalosporanic acid was added 3 liters of a 0.2 M phosphate buffer solution, which had been prepared by dissolving 62.1 g of sodium biphosphate dihydrate and 25.5 g of disodium hydrogen phosphate in 3 liters of water, and the resulting mixture was adjusted to pH 6.5 with an aqueous 2N sodium carbonate solution. 154.6 g of 1-hexyl-1H-tetrazole-5-thiol was added to the mixture, and the resulting mixture was kept at 60 to 65 ° C for 2 hours at a pH of 6.0 to 6.5 stirred while introducing nitrogen gas. The reaction mixture was adjusted to pH 3.5 with concentrated hydrochloric acid with ice cooling. The precipitates were collected by filtration and washed with water, and 41 methanol and 400 ml of concentrated hydrochloric acid were added. The mixture was stirred for 2 hours and an insoluble material was filtered off. The filtrate was treated with activated carbon and adjusted to pH 3.5 with a 28% aqueous ammonia solution. The precipitates were collected by filtration, washed successively with water, acetone and diethyl ether and dried, giving 116.38 g of 7-amino-3- (1-hexyl-1H-tetrazol-5-yl) thiomethyl-3-cephem- 4-carboxylic acid was obtained in the form of a powder.

LR. (Nujol): 1803.1620.1350 cm- '

18th

N.M.R. (ds-DMSO, 5): 0.95 (3H, t, J = 6.5Hz), 1.26 (6H, m), 1.80 (2H, m), 3.65 (2H, ABq, J = 18Hz), 4.00-4.50 (4H , m), 4.79 (1H, d, J = 6.0Hz), 4.95 (1H, d, J = 6.0Hz)

5 Production example 7

283.0 g of 7-aminocephalosporanic acid and 225.0 g of 1-propyl-1H-tetrazole-5-thiol were treated in 5.5 l of a 0.2 M phosphate buffer solution in a manner similar to that in Preparation 6 (3), to obtain 125.0 g of 7-amino-3- (l-propyl-io 1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid.

LR. (Nujol): 3300.1795, 1610 cm ~ '

N.M.R. (de-DMSO, Ô): 0.91 (3H, t, J = 7.5Hz), 1.60-2.28 (2H, m), 3.63 (2H, ABq, J = 18.0Hz), 3.98-4.58 (4H, m), 5.08 (1H, d, J = 5.0Hz), 5.49 (1H, d, J = 5.0Hz)

15

Production Example 8

1.3.7 g of 3-chlorophenyl isocyanate were at ambient temperature to a solution of 10.3 g of benzhydryl 7- (2-phe-nylacetamide) -3-hydroxymethyl-3-cephem-4-carboxylate in a mixture of 200 ml of tetrahydrofuran and 2.4 g of triethylamine was added and the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in 200 ml of ethyl acetate, and the solution was washed successively with 10% hydrochloric acid, a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution to obtain a solution containing a mixture of benzhydryl-7- (2-phenylacetamide ) -3- [N- (3-chlorophenyl) carbamoyloxymethyl] -3-cephem-4-carboxylate 30 and benzhydryl-7- (2-phenylacetamido) -3- [N- (3-chlorophenyl) carbamoyloxymethyl] -2- cephem-4-carboxylate contained.

2. To the ethyl acetate solution obtained above, a solution of 5.2 g of 3-chloroperbenzoic acid in ethyl acetate was added dropwise at 7 to 10 ° C, and the mixture was stirred for 1 hour

Stirred for 35 at the same temperature. The precipitates were collected by filtration, washed with diethyl ether and dried, giving 7.7 g of benzhydryl-7- (2-phe-nylacetamido) -3- [N- (3-chlorophenyl) carbamoyloxymethyl] -3-cephem- 4-carboxylate-1 oxide was obtained.

40 I.R. (Nujol): 3280, 1790, 1700, 1650, 1600, 1530 cm- '

3. 3.2 g of phosphorus trichloride were at - 40 ° C to a stirred solution of 7.6 g of benzhydryl-7- (2-phenylacetamido) -3- [N- (3-chlorophenyl) carbamoyloxymethyl] -3-cephem -4-carboxylate-l-oxide added in 50 ml of dimethylformamide,

45 and the mixture was stirred at -20 to -40 ° C for 1 hour. The reaction mixture was poured into chilled water. The precipitates were collected by filtration, washed with water and dried, yielding 5.0 g of benzhydryl-7- (2-phenylacetamido) -3- [N- (3-chlorophenyl) car-5o bamoyloxymethyl] -3-cephem-4 -carboxylate received.

I.R. (Nujol): 3280.3190.1780.1730, 1710, 1660, 1620, 1600, 1540 cm- '

N.M.R. (de-DMSO, Ô): 3.56 (2H, s), 3.64 (2H, s), 4.86 (2H, ABq, J = 12Hz), 5.14 (1H, d, J = 5Hz), 5.76 (1H, d, d, J = 5 and 55 8Hz), 6.95 (1H, s), 7.00-7.70 (19H, m), 9.10 (1H, d, J = 8Hz), 10.00 (1 H, s)

4.1.9 g of pyridine was added to a solution of 4.93 g of phosphorus pentachloride in 50 ml of methylene chloride at 5 ° C and the suspension was stirred at 60 ambient temperature for 30 minutes. To the reaction mixture was added 5.0 g of benzhydryl 7- (2-phenylacetamido) -3- [N- (3-chlorophenyl) carbamoyloxymethyl] -3-cephem-4-carboxylate at 5 ° C, and it became 1.5 Stirred at 5 to 7 ° C for hours to form a homogeneous solution. To the 65 solution obtained above, which had been cooled to -30 ° C, 8 ml of methanol was added. After the solution was stirred at -10 to -20 ° C for 1 hour, 5 ml of water was added and the stirring became 30 minutes

continued at 0 to 5 ° C. After removing the solvent under reduced pressure, 80 ml of water and 100 ml of diethyl ether were added to the residue, and the oil layer containing oil was separated. The aqueous solution containing the oil was adjusted to pH 8.0 with a 20% aqueous sodium carbonate solution and extracted with ethyl acetate. The extracts were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was pulverized with diisopropyl ether to give 2.2 g of benzhydryl-7-amino-3- [N- (3-chlorophenyl) carbamoyloxymethyl] -3-cephem-4-carboxylate.

1st row (Nujol): 3410, 3360, 1760, 1700, 1650, 1595, 1520 cm-1

N.M.R. (de-DMSO, 5): 3.60 (2H, broad s), 4.80 (1H, d, J = 5Hz), 4.83 (2H, ABq, J = 13Hz), 5.05 (1H, d, J = 5Hz), 6.93 (1H, s), 6.90-7.70 (14H, m), 9.97 (1H, s)

Production Example 9

1.10.3 g of benzhydryl-7-2-phenylacetamido) -3-hydroxymethyl-3-cephem-4-carboxylate and 7.4 g of 2- (4-methoxyphenoxy) acetyl chloride were prepared in a manner similar to that in Preparation Example 8 ( 1) reacted together to form a solution containing a mixture of benzhydryl 7- (2-phenylacet-amido) -3- [2- (4-methoxyphenoxy) acetoxymethyl] -3-cephem-4-carboxylate and benzhydryl-7- (2-phenylacetamido) -3- [2- (4-methoxyphenoxy) acetoxymethyl] -2-cephem-4-carboxy-ylate.

2. The solution obtained above was reacted with 4.7 g of 3-chloroperbenzoic acid in a similar manner as in Preparation Example 8 (2), whereby 7.1 g of benzhydryl-7- (2-phe-nylacetamido) -3- [2- (4-methoxyphenoxy) acetoxymethyl] - 3-cephem-4-carboxylate-1 oxide was obtained.

I.R. (Nujol): 3270, 1780, 1760, 1720, 1650, 1520, 1500 cm-1

N.M.R. (de-DMSO, S): 3.63 (2H, s), 3.67 (3H, s), 3.75 (2H, ABq, J = 19Hz), 4.65 (2H, s), 4.90 (1H, d, J = 5Hz) , 4.97 (2H, ABq, J = 13Hz), 5.93 (1H, d, d, J = 5 and 8Hz), 6.85 (4H, s), 6.96 (1H, s), 7.00-7.70 (15H, m), 8.41 (1H, d, J = 8Hz).

3. 6.9 g of benzhydryI-7- (2-phenylacetamido) 3- [2- (4-methoxy-yphenoxy) acetoxymethyl] -3-cephem-4-carboxylate 1-oxide and 2.7 g of phosphorus trichloride were added similar manner as in Preparation Example 8 (3) reacted with each other to form 6.1 g of benzhydryl-7- (2-phenyl-acetamido) -3- [2- (4-methoxyphenoxy) acetoxymethyl] -3-cephem-4- carboxylate.

I.R. (Nujol): 3300, 1775, 1740, 1730, 1650 cm-1

N.M.R. (de-DMSO, 5): 3.50 (4H, broad s), 3.63 (3H, s), 4.62 (2H, s), 4.83 (2H, ABq, J = 13Hz), 5.07 (1 H, d, J = 5Hz), 5.72 (1H, d, d, J = 5 and 8Hz), 6.77 (4H, s), 6.85 (1H, s), 6.70-7.60 (15H, m), 9.00 (1H, d, J = 8Hz )

4. 6.0 g of benzhydryl 7- (2-phenylacetamido) 3- [2- (4-methoxyphenoxy) acetoxymethyl] -3cephem-4-carboxylate, 5.65 g of phosphorus pentachloride, 2.2 g of pyridine and 7 , 3 ml of methanol was reacted with each other in a similar manner as in Production Example 8 (4) to form 4.6 g of benzhydryl-7-amino-3- [2- (4-methoxyphenoxy) acetoxymethyl] -3-cephem-4- carboxylate.

N.M.R. (de-DMSO, 5): 3.52 (2H, broad s), 3.68 (3H, s), 4.69 (2H, s), 4.60-5.10 (4H, m), 6.89 (4H, s), 6.96 (1H, s), 7.00-7.70 (10H, m)

Production Example 10

The following compounds were prepared in a similar manner to that in Preparation Example 8:

(1) benzhydryl-7-amino-3- (2-thenoyl) oxyme-

19 643 266

thyl3-cephem-4-carboxylate,

LR. (Nujol): 3400-3300, 1770, 1710, 1610.1520 cm "1

N.M.R. (de-DMSO, 5): 3.68 (2H, broad s), 4.90 (1H, d, J = 5Hz), 5.03 (2H, ABq, J = 13Hz), 5.12 (1H, d, J = 5Hz), 6.97 5 (lH, s), 7.17-7.67 (llH, m), 7.73-8.1 (2H, m)

(2) Benzhydryl-7-amino-3-cyclohexane-carbonyloxymethyl-3-cephem-4-carboxylate.

I.R. (Nujol): 3200, 1800, 1730, 1620 cm "1

N.M.R. (de-DMSO, 5): 0.83-2.0 (10H, m), 3.07-3.40 i «(1H, m), 3.58 (2H, broad s), 4.66-5.33 (4H, m), 6.93 (1H, s ), 7.0-7.58 (10H, m)

(3) Benzhydryl-7-amino-3- (N-phenylcarbamoyloxymethyl) -3-cephem-4-carboxylate.

I.R. (Nujol): 3420.3380, 1770.1725, 1660.1600, 1530 15 cm-1

N.M.R. (de-DMSO, Ô): 3.65 (2H, broad s), 4.83 (2H, ABq, J = 13Hz), 4.90 (1H, d, J = 5Hz), 5.10 (1H, d, J = 5Hz), 7.00 (IH, s), 6.83-7.73 (15H, m), 9.78 (1H, s)

(4) benzhydryl-7-amino-3- (4-nitrobenzoyloxymethyl) -

20 3-cephem-4-carboxylate hydrochloride.

I.R. (Nujol): 3400, 3350.1770, 1720, 1630, 1600, 1540 cm-1

N.M.R. (de-DMSO, 5): 3.74 (2H, broad s), 4.72-5.32 (4H, m), 6.92 (1H, s), 7.0-7.64 (10H, m), 8.12 (2H, d, J = 9Hz ), 8.32 «(2H, d, J = 9Hz)

example 1

3.0 g of ethoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer) and 40 ml of dry ethyl acetate were added at 0 30 to 5 ° C. with stirring to a suspension of a Vilsmeier reagent, which was based on conventional Was prepared from 1.0 g of dry dimethylformamide and 2.1 g of phosphorus oxychloride in 4.0 ml of dry ethyl acetate, and the resulting mixture was stirred at the same temperature for 30 minutes. The solution became at -10 ° C. with stirring to a solution of 3.7 g of 7-amino-3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid, 10.3 g of trimethylsilylacetamide and 6.8 g of bis (trimethylsilyl) acetamide in 80 ml of dry ethyl acetate 40 were added and the mixture was stirred at the same temperature for 1.5 hours. After adding 50 ml of water to the reaction mixture, an insoluble material was filtered off, the ethyl acetate layer in the filtrate was separated and extracted with 50 ml of an aqueous sodium bicarbonate solution. The aqueous extract was washed with ethyl acetate and acidified to pH 2.0 with concentrated hydrochloric acid. The precipitates were collected by filtration, washed with water and dried, yielding 2.3 g of 7- [2-ethoxyimino-2- (2-formami-50 dothiazol-4-yl) acetamido] -3 (1,3,4 -thiadiazoI-2-yl) thiomethyl ~ 3-cephem-4-carboxylic acid (syn isomer) was obtained in the form of a powder.

I.R. (Nujol): 3250, 1780, 1680 cm- '

N.M.R. (de-DMSO, 8): 1.31 (3H, t, J = 7.0Hz), 3.77 (2H, ss m), 4.28 (2H, q, J = 7.0Hz), 4.43 (2H, ABq, J = 13.0Hz ), 5.18 (1 H, d, J = 5.4Hz), 5.84 (1 H, d, d, J = 5.4 and 9.8Hz), 7.42 (1H, s), 8.53 (1H, s), 9.57 (1H, s), 9.66 (1H, d, J = 9.8Hz).

Example 2

0.96 g of phosphorus oxychloride were added at once to a suspension of 1.13 g of 2- (2-propynyloxyiminio) -2- (2-aminothiazol-4-yl) acetic acid (syn isomer) in 10 ml of dry tetrahydrofuran 2 ° C was added and the mixture was stirred at 2 to 4 ° C for 15 minutes. 1.0 g of 65 trimethylsilylacetamide was added dropwise and the resulting mixture was stirred at 2 to 6 ° C for 20 minutes. 0.96 g of phosphorus oxychloride was added and the mixture was stirred for 20 minutes. There were 0.45 g

643 266

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Dry dimethylformamide was added all at once at 4-6 ° C and the mixture was stirred for 1 hour to give a clear solution. On the other hand, 4.6 g of trimethylsilylacetamide became a stirred suspension of 1.65 g of 7-amino-3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-car-bonic acid in 20 ml of dry Ethyl acetate was added and the solution was stirred at 40 ° C for 30 minutes. To this solution, the tetrahydrofuran solution obtained above was added all at once at -30 ° C, and the resulting mixture was stirred at -5 to -20 ° C for 1 hour. 30 ml of water and 20 ml of ethyl acetate were added to the reaction mixture. An organic layer was separated and extracted with an aqueous sodium bicarbonate solution. The extract was adjusted to pH 3.0 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water, 1.4 g of 7- [2- (2-propynyl) -oxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1 , 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-car-bonic acid (syn isomer).

I.R. (Nujol): 3300, 1780.1680 cm- '

N.M.R. (da-DMSQ, 5): 3.43 (IH, m), 3.67 (2H, broad s), 4.42 (2H, ABq, J = 13Hz), 4.68 (2H, broad s), 5.13 (IH, d, J = 5Hz), 5.77 (1 H, d, d, J = 5 and 8Hz), 6.77 (1 H, s), 7.18 (2H, broad s), 9.50 (1 H, s), 9.60 (1 H, d, J = 8Hz)

Example 3

The Vilsmeier reagent was prepared in a conventional manner from 1.0 g of dry dimethylformamide, 4 ml of dry ethyl acetate and 2.1 g of phosphorus oxychloride. Then 45 ml of dry ethyl acetate and 2.85 g of 2-methoxy-imino-2- (2-formamidothiazol-4-yI) acetic acid (syn isomer) were added. This solution was added at -10 ° C to a stirred solution which was prepared by stirring 1 hour at 40 ° C of a mixture of 4.5 g of 7-amino-3- (1-hexyl-1 H-tetrazole-5 -yl) thiomethyl-3-cephem-4-carboxylic acid, 10.4 g of trimethylsilylacetamide and 90 ml of dry ethyl acetate, and the resulting mixture was stirred at -5 to -10 ° C for 1.5 hours. 50 ml of water were added to the reaction mixture and the ethyl acetate layer was separated. 40 ml of water was added and the mixture was adjusted to pH 7.0 with a saturated aqueous sodium bicarbonate solution. The aqueous layer was separated, washed with ethyl acetate and adjusted to pH 2.5 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water and dried under reduced pressure, whereby 6.18 g of 7- [2-methoxyimino-2- (2-form-amidothiazol-4-yl) acetamido] -3- (1 - hexyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) was obtained in the form of a powder.

I.R. (Nujol): 3250, 1777, 1680 cm- '

N.M.R. (dô-DMSO, 8): 0.85 (3H, t, J = 5.5Hz), 1.65 (6H, m), 2.78 (2H, m), 3.72 (2H, m), 3.93 (3H, s), 4.07- 4.59 (4H, m), 5.17 (1H, d, J = 5.0Hz), 5.83 (1H, d, d, J = 5.0, 8.2Hz), 7.46 (1H, s), 9.56 (1H, s), 9.70 (1 H, d, J = 8.2Hz)

Example 4

0.92 g of phosphorus oxychloride was added dropwise over a period of 3 minutes at -5 to -10 ° C. to a solution of 0.44 g of dimethylformamide in 2 ml of ethyl acetate. 20 ml of ethyl acetate was added and after 10 minutes, 1.29 g of 2-isopropoxyimino-2- (2-formamido-l, 3-thiazol-4-yl) acetic acid (syn isomer) at -5 to -10 ° C added. The mixture was stirred for 10 minutes to give a clear solution. On the other hand, 1.37 g of 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid was dissolved with stirring in a solution of 1.68 g of sodium bicarbonate in 30 ml of water, and then 20 ml of acetone was added. The ethyl acetate solution obtained above was added dropwise to the solution with stirring at 0 to 5 ° C. and at a pH of 6.5 to 7.5. After stirring at the same temperature for 20 minutes, the aqueous layer was separated and the acetone was distilled off. The remaining aqueous layer was adjusted to pH 3.0 with 10% hydrochloric acid with ice cooling and with stirring. The precipitates were collected by filtration, washed with water and dried, giving 1.5 g

7- [2-Isopropoxyimino-2- (2-formamido-1,3-thiazol-4-yl) aceta-mido] -3carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) was obtained.

I.R. (Nujol): 3460.3240, 1780, 1710, 1690, 1650 cm- '

N.M.R. (dó-DMSO, 8): 9.63 (1 H, d, J = 8Hz), 8.53 (1 H, s), 7.43 (1H, s), 6.60 (1H, s), 5.83 (1H, dd, J = 5, 8Hz), 5.20 (1H, d, J = 5Hz), 4.77 (2H, ABq J = 14Hz), 4.40 (1 H, m), 3.57 (2H,

wide s), 1.27 (6H, d, J = 6Hz)

Example 5

0.05 g of water was added to a suspension of 1.0 g of 2-allyloxyimino-2- (2-amino-1,3-thiazol-4-yl) acetic acid (syn isomer) in 10 ml of tetrahydrofuran. At 0 to 5 ° C, 0.84 g of phosphorus oxychloride was added and the mixture was stirred at the same temperature for 20 minutes. 0.66 g of trimethylsilylacetamide was added and the mixture was stirred at the same temperature for 20 minutes, then 0.84 g of phosphorus oxychloride was added, the resulting mixture was stirred at 0 to 5 ° C. for 20 minutes, then 45 g of dimethylformamide were added, and the resulting mixture was stirred at the same temperature for 1 hour. The solution obtained was added dropwise at -5 to 5 ° C. and at a pH of 7.0 to 8.0 to a solution which had been prepared by adding 15 ml of acetone and 15 ml of tetrahydrofuran to a solution of 1 , 45 g of 7-amino-3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid in a mixture of 0.42 g of sodium bicarbonate and 10 ml of water. The resulting mixture was stirred under ice cooling for 2 hours while keeping the pH of the mixture at 7.0 to 8.0, and then the pH was adjusted to 7.5. The insoluble material was filtered off and the filtrate was washed with ethyl acetate. The aqueous layer was adjusted to pH 6.0 and the organic solvent in the aqueous layer was distilled off under reduced pressure. The remaining aqueous layer was adjusted to pH 4.0 and an insoluble material was filtered off. The filtrate was adjusted to pH 3.0 and the precipitates were collected by filtration and dried to give 1.5 g of 7- [2-allyloxyimino-2- (2-amino-1,3-thiazole-4- yl) acetamido] -3- (1,3,4-thiadia-zol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

1st row (Nujol): 3350.1780.1680, 1630 cm- '

N.M.R. (dó-DMSO, 8): 9.63 (IH, d, J = 8Hz), 9.57 (IH, s), 7.23 (2H, m), 6.77 (1 H, s), 6.10 (1 H, m), 5.83 (1 H, dd, J = 5, 8Hz), 5.43 (1 H, m), 5.25 (1 H, m), 5.17 (1 H, d, J = 5Hz), 4.61 (2H, m), 4.47 ( 2H, ABq, J = 14Hz), 3.72 (2H, m)

Example 6

0.1 ml of water was added to a suspension of 2.0 g of 2-hexyloxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetic acid (syn isomer) in 20 ml of tetrahydrofuran. At 0 to 5 ° C, 1.4 g of phosphorus oxychloride was added and the mixture was stirred at the same temperature for 20 minutes. 1.3 g of trimethylsilylacetamide was added, and the mixture was stirred at the same temperature for 20 minutes, then 1.4 g of phosphorus oxychloride was added, and the resulting mixture became 20

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643 266

Stirred at 0 to 5 ° C for minutes, 0.75 g of dimethylformamide was added, and the resulting mixture was stirred at the same temperature for 1 hour. The solution obtained was suddenly at -20 ° C. to a solution of 3.3 g of 7-amino-3- (1H-l, 2,3-triazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid in a mixture of 30 ml of tetrahydrofuran and 6.8 g of trimethylsilylacetamide was added. The resulting mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was post-treated in a manner similar to that in the above examples, 1.5 g of 7- [2-hexyloxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- ( 1 H-1,2,3-triazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) was obtained.

I.R. (Nujol): 3100, 1780.1630 cm ~ '

N.M.R. (dó-DMSO, ô): 10.17 (IH, d, J = 8Hz), 8.17 (2H, m), 7.97 (IH, s), 7.25 (IH, m), 6.70 (IH, s), 5.73 (IH , dd, J = 5.8Hz), 5.13 (1H, d, J = 5Hz), 3.97 (2H,), 3.60 (2H, m), 1.25 (8H, m), 0.83 (3H, m)

Example 7

1.2 g of 2- (2-propynyl) oxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetic acid (syn isomer) were suspended in 15 ml of tetrahydrofuran. 1.0 g of phosphorus oxychloride was added at 0 to 5 ° C, and the mixture was added at 5 ° C for 20 minutes, and the mixture was stirred at the same temperature for 20 minutes. 0.5 g of trimethylsilylacetamide was added and the mixture was stirred at the same temperature for 20 minutes, then 1.0 g of phosphorus oxychloride was added, the resulting mixture was stirred at 0 to 5 ° C for 20 minutes, then 0.5 g of dimethylformamide was added, and the resulting mixture was stirred at the same temperature for 1 hour. The solution obtained was added dropwise at -5 to 5 ° C. and at a pH of 6.5 to 8.5 to a solution which had been prepared by adding 10 ml of acetone and 10 ml of tetrahydrofuran to a solution of 1. 9 g of 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid in a mixture of 0.4 g of sodium bicarbonate and 15 ml of water. The resulting mixture was stirred under ice-cooling for 2 hours while maintaining the pH of the mixture at 7.0 to 8.0, then the pH was adjusted to 7.5. An insoluble material was filtered off and the filtrate was washed with ethyl acetate. The aqueous layer was adjusted to pH 6.0 and the organic solvent in the aqueous layer was distilled off under reduced pressure. The remaining aqueous layer was adjusted to pH 4.0 and an insoluble material was filtered off. The filtrate was adjusted to pH 3.0 and the precipitates were collected by filtration and dried, yielding 2.2 g of 7- [2- (2-propynyl) oxyimino-2- (2-amino-l, 3-thiazole -4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3300, 1770, 1720, 1640 cm- '

N.M.R. (de-DMSO, S)

9.63 (IH, d, HJ = 8Hz), 7.27 (2H, m), 6.80 (1 H, s), 6.58 (2H, m), 5.77 (1H, dd, J = 5, 8Hz), 5.15 (1H , d, J = 5Hz), 4.76 (2H, ABq-J = 12Hz), 4.73 (2H, s), 3.50 (2H, m), 3.45 (1H, m)

Example 8

0.92 g of phosphorus oxychloride was added dropwise over a period of 3 minutes at -5 to -10 ° C. to a solution of 0.44 g of dimethylformamide in 2 ml of ethyl acetate. 20 ml of ethyl acetate was added and after 10 minutes, 1.29 g of 2-isopropoxyimino-2- (2-formamido-l, 3-thiazol-4-yl) acetic acid (syn isomer) at -5 to -10 ° C added. The mixture was stirred for 10 minutes to give a clear solution. On the other hand, 1.64 g of 7-amino3- (1-methyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-

4-carboxylic acid was dissolved in a solution of 1.68 g of sodium bicarbonate in 30 ml of water with stirring, and then 20 ml of acetone was added. The ethyl acetate solution obtained above was added dropwise to the solution with stirring at 0 to 5 ° C. and at a pH of 6.5 to 7.5. After stirring at the same temperature for 20 minutes, the aqueous layer was separated and the acetone was distilled off. The remaining aqueous layer was adjusted to pH 3.0 with 10% hydrochloric acid with ice cooling and with stirring. The precipitates were collected by filtration, washed with water and dried, giving 1.7 g of 7- [2-isopropoxyimino-2- (2-formamido-1,3-thiazol-4-yl) -acet-amido] -3 - (1-Methyl 1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) was obtained.

I.R. (Nujol): 3500, 3300, 1780, 1730, 1680 cm-1

N.M.R. (dó-DMSO, S): 9.62 (IH, d, J = 8Hz), 8.53 (IH, s) 7.40 (IH, s), 5.83 (IH, dd, J = 5, 8Hz), 5.17 (IH, d , J = 5Hz), 4.17 (2H, m), 3.97 (3H, s), 3.73 (2H, broad s), 1.27 (6H, d, J = 6Hz)

Example 9

0.51 g of phosphorus oxychloride was added dropwise over a period of 5 minutes at 5 ° C. to a solution of 0.24 g of dimethylformamide in 1 ml of dry ethyl acetate. After crystal precipitation, the mixture was stirred at 10 ° C for 30 minutes, then 9 ml of dry ethyl acetate and 0.89 g of 2-methoxyimino-2- [2- (2,2,2-trifluoroacetamido) -l, 3-thiazol-4-yl] acetic acid (syn isomer)

- Stirred 10 ° C to -5 ° C. The solution obtained was over a period of 5 minutes at -15 ° C to a solution of 1.0 g of 7-amino-3-benzoyloxymethyl-3-cephem-4-carboxylic acid and 3.2 g of trimethylsilylacetamide in 10 ml of dry Ethyl acetate was added dropwise, and the resulting mixture was stirred at -10 to -15 ° C for 1 hour. 10 ml of water was added to the reaction mixture and the ethyl acetate layer was separated. The aqueous layer was extracted with a further 10 ml of ethyl acetate. The ethyl acetate layers were combined and 20 ml of water was added. The resulting mixture was adjusted to about pH 6 with sodium bicarbonate. The aqueous layer was separated and 25 ml of ethyl acetate was added. The mixture was adjusted to pH 2.5 with ice cooling and with stirring with 10% hydrochloric acid. The ethyl acetate layer was separated, and the aqueous layer was further extracted with 15 ml and 10 ml of ethyl acetate. The ethyl acetate layers were combined with one another, washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, treated with activated carbon and evaporated under reduced pressure,

to obtain crystals which were dried under reduced pressure to give 1.15 g of 7- [2-methoxy-imino-2- {2- (2,2,2-trifluoroacetamido) -1,3-thiazole-4- yl} acet-amido] -3-benzoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).

1st row (Nujol): 3250, 1790, 1730, 1650 cm- '

N.M.R. (dö-DMSO, 8): 9.95 (1H, d, J = 8Hz), 7.92-8.16 (2H, m), 7.4-7.84 (3H, m), 7.6 (1H, s), 5.92 (1H, dd, J = 5, 8Hz), 5.26 (1H, d, J = 5Hz), 5.18 (2H, ABq, J = 13Hz), 3.96 (3H, s), 3.76 (2H, broad s)

Example 10

0.56 g of phosphorus oxychloride was suddenly added below 5 ° C. to a mixture of 0.6 g of 2-methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetic acid (syn isomer) and 6 ml of dry ethyl acetate was added and the mixture was stirred at 4-6 ° C for 20 minutes. At the same temperature, 0.3 g of bis (trimethylsilyl) -

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acetamide was added and the mixture was stirred at the same temperature for 10 minutes. To the obtained mixture, 0.56 g of phosphorus oxychloride was added all at once, and the mixture was stirred at the same temperature for 30 minutes, then 0.24 g of dimethylformamide was added dropwise, and the obtained mixture was stirred at 4 to 6 ° C for 30 minutes . The solution obtained was suddenly stirred at - 15 ° C to a solution of 1.1 g of 7-amino-3- (4-nitrobenzoyl) oxymethyl-3-cephem-4-carboxylic acid and 3.5 g of trimethylsilylacetamide in 20 ml Dry ethyl acetate was added and the resulting mixture was stirred at -5 to -10 ° C for 2 hours. The reaction mixture was adjusted to pH 7 to 7.5 at 0 ° C with a saturated aqueous sodium bicarbonate solution, stirred at pH 7 below 5 ° C for 1 hour, adjusted to pH 2.5 and filtered. The organic layer in the filtrate was separated and 20 ml of water was added. The mixture was adjusted to pH 6.5 with sodium bicarbonate. The aqueous layer was separated and washed with diethyl ether. The solvent remaining in the aqueous layer was removed by introducing nitrogen gas, and the aqueous layer was adjusted to pH 2.5 with 10% hydrochloric acid under ice-cooling. The precipitates were collected by filtration, washed with water and dried, giving 0.7 g

7- [2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (4-nitrobenzoyl) oxymethyl-3-cephgem-4-carboxylic acid (syn- Isomeres), mp 151 to 163 ° C (dec.), In the form of a pale yellow powder.

I.R. (Nujol): 3250-3350,2500-2600, 1780, 1725, 1680, 1650, 1600, 1535, 1350 cm- '

N.M.R. (dó-DMSO, ô): 9.68 (IH, d, J = 8Hz), 8.5 (4H, m), 7.28 (2H, s), 6.80 (1H, s), 5.88 (1H, dd, J = 5, 8Hz), 5.24 (1H, d, J = 5Hz), 5.20 (2H, ABq, J = 13Hz), 3.82 (3H, s), 3.72 f2H, ABq J = 18Hz)

Example 11

The following compounds were prepared in a manner similar to Examples 1 to 10:

(1) 7- [2-isopropoxyimino-2- (2-formamidothiazol-4-yl) ace-tamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl l-3-cephem-4- car-bonic acid (syn isomer).

LR. (Nujol): 3300, 3050, 1777, 1727, 1672 cm- '

N.M.R. (de-DMSO, 8): 1.28 (6H, d, J = 6Hz), 3.75 (2H, broad s), 4.43 (3H, m), 4.8 ~ 5.6 (1H), 5.90 (1 H, d, d, J = 5 and 8Hz), 7.45 (1H, s), 8.58 (1H, broad s), 9.60 (1H, s), 9.77 (1H, d, J = 8Hz), 12.80 (1H, broad s)

(2) 7- [2-Pentyloxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (l, 3,4thiadiazol-2-yl) thiomethyl-3-cephem-4-car- bonic acid (syn isomer).

I.R. (Nujol): 3300.3250, 1785, 1680 cm-1

N.M.R. (de-DMSO, Ô): 0.6-1.9 (9H, m), 3.72 (2H, broad s), 4.11 (2H, t, J = 6Hz), 4.47 (2H, ABq, J = 13Hz), 5.18 (1H , d, J = 5Hz), 5.82 (1H, d, d, J = 5 and 8Hz), 7.41 (1H, s), 8.53 (1H, s), 9.57 (1H, s), 9.64 (1H, d, J = 8Hz), 12.65 (1H, s)

(3) 7- [2-butoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (l-methyl-lH-tetrazol-5-yl) thiomethyl -3-cephem-4- carboxylic acid (syn isomer).

I.R. (Nujol): 3300.2550-2600, 1775.1710.1690.1670, 1645 cm-1

N.M.R. (de-DMSO, 5): 0.90 (3H, m), 1.2-1.8 (4H, m), 3.70 (2H, ABq, J = 18Hz), 3.94 (3H, s), 4.12 (2H, m), 4.32 (2H, ABq, J = 13Hz), 5.16 (1 H, d, J = 5Hz), 5.80 (1 H, d, d, J = 5 and 8Hz), 7.37 (1H, s), 8.50 (1H, s ), 9.62 (1H, d, J = 8Hz), 12.6 (1H, s)

(4) 7- [2- (2-propynyloxyimino) -2- (2-formamidothiazol-4-yl) acetamido] -3- (l-methy] -lH-tetrazol-5-yl) thiome-

thyl3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3240, 2110, 1770, 1665 cm- '• N.M.R. (de-DMSO, 5): 3.49 (1H, m), 3.70 (2H, m), 3.96 (3H, s), 4.33 (2H, ABq, J = 15.0Hz), 4.76 (2H, m), 5.14 ( 1H, d, J = 5.0Hz), 5.80 (1 H, d, d, J = 5.0 and 8.0Hz), 7.44 (1H, s), 8.53 (IH, s), 9.74 (IH, d, J = 8.0 Hz)

(5) 7- [2-methoxyimino-2- (2-formamidothiazol-4-yl) acet- "amido] -3- (1-propyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem- 4-carboxylic acid (syn isomer).

I.R. (Nujol): 3180, 1775, 1665 cm-1.

N.M.R. (de-DMSO, ô): 0.85 (3H, t, J = 8.0Hz), 1.82 (2H, m), 3.69 (2H, m), 3.88 (3H, s), 4.06-4.66 (4H, m), 5.13 (1H, d, J = 5.0Hz), 5.81 (1H, d, d, J = 5.0 and 8.0 Hz), 7.42 (lH, s), 8.52 (1H, s), 9.65 (1H, d, J = 8.0Hz)

(6) 7- [2-allyloxyimino-2- (2-formamidothiazol-4-yl) aceta-mido] -3-propyl-lH-tetrazol-5-yl) thiomethyl-3cephem-4-car-bonic acid (syn- Isomeres).

I.R. (Nujol): 3180, 1775, 1670 cm-'N.M.R. (de-DMSO, S): 0.87 (3H, t, J = 8.0Hz), 1.65 (2H, m), 3.73 (2H, ABq, J = 16.0Hz), 4.00 - 4.53 (4H, m), 4.69 ( 2H, d, JH = 5.0Hz), 5.00-5.68 (3H, m), 5.68-6.36 (2H, m), 7.45 (1H, s), 8.56 (1H, s), 9.72 (1 H, d, J = 8.0Hz)

(7) 7- [2- (2-propynyloxyimino) -2- (2-formamidothiazol-4-yl) acetamido] -3- (l-propyl-lH-tetrazol-5-yl) thiomethyl-

3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3270.2125.1780, 1680 cm- '

N.M.R. (de-DMSO, 5): 0.87 (3H, t, J = 8.0Hz), 1.84 (2H, m), 3.50 (1H, m), 3.73 (2H, broad s), 4.03-4.59 (4H, m) , 4.78 (2H, m), 5.17 (1 H, d, J = 5.0Hz), 5.84 (1 H, dd, J = 5.0 and 8.0 Hz), 7.47 (1H, s), 8.56 (1H, s), 9.76 (1H, d, J = 8.0Hz)

(8) 7- [2-isopropoxyimino-2- (2-formamidothiazol-4-yl) ace-tamido] -3- (l-hexyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-

4-carboxylic acid (syn isomer).

I.R. (Nujol): 3175, 1780, 1670 cm- '

N.M.R. (de-DMSO, S): 0.66 (3H, t, J = 5.0Hz), 1.05-1.57 (6H, m), 1.92 (2H, m), 3.77 (2H, m), 4.10-4.72 (5H, m ), 5.24 (1H, d, J = 5.0Hz), 5.90 (1H, d, d, J = 5.0 and 8.4Hz), 7.43 (1H, s), 8.56 (1H, s), 9.64 (1H, d, J = 8.4Hz)

(9) 7- [2-Hexyloxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-hexyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4 -carboxylic acid (syn isomer).

I.R. (Nujol): 3175, 1785, 1642 cm- '

N.M.R. (de-DMSO, ô): 0.86 (6H, m), 1.00-1.57 (12H, m), 1.57-2.07 (4H, m), 3.75 (2H, m), 3.97-4.60 (8H, m), 5.18 (1H, d, J = 5.2Hz), 5.85 (1H, d, d, J = 5.2 and 8.4Hz), 7.41 (1H, s), 8.56 (1H, s), 9.65 (1H, d, J = 8.4 Hz).

(10) 7- [2-Allyloxyimino-2- (formamidothiazol-4-yl) acetamido] -3 (l-hexyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomeres).

I.R. (Nujol): 3180, 1780, 1680 cm-1

N.M.R. (de-DMSO, 8): 0.64-1.97 (11H, m), 3.68 (2H, AB ,, J = 18Hz), 4.30 (4H, m), 4.64 (2H, m). 5.00-5.46 (3H, m), 5.56-6.24 (2H, m), 7.37 (1H, s), 8.48 (1H, s), 9.67 (1H, d, J = 8Hz)

(11) Benzhydryl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3cyclohexane-carbonyloxymethyl-3-cephem-4-carboxylate (syn isomer).

I.R. (Kbr): 3300.1780.1730, 1690, 1630 cm- '

N.M.R. (de-DMSO, 8): 1.0-2.10 (10H, m), 3.13 (1H, m), 3.60 (2H, broad s), 3.93 (3H, s), 4.93 (2H, ABq, J = 13Hz), 5.22 (1H, d, J = 5Hz), 5.83 (1H, d, d, J = 5 and 8Hz), 6.87 (1H, s), 6.96 (1 H, s), 7.17 - 7.67 (10H, m), 9.70 (1 H, d, J = 8Hz)

(12) Benzhydryl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (4-methoxyphenoxy) acetoxymethyl] -3-cephem-4-carboxylate (syn isomer ).

I.R. (Nujol): 3300, 1780, 1725, 1680, 1620, 1530, 1510 cm-1

N.M.R. (de-DSMO, S): 3.58 (2H, broad s), 3.70 (3H, s), 3.87

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(13) Benzhydryl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3pivaloyloxymethyl-3-cephem-4-carboxylate (syn isomer).

I.R. (Nujol): 3300.1780.1725, 1680, 1620, 1530 cm- 'N.M.R. (dó-DMSO, 8): 1.13 (9H, s), 3.62 (2H, broad s), 3.88 (3H, s), 4.86 (2H, ABq, J = 14Hz), 5.26 (1H, d, J = 5Hz ), 5.96 (1H, d, d, J = 5 and 8 Hz), 6.80 (1H, s), 6.98 (1H, s), 7.12-7.68 (10H, m), 9.73 (1H, d, J = 8Hz )

(14) Benzhydryl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (2-thenoyl) oxymethyl-3-cephem-4-carboxy-ylate (syn isomer).

I.R. (Nujol): 3300, 1780, 1710, 1670, 1610, 1510 cm- 'N.M.R. (dó-DMSO, 8): 3.73 (2H, broad s), 3.87 (3H, s), 5.03 (2H, ABq, J = 13Hz), 5.27 (1H, d, J = 5Hz), 5.93 (1 H, d, d, J = 5 and 8Hz), 6.77 (1H, s), 6.97 (1H, s), 7.1-7.67 (11H, m), 7.77-8.1 (2H, m), 9.67 (1 H, d, J = 8Hz)

(15) BenzhydryI-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3 [N- (3-chlorophenyl) carbamoyloxymethyl] - 3-cephem-4-carboxylate (syn isomer ).

I.R. (Nujol): 3300, 1770, 1720, 1670, 1600, 1530 cm- 'N.M.R. (dó-DMSO, 8): 3.70 (2H, broad s), 3.90 (3H, s), 4.90 (2H, ABq, J = 13Hz), 5.27 (1H, d, J = 5Hz), 5.93 (1H, d , d, J = 5 and 8Hz), 6.80 (1H, s), 6.97 (1H, s), 6.87-7.77 (14H, m), 9.60 (1H, d, J = 8Hz), 10.00 (1H, s)

(16) Benzhydryl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (N-phenylcarbamoyloxymethyl) -3-cephem-4-carboxylate (syn isomer).

I.R. (Nujol): 3300, 1780, 1720, 1675, 1600, 1530, 1500 cm-1

N.M.R. (dó-DMSO, 8): 3.63 (2H, broad s), 3.80 (3H, s), 4.80 (2H, AB ,, J = 13Hz), 5.20 (1H, d, J = 5Hz), 5.86 (1H, d, d,) <5 and 8 Hz), 6.73 (1H, s), 6.93 (17) 7- [2- (2-propynyloxyimino) - 2- (2-formamidothiazol-4-yl) acetamido] -3 - (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3250, 1780, 1690, 1660, 1620, 1550, 1530 cm-1

N.M.R. (dó-DMSO, 8): 3.44 (IH, m), 3.68 (2H, ABq, J = 18Hz), 4.44) 2H, ABq, J = 13Hz), 4.74 (2H, m), 5.16 (1H, d, J = 5Hz), 5.80 (IH, d, d, J = 5 and 8Hz), 7.44 (1H, s), 8.50 (1H, s), 9.76 (1H, d, J = 8Hz), 12.66 (1H, broad s)

(18) 7- [2-ethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3 (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn- Isomeres).

I.R. (Nujol): 3300, 1775, 1660 cm- '(19) 7- [2-isopropoxyimino-2- (2-aminothiazol-4-yl) -acet-amido] -3- (l, 3,4-thiadiazole- 2-yl) thiomethyl-3-cephem-4-car-bonic acid (syn-isomer).

I.R. (Nujol): 3325, 1774, 1656 cm "1 (20) 7- [2-pentyloxyimino-2- (2-aminothiazol-4-yl) -acet-amido] -3 (1,3,4-thiadiazol-2 -yl) thiomethyl-3-cephem-4-car-bonic acid (syn-isomer).

I.R. (Nujol): 3350.3200.1775.1675 cm "1 (21) 7- [2-butoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3 (1-methyl-1 H-tetrazol-5 -yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3350, 3250, 2550-2600, 1780, 1700, 1670, 1630 cm-1

(22) 7- [2- (2-Propynyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (lmethyl-1H-tetrazol-5-yl) thiomethyl3-cephem-4-carboxylic acid ( syn isomer).

I.R. (Nujol): 3280, 2130, 1765, 1690, 1630 cm "1

(23) 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-propyl-1H-tetrazole -5-yl) thiomethyl-3-cephem-4- carboxylic acid (syn isomer).

I.R. (Nujol): 3350.1780.1670, 1630 cm- '

(24) 7- [2-Alyloxyimino-2- (2-aminothiazol-4-yl) acetamido] 3 (l-propyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn- Isomeres).

I.R. (Nujol): 3340, 3230, 1780, 1680, 1630 cm-1

(25) 7- [2- (2-propynyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3 (1-propyl-1 H-tetrazol-5-yl) thiomethyl3-cephem-4- carboxylic acid (syn isomer).

I.R. (Nujol): 3330, 2150, 1770, 1677, 1635 cm- '

(26) 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-hexyl-1-htetrazol-5-yl) thiomethyl-3-cephem-4- carboxylic acid (syn isomer).

I.R. (Nujol): 3350, 3230, 1777, 1675, 1627 cm- '

(27) 7- [2-Isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-hexyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4 -carboxylic acid (syn isomer).

I.R. (Nujol): 3320, 1780, 1675, 1630 cm- '

(28) 7- [2-Hexyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-hexyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4 -carboxylic acid (syn isomer).

I.R. (Nujol): 3350, 3230, 1765, 1670, 1615 cm "1

(29) 7- [2-Allyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-hexyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4 -carboxylic acid hydrochloride (syn isomer).

I.R. (Nujol): 3240, 1780, 1720, 1675 cm- '

(30) 7-2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -

3 [N- (3-chlorophenyl) carbamoyloxymethy] -

3-cephem-4-carobic acid (syn isomer).

I.R. (Nujol): 3320, 1780, 1710, 1680, 1600, 1540 cm "1

(31) 7- [2-Methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3cyclohexane-carbonyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3300, 1780, 1730, 1670 cm- '

(32) 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (4-methoxyphenoxy) acetoxymethyl] -3-cephem-

4-carboxylic acid (syn isomer).

I.R. (Nujol): 3300, 1780, 1730, 1680, 1635 cm- '

(33) 7- [2-Methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3pivaloyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3300, 1780, 1720, 1670, 1540 cm- '

(34) 7- [2-Methoxyimino-2- (2-aminothiazoI-4-yl) acetamido] -3- (2-thenoyl) oxymethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3250, 1780, 1710, 1680, 1635, 1530 cm - '(35) Benzhydryl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3 (4- nitrobenzoyloxymethyl) -3-cephem-4-carboxylate (syn isomer).

I.R. (Nujol): 3300, 1780, 1720, 1670, 1600, 1520 cm- '

N.M.R. (dó-DMSO, 8): 3.43 (2H, broad s), 3.92 (3H, s), 5.08 (2H, ABq, J = 13 Hz), 5.2 (1 H, d, J = 5Hz), 6.00 (1 H, d, d, J = 5 and 8Hz), 6.83 (1H, s), 7.00 (1H, s), 7.10-7.80 (10H, m), 8.15 (2H, d, J = 9Hz), 8.38 (2H, d. J = 9Hz), 9.73 (1H, d, J = 8Hz)

(36) Benzhydryl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (4-aminobenzoyloxymethyl) -3-cephem-4-carboxylate (syn isomer).

I.R. (Nujol): 3280, 1780, 1710, 1670, 1605, 1520 cm- '

(37) 7- [2-Methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3 (4-aminobenzoyloxymethyl) -3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3350, 1780, 1680, 1605, 1540 cm- '

(3 8) 7- [2-Methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (N-phenylcarbamoyloxymethyl) -3-cephem-4-car-bonic acid (syn-isomer).

I.R. (Nujol): 3300, 1780, 1710, 1670, 1600 cm- '

(39)

7- [2-isobutoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] cephalosporanic acid (syn isomer).

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N.M.R. (de-DMSO, S): 9.56 (1H, d, J = 8Hz), 6.72 (1H, s), 5.78 (1H, dd, J = 5, 8Hz), 5.14 (1H, d, J = 5Hz), 4.83 (2H, ABq, J = 14Hz), 3.82 (2H, d, J = 7Hz), 3.54 (2H, ABq, J = 17Hz), 2.02 (3H, s), 1.98 (1 H, m), 0.88 ( 6H, d, J = 7Hz)

(40) 7- [2-Cyclohexyloxyimino-2- (2-amino-1,3-thiazol-4-y]) acetamido] cephalosporanoic acid (syn isomer).

I.R. (Nujol): 3400-3200, 1780, 1740, 1670, 1630, 1530 cm-1

N.M.R. (de-DMSO, 5): 9.46 (1H, d, J = 8Hz), 6.72 (1H, s),

5.76 (1H, dd, J = 5, 8Hz), 5.10 (1H, d, J = 5Hz), 4.84 (2H, ABq, J = 13Hz), 4.00 (1H, m), 3.50 (2H, broad s), 2.00 (3H, s), 1.00-2.00 (10H, m)

(41) 7- [2- (2-propynyl) oxyimino-2- (2-amino-

1,3thiazol-4-yl) acetamido] cephalosporanoic acid (syn isomer).

I.R. (Nujol): 3310, 1780, 1740, 1670 cm- 'N.M.R. (de-DMSO, 8): 9.72 (1 H, d, J = 8Hz), 7.3 (2H, m), 6.83 (1H, s), 5.83 (1H, dd, J = 5, 8Hz), 5.20 (1H , d, J = 5Hz), 4.87 (2H, ABq J = 13Hz), 4.77 (2H, d, J = 2Hz), 3.60 (2H, m), 3.50 (IH, m), 2.11 (3H, s)

(42) 7- [2-Propoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (l-methyl-lH-tetrazol-5-yl) thiomethyl- 3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3400-3200, 1780, 1670, 1630, 1535 cm- 'N.M.R. (de-DMSO, 5) 9.57 (1 H, d, J = 8Hz), 6.72 (1H, s),

5.77 (1H, dd, J = 5, 8Hz), 5.13 (1H, d, J = 5Hz), 4.30 (2H, ABq, J = 14Hz), 4.02 (2H, t, J = 7Hz), 3.93 (3H, s), 3.69 (2H, ABq, J = 18Hz), 1.64 (2H, m), 0.90 (3H, t, J = 7Hz)

(43) 7- [2-Pentyloxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3300, 1770, 1660, 1630 cm- 'N.M.R. (de-DMSO, 5): 9.52 (1H, d, J = 8Hz), 7.20 (2H, m), 6.68 (1H, s), 5.74 (1H, dd, J = 4, 8Hz), 5.10 (1H , d, J = 4Hz), 4.30 (2H, ABq. J = 13Hz), 4.02 (2H, t, J = 6Hz). 3.90 (3H, s), 3.66 (2H, ABq, J = 18Hz), 1.60 (2H, m), 1.30 (4H, m), 0.82 (3H, t, J = 6Hz)

(44) 7- [2-Hexyloxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (l-methyl-1H-tetrazol-5-yl) thiomethyl- 3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3350, 3250, 1780, 1670, 1630 cm'1 N.M.R. (de-DMSO, 8): 10.25 (1H, d, J = 5Hz), 7.25 (2H, m), 6.73 (1H, s), 5.77 (1H, dd, J = 5, 8Hz), 5.13 (1H, d, J = 5Hz), 4.17 (2H, m), 3.91 (3H, s), 3.67 (2H, m), 1.33 (8H, m), 0.83 (3H, m)

(45) 7- [2-ethoxyimino-2- (2-formamido-l, 3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3500.3300, 1780.1710, 1660 cm- 'N.M.R. (de-DMSO, 8): 9.67 (1H, d, J = 8Hz), 8.53 (1H, s), 7.43 (1H, s), 6.58 (1H, s), 5.87 (1H, dd, J = 5, 8Hz), 5.23 (1H, d, J = 5Hz), 4.80 (2H, ABq, J = 13Hz), 4.23 (2H, q, J = 7Hz), 3.57 (2H, broad s), 1.3 (3 H, t , J = 7Hz)

(46) 7- [2-ethoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3300, 3200, 1780, 1720, 1660 cm- 'N.M.R. (de-DMSO, 8): 9.58 (1H, d, J = 8Hz), 7.33 (1H, broad s), 6.77 (1 H, s), 6.58 (1 H, s), 5.83 (1H, dd, J = 4.8 Hz), 5.20 (1 H, d, J = 4 Hz), 4.77 (2H, ABq, J = 12 Hz), 4.16 (2H, q, J = 7 Hz), 3.53 (2H, broad s), 1.23 ( 3H, t, J = 7Hz)

(47) 7- [2-Propoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3250, 3200, 1780, 1700, 1660, 1525 cm "1 N.M.R. (de-DMSO, 8): 9.62 (1H, d, J = 8Hz), 8.50 (1H, s),

7.43 (1H, s), 6.57 (2H, broad s), 5.84 (1H, dd, J = 5, 8Hz), 5.18 (1H, d, J = 5Hz), 4.58 (2H, ABg, J = 13Hz), 4.08 (2H, t, J = 7Hz), 3.54 (2H, ABq, J = 18Hz), 1.68 (2H, m), 0.92 (3H, t, J = 7Hz)

(48) 7- [2-isobutoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3450,3300,1780, 1710, 1680, 1610 cm- 'N.M.R. (de-DMSO, 8). 9.6 (1H, d, J = 8Hz), 8.5 (1H, s), 7.18 (1H, s), 6.6 (2H, broad s), 5.8 (1H, dd, J = 5, 8Hz), 5.15 (1H, d, J = 5Hz), 4.76 (2H, ABq, J = 13Hz), 3.84 (2H, d, J = 6Hz), 3.5 (2H, ABq, J = 18Hz), 2.04 (1H, m), 0.88 (6H , d, J = 6Hz)

(49) 7- [2-Isobutoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3300, 1770, 1730, 1660 cm "1 NMR (de-DMSO, 8): 9.55 (1H, d, J = 9Hz), 7.27 (2H, broad s), 6.73 (1H, s), 6.60 (1H, broad s), 5.83 (1H, dd, J = 5, 9Hz), 5.20 (1H, d, J = 5Hz), 4.80 (2H, ABq, J = 12 Hz), 3.87 (2H, d, J = 7Hz), 3.53 (2H, ABq, J = 18Hz), 0.90 (6H, d, J = 7Hz)

(50) 7- [2-Allyloxyimino-2- (2-amino-1,3-thiazole -4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3300, 1770, 1720, 1660, 1630 cm- 'N.M.R. (de-DMSO, 8): 9.82 (1H, d, J = 8Hz), 7.20 (2H, m), 6.92 (1H, s), 6.7 (2H, m), 6.0 (1H, m), 5.80 (1H , dd, J = 5, 8Hz), 5.40 (1H, m), 5.22 (1H, m), 5.13 (1H, d, J = 5Hz), 4.70 (2H, ABq, J = 14Hz), 4.65 (2H, m), 3.50 (2H, ABq, J = 16Hz).

(51) 7- [2-Propoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3 - (1,3,4-thiadiazol-2-yl) thiomethyl -3 -cephem-4-car-bonic acid (syn isomer).

I.R. (Nujol) :) 3400-3200, 1780, 1670, 1625, 1540 cm- 'N.M.R. (de-DMSO 8): 9.50 (1 H, s), 9.50 (1 H, d, J = 8HZ), 6.68 (1H, s), 5.74 (1H, dd, J = 5, 8Hz), 5.12 (1H , d, J = 5Hz), 4.40 (2H, ABq, J = 14Hz), 3.98 (2H, t, J = 7Hz), 3.66 (2H, ABq, J = 17Hz), 1.62 (2H, m), 0.87 ( 3H, t, J = 7Hz)

(52) 7- [2-ethoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetamido] -3- (1 H-1,2,3-triazol-5-yl) thiomethyl -3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3500, 3200, 1780, 1670, 1620 cm- 'N.M.R. (de-DMSO, 8): 9.64 (1H, d, J = 8Hz), 8.5 (1H, s), 7.9 (1H, s), 7.4 (1H, s), 5.76 (1H, dd, J = 4, 8Hz), 5.14 (1H, d, J = 4Hz), 4.1 (2H, q, J = 7Hz), 3.92 (2H, ABq, J = 13Hz) (, 3.58 (2H, AB ,, J =: 18Hz), 1.26 (6H, t, J = 7Hz)

(53) 7- [2-ethoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (1 H-1,2,3-triazol-5- yl) thiomethyl-3-cephem-4-car-bonic acid (syn-isomer).

I.R. (Nujol): 3350, 3150, 1770, 1670 cm- 'N.M.R. (de-DMSO, 8): 9.56 (1H, d, J = 9Hz), 7.92 (1H, s), 7.28 (1H, m), 6.75 (1H, s), 5.75 (1H, dd, J = 5, 9Hz), 5.06 (1H, d, J = 5Hz), 4.05 (2H, q, J = 7Hz), 3.9 (2H, m), 3.64 (2H, ABq, J = 17Hz), 1.24 (3H, t, J = 7Hz)

(54) 7- [2-Propoxyimino-2- (2-formamido-l, 3-thiazol-4-yl) acetamido] -3- (1 H-1,2,3-triazol-5-yl) thiomethyl -3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3300-3100, 1780, 1680, 1650, 1550 cm "1 NMR (de-DMSO, 8): 9.62 (1H, d, J = 8Hz), 8.50 (1H, s), 7.92 (1H, s ), 7.38 (1H, s), 5.78 (1H, dd, J = 5, 8Hz), 5.15 (1H, d, J = 5Hz), 4.20-3.70 (4H, m), 3.65 (2H, ABq, J = 17Hz), 1.66 (1H, m), 0.90 (3H, t, J = 7Hz)

(55) 7- [2-propoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (1 H-1,2,3-triazol-5-yl) thiomethyl-3-cephem-4-car-bonic acid (syn-isomer).

I.R. (Nujol): 3400-3100, 1770, 1670, 1630, 1530 cm- 'N.M.R. (de-DMSO, 8): 9.58 (1H, d, J = 8Hz), 7.97 (1H, s), 6.77 (1H, s), 5.78 (1H, dd, J = 5, 8Hz), 5.18 (1H, d, J = 5Hz),

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4.23-3.76 (4H, m), 3.67 (2H, broad s), 1.67 (2H, m), 0.93 (3H, t, J = 7Hz)

(56) 7- [2-Isopropoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (1 H-1,2,3-triazol-5-yl) thiomethyl -3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3300, 3150, 1780, 1670, 1640 cm- '

N.M.R. (dó-DMSO, 8): 9.50 (1H, d, J = 9Hz), 7.97 (1H, s), 6.73 (1H, s), 5.77 (1H, dd, J = 5.9Hz), 5.17 (1H, d, J = 5Hz), 4.33 (1H, m), 4.0 (2H, ABq, J = 13Hz), 3.67 (2H, ABq, J = 18Hz), 1.23 (6H, d, J = 6Hz)

(57) 7- [2-isobutoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (1 H-1,2,3-triazol-5-yl) thiomethyl-3-cephem-4-car-bonic acid (syn-isomer)

I.R. (Nujol): 3470, 3320, 3200, 3160, 1770, 1660 cm-1

N.M.R. (dô-DMSO, 8): 9.57 (1H, d, J = 9Hz), 7.97 (1H, s), 7.22 (2H, broad s), 6.75 (1H, s), 5.77 (1H, dd, J = 5 , 9Hz), 5.18 (1H, d, J = 5Hz), 4.03 (2H, ABq, J = 12Hz), 3.88 (2H, d, J = 6Hz), 3.70 (2H, ABq, 3.88 (2H, d, J = 6Hz), 3.70 (2H, ABq, J = 18Hz), 2.0 (1H, m), 0.92 (6H, d, J = 6Hz)

(58) 7- [2- (2-Propynyl) oxyimino-2- (2-amino-l, 3-thiazoI-4-yl) acetamido] -3- (1 H-1,2,3-triazol-5 -yl) -thiome-thyl3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3320, 3150, 1770, 1670, 1630 cm- '

N.M.R. (de-DMSO, 8): 9.67 (1H, d, J = 8Hz), 7.98 (1H, s), 6.83 (1H, s), 5.75 (1H, dd, J = 4, 8Hz), 5.18 (1H , d, J = 4Hz), 4.77 (2H, m), 4.0 (2H, ABq, J = 13Hz), 3.70 (2H, ABq, J = 18Hz), 3.48 (1H, m)

(59) 7- [2-Isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3300, 3200, 1780, 1720, 1640 cm- '

(60)

7- [2-propoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-car-

bamoyloxymethyl-3-cephem-4-carboxylic acid hydrochloride

(syn isomer).

I.R. (Nujol): 3350.3200.1770, 1720.1665.1630.1550 cm-1

(61) 7- [2-Isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (l-methyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3330.3250.1780, 1680 cm- '

(62) 7- [2-Methoxyimino-2- {2- (2,2,2-trifluoroacetamido) -l, 3thiazol-4-yl} acetamido] -3- (4-nitrobenzoyl) ocyme-thyl3-cephem-4 -carboxylic acid (syn isomer), pale yellow powder

I.R. (Nujol): 3200, 2500-2600, 1785, 1720, 1680, 1650, 1600, 1525, 1355 cm- '

N.M.R. (de-DMSO, 8): 9.80 (1H, d, J = 8Hz), 8.4 (4H, m), 7.60 (1H, s), 5.78 (1H, dd, J = 5, 8Hz), 5.25 (1H, d, J = 5Hz), 5.15 (2H, ABq, J = 13Hz), 3.94 (3H, s), 3.75 (2H, ABq,

J = 18Hz)

(63) 7- [2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-benzoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3300.1780.1720.1680 cm ~ '

N.M.R. (de-DMSO, 8): 9.63 (1H, d, J = 8Hz), 7.87-8.1 (2H. m), 7.48-7.75 (3H, m), 6.75 (1H, s), 5.83 (1H, dd, J = 5, 8Hz), 5.19 (1H, d, J = 5Hz), 5.15 (2H, ABq, J = 13Hz), 3.83 (3H, s), 3.72 (2H, broad s)

(64) 7- [2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-phenylacetoxymethyi-3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3350, 3300, 1780, 1710, 1660, 1542, 1535, 1460, 1400,1380, 1320, 1280,1260,1240, 1130,1115,1065, 1042,965,720 cm- '

N.M.R. (de-DMSO, 8): 7.33 (5H, s), 7.23 (2H, broad s), 6.78 (1 H, s), 5.81 (1 H, dd, J = 4, 8Hz), 5.16 (1 H, d, J = 4Hz), 4.78 and 5.06 (2H, ABq, J = 8Hz), 3.9 (3H, s), 3.73 (2H, s), 3.5 (2H,

wide s)

(65) 7- [2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-hexanoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3350,3300,1780,1700, 1660, 1535,1460, 1400,1375, 1340,1315, 1280,1255,1045 cm- '

N.M.R. (de-DMSO, 8): 9.63 (1H, d, J = 8Hz), 7.24 (2H, broad s), 6.76 (1H, s), 5.81 (1H, dd, J = 4, 8Hz), 5.17 (1H , d, J = 4Hz), 4.75 and 5.03 (2H, ABq, J = 12Hz), 3.84 (3H, s), 3.45 and 3.67 (2H, ABq J = 18Hz), 2.32 (2H, t, J = 8Hz) , 1-1.7 (6H, m), 0.85 (3H, t, J = 3Hz)

(66) 7- [2-Methoxyimino-2- (2-formamido-l, 3-thiazol-4-yl) acetamido] -3 (2-benzothiazolyl) thiomethyl-3-cephem-4-car-bonic acid (syn -Isomeres).

I.R. (Nujol): 3200, 1780, 1680, 1620, 1545, 1460, 1435, 1385, 1040, 1000 cm- '

N.M.R. (de-DMSO, 8): 9.7 (1H, d, J = 8Hz), 8.53 (1H, s), 7.66-8.16 (2H, m), 7.16-7.66 (3H, m), 5.83 (1H, dd, J = 5, 8Hz), 5.18 (1 H, d, J = 5Hz), 4.23 and 4.81 (2H, ABq, J = 15Hz), 3.93 (3H, s), 3.73 (2H, broad s)

(67) 7- [2-Propoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3methyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3450, 3300, 1775, 1725, 1680, 1655, 1620, 1590, 1555 cm- '

N.M.R. (de-DMSO, 8): 0.88 (3H, t, J = 7Hz), 1.67 (2H, m), 2.00 (3H, s), 3.43 (2H, ABq, J = 14Hz), 4.03 (2H, 6, J = 7Hz), 5.10 (1H, d, J = 5Hz), 5.75 (1H, d, d, J = 5 and 8 Hz), 7.40 (1H, s), 8.53 (1H, s), 9.60 (1H, d, J = 8Hz), 12.7 (1H, broad s)

(68)

7- [2-Hexyloxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3methyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3310, 3230, 3080, 1780, 1690, 1660 cm- '

N.M.R. (de-DMSO, 8): 0.6-2.2 (11H, m), 2.05 (3H, s), 3.64 (2H, AB ,, J = 19Hz), 4.12 (2H, t, J = 6 Hz), 5.13 ( 1H, d, J = 5Hz), 5.74 (1H, d, d, J = 5 and 8Hz), 7.41 (1 H, s), 8.52 (1 H, s), 9.57 (1 H, d, J = 8Hz ), 12.69 (1 H, broad s)

(69) 7- [2-Propoxyimino-2- (2-aminothiazol-4-yl) acetamido] 3-methyl-3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3300.1775.1655.1635.1545 cm- '

(70) 7- [2-Hexyloxyimino-2- (2-aminothiazol-4-yl) aceta-mido] -3methyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3420.3170.3070.1765, 1720, 1670 1630 cm- '

Example 12

0.85 g of concentrated hydrochloric acid was cooled to a stirred solution of 2.3 g of 7- [2-ethoxy-imino-2- (2-formamidothiazol-4-yl) acetamido] -3- (l, 3,4-thia- diazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) was added in a mixture of 23 ml of methanol and 23 l of tetrahydrofuran, and the mixture was stirred at ambient temperature for 2.5 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in a saturated aqueous sodium bicarbonate solution (pH 7.0). The aqueous solution was washed with ethyl acetate and adjusted to pH 3.5 with concentrated hydrochloric acid. The precipitates were collected by filtration, washed with water and dried, giving 1.865 g of 7- [2-ethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazole -2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) was obtained in the form of a powder.

1st row (Nujol): 3300, 1775.1660 cm- '

N.M.R. (de-DMSO, 8): 1.67 (3H, t, J = 7.6 Hz), 3.75 (2H, m), 4.16 (2H, q, J = 7.6Hz), 4.48 (2H, ABq, J = 13.6Hz) , 5.18 (1 H, d, J = 5.2Hz), 5.83 (1 H, d, d, J = 5.2 and 8.0Hz), 6.79 (1H, s), 7.38 (2H, broad s), 9.63 (1H, s), 9.63 (1H, d, J = 8.0Hz).

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Example 13

2.1 g of concentrated hydrochloric acid were cooled to a solution of 6.0 g of 7- [2-methoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3 (1-hexyl-1H-tetrazole) while cooling with ice and with stirring -5-yl) -thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) in 60 ml of methanol was added and the mixture was stirred at ambient temperature for 4 hours. The solvent was removed from the reaction mixture and 50 g of ethyl acetate was added. The mixture was adjusted to pH 7.0 with a saturated aqueous sodium bicarbonate solution. The aqueous layer was separated, washed with ethyl acetate and adjusted to pH 3.5 with concentrated hydrochloric acid. The precipitates were collected by filtration, washed with water and dried under reduced pressure, giving 4.62 g

7- [2-Methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-h-exyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomeres) received.

LR. (Nujol): 3350, 3230, 1777, 1675, 1627 cm- '

N.M.R. (de-DMSO, 8): 0.82 (3H, t, J = 5.0Hz), 1.23 (6H, m), 1.80 (2H, m), 3.69 (2H, m), 3.85 (3H, s), 4.05- 4.63 (4H, m), 5.12 (1H, d, J = 5.0Hz), 5.75 (1H, d, d, J = 5.0, 8.6Hz), 6.76 (1 H, s), 7.23 (2H, broad s) , 9.59 (1 H, d, J = 8.6Hz)

Example 14

1 ml of concentrated hydrochloric acid became a solution of 1.3 g of 7- [2-isopropoxyimino-2- (2-formamido-l, 3-thiazol-4-yl) -acetamido] -3carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) added in a mixture of 10 ml of tetrahydrofuran and 10 ml of methanol. The mixture was stirred at ambient temperature for 3.5 hours and then concentrated to dryness. Water was added to the residue and sodium bicarbonate was added to the mixture to form a solution. The solution was adjusted to pH 3.0 with concentrated hydrochloric acid with ice cooling. The precipitates were collected by filtration, washed with water and dried, giving 0.25 g of 7- [2-isopropoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3carbamoyloxyme-methyl- 3-cephem-4-carboxylic acid (syn isomer) was obtained.

I.R. (Nujol): 3300.3200, 1780, 1720, 1640 cm- '

N.M.R. (de-DMSO, 8): 9.48 (1H, d, J = 8Hz), 7.24 (2H, broad s), 6.7 (1H, s), 6.54 (1H, s), 5.75 (1H, dd, J = 5 , 8Hz), 5.16 (1H, d, J = 5Hz), 4.72 (2H, ABq, J = 13Hz), 4.3 (1H, m), 3.5 (2H, broad s), 1.22 (6H, d, J = 6Hz )

Example 15

0.5 g of 7- [2-propoxyimino-2- (2-formamido-l, 3-thiazol-4-yl) acetamido] -3carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) was suspended in 15 ml of methanol . 0.2 ml of concentrated hydrochloric acid was added to the suspension and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated and the residue was washed with tetrahydrofuran, collected by filtration and dried to give 0.4 g of 7- [2-propoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetamido ] -3carbamoyloxymethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer) was obtained.

1st row (Nujol): 3350, 3200, 1770, 1720, 1665, 1630, 1550 cm-1

N.M.R. (de-DMSO, 8) 9.82 (1H, d, J = 8Hz), 6.98 (1H, s), 5.80 (1H, dd, J = 5, 8Hz), 5.22 (1 H, d, J = 5Hz), 4.80 (2H, ABq, J = 14Hz), 4.15 (2H, t, J = 7Hz), 3.58 (2H, broad s), 1.72 (2H, m), 0.92 (3 H, t, J = 7Hz)

Example 16

1 ml of concentrated hydrochloric acid became one

Solution of 1.5 g of 7- [2-isopropoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetamido] -3- (1-methyl-1 H-tetrazol-5-yl) thio-methyl-3-cephem-4-carboxylic acid (syn isomer) added in a mixture of 12 ml of tetrahydrofuran and 12 ml of methanol. The mixture was stirred at ambient temperature for 3.5 hours and then concentrated to dryness. Water was added to the residue and sodium bicarbonate was added to the mixture to form a solution. The solution was adjusted to pH 3.0 with concentrated hydrochloric acid with ice cooling. The precipitates were collected by filtration, washed with water and dried, yielding 0.8 g of 7- [2-isopropoxyimino-2- (2-amino-1,3-thiazol-4-yl) aceta mido] -3 - (1-Methyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) was obtained.

I.R. (Nujol): 3330, 3250.1780, 1680 cm- '

N.M.R. (de-DMSO, 8): 9.50 (1H, d, J = 8Hz), 6.70 (1H, s), 5.83 (1H, dd, J = 5, 8Hz), 5.17 (1H, d, J = 5Hz), 4.33 (2H, broad s), 3.97 (3H, s), 3.71 (2H, broad s), 1.25 (6H, d, J = 6Hz)

Example 17

A solution of 1.1g 7- [2-methoxyimino-2- {2- (2,2,2-tri-fluoroacetamido) -1,3-thiazol-4-yI} acetamido] -3-benzoyloxy-methyl-3-cephem -4-carboxylic acid (syn isomer) in 4 ml of acetone was added to a solution of 2.4 g of sodium acetate trihydrate in 10 ml of water at ambient temperature and the mixture was allowed to stand at ambient temperature for 3 hours. The acetone was distilled off under reduced pressure and 10 ml of water was added. The resulting mixture was adjusted to pH 2.5 with 10% hydrochloric acid with ice cooling. The precipitates were collected by filtration, washed with water and dried under reduced pressure to give 0.62 g of 7- [2-methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetamido] -3benzoyloxymethyl-3-cephem-4-carboxylic acid (syn-isomer) was obtained.

I.R. (Nujol): 3300, 1780, 1720, 1680 cm- '

N.M.R. (de-DMSO, 8): 9.63 (1H, d, J = 8Hz), 7.87-8.1 (2H, m), 7.48-7.75 (3H, m), 6.75 (1H, s), 5.83 (1H, dd, J = 5, 8Hz), 5.19 (1H, d, J = 5Hz), 5.15 (2H, ABq, J = 13Hz), 3.83 (3H, s), 3.72 (2H, broad s)

Example 18

The compounds listed below were prepared in a similar manner as in Examples 12 to 17:

(1) 7- [2-isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4- car-bonic acid (syn isomer).

I.R. (Nujol): 3325, 1774, 1656 cm- '

N.M.R. (de-DMSO, 8): 1.22 (6H, d, J = 6Hz), 3.70 (2H, broad s), 4.37 (3H, m), 5.15 (1H, d, J = 5Hz), 5.77 (1H, d , d, J = 5 and 8Hz), 6.70 (1H, s), 7.20 (2H, m), 9.50 (1H, d, J = 8Hz), 9.55 (1H, s)

(2) 7- [2-pentyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4- car-bonic acid (syn isomer).

I.R. (Nujol): 3350.3200.1775.1675 cm- '

N.M.R. (de-DMSO, 8): 0.62-2.0 (9H, m), 3.72 (2H, broad s), 4.06 (2H, t, J = 6Hz), 4.45 (2H, ABq, J = 13Hz), 5.17 (1H , d, J = 5Hz), 5.78 (1H, d, d, J = 5 and 8Hz), 6.73 (1H, s), 7.2 (2H, s), 9.5 (1H, d, J = 8Hz), 9.55 ( 1H, s)

(3) 7- [2-butoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-methyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carbon- acid (syn isomer).

I.R. (Nujol): 3350, 3250, 2550-2600, 1780, 1700, 1670, 1630 cm-1

N.M.R. (de-DMSO, 8): 1.0 (3H, m), 1.2-1.7 (4H, m), 3.77 (2H, ABq, J = 19Hz), 3.95 (3H, s), 4.15 (2H, m), 4.33 (2H, ABq,

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J = 13Hz), 5.20 (IH, d, J = 5Hz), 5.82 (1 H, d, d, J = 5, 8Hz), 6.73 (1H, s), 9.56 (1 H, d, J = 8Hz)

(4) 7- [2- (2-propynyloxyimino) -2- (2-aminothiazol-4-yl) ace-tamido] -3- (l-methyl-lH-tetrazol-5-yl) thiomethyl-3- cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3280.2130.1765, 1690, 1630 cm- 'N.M.R. (de-DMSO, ô): 3.45 (1H, m), 3.70 (2H, m), 3.96 (3H, s), 4.33 (2H, ABq, J = 16Hz), 4.71 (2H, m), 5.14 (1 H, d. J = 5.0Hz), 5.79 (1H, d, d, J = 5.0 and 8.0Hz), 6.79 (1H, s), 7.65 (2H, broad s), 9.33 (1H, d, J = 8.0) Hz)

(5) 7- [2-Methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3 (1-propyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carbonic acid (syn isomer).

I.R. (Nujol): 3350.1780, 1670, 1630 cm- 'N.M.R. (dó-DMSO, 5): 0.87 (3H, t, J = 7.0Hz), 1.84 (2H, m), 3.73 (2H, broad s), 3.89 (3H, s), 4.06-4.72 (4H, m) , 5.14 (1 H, d, J = 5.0Hz), 5.80 (1 H, d, d, J = 5.0 and 8.0Hz), 6.78 (1 H, s), 7.23 (2H, broad s), 9.59 (1H , d, J = 8.0Hz)

(6) 7- [2-allyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -

3- (1-propyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3340, 3230, 1780, 1680, 1630 cm "1 NMR (dó-DMSO, 8): 0.86 (3H, t, J = 7.0Hz), 1.83 (2H, m), 3.71 (2H, broad s ), 4.05 - 4.80 (6H, m), 5.01 - 5.53 (3H, m), 5.63 - 6.42 (2H, m), 6.75 (1 H, s), 7.20 (2H, broad s), 9.59 (1 H, d, J = 8.2Hz)

(7) 7- [2- (2-Propynyloxyimino) -2- (2-aminothiazol-4-yl) -acetamido-3 (1-propyl-1H-tetrazol-5-yl) thiomethyl-3-cephem -

4-carboxylic acid (syn isomer).

I.R. (Nujol): 3330, 2150, 1770, 1677, 1635 cm- 'N.M.R. (de-DMSO, S): 0.86 (3H, t, J = 7.0Hz), 1.84 (2H, m), 3.49 (1H, m), 3.73 (2H, m), 3.91-4.60 (4H, m), 4.75 (2H, m), 5.17 (1 H, d, J = 5.0 Hz), 5.80 (1 H, d, d, J = 5.0 and 8.0Hz), 6.86 (IH, s), 9.72 (1H, d, J = 8.0Hz)

(8) 7- [2-isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3 (1-hexyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4- carboxylic acid (syn isomer).

I.R. (Nujol): 3320, 1780, 1675, 1630 cm "1 NMR (de-DMSO, 8): 0.84 (3H, t, J = 6.0Hz), 1.00-1.50 (12H, m), 1.80 (2H, m) , 3.72 (2H, ABq, J = 17.0Hz), 4.10 - 4.60 (5H, m), 5.15 (1H, d, J = 5.0 Hz), 5.81 (1H, d, d, J = 5.0, 8.0Hz), 6.77 (1 H, s), 9.59 (1 H, d, J = 8.0 Hz)

(9) 7- [2-Hexyloxyimino-2- (2-aminothiazol-4-yl) acetamido] 3- (1-hexyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3350, 3230, 1765, 1670, 1615 cm- 'N.M.R. (de-DMSO, 8): 0.84 (6H, m), 1.26 (12H, m), 1.70 (4H, m), 3.20-4.60 (8H, m), 5.40 (1H, d, J = 5.0Hz), 5.68 (1H, d, d, J = 5.0, 8.0Hz), 6.72 (1 H, s), 7.23 (2H, broad s), 9.49 1 H, d, J = 8.0Hz)

(10) 7- [2-Allyloxyimino-2- (2-aminothiazol-4-yl) acetamido] 3- (l-hexyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid -hydrochloride (syn isomer).

I.R. (Nujol): 3240, 1780, 1720, 1675 cm- 'N.M.R. (de-DMSO, 8): 0.63-2.13 (11 H, m), 3.73 (2H, ABq, J = 18Hz), 4.08 - 4.90 (6H, m), 5.10 - 6.30 (5H, m), 6.94 (1H , s), 7.93 (2H, broad s), 9.80 (1H, d, J = 8Hz)

(11) 7- [2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] 3- (4-nitrobenzoyl) oxymethyl-3-cephem-4-carboxylic acid (syn- Isomeres), pale yellow powder, mp 151-163 ° C (dec.).

I.R. (Nujol): 3250-3350,2500-2600, 1780, 1725, 1680, 1650, 1600, 1535, 1350 cm "1

N.M.R. (de-DMSO, 8): 9.68 (1H, d, J = 8Hz), 8.5 (4H, m), 7.28 (2H, s), 6.80 (1H, s), 5.88 (1H, dd, J = 5, 8Hz), 5.24 (1H, d, J = 5Hz), 5.20 (2H, ABq, J = 13Hz), 3.82 (3H, s), 3.72 (2H, ABq, J = 18Hz)

(12) 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3phenylacetoxymethyl-3-cephem-4-carboxylic acid (syn-

Isomeres).

I.R. (Nujol): 3350, 3300, 1780, 1710, 1660, 1542, 1535, 1460, 1400, 1380, 1320, 1280, 1260, 1240, 1130, 1115, 1065, 1042, 965.720 cm- '

N.M.R. (de-DMSO, 8): 7.33 (5H, s), 7.23 (2H, broad s), 6.78 (1H, s), 5.81 (1H, dd, J = 4.8 Hz), 5.16 (1H, d, J = 4Hz), 4.78 and 5.06 (2H, ABq, J = 8Hz), 3.9 (3H, s), 3.73 (2H, s), 3.5 (2H, broad s)

(13) 7- [2-Methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetamido] -3hexanoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3350, 3300, 1780, 1700, 1660, 1535, 1460, 1400, 1375, 1340, 1315, 1280, 1255, 1045 cm "1

N.M.R. (de-DMSO, 8): 9.63 (1H, d, J = 8Hz), 7.24 (2H, broad s), 6.76 (1H, s), 5.81 (1H, dd, J = 4, 8Hz), 5.17 (1 H, d, J = 4Hz), 4.75 and 5.03 (2H, ABq, J = 12Hz), 3.84 (3H, s), 3.45 and 3.67 (2H, ABq, J = 18Hz), 2.32 (2H, t, J = 8Hz), 1-1.7 (6H, m), 0.85 (3H, t, J = 3Hz)

In addition, in a manner similar to Examples 12 to 17, the compounds of Examples 2 and 5 to 7 and the compounds of Examples 11 (11) to 11 (16), 11 (30) to (44), 11 (46), 11 (49) to 11 (51), 11 (53), 11 (55) to 11 (58) and 11 (69) to 11 (70).

Example 19

10.1 g of trifluoroacetic acid were cooled to a stirred solution of 3.1 g of benzhydryl-7- [2-methoxy-imino-2- (2-aminothiazol-4-yl) acetamido] -3- (N-phenylcarbamoyloxymethyl) with ice cooling ) -3-cephem-4-carboxylate (syn isomer) and 3.8 g of anisole in 30 ml of methylene chloride were added and the mixture was stirred at ambient temperature for 30 minutes. After the methylene chloride was removed from the reaction mixture, diethyl ether was added. The precipitates were collected by filtration. Water and ethyl acetate were added to the precipitates, and the mixture was adjusted to pH 7.5 with an aqueous sodium bicarbonate solution. The separated aqueous solution was adjusted to pH 6.0 with 10% hydrochloric acid, washed with ethyl acetate and evaporated to remove the organic solvent. The aqueous solution was adjusted to pH 3.0 with 10% hydrochloric acid under ice-cooling, and the precipitates were collected by filtration and dried to give 1.35 g of 7- [2-methoxyimino-2- (2-aminothiazole-4- yl) acetamido] - 3- (N-phenylcarbamoyloxymethyl) -3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3300, 1780, 1710, 1670, 1600 cm- 'N.M.R. (de-DMSO, 8): 3.67 (2H, broad s), 3.91 (3H, s), 4.98 (2H, ABq, J = 13Hz), 5.23 (1H, d, J = 5Hz), 5.83 (1H, d , d, J = 5 and 8Hz), 6.83 (1H, s), 6.97-7.67 (5H, m), 9.67 (1H, d, J = 8Hz), 9.8 (1H, s)

Example 20

The following compounds were prepared in a similar manner to that in Example 19:

(1) 7- [2-Methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [N- (3-chlorophenyl) carbamoyloxymethyl] -3-cephem-4-car-bonic acid (syn-isomer ).

I.R. (Nujol): 3320, 1780, 1710, 1680, 1600, 1540 cm- 'N.M.R. (de-DMSO, 8): 3.67 (2H, broad s), 3.90 (3H, s), 4.95 (2H, ABq, J = 13Hz), 5.20 (1H, d, J = 5Hz), 5.81 (1H, d , d, J = 5 and 8Hz), 6.78 (1H, s), 6.83-7.76 (4H, m), 9.63 (1H, d, J = 8Hz), 10.1 (1H, s)

(2) 7- [2-Methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cyclohexane-carbonyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3300, 1780, 1730, 1670 cm "1

N.M.R. (de-DMSO, 8): 1.0-2.03 (10H, m), 3.53 (2H, broad

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

28

s), 383 (IH, m), 3.87 (3H, s), 4.88 (2H, ABq, J = 13 Hz), 5.18 (1 H, d, J = 5Hz), 5.82 (1 H, d, d, J = 5 and 8Hz), 6.77 (1H, s), 7.28 (2H, broad s), 9.62 (1H, d, J = 8Hz)

(3) 7- [2-Methoxyimino-2- (2-aminothiazol-4-yl) acetamido] 3- [2- (4-methoxyphenoxy) acetoxymethyl] -3-cephem-4-carboxylic acid (syn isomer ).

I.R. (Nujol): 3300, 1780, 1730, 1680, 1635 cm- '

N.M.R. (de-DMSO, 5): 3.52 (2H, ABq, J = 17Hz), 3.68 (3H, s), 3.93 (3H, s), 4.74 (2H, s), 4.96 (2H, ABq, J = 13Hz) , 5.14 (1H, d, J = 5Hz), 5.78 (1 H, d, d, J = 5 and 8Hz), 6.90 (1 H, s), 6.86 (4H, s), 9.80 (1 H, d, J = 8Hz)

(4) 7- [2-Methoxyimino-2- (2-aminothiazol-4-yl) acetamido] 3-pivaloyloxymethyl -3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3300, 1780, 1720, 1670, 1540 cm-1

N.M.R. (de-DMSO, 5): 1.06 (9H, s), 3.50 (2H, broad s), 3.80 (3H, s), 4.83 (2H, ABq, J = 13Hz), 5.13 (1H, d, J = 5Hz ), 5.76 (1H, d, d, J = 5 and 8Hz), 6.75 (1H, s), 9.58 (1H, d, J = 8Hz)

(5) 7- [2-Methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3 (2-thenoyl) oxymethyl-3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3250, 1780, 1710,1680,1635,1530 cm- '

N.M.R. (de-DMSO, ô): 3.70 (2H, broad s), 3.92 (3H, s), 5.15 (2H, ABa, J = 13Hz), 5.22 (1H, d, J = 5Hz), 5.83 (1H, d , d, J = 5 and 8Hz), 6.85 (1H, s), 7.27 (1H, m), 7.83-8.12 (2H, m), 9.72 (1H, d, J = 8Hz)

(6) 7- [2-Methoxyimino-2- (2-aminothiazol-4-yl) aceta-mido] -3- (4-aminobenzoyloxymethyl) -3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3350, 1780,1680,1605, 1540 cm- '

N.M.R. (de-DMSO, 5): 3.72 (2H, broad s), 3.87 (3H, s), 5.08 (2H, ABq, J = 13 Hz), 5.20 (1 H, d, J = 5Hz), 5.83 (1H , d, d, J = 5

and 8Hz), 6.77 (1H, s), 6.88 (2H, d, J = 9Hz), 7.80 (2H, d, J = 9Hz), 9.67 (1 H, d, J = 8Hz)

In a manner similar to that in Example 19, the compounds of Examples 1 to 10 and the compounds of Examples 11 (1) to 11 (10), 11 (17) to 11 (34) and 11 (37 to 11 ( 70).

Example 21

To a solution of 4.3 g of benzhydryl 7- [2-methoxy-10 imino-2- (2-aminothiazol-4yl) acetamido] -3- (4-nitrobenzoyloxymethyl) -3-cephem-4-carboxylate ( syn-isomer) in a mixture of 50 ml of ethanol and 50 ml of tetrahydrofuran, 0.4 g of platinum (IV) oxide was added, and the suspension was subjected to a catalytic reduction at ambient temperature under atmospheric pressure for 3 hours. To . removal of the catalyst from the obtained

Mixing by filtration, the filtrate was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and the solution was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. The residue was pulverized in diethyl ether, giving 3.0 g of benzhydryl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (4-aminobenzoyloxymethyl) -3-cephem- 4-carboxylate (syn-25 isomeres) was obtained.

I.R. (Nujol): 3280, 1780, 1710, 1670, 1605, 1520 cm-1 N.M.R. (de-DMSO, 8): 3.76 (2H, broad s), 3.88 (3H, s), 5.02 (2H, ABq, J = 13Hz), 5.26 (1 H, d, J = 5Hz), 5.96 (1 H , d, d, J = 5 and 8Hz), 6.82 (1H, s), 6.90 (2H, d, J = 9Hz), 6.98 (1H, s), 30 7.04-7.66 (10H, m), 7.82 (2H , d, J = 9Hz), 9.72 (1H, d, J = 8Hz)

G

Claims (93)

643 266 2nd PATENT CLAIMS 1,3,7-Disubstituted 3-cephem-4-carboxylic acid compounds, characterized by the general formula R -conh Ci) in which mean: R1 amino, acylamino or aryl (lower) alkylamino R3 carboxy or esterified carboxy, R2 isobutyl and R4 acetoxy or R2 cyclo (lower) alkyl or lower alkynyl and R4 lower alkanoyloxy or R2 lower alkyl and R4 (Cs-CoJ alkanoyloxy or R2 (C2-C6) alkyl, lower alkenyl, cyclo (lower) alkyl or lower alkynyl and R4 hydrogen, carbamoyloxy, thiadiazolylthio, which can be substituted by a lower alkyl, or triazolylthio or R2 (C2-C6) alkyl, cyclo (lower) alkyl or lower alkynyl and R4 tetrazolylthio substituted by a methyl radical or R2 lower alkyl, lower alkenyl, cyclo (lower) alkyl or lower alkynyl and R4 aroyloxy which can be substituted by nitro or amino, cyclo (lower) alkane carbonyloxy, carbamoyloxy substituted by an aryl radical which in turn can be substituted by halogen, Aryl (lower) alkanoyloxy, aryloxy (lower) alkanoyloxy substituted with lower alkoxy, thenoyloxy, tetrazolylthio substituted with a (C3-C6) alkyl radical, or benzothiazolylthio, as well as their salts. 2. As salts according to claim 1, the pharmaceutically acceptable salts of the compounds of formula I. 3. A compound according to claim 1, characterized in that it is the syn isomer of a compound of general formula I. 4. A compound according to claim 3, characterized in that it is a compound of the following general formula and its salts, in particular its pharmaceutically acceptable salts. 5. A compound according to claim 4, characterized in that in the general formula R1 is amino or acylamino and R3 is carboxy or esterified carboxy. 6. A compound according to claim 5, characterized in that: R1 amino, lower alkanoylamino or halogen (lower rig) alkanoylamino, R3 carboxy or Ar (lower) alkoxycarbonyl, R2 isobutyl and R4 acetoxy or R2 cyclo (lower) alkyl or lower alkynyl and R4 lower alkanoyloxy or R2 lower alkyl and R4 (Cs-Cs) alkanoyloxy or R2 (C2-Cö) alkyl, lower alkenyl or lower alkynyl and R4 hydrogen, carbamoyloxy, thiadiazolylthio or Triazolylthio or R2 (C2-C6) alkyl or lower alkynyl and R4 tetrazolylthio substituted with a methyl radical or R2 lower alkyl, lower alkenyl or lower alkynyl and R4 aroyloxy, which may have nitro or amino, cyclo (lower) alkanecarbonyloxy, carbamoyloxy substituted with an aryl radical which may be substituted by halogen, aryl (lower) alkanoyloxy, aryloxy (low) alkanoyloxy substituted with lower alkoxy, thenoyloxy, tetrazolylthio substituted with a (C3-C6) alkyl group, or benzothiazolylthio. 7. Compound according to claim 6, characterized by the formula 7- [2-isobutoxyimino-2- (2-aminothiazol-4-yl) acetamido] cephalosporanic acid, syn isomer. 8. A compound according to claim 6, characterized in that R1 is amino, R3 is carboxy, R2 is cyclo (lower) alkyl or lower alkynyl and R4 is lower alkanoyloxy. 9. A compound according to claim 6, characterized in that R2 is cyclohexyl or 2-propynyl and R4 is acetoxy. 10. A compound according to claim 7, characterized by the formula 7- [2-cyclohexyloxyimino-2- (2-aminothiazol-4-yl) acetamido] cephalosporanic acid, syn isomer. 11. A compound according to claim 9, characterized by the formula 7- [2- (2-propynyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] - cephalosporanic acid, syn isomer. 12. A compound according to claim 6, characterized in that R1 is amino, R3 is carboxy or Ar (lower) alkoxycarbonyl, R2 is lower alkyl and R4 (Cs-Cej-alkanoyloxy). 13. A compound according to claim 12, characterized in that R3 is carboxy or diphenyl (lower) alkoxycarbonyl. 14. A compound according to claim 13, characterized in that R3 is carboxy or benzhydryloxycarbonyl, R2 is methyl and R4 is pivaloyloxy or hexanoyloxy. 15. A compound according to claim 14, characterized by the formula 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-pivaloyloxymethyl-3-cephem-4-carboxylic acid, syn-isomer. 16. A compound according to claim 14, characterized by the formula 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-hexanoyloxymethyl-3-cephem-4-carboxylic acid, syn-isomer. 17. A compound according to claim 6, characterized in that R1 is amino or lower alkanoylamino, R3 carboxy, R2 (C2-Cö) alkyl, lower alkenyl or lower alkynyl and R4 is hydrogen, carbamoyloxy, thiadiazolylthio or triazolylthio. 18. A compound according to claim 17, characterized in that R2 (C2-Cs) alkyl and R4 are hydrogen. 19. A compound according to claim 18, characterized in that R1 is amino or formamido and R2 is propyl or hexyl. 20. A compound according to claim 19, characterized by the formula 7- [2-propoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3methyl-3-cephem-4-carboxylic acid, syn-isomer. 21. A compound according to claim 19, characterized by the formula 7- [2-hexyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3methyI-3-cephem-4-carboxylic acid, syn-isomer. 22. A compound according to claim 17, characterized in that R4 is carbamoyloxy. 23. A compound according to claim 22, characterized in that R1 is amino or formamido and R2 is ethyl, propyl, isopropyl, isobutyl, allyl or 2-propynyl. 24. A compound according to claim 23, characterized by the formula 7- [2-ethoxyimino-2- (2-aminothiazol-4-yl) aceta- 5 10th 15 20th 25th 30th 35 40 45 50 55 60 55 mido] -3carbamoyloxymethyl-3-cephem-4-carboxylic acid, syn isomer. 25. A compound according to claim 23, characterized by the formula 7- [2-propoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3carbamoyloxymethyl-3-cephem-4-carboxylic acid and its hydrochloride, syn-isomer . 26. A compound according to claim 23, characterized by the formula 7- [2-isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3carbamoyloxymethyl-3-cephem-4-carboxylic acid, syn isomer. 27. A compound according to claim 23, characterized by the formula 7- [2-isobutoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3carbamoyloxymethyl-3-cephem-4-carboxylic acid, syn-isomer. 28. A compound according to claim 23, characterized by the formula 7- [2-allyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3carbamoyloxymethyl-3-cephem-4-carboxylic acid, syn-isomer. 29. A compound according to claim 23, characterized by the formula 7- [2- (2-propynyloxyimino) -2- (2-aminothiazol - 4-yl) - acetamido] -3carbamoyloxymethyl-3-cephem-4-carboxylic acid, syn isomer. 30. A compound according to claim 17, characterized in that R4 is thiadiazolylthio. 31. A compound according to claim 30, characterized in that R1 is amino or formamido, R2ethyl, propyl, isopropyl, pentyl, allyl or 2-propynyl and R4 is 1,3,4-thiadiazol-2-ylthio. 32. Compound according to claim 31, characterized by the formula 7- [2-ethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (l, 3,4-thiadiazol-2-yl) thiomethyl -3-cephem-4-car-bonic acid, syn isomer. 33. Compound according to claim 31, characterized by the formula 7- [2-propoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (l, 3,4-thiadiazol-2-yl) thiomethyl -3-cephem-4-car-bonic acid, syn isomer. 34. Compound according to claim 31, characterized by the formula 7- [2-Isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3 (l, 3,4-thiadiazol-2-yI) thiomethyl-3-cephem-4-car-bonic acid, syn -Isomeres. 35. Compound according to claim 31, characterized by the formula 7- [2-pentyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl -3-cephem-4-car-bonic acid, syn isomer. 36. Compound according to claim 31, characterized by the formula 7- [2-allyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (l, 3,4-thiadiazol-2-yl) thiomethyl -3-cephem-4-car-bonic acid, syn isomer. 37. Compound according to claim 31, characterized by the formula 7- [2- (2-propynyloxyimino) -2 - (2-aminothiazol-4-yl) - acetamido] -3 (l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid, syn isomer. 38. Compound according to claim 17, characterized in that R2 (C2-G>) alky] or lower alkynyl and R4 are triazolylthio. 39. Compound according to claim 38, characterized in that R1 is amino or formamido, R2 is ethyl, propyl, isopropyl, isobutyl, hexyl or 2-propynyl and R4 is 1H-1,2,3-tri-azol-5-ylthio . 40. Compound according to claim 39, characterized by the formula 7- [2-ethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1 H-1,2,3-triazol-5- yl) thiomethyl-3-cephem-4-car-bonic acid, syn isomer. 41. Connection according to claim 39, characterized by 643 266 the formula 7- [2-propoxyimino-2- (2-aminothiazol-4-yl) aceta-mido] -3- (1H-l, 2,3-triazol-5-yl) thiomethyl-3-cephem-4- carboxylic acid, syn isomer. 42. Compound according to claim 39, characterized by the formula 7- [2-isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1H-l, 2,3-triazol5-yl) thiomethyl-3-cephem-4-car-bonic acid, syn isomer. 43. Compound according to claim 39, characterized by the formula 7- [2-isobutoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (lH-l, 2,3-triazol-5-yl ) thiomethyl-3-cephem-4-car-bonic acid, syn isomer. 44. Compound according to claim 39, characterized by the formula 7- [2-hexyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3 (1 H-1,2,3-triazol-5-yl ) thiomethyl-3-cephem-4-car-bonic acid, syn isomer. 45. Compound according to claim 39, characterized by the formula 7- [2- (2-propynyloxyimino) -2- (2-aminothiazol-4-yl) - acetamido] 3 (1H-1,2,3-triazol-5-yl) thiomethyl-3-cephem-4-car-bonic acid, syn isomer. 46. Compound according to claim 6, characterized in that R1 is amino or lower alkanoylamino, R3 carboxy, R2 (C2-Có) alkyl or lower alkynyl and R4 is methyl-substituted tetrazolylthio. 47. Compound according to claim 46, characterized in that R1 is amino or formamido, R2 is propyl, isopropyl, butyl, pentyl, hexyl or 2-propynyl and R4 is 1-methyl-1H-tetrazol-5-ylthio. 48. Compound according to claim 47, characterized by the formula 7- [2-propoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3 (1-methyl-1 H-tetrazol-5-yl) thiomethyl -3-cephem-4-carboxylic acid, syn isomer. 49. Compound according to claim 47, characterized by the formula 7- [2-isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (l-methyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, syn- Isomeres. 50. Compound according to claim 47, characterized by the formula 7- [2-butoxyimino-2- (2-aminothiazol-4-yl) aceta-mido] -3- (1-methyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, syn isomer. 51. Compound according to claim 47, characterized by the formula 7- [2-pentyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-methyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, syn isomer. 52. Compound according to claim 47, characterized by the formula 7- [2-hexyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (l-methyl-lH-tetrazol-5-yl) thiomethyl -3-cephem-4-carboxylic acid, syn isomer. 53. Compound according to claim 47, characterized by the formula 7- [2- (2-propynyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1-methyl-1 H-tetrazole-5- yl) thiomethyl-3-cephem-4-carboxylic acid, syn isomer. 54. Compound according to claim 6, characterized in that R2 is lower alkyl, lower alkenyl or lower alkynyl and R4 aryloxy, which may have nitro or amino, cyclo (lower) alkanecarbonyloxy, carbamoyloxy, substituted with an aryl radical which may be substituted by halogen may mean aryl (lower) alkanoyloxy, aryloxy (lower) alkanoyloxy substituted with lower alkoxy, thenoyloxy, tetrazolylthio substituted with a (C3-Có) alkyl radical, or benzothiazolylthio. 55. Compound according to claim 54, characterized in that R1 is amino or halogen (lower) alkanoylamino, R2 is lower alkyl and R4 is aroyloxy, which may have nitro or amino. 56. Connection according to claim 55, characterized in 3rd 5 10th 15 20th 25th 30th 35 40 45 50 55 60 65 643 266 net that R1 is amino or 2,2,2-trifluoroacetamido, R3 carboxy or benzhydryloxycarbonyl, R2 methyl and R4 benzoyloxy, 4-nitrobenzoyloxy or 4-aminobenzoyloxy. 57. Compound according to claim 56, characterized by the formula 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3benzoyloxymethyl-3-cephem-4-carboxylic acid, syn-isomer. 58. Compound according to claim 56, characterized by the formula 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (4-nitrobenzoyl) oxymethyl-3-cephem-4-carbon -acid, syn-isomer. 59. Compound according to claim 56, characterized by the formula 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (4-aminobenzoyl) oxymethyl-3-cephem-4-carbon -acid, syn-isomer. 60. Compound according to claim 54, characterized in that R1 is amino, R2 is lower alkyl and R4 is cyclo (lower) alkanecarbonyloxy. 61. Compound according to claim 60, characterized in that R3 is carboxy or benzhydryloxycarbonyl, R2 is methyl and R "is cyclohexane carbonyloxy. 62. Compound according to claim 61, characterized by the formula 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cyclohexanecarbonyloxymethyl-3-cephem-4-carboxylic acid, syn- Isomeres. 63. Compound according to claim 54, characterized in that R1 is amino, R2 is lower alkyl and R4 is carbamoyloxy substituted by an aryl radical which may be substituted by halogen. 64. Compound according to claim 63, characterized in that R3 is carboxy or benzhydryloxycarbonyl, R2 is methyl and R4 is N-phenylcarbamoyloxy or N- (3-chlorophenyl) car-bamoyloxy. 65. Compound according to claim 64, characterized by the formula 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (N-phenylcarbamoyloxymethyl) -3-cephem-4-car- bonic acid, syn isomer. 66. Compound according to claim 64, characterized by the formula 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [N- (3-chlorophenyl) carbamoyloxymethyl] -3-cephem -4-carboxylic acid, syn isomer. 67. Compound according to claim 54, characterized in that R1 is amino, R3 carboxy, R2 is lower alkyl and R4 is aryl (lower) alkanoyloxy. 68. Compound according to claim 67, characterized by the formula 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-phenylacetoxymethyl-3-cephem-4-carboxylic acid, syn-isomer. 69. Compound according to claim 54, characterized in that R1 is amino, R2 is lower alkyl and R4 is aryloxy (lower rig) alkanoyloxy, substituted by lower alkoxy. 70. Compound according to claim 69, characterized in that R3 is carboxy or benzhydryloxycarbonyl, R2 is methyl and R4 is 4-methoxyphenoxyacetoxy. 71. Compound according to claim 70, characterized by the formula 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (4-methoxyphenoxy) acetoxymethyl-3-cephem-4-carboxylic acid , syn isomer. 72. Compound according to claim 54, characterized in that R 'amino, R2 is lower alkyl and R4 thenoyloxy. 73. Compound according to claim 72, characterized in that R3 is carboxy or benzhydryloxycarbonyl, R2 is methyl and R4 is 2-thenoyloxy. 74. Compound according to claim 73, characterized by the formula 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (2-thenoyl) oxymethyl-3-cephem-4- carboxylic acid, syn isomer. 75. Compound according to claim 54, characterized in that R1 is amino or lower alkanoylamino, R3 carboxy and R4 tetrazolylthio, substituted by a (C3-Ce) alkyl radical. 76. Compound according to claim 75, characterized in that R1 amino or formamido, R2 methyl, isopropyl, hexyl, allyl or 2-propynyl and R4 1-propyl-1H-tetrazol-5-ylthio or 1-hexyl-1 H-tetrazole -5-ylthio mean. 77. Compound according to claim 76, characterized by the formula 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-propyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, syn isomer. 78. Compound according to claim 76, characterized by the formula 7- [2-allyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (l-propyl-lH-tetrazole -5-yl) thiomethyl -3-cephem-4-carboxylic acid, syn isomer. 79. Compound according to claim 76, characterized by the formula 7- [2- (2-propynyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1-propyl-1 H-tetrazole-5- yl) thiomethyl3-cephem-4-carboxylic acid, syn isomer. 80. Compound according to claim 76, characterized by the formula 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-hexyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, syn isomer. 81. Compound according to claim 76, characterized by the formula 7- [2-isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-hexyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, syn -Isomeres. 82. Compound according to claim 76, characterized by the formula 7- [2-hexyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1 hexyl-1 H-tetrazol-5-yl) thiomethyl -3-cephem-4-carboxylic acid, syn isomer. 83. Compound according to claim 76, characterized by the formula 7- [2-allyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (lhexyl-lH-tetrazol-5-yl) thiomethyl-3 -cephem-4-carboxylic acid, syn isomer. 84. Compound according to claim 54, characterized in that R1 is lower alkanoylamino, R3 is carboxy, R2 is lower alkyl and R4 is benzothiazolylthio. 85. Process for the preparation of 3,7-disubstituted 3-cephem-4-carboxylic acid compounds of the general formula: in which mean: R1 amino, acylamino or aryl (lower) alkylamino, R3 carboxy or esterified carboxy, R2 isobutyl and R4 acetoxy or R2 cyclo (lower) alkyl or lower alkynyl and R4 lower alkanoyloxy or R2 lower alkyl and R4 (Cs-Cóalkanoyloxy or R2 (C2-Ce) alkyl, lower alkenyl, cyclo (lower) alkyl or lower alkynyl and R4 hydrogen, carbamoyloxy, thiadiazolylthio, which may have a lower alkyl, or triazolylthio or R2 (C2-C6) alkyl, cyclo (lower) alkyl or lower alkynyl and R4 tetrazolylthio substituted with a methyl radical or R2 lower alkyl, lower alkenyl, cyclo (lower) alkyl or lower alkynyl and R4 aroyloxy, the nitro or 4th 5 10th 15 20th 25th 30th 35 40 45 50 55 60 65 5 643 266 May have amino, cyclo (lower) alkanecarbonyloxy, carbamoyloxy substituted with an aryl radical which may be substituted by halogen, aryl (lower) alkanoyoloxy, aryloxy (lower) alkanoyloxy substituted with lower alkoxy, thenoyloxy, tetrazolylthio substituted with a (Ci -CójAlkylrest, or Benzothiazolylthio or their salts, characterized in that a compound of the general formula: N R la con ii ÒR2 V-r-T8 1_ < oJ_nYJ_ch2-R (n) R ~ wherein R3 and R4 each have the meanings given above, or a salt or a Schiff base thereof, or a silyl derivative of the amino group or the reaction product thereof with phosphorus trichloride or phosphine, with a compound of the general formula: wherein R, a is acylamino and R2, R3 and R4 each have the meanings given above, or a salt thereof is subjected to hydrolysis to split off the acyl group. 87. Process for the preparation of a compound of the general formula: im2 "h R (Ib) 25th «^ Ors- cooh (III) n V 2 OR (Ib) 30th wherein R1 and R2 each have the meanings given above, or a reactive functional derivative on the carboxy group or a salt thereof. 86. Process for the preparation of a compound of general formula j) r2 £ 3 40 45 in which mean: R3 carboxy or esterified carboxy, R2 isobutyl and R4 acetoxy or R2 cyclo (lower) alkyl or lower alkynyl and R4 no lower alkanoyloxy or R2 lower alkyl and R4 (Cs-Cf,) alkanoyloxy or R2 (C2-C6) alkyl, lower alkenyl, cyclo (lower) alkyl or lower alkynyl and R4 is hydrogen, carbamoyloxy, thiadiazolylthio, which may have a lower alkyl, or 55 triazolylthio or R2 (C2-C6) alkyl, cyclo (lower) alkyl or lower alkynyl and R4 tetrazolylthio substituted with a methyl radical, or lower alkyl, lower alkenyl, cyclo (lower) alkyl or lower alkynyl and R4 aroyloxy, the nitro or 60 May have amino, cyclo (lower) alkanecarbonyloxy, carbamoyloxy substituted with an aryl radical which may be substituted by halogen, aryl (lower) alkanoyloxy, aryloxy (lower) alkanoyloxy substituted with lower alkoxy, thenoyloxy, tetrazolylthio substituted with a 65 ( C3-C6) alkyl radical, or benzothiazolylthio or their salts, characterized in that a compound of the general formula: in which mean: R3 carboxy or esterified carboxy, R2 isobutyl and R4 acetoxy or R2 cyclo (lower) alkyl or lower alkynyl and R4 lower alkanoyloxy or R2 lower alkyl and R4 (C5-C6) alkanoyloxy or R (Cz-CöJalkyl, lower alkenyl, cyclo (lower) alkyl or lower alkynyl and R4 hydrogen, carbamoyloxy, thiadiazolylthio, which may have a lower alkyl, or triazolylthio or R2 (C2-C6) alkyl, cyclo (lower) alkyl or lower alkynyl and R4 tetrazolylthio substituted with a methyl radical, or R2 lower alkyl, lower alkenyl, cyclo (lower) alkyl or lower alkynyl and R4 aroyloxy, which may have nitro or amino, cyclo (lower) alkane carbonyloxy, carbamoyloxy substituted with an aryl radical which may be substituted by halogen, aryl (low) alkanoyloxy, aryloxy (lower) alkanoyloxy, substituted with lower alkoxy, thenoyloxy, tetrazolylthio, substituted with a (C3-Cf,) alkyl radical, or benzothiazolylthio or their salts, characterized in that a compound of the general formula: r la n- y c-conh "I or2 ) , 3 (Ia) wherein Rla means acylamino and R \ R3 and R4 each have the meanings given above, or a salt thereof is subjected to a reduction to split off the acyl group. 88. Process for the preparation of a compound of the general formula: r0NTl> CH2-R < î) r2 I X r ' (Ib) 643 266 6 in which mean: R3 carboxy or esterified carboxy, R2 isobutyl and R4 acetoxy or R2 cyclo (lower) alkyl or lower alkynyl and R4 lower alkanoyloxy or R2 lower alkyl and R4 (Cs-C6) alkanoyloxy or R2 (C2-Ce) alkyl, lower alkenyl, cyclo (lower) alkyl or lower alkynyl and R4 hydrogen, carbamoyloxy, thiadiazolylthio, which may have a lower alkyl, or triazolylthio or R2 (C2-C6) alkyl, cyclo (lower) alkyl or lower alkynyl and R4 tetrazolylthio substituted with a methyl radical, or R2 lower alkyl, lower alkenyl, cyclo (lower) alkyl or lower alkynyl and R4 aroyloxy, which may have nitro or amino, cyclo (lower) alkanecarbonyloxy, carbamoyloxy substituted with an aryl radical which may be substituted by halogen, aryl (low) alkanoyloxy, aryloxy (lower) alkanoyloxy substituted with lower alkoxy, thenoyloxy, tetrazolylthio substituted with a (C3-C6) alkyl radical, or benzothiazolylthio or their salts, characterized in that a compound of the general formula: Alkoxy, thenoyloxy, tetrazolylthio substituted with a (C3-Có) alkyl radical, or benzothiazolylthio or their salts, characterized in that a compound of the general formula: n R1-tsrf1-C0NH-rf c-c0nh -] - f f O ^ NY_CH2 "R ° R2 Js« (Je) wherein R3a is esterified carboxy and R1, R2 and R4 '5 each have the meanings given above, is subjected to hydrolysis to split the ester group. 90. Process for the preparation of a compound of the general formula: N R la JS V c-cohh-j — r i £ V Ji j-kJ-Wz-z 25th Ì 2 OR I x r * (la) wherein Rla means acylamino and R2, R3 and R4 each have the meanings given above, or a salt thereof is subjected to treatment with an imino halogenating agent thereafter with an imino etherifying agent and finally to hydrolysis to split off the acyl group. 89. Process for the preparation of a compound of the general formula: R1C-CONH-i— ^, Vii UJ-CH2-R * n OR2 0 cooh (Id) in which mean: R1 amino, acylamino or aryl (lower) alkylamino, R2 isobutyl and R4 acetoxy or R2 cyclo (lower) alkyl or lower alkynyl and R4 lower alkanoyloxy or R2 lower alkyl and R4 (C5-Co) alkanoyloxy or R2 (C2-C6) alkyl, lower alkenyl, cyclo (lower) alkyl or lower alkynyl and R4 is hydrogen, carbamoyloxy, thiadiazolylthio, which may have a lower alkyl, or triazolylthio or R2 (C2-Câ) alkyl, cyclo (lower) alkyl or lower alkynyl and R4 tetrazolylthio substituted with a methyl radical, or R2 lower alkyl, lower alkenyl, cyclo (lower) alkyl or lower alkynyl and R4 aroyloxy, which may have nitro or amino, cyclo (lower) alkane carbonyloxy, carbamoyloxy substituted with an aryl radical which may be substituted by halogen, aryl (low) alkanoyIoxy, aryloxy (lower) alkanoyloxy substituted with lower R • C0NH ' s n 0R2a r * (If) in which mean: R1 amino, acylamino or aryl (lower) alkylamino, 3o R3 carboxy or esterified carboxy, R2a lower alkyl, lower alkenyl, cyclo (lower) alkyl or lower alkynyl and R4b aroyloxy with one or more amino groups, or their salts, characterized in that a compound of the general formula: -CONH & R2a NH ~ n 1 QJ- N - <^ CH2 " R 4a r3 (Ie) 45 wherein R1, R3 and R2a each have the meanings given above and R4a means aroyloxy having one or more nitro groups, or a salt thereof is subjected to a reduction. 91. Compound of the general formula: 50 55 N - ^ - CH2-S N-N Ii * ■ à? wherein R3 is carboxy or esterified carboxy and R7 is 60 (C3-Cö) alkyl, and their salts, as starting material for carrying out the process according to claim 85. 92. Compound according to claim 91, characterized in that in the general formula R3 is carboxy and R7 is propyl or hexyl. 65 93. Pharmaceutical agent with antibacterial activity, characterized in that it contains at least one 3,7-disubstituted 3-cephem-4-carboxylic acid compound of the formula I as claimed in claim 1 as active ingredient. 7 643 266 94. Pharmaceutical composition according to claim 93, characterized in that the active ingredient is present in combination with a pharmaceutically acceptable, non-toxic excipient.