HU183006B - Process for producing 7-substituted-3-cepheme- and cephame-4-carboxylic acid derivatives - Google Patents

Abstract

NEW MATERIAL:Compounds of formula I [R<1> is amino, protected amino; R<2> is H, acyl, aryl, lower alkyl, alkenyl, cycloalkyl,; R<3> is H, lower alkyl; R<4> is H, acyloxy (lower)alkyl, pyridinium(lower)alkyl; R<5> is carboxy, pretected carboxy; the thick line is single or double bonds]. EXAMPLE:7-[ 2-cyclopentyloxyimino-2-( 5-amino-1,2,4-thiadiazol-3-yl )acetamide ]- 3-cephem-4-carboxylic acid (syn-isomer). USE:Antibacterial or its intermediate: they are effective on gram-positive and -negative bacteria. PREPARATION:A compound of formula II or its reactive derivative in the amino group is made to react with a compound of formula III or its reactive derivative to form the compound of formula I.

Description

The present invention relates to 7-substituted-3-cephem and cepham-4-carboxylic acid derivatives and their pharmaceutically acceptable salts which have microbial activity and pharmaceutical compositions containing these compounds as active ingredients. The pharmaceutical compositions of the present invention are useful for the prophylactic and symptomatic onset of these infectious diseases in humans and animals.

The novel compounds and pharmaceutical compositions of the present invention are active against microorganisms such as both Gram-negative and Gram-positive bacteria.

The present invention also relates to a process for the preparation of compounds useful as intermediates in the preparation of the active pharmaceutical ingredient 7-substituted-3-cephernic or 4-cepham-4-carboxylic acid.

The 7-substituted-3-cephem and -cepham-4-carboxylic acid derivatives are novel compounds and have the general formula (1). In the general formula I

R ^{1 is} amino- or C 1-4 -actaapoitanino; R ^{2 is} hydrogen, phenyl; With 1-3 halogens,

C 1 -C 6 alkoxy, C 1 -C 6 alkyl, nitro, halo-C 6 -C 6 alkyl, and C 1 -C 6 alkoxycarbonyl substituted phenyl; phenyl-C 1-6 -alkyl; tri-, phenyl-C 1-6 -alkyl; C 1-6 -alkylthio (C 1-6 -alkyl); halo-C 6 -C 6 -alkyl; phenoxy- (C 1-6) -alkyl; Cyano-C 1-6 -alkylalkyl; C 1-6 -alkoxycarbonyl / C 1-6 -alkyl, phenyl / C 1-6 -alkoxycarbonyl / C 1-6 -alkyl or cyclo-C 3-8 -alkyl; -alkoxycarbonyl / C 1 -C 6 -alkylalkyl; C 1 -C 6 -C 6 -alkylcarbamoyl (C 1 -C 6 -alkyl); C 1 -C 6 -alkoxy / C 1 -C 6 -alkoxy-C 1 -C 6) -alkoxy; C 1 -C 6 -alkylsulfonyl; (C 1 -C 6) alkyl; acylarnino (C 1 -C 6) alkyl; ainino (C 1 -C 6) alkyl; carboxy (C 1 -C 6) alkyl; phenyl (C 1 -C 6) alkyl, C 6 -C 6 alkoxycarbonyl-substituted Carboxy-substituted phenyl / C 1 -C 6 -alkyl; C 1 -C 6 -alkoxycarbonylamino / 1-6 carbon atoms phenyl substituted with 0 to 6 alkyl); amirto (C 1 -C 6 -alkyl) -phenyl (C 1 -C 6 -alkyl); C 2 -C 6 -alkenyl; C 2 -C 6 -alkynyl; C 3 -C 8 -cycloalkyl; carboxy or C 1 -C 6 -alkoxycarbonyl substituted C 3 -C 8 -cycloalkyl cyclo (C3-C6) alkenyl; two oxo-substituted thiolanyl; or oxo-substituted tetrahydrofuryl;

R ^{3 is} hydrogen or C 1-6 alkyl;

R ^{4 is} hydrogen, carbamoyloxy-C 1-6 -alkyl or C 1-6 -alkanoyloxy / C 1-6 -alkyl; pyrithione (C 1 -C 6) alkyl optionally substituted with carbamoyl; thiadlazolylthio / C 1 -C 6 alkyl; thiadiazolylthio optionally substituted with C 1 -C 6 alkyl, hydroxide C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonylamino / C 1 -C 6 alkyl or amines with C 1 -C 6 alkyl 2 ' -C 6 -alkyl; C 1-6 -alkyl, hydroxy- (C 1-6 -alkyl) amino / C 1-6 -alkyl, C 1-6 -alkoxycarbonylamino (C 1-6 -alkoxy) or C 1-6 -alkanoylamino - (C 1 -C 6) -alkyl, di- (C 1 -C 6) -alkylamino / C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, carboxy / C 1 -C 6 -alkyl, C 1 -C 6 -alkoxycarbonyl Tetrazolyl substituted with C 1-6 -alkyl, phenyl, morpholino (C 1-6 -alkyl), piperidino (C 1-6 -alkyl) or C 1-6 -alkyl (C 1-6) -alkyl (C 1-6 -alkyl) C 1-6 -alkyl; tetrazolopyridazinylthio (C 1-6 -alkyl); oxo and carboxyl (C 1-6 -alkyl) -dihydrotriazolopyridazinylthio / C 1-6 -alkyl *; oxo, hydroxy, and hydroxy; or C 1 -C 6 -alkyl-dihydro-tri3zinylthio-C 1 -C 6 -alkyl; C 1 -C 6 -alkyl; hydroxy or halogen; and

^R5 is carboxy or nitro-substituted phenyl (C1-6 szénatomosj-alkoxycarbonyl, C1-6 alkanoyloxy (Ci-6-szénatomosj afkoxikarbonil-, C1-6 alkoxycarbonyloxy / 1-6 szénatomosjalkoxikarbonil-, azido substituted 1- C6 alkoxycarbonyloxy / 1 -C 6) alkoxycarbonyl, benzoyloxy / l 6 szénatomosjalkoxikarbonil- or ftalidiloxi-carbonyl, and a bond or a double bond with the thick black line represents, with the proviso that ^R5 is COO group, where R ⁴ pyridinium / C 1 -C 6 alkyl optionally substituted with carbamoyl.

According to the present invention, 7-substituted-3-cephem and

-cefam-4-carboxylic acid derivatives of the general formula I can be prepared by the following processes:

a. compound of the formula or a reactive aml.noszármazékát or a salt thereof, wherein R ^3, R ⁴ and ^R! and the thick black line is reacted with a compound of formula 111 as defined above, a reactive carboxyl derivative thereof or a salt thereof, wherein

b) R * and R ^{5 for} the preparation of a compound of formula Ib, or a salt thereof, wherein R ', R ² , R ³ and R ⁴ , and a thick black line are a compound of formula Ia as defined above or a salt thereof, wherein R *, R ² , R ³ , R ⁴ and the bold black line are as defined above and R ^a is a protected carboxy group, preferably nitro-substituted phenyl / C 1-6 -alkoxycarbonyl, 1-6; C 1 -C 6 alkanoyloxy / C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkoxycarbonyloxy / C 1 -C 6 alkyloxycarbonyl, azido; substituted C 1 -C 6 alkoxycarbonyloxy (C 1 -C 6 alkoxycarbonyl, benzoyloxy / C 1 -C 6 alkoxycarbonyl or ptaHdHoxycarbonyl), the carboxyl group of which is deprotected, or

c) for the preparation of compounds of formula Id, wherein R *, R ² , R ³ , R ^s and the bold black line are as defined above, and

-2i 83 006

R ^{4f is} a pyridinium group optionally substituted by carbamoyl or a group -SR ^4e wherein

R ^{4e is} thiadiazolyl; C 1-6 alkyl, hydroxy (C 1-6) alkyl, protected amino (C 1-6) alkyl; preferably thiadiazolyl substituted with C 1-6 -alkoxycarbonylamino-C 1-6 -alkoxy or amino- (C 1 -C 6) -alkyl; tetrazolyl; C 1-6 alkyl, hydroxy (C 1-6) alkyl, amino (C 1-6) alkyl, protected amino (C 1-6) alkyl, preferably 1-6; C 1-6 -alkoxycarbonylamino-C 1-6 -alkyl or di-C 1-6 -alkylanuno-C 1-6 -alkyl, C 1-6 -alkanoyl-amino- (C 1-6) -alkyl, C2-C6-alkenyl, carboxy (C1-C6) -alkyl, protected carboxy (C1-C6) -alkyl, preferably C1-C6-alkoxycarbonyl (C1-C6) -alkoxy. tetrazolyl substituted with alkyl, phenyl, morpholino, C 1-6 alkyl, piperidino (C 1-6) alkyl and C 1-6 alkyl; tetrazolo-pyridazinyl; dihydro-triazolo-pyridazinyl substituted with oxo and carboxy (1-6C) alkyl; or dihydro-triazinyl substituted with oxo, hydroxy and C 1-6 alkyl; and

C 1-6 alkylene;

or a salt of these compounds, a compound of formula Ic wherein R *, R ² , R ³ , R ⁵ and the bold black line are as defined above, R ^{4a is} substituted by a R ^4f group, wherein R ^4f is as defined above or a salt thereof with a compound of formula R ^4b , wherein R ^4b is pyridine optionally substituted with a carbamoyl group, or a compound of formula R ^4e -SH or a reactive derivative thereof, wherein R ^4e is as defined above, or

d) for the preparation of compounds of the formula If, wherein R ¹ , R ² , R ³ , R ⁵ and the bold black line are as defined above and thiadiazolylthio (1-6) substituted with R ^4d amino- (C 1-6) alkyl; C 1-6 alkyl or tetrazolylthio (C 1-6) alkyl substituted with amino (C 1-6) alkyl, or salts thereof, from a compound of formula I, R ² , R ² , R ³ , R ^s and the thick black line are as defined above, and ^R4c is protected amino (Cl-C6 jalkilcsoporttal, preferably C 1-6 alkoxycarbonylamino (C 1-6 ízénatomos) -alkyl thiadiazolylthiomethyl substituted (1-6C) - tetrazolylthio substituted with alkyl or protected amino (C 1-6) alkyl, preferably C 1-6 alkoxycarbonylamino (C 1-6) alkyl or C 1-6 alkanoylamino (C 1-6) alkyl. -C 6) or a salt thereof, or an amino protecting group thereof; or

e) for the preparation of compounds of formula Ij or salts thereof, wherein R ¹ , R ³ , R ⁴ , R ⁵ and the bold black line are as defined above and R ^{2 is} amino (C 1-6) alkyl or amino <1-6; -C) -alkyl substituted phenyl (Cl-C6) alkyl, a compound of formula II wherein R ^1, R ^J, R ^4, R ⁵ and the thick black line are as defined above and R ^f is protected amino ( C 1-6 -alkyl, preferably acylamino-C 1-6 -alkyl, or substituted with protected amino-C 1-6 -alkyl, preferably C 1-6 -alkoxycarbonylamino-C 1-6 -alkyl phenyl (C 1 -C 6) alkyl, or a salt thereof, deprotecting the amino protecting group, or

f) for the preparation of compounds of formula 11 or salts thereof wherein R ¹ , R ³ , R ⁴ , R ⁵ and the bold black line are as defined above and R ^{2e is} substituted with carboxy (C 1 -C 6) alkyl, carboxy C 3 -C 8 cycloalkyl substituted with phenyl (C 1 -C 6) alkyl or carboxy, a compound of formula lk or a salt thereof, wherein R ¹ , R ³ , R ⁴ , R ⁵ and the bold black line are as defined above and R ^{2d is} protected carboxy (C 1 -C 6) -alkyl, preferably C 1 -C 6 -alkoxycarbonyl (C 1 -C 6) -alkyl, phenyl (C 1 -C 6) -alkoxycarbonyl (C 1 -C 6) - alkyl, or cycloalkoxycarbonyl (C 1 -C 6) -α (alkyl) having 3 to 8 carbon atoms; phenyl (C 1-6) alkyl substituted with a protected carboxy group, preferably C 1-6 alkoxycarbonyl; or C3-C8 cycloalkyl substituted with a protected carboxy group, preferably C1-C6 alkoxycarbonyl, cleaving the carboxyl protecting group, or

g) for the preparation of compounds of the general formula In or salts thereof, wherein R ¹ , R ² , R ³ , R ⁴ and the bold black line are the above esterified portion of R ⁸ is an esterified carboxy group of formula -COOR ⁸ , preferably phenyl substituted with nitro group; - (C 1-6) alkoxycarbonyl, C 1-6 alkanoyloxy (C 1-6) alkoxycarbonyl, C 1-6 alkoxycarbonyloxy (C 1-6) alkoxycarbonyl, C 1-6 alkoxycarbonyloxy (1) A (C 6 -C 6) alkoxycarbonyl, benzoyloxy (C 1 -C 6) -alkoxycarbonyl or phthalidyloxycarbonyl group, a compound of formula 1m or a salt thereof wherein R ¹ , R ² , R ³ , R ⁴ and the bold black line are as defined above , esterified with an esterifying agent corresponding to R ⁸ , or

h) for the preparation of compounds of formula Ih or salts thereof, wherein R, R ³ , R ⁴ , R ⁵ and the bold black line are as defined above for a compound of formula Ig or a salt thereof, wherein R ¹ , R ³ , R ⁴ , R ^J and the thick black line are as defined above and R ² 'is a hydroxy protecting group, preferably triphenyl (C 1-6) alkyl, this hydroxy protecting group being cleaved, or

i) a compound or salt thereof, the Ip of the formula wherein ^{R1, R2} and ^R5 are as defined above, one described compound or a salt thereof, wherein R ^1, R ^{2 and} R are as defined above, is dehydrated, obsession

j) for the preparation of compounds of the general formula (I) or their salts, wherein R ¹ , R ³ , R ⁴ , R ⁵ and the bold black line are as defined above and R ^{2b is a} protected amino (C 1 -C 6) alkyl, preferably acylamino (1); (C 6 -C 6) alkyl, a compound of formula Iq or a salt thereof wherein R ¹ , R ³ , R ⁴ , R ⁵ and the bold black line are as defined above and R ² 'is amino 3

-3.1 SJ (C16) alkyl protected with an aniline protecting group.

Közül of the starting materials of the process of the invention

Compounds of formula 111 are novel and can be prepared according to Schemes 1-7. In the above reaction schemes R ² . R ^JB .R ^2f ,

R ^2g and R ¹ are as defined above,

R ^zh optionally substituted aryl, or optionally substituted cycloalkyl,

Z is a carboxy or protected carboxyl group,

R ^{10 is a} protected amino (C 3 -C 6) alkyl,

R ^{11 is} amino (C 3 -C 6) alkyl,

R ⁶ carboxyl protecting group,

My alkali metal M,

X is a hydroxyl group or a reactive derivative thereof,

R ^{9 is} a protected amino group,

R ^{1a is a} protected amino group, and

R ^? lower alkyl.

In Formula 1, as well as Formula H1, the A, A 'partial structure includes both A and A' geometric sub-structures.

Hereinafter, all compounds having the above sub-structure will be referred to as the color isomer for the compounds having the sub-structure A and the anti-isomer for the compounds having the geometric structure A '.

The compounds of formula I and III. In the case of the starting materials of general formula (I), it should be noted that these compounds may exist in the form of tautomeric isomers which occur on the thiadiazolyl group. This means that in the above compounds, the group of formula Β, B ', where ah! R ^{1 is} amino or protected amino, may exist in two forms; namely in the form of formula B, and the corresponding B 'form with the general formula wherein R ¹ is as defined above, and R ^{r is} imino or a protected imino group. That is, the above groups of formulas B and 8 'are in a so-called Lautomeric balance.

However, in view of the difficulties of representation, one of the groups represented in the claims and examples and in the description of the final products and starting materials is the group B.

Pharmaceutically acceptable salts of the compounds of Formula 1 of the present invention are non-toxic salts generally used, which may be inorganic salts such as metal salts or alkali metal salts (e.g., sodium, Xalium salt, etc.) or alkaline earth metal salts (e.g., calcium salt, magnesium salt, etc.). , ammonium salt, etc .; or an organic salt such as an organic ammonium salt, an amine salt (e.g., trimethylamine, triethylamine, pyridine, procaine, plcholine, dicyclohexylamine, N, N'-dibenzylethylenediamine salt, N-methylglucamine salt, diethanolamine salt, triethanolamine salt, tris (hydroxymethylamine) ) -methan salt, phenylethylbenzylamine salt, dibenzylethylene, diamine salt, etc.), etc .; a salt with an organic carboxylic acid or a sulfonic acid (e.g. formate, acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); salts with an inorganic acid (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.); some basic or acidic amino acid! salts thereof (e.g., salts with arginine, aspartic acid, glutamic acid, lysine) and the like. Halogen is chlorine, bromine, iodine or fluorine.

The lower alkylene group is a straight or branched divalent aliphatic hydrocarbon group containing from 1 to 6 carbon atoms of 4 to 10 thiol; such as methylene, ethylene, methylene-propylene, trimethylene, 2-methyl-trimethylene or the like, preferably having 1 to 4, in particular 1 or 2, carbon atoms.

Preferred compounds of formula 1 are:

Preferred compounds of formula I are those wherein R 'is amino, acylamino, preferably lower alkanoylamino or di- (lower) alkylamino (lower) alkylideneamino;

R ^{J is} hydrogen, phenyl, lower alkenyl, lower alkynyl, cyano (lower) alkyl, phenyl (lower) alkyl or triphenyl (lower) alkyl, phenoxy (lower) halo, ) -alkyl, preferably tri-halo-lower-alkyl, lower-alkylthio-lower-alkyl, lower-alkoxycarbonyl-lower-alkyl, di- (lower) -alkylcarbamoyl- (lower) -alkyl-lower-alkyl -alkoxy (lower) -alkyl, lower-alkylsulfonyl-lower-alkyl, lower-alkoxycarbamoyl-lower alkyl, lower-alkoxy (lower) -alkoxy (lower) lower alkyl, a lower alkoxycarbonylamino- lower alkyl, amino (lower) alkyl, carboxy (lower) alkyl, cycloalkylcyclo (lower) alkenyl, phenyl having halogen, nitro and lower alkoxy, halo (lower) may be substituted by alkyl groups or lower alkoxikarbonilcsoportokkal two substituted by oxo tiolanilcsoport, phenyl (lower) alkyl which is substituted by carboxy or lower alkoxycarbonyl, carboxy substituted lower alkoxycarbonyl-cycloalkyl, amino (lower) -alkyl or lower alkoxycarbonylamino (lower) alkyl groups substituted phenyl (lower) alkyl, cycloalkoxycarbonyl (lower) alkyl, phenyl (lower) alkoxycarbonyl (lower alkyl), amino or lower alkoxycarbonylamino allyl-substituted phenyl (lower) -alkanoylamino (lower) -alkyl, cyclo (lower) -alkyl (lower) -alkanoylamino (lower) -alkyl, oxo-substituted tetrahydrofuryl,

R ^{3 is} hydrogen or lower alkyl,

R ^{4 is} hydrogen, acyloxy (lower) alkyl, preferably lower alkanoyloxy (lower) alkyl or carbamoyloxy (lower) alkyl, in particular lower alkanoyloxymethyl or carbamoyloxymethyl (especially lower alkanoyl) lower (acyloxy) lower alkyl (carbamoyloxy) -alkyl; lower alkyl, especially lower alkanoylthiomethyl, tetrazolylthio (lower) alkyl, preferably tetrazolylthiomethyl, which is lower alkyl, lower alkenyl, lower alkoxy (lower), lower alkoxy (lower) - (lower) alkyl, amino (lower) alkyl, lower alkoxycarbonylamino (lower) alkyl, lower-41

Lower alkanoylamino (lower) alkyl, di (lower) alkyl (lower) alkyl, sulfo (lower) alkyl, carboxy (lower) alkyl, phenyl (lower), alkyl, morpholino (lower) alkyl, piperidino (lower) alkyl or lower alkyl substituted piperazinyl (lower) alkyl, preferably thiadiazolylthio (lower alkyl) -, lower alkoxy (lower) alkyl groups, lower alkyl thio (lower) alkyl groups, lower alkanoylthio, carboxy (lower) alkoxycarbo-1-, hydroxy (lower) amino (lower) alkyl (lower) alkyl or lower alkoxycarbonylammonium (lower carbon lower alkylsulphonyl lower alkyl, lower alkyl, lower alkyl, lower alkyl, lower alkyl, lower alkyl, lower alkyl, lower alkyl, lower alkyl, lower alkyl, lower alkyl, lower alkyl, lower alkyl, lower alkyl, lower alkyl, lower alkyl, lower alkyl, lower alkyl, lower alkyl, a dihydrotriazolopyridazinylthio (short-chain) alkyl, preferably a dihydrotriazolopyridazinylthio group, a hydroxy or a lower alkylthio group; (lower) alkyl, preferably tetrazolopyridazinylthiomethyl, and R ^s carboxyl, nitro-substituted phenyl (lower) alkoxycarbonyl, lower alkanoyloxy; (lower) -alkoxycarbonyl, optionally substituted by azido or amino substituted lower aJkoxikarboniloxi- (lower) alkoxycarbonyl, ftalidiloxikarbonil group, benzoyloxy (loweralkylsulphonic) -aíkoxikarbonilcsoport wherein ^R5 C00 ^- a group of formula where R is a substituted pyridinium (lower) alkyl ⁴ alkylcarbamoyl.

Various embodiments of the present invention will now be described in detail.

Procedure J.

According to this variant of procedure 1. Compounds of formula II may be prepared by reacting a compound of formula II. or a reactive amino derivative thereof, or a salt thereof, with a compound of formula 111, or a reactive carboxyl derivative or salt thereof.

The appropriate amine derivative of a compound of formula II may be a commonly used reactive amino derivative such as a SCHX-type imine derivative or its corresponding tautomeric enamine derivative which may be prepared by reacting a compound of formula 11 with a carbonyl compound, or a silyl derivative prepared by reacting a compound of Formula 11 with a silyl compound such as bis (trimethylsilyl) acetamide, trimethylsilylacetanoate, trimethylsilylacetamide, or the like; derivatives of the compound of general formula J with phosphorus trichloride or phosgene and the like.

An example of a salt of a compound of Formula 11 is an acid addition salt such as an acid addition salt of an organic acid such as acetate, maleate, tartrate, benzenesulfonate. toluenesulfonate or a salt with an inorganic acid such as hydrochloride, hydrobromide, sulfonate cut phosphate, a metal salt such as sodium, potassium, calcium, magnesium salt, an ammonium salt, an organic 10-amine salt such as triethylamine or dicyclo like that.

In III. The reactive carboxyl derivative of the compound of formula (I) is, for example, an acid halide, an acid hydride, an activated amide or an activated ester and the like. Such derivatives include, for example, an acid chloride, an acid azide, an acid such as a substituted phosphoric acid, e.g. aliphatic carboxylic acid such as pivalic acid, isopentanoic pentánsawavagy, 2-etilvajsawal, acetic acid or trichloroacetic acid, or ^- consisting of an aromatic carboxylic acid such as benzoic acid mixed anhydride, a symmetrical savanhidtid, imidazole, dimetilpirazo! with triazole or tetrazole! an activated amide formed or an activated ester such as cyanomethyl ester; methoxymethyl ester, dimethyl iminomethyl ester, vinyl ester propargyl ester, p-nyrophenyl ester, 2,4-dinitrophenyl ester trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester phenylazophenyl ester, phenyl thioester, p-nitrophenyl ester. p-cresylthioester, carboxymethylthioester, pyranyl ester. pyridyl ester, piperidyl ester, 8-quinolylthioester or Ν, Ν-dimethylhydroxtl-amine, 1-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, or 1-hydroxy-6-chloro an ester with -1H-benzotriazole and the like. The use of suitable reactive derivatives depends on the type of compound of formula III used.

Salts of compounds of Formula 111 include salts with an inorganic base such as an alkali metal salt such as a sodium or potassium salt, an alkaline earth metal salt such as a calcium or magnesium salt, an organic base such as trimethylamine, triethylamine, pyridine or a salt thereof. a salt such as hydrochloric acid or hydrobromic acid or the like.

The reaction is usually carried out in a solvent known per se, such as water, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, Ν, Ν-dimethylformamide, pyridine or any other organic solvent which does not interfere with the reaction. Of these solvents, hydrophilic solvents may also be used as a mixture with water.

If IH. the reaction is preferably carried out in the form of a free acid or a salt thereof, the reaction is preferably a condensing agent known per se, such as Ν, Ν-dicyclohexylcarbodiimide, N-cyclohexyl60 N'-morpholinoethylcarbodiimide, N-cyclohexyl-N ' N, N-diethylcarbodiimide, Ν, Ν-diisopropylcarbodiimide, N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide, N, N-carbonylbis (2-methylimidazole), pentamethylene ketene-N-cyclohexylimine, diphenylketene- N-di65 eiclohexylimine, ethoxyacetylene, ethyl polyphosphate, isopropyl

-5I polyphosphate, diethyl phosphofluorochlorite, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride, oxalyl chloride, triphenylphosphine, N-ethyl-7-hydroxybenzisoxazolium fluoroborate, N-ethyl-5-phenylisoxazolium, chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole (the so-called Willsmeyer reagent such as (chloromethylene dimethylammonium chloride (prepared by reacting dTmethylformamide with thionyl chloride or phosgene), dimethylformamide and these) .

The reaction may be carried out on an inorganic or organic base such as an alkali metal hydroxide, an alkali metal hydrogencarbonate, an alkali metal carbonate, an alkali metal acetate, a tri- (lower) alkylamine, pyridine, N- (lower alkyl) morpholine, N, N-di (N-alkyl) Also, in the presence of N-di- (lower) alkylaniline and the like, if the base or condensing agent is a liquid, it can be used as a solvent, the reaction temperature is not critical and the reaction is usually carried out under cooling or at room temperature.

In the reaction, the color isomer of the compound of formula I is preferably obtained by reacting the compound of formula II. a compound of formula III. is reacted with the color isomer of the starting compound of the formula.

In the reaction, III. The R ¹ amino group of a compound of formula I can be converted to a protected amino group, whereby a compound of formula I wherein R ^{1 is a} protected amino group and R ² aryl can be converted to a hydrogen atom depending on the reaction conditions is also within the scope of the invention. .

Procedure 2

Compounds of formula Ib or salts thereof may be prepared by reacting a compound of formula Ia. The protecting group is deprotected from the protected carboxyl group of compound ¹ or a salt thereof.

The salt of the compound of formula I may be an acid addition salt which may be used as the salt of formula II. Compounds of formula I have been described.

The reaction may be carried out by any conventional method, such as hydrolysis, reduction, or the like.

In the case where the protecting group is an ester, the protecting group may be removed by hydrolysis. The hydrolysis is preferably carried out in the presence of a base or an acid. Preferred bases are, for example, an inorganic or organic base such as an alkali metal such as sodium, potassium, an alkaline earth metal such as magnesium, calcium, their hydroxides, carbonates or bicarbonates, trialkylamines such as trimethylamine, triethylamine, etc., picoline, l, 5-diazabicyclo [4,3,0] -non-5-ene, 1,4-diazabicyclo (2,2,2] octane, 1,8-diazabicyclo [5.4.0] undecene-7, or the like. A suitable acid is, for example, an organic acid such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, etc., or an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc.

The reaction is usually carried out in a solvent such as water, alcohol such as methanol or ethanol, a mixture thereof or any other solvent which does not interfere with the reaction. A liquid base or acid may also be used as a solvent. The reaction temperature is not a determining factor; the reaction is usually carried out under cooling or heating.

The reactor is preferably used for deprotection when 4-nitrobenzyl, 2-iodoethyl, 2,2,2-trichloroethyl or the like. The reduction may be carried out, for example, on a metal such as zinc, zinc amalgam, etc., or on a salt of a chromium compound such as chromium chloride, chromium acetate, etc., and on an organic or inorganic acid such as acetic, propionic, hydrochloric, etc. combination. Conventional catalytic reduction may be carried out in the presence of a known metal catalyst such as palladium-on-carbon.

Option 3

The compound of Formula Id or its salt may be prepared by reacting a compound of Formula Ic or a salt thereof with a compound of formula IV. or a reactive derivative thereof.

Suitable salts of the compound of formula Ic are the same as the salts of formula II. Compound of Formula I. The IV. A suitable reactive derivative of a compound of the formula I is, for example, a metal salt such as an alkali metal salt such as sodium or potassium or the like.

The reaction may be carried out in a solvent such as water, phosphate buffer, acetone, chloroform, nitrobenzene, methylene chloride, ethylene chloride, dimethylformamide, methanol, ethanol, ether, tetrahydrofuran, dimethyl sulfoxide, or any other solvent which does not affect the reaction; preferably in solvents which are highly polar. Of these solvents, the hydrophiles may also be used as a mixture with water. The reaction is preferably carried out at a neutral pH. If Ic or IV. The compound of formula I is used in free form, preferably in the presence of a base such as an inorganic base such as an alkali metal hydroxide, an alkali metal carbonate, an alkali metal hydrogencarbonate, an organic base such as a trialkylamine or the like. The reaction temperature is not critical; the reaction is usually carried out at room temperature or under slight heating.

This reaction also encompasses an embodiment wherein the protected carboxyl group is converted to the free carboxyl group during the reaction.

Procedure 4

The If. or a salt thereof may be prepared so that a 1 µg. or in a salt thereof, the amino protecting group is deprotected.

That's down. Suitable salts of the compounds of the general formula (I) are a metal salt, an ammonium salt or a salt with an organic amine, as described above.

The cleavage reaction is carried out by methods known per se, such as hydrolysis or reduction; in case it's down. In the compound of formula I, the protecting group is an aryl group, the compound is reacted with an iminohalogenating agent and then with an iminoetherizing agent and, if desired, the resulting compound is hydrolyzed. Acid or base or hydrazine and the like can be used for hydrolysis. These methods are selected according to the nature of the protecting group.

Which of the above methods? One of the preferred and commonly used methods is acid hydrolysis. This is used when the protecting group to be removed is substituted or unsubstituted alkoxycarbonyl, tert-pentyloxycarbonyl or tert-butoxycarbonyl, alkanoyl, e.g. alkylidene, substituted cycloalkylidene, aryl-lower alkyl such as benzyl or trityl, or the like.

A suitable acid, an organic or inorganic acid, such as formic acid, trifluoroacetic acid, benzenesulfonic acid, ptoluenesulfonic acid, hydrochloric acid and the like; preferred acids are, for example, formic acid, trifluoroacetic acid or hydrochloric acid. The acid used in this reaction is selected according to the nature of the protecting group to be cleaved. When the cleavage reaction is carried out with an acid, it may be carried out in the presence or absence of a solvent. Suitable solvents are generally used organic solvents, water, or mixtures thereof. When the trifluoroacetate band is used, the cleavage reaction is preferably carried out in the presence of anisole

The hydrazine in the presence of hydrazine is preferably used for the cleavage of protecting groups such as succinyl or phthaloyl.

Base hydrolysis is preferably used to cleave acetic acids, such as haloalkanoyl such as dichloroacetyl or trifluoroacetyl.

A preferred base is an inorganic base such as an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide, kalclumhidroxid, alkali metal carbonate such as sodium carbonate or potassium carbonate, alkaline earth metal carbonate such as magnesium carbonate or calcium carbonate, alkali metal bicarbonate such as sodium bicarbonate or potassium bicarbonate, alkálifémacetát, such as sodium acetate or potassium acetate , alkaline earth metal phosphate such as magnesium phosphate, calcium phosphate, alkaline metal hydrogen phosphate such as disodium hydrogen phosphate, dipotassium hydrogen phosphate or the like, or an organic base such as trialkylamine, trimethylamine, N-methylmethyl, N-methylmethyl, , 0] non5-ene, 1,4-diazabicyclo (2,2,2] octane, 1,5-diazabicyclo [5,4,0] undecene-5, or the like. hydrolysis is generally carried out in the presence of water, an organic solvent or a mixture thereof.

Of the protecting groups, the acyl groups are generally cleaved by any of the above hydrolysis methods or any other hydrolysis method known per se. In the case where the acyl group is halogen substituted, alkoxycarbonyl or 8-cinnolyloxycarbonyl, these can be cleaved by treatment with a heavy metal such as copper, zinc or the like.

Reductive cleavage is generally used for protecting groups such as haloalkoxycarbonyl groups such as trichloroethoxycarbonyl groups, substituted or unsubstituted aralkoxycarbonyl groups such as benzyloxycarbonyl, substituted benzyloxycarbonyl groups, 2-pyridylmethoxycarbonyl groups and the like. Preferred reduction is for example an extreme reduction with an alkali metal borohydride, such as sodium borohydride, or the like.

The reaction temperature is not critical and depends on the nature of the amine protecting group and the cleavage method used. The above reactions are preferably carried out under mild conditions such as cooling, room temperature or slightly elevated temperature.

The above reactions also include variants in which the protected carboxyl groups R ² and / or R ^{3 are} converted to a free carboxyl group or after the reaction mixture is treated.

Procedure 5

The Bow. compounds of the general formula or salts thereof may be prepared by reacting a compound of formula Ii. The compound of formula (I) or a salt thereof is deprotected.

II. The corresponding salt of a compound of formula II is a compound of formula II. in the case of the compounds of the general formula (I), said salt.

The cleavage reaction can be carried out by the methods given in Process variant 4 above. The above process also encompasses variants in which a protected amino lower alkyl group substituted as a substituent on a R ⁴ heterocyclic-thio (lower) -aflaS group is converted to an amino (lower-carbon) - alkyl group.

6. etyirdsvití & z & t

The Π. A compound of formula (I) or a salt thereof may be prepared by treating one of Ik. cleavage of the carboxyl protecting group from a compound of formula (I) or a salt thereof.

The Ik. Preferred salts of the compound of formula (II) are the same as described above for II. with the general formula.

The present cleavage reaction is shown in Table II. may be carried out according to the methods given in the variant.

The above process also encompasses embodiments in which a protected amino (lower) alkyl group which is a substituent on a heterocyclo-thio (lower) alkyl group of R ⁴ is converted to an amino (lower) alkyl.

Procedure 7

Compounds of formula In can be prepared by employing an im. or esterifying a compound of formula (I).

The lm. Suitable salts of the compounds of formula II may be the same as those of the compounds of formula II. listed above for compounds of the general formula.

The reaction is carried out such that one of the im. or a salt thereof is reacted with an esterifying agent.

Suitable esterifying an XR ⁸ (XVII) wherein R ⁸ and X are as defined above.

The above reaction is preferably carried out in a solvent such as dimethylformamide, pyridine, hexomethylphosphoric triamide or any other solvent which does not interfere with the reaction. In the case where lm. The compound of Formula I is prepared in the form of the free acid, preferably in the presence of a base as defined above.

-7183 006

Λ reaction temperature is not critical; however, the reaction is preferably carried out under cooling to room temperature or with slight heating.

Procedure Version 8

The Ih. or a salt thereof, such that an Ig. the compound of formula (I) or a salt thereof is deprotected.

The lg. The salts of the compound of formula II correspond to those of formula II. with the salts listed for the compound of formula (I).

The above reaction is carried out in the same manner as described in Method 4.

Procedure Version 9

The Ip. The compound of formula (I) or a salt thereof may be prepared by lo. dehydrogenating the compound of formula (I).

Preferably, the above reaction is carried out such that lo. or a salt thereof, with a dehydrogenating agent.

A suitable dehydrogenating agent is, for example, an acid such as an alkane carboxylic acid which may be substituted with hydrogen, e.g. , etc., or their symmetric acid anhydrides, reactive derivatives of asymmetric mixed acid anhydrides, diketenes or the like, fluorosilic, chiral reagent T-ethylcarboxysulfamoyl compound, an intramolecular salt of an ylide compound such as triethylammonium hydroxide and the like.

The reaction is preferably carried out in the presence of a base.

Preferred bases include an inorganic base such as a metal hydroxide such as sodium hydroxide, potassium hydroxide, a metal carbonate such as sodium carbonate, potassium carbonate, magnesium carbonate; a metal hydrogencarbonate such as sodium hydrogencarbonate, potassium hydrogencarbonate, an organic base such as a tertiary amine such as trimethylamine, triethylamine, pyridine; an alkali metal alkoxide such as sodium methoxide, sodium ethoxide, etc.

The reaction is usually carried out in the presence of a solvent known per se, such as alcohol, tetrahydrofuran, dimethyl, m-amide, chloroform, methylene chloride, or any other solvent which does not interfere with the reaction, either under cooling or at room temperature or slightly elevated temperature.

Process variant 10

It's Irish. or a salt thereof can be prepared by reacting a compound of formula Iq. an amino protecting group is added to a compound of formula I or a salt thereof.

The Iq. The corresponding salt of the compound of formula II is the same as the compound of formula II. exemplified by the salts of the compounds of formula (I).

The reaction may be carried out in the same manner as described above for Process variant 1.

Below is a summary of Annex III. the preparation of starting materials of the general formula:

A. Production Method

VII. A compound of Formula V may be prepared by reacting a compound of Formula V or a salt thereof with a halogenating agent and a compound of Formula VI. with a compound of formula (I).

The halogenated carbon used in the reaction can be, for example, chlorine, bromine or the like. The reaction is preferably carried out in the presence of a base such as an inorganic base or an organic base. Examples of such bases include alkali metal carbonates, alkali metal alkoxides, trialkylamines and the like. The reaction is usually carried out in a solvent such as an alcohol such as methanol, ethanol or any other solvent which does not interfere with the reaction. The reaction temperature is not critical and the reaction is usually carried out under cooling or at room temperature. In the present reaction, the R ⁶ substituent of the compound of formula V may be converted to another carboxyl protecting group depending on the reaction conditions, and these changes are within the scope of the present reactions.

B. Production Method

VIII. can be prepared by reacting a compound of formula VII. an amino protecting group is introduced into the compound of formula.

The reaction may be carried out by methods known per se, and when the protecting group to be attached to the amino group is an acyl group, the reaction may be carried out essentially according to the methods given in Process 1. Accordingly, a detailed description of the reaction is given above in Procedure 1.

Production Method C.

The compound of formula X is prepared in one of the formulas VIII. and IX. is prepared by reaction of a compound of formula (I).

The process is generally carried out in the presence of a base such as an alkali metal hydride, sodium hydride, potassium hydride, etc., an alkaline earth metal hydride such as calcium hydride and the like, and is generally employed in the presence of a solvent such as dimethylformamide or any other solvent. The reaction temperature is not critical and the reaction is usually carried out under cooling to room temperature or heating.

D. Production Method

The XI. A compound of formula (X) may be prepared by reacting a compound of formula (X) with an acid and / or an acid anhydride such as acetic acid and / or acetic anhydride. Preferably, the present reaction is carried out in the presence of an alkali metal perhalate, such as sodium perchlorate, sodium periodate, potassium perchlorate, alkaline earth metal perchlorate, such as magnesium perchlorate, calcium perchlorate, and the like in an organic acid such as formic acid or inorganic acid.

The reaction temperature is not critical and the reaction is usually carried out under heating.

Methods E and G.

The present methods of preparation are carried out according to the methods given in Process variants 2 and 4 above.

183,006

Is E. production nródszc? Depending on the reaction conditions, the substituent R, ^A substituent or R, ^A may form a latlinase compound which is then reacted with a compound of the general formula XII or a salt thereof to give 111. or IHB. A compound of formula (I) is obtained as shown in the method f ^:

/ · '. method of production

Xll. a salt of a compound of the formula (I) is generally a salt of a known acid, such as a salt of an inorganic acid, such as hydrochloride, or a salt of an organic acid, such as phthaloyl sulfofiswa. If, during the procedure, XII. The reaction is preferably carried out in the presence of a base such as an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide. The reactions are generally carried out in a solvent such as water, alcohol, e.g. methanol, ethanol, or any other solvent which does not interfere with the reaction. The reaction temperature is not critical and the reaction is usually carried out at room temperature.

//. method of production

THE BRIDGE. The compound of formula I can be prepared by reacting the NIC. a hydroxyl protecting group is introduced into the compound of formula.

The process may be carried out by any of the methods known per se, and if the protecting group to be attached to the hydroxyl group is an acyl group, the reaction may be carried out by the methods described in Method 1.

In the case where the protecting group to be introduced is an aryl (lower) alkyl group, the reaction is carried out by reacting the compound of formula IIIC. a compound of formula R ^2f Y XVIII. with R ^2f aryl-lower alkyl and Y is an acid residue.

Suitable acid residues include an acid such as an inorganic acid such as a halohydrogen acid such as hydrochloric or hydrobromic acid, a sulfuric acid and the like, or an organic acid such as a lower alkanesulfonic acid such as methanesulfonic acid, ethenesulfonic acid, e.g. acid residues of toluenesulfonic acid and the like. Preferably, the reaction is carried out in the presence of a base as described above. The reaction is preferably carried out using a solvent such as dimethylformamide or the like. The reaction temperature is not critical and the reaction is usually carried out under cooling, at room temperature or under heating.

Production Method I

In the XV. a compound of formula XIII. and XIV. is prepared by reaction of a compound of formula (I).

The reaction is preferably carried out in the presence of a base already mentioned in Process variant 1. In the case where X is in the presence of an acid residue and a condensing agent, for example in the presence of a reaction product of triphenylphosphine and diethyl azoformate, in the case where X is a hydroxy group.

The reaction is preferably carried out in a solvent such as, for example, acetonitrile, dimethylformamide. The reaction temperature is not critical, and is preferably carried out at any temperature between cooling and heating to the reflux temperature of the solvent used.

./. method of production

XVI. A compound of formula (XV) or a salt thereof may be prepared by deprotecting an amino compound of formula (XV).

In the XV. The deprotection of the amino protecting group of a compound of formula (I) may be carried out in the same manner as described in Method 4.

Suitable solvents include water, ethanol, chloroform, diethyl ether and the like. The reaction temperature is not critical and the reaction is usually carried out under heating or boiling. The reaction also encompasses an embodiment wherein the protected amino group R ^{1 is} converted to the free amino group.

K. Production Method

Λ XX. or a salt thereof may be prepared by reacting a compound of formula XIX. an amino protecting group is applied to a compound of formula I or a salt thereof.

The reaction is carried out under substantially the same conditions as those described for Process 1.

In the case where the protecting group to be introduced is a lower alkoxycarbonyl group, the reaction is preferably carried out in accordance with formula XIX. and a compound of formula XXIX. is carried out by reacting a compound of formula wherein R ¹² a lower alkoxycarbonyl group and R ¹³ aryl.

Method of preparation

In the XXII. or a salt thereof may be prepared by reacting a compound of formula XXI. or a salt thereof, a substituent is added to the hydroxyl group.

In the case where the substituent intended to be introduced is a substituent aryl group which may be substituted, the reaction is carried out in accordance with formula XXI. or a salt thereof, and a compound of formula XXX. is carried out by reacting a compound of formula wherein R 'aryl which may be optionally substituted, X ² and Y is a halogen atom sav50 residue.

Suitable acid residues include, for example, a halogen atom, a toluenesulfonyloxy group, a sulfuric acid residue, or the like.

The reaction is usually carried out in a solvent such as an alcohol such as methanol or ethanol, water or a mixture thereof, or any other solvent which does not interfere with the reaction, and is preferably carried out in the presence of a base.

The reaction temperature is not critical, and the θθ reaction is usually carried out under cooling to room temperature or under heating.

In the case where the substituent to be introduced is an optionally substituted cycloalkyl group, the reaction is carried out according to formula XXI. The compound or salt thereof, and ^{65 microliters of} a R Y XXXUI formula. Reaction 9

It is carried out from other types of 006 -9183, wherein R represents optionally substituted ²ⁱ "fitiiáll cycloalkyl, and Y are as defined above.

The reaction is carried out under the same conditions as described in Preparation H.

M. Production Method

XXIV. or a salt thereof may be prepared by reacting a compound of formula XXIII. cyclizing a compound of formula (I) or a salt thereof.

The reaction is usually carried out in a solvent such as an alcohol such as methanol, ethanol or the like.

The reaction is carried out in the presence of a dehydrating agent such as magnesium sulfate or an acid anhydride such as acetic anhydride or the like.

The reaction temperature is not critical and may be carried out under heating or at reflux or at room temperature.

TV. method of production

In the XXVI. or a salt thereof may be prepared by reacting a compound of formula XXV. reacting a compound of formula I with ammonia or a salt thereof.

A suitable salt of ammonia may be, for example, an alkali metal salt.

The reaction is usually carried out in a solvent such as water, dioxane, a mixture thereof, or any other solvent which does not substantially affect the reaction.

The reaction temperature is not critical and the reaction is usually carried out under heating.

Production Method 0

XXVII. or a salt thereof may be prepared by reacting a compound of formula XXVI. The compound of formula I or its salt is deprotected.

The reaction may be carried out by the method described above for Process 4.

P. Production Method

In the XXVIII. or a salt thereof may be prepared by reacting a compound of formula XXVII. an amino protecting group is added to a compound of formula I or a salt thereof. The reaction is carried out as described above for Preparation K.

In the above reactions and / or in the subsequent conversion reactions according to the invention, the tautomeric isomers mentioned above can be converted to another tautomeric isomer and these conversions are also within the scope of the invention.

In the case where the compound of formula I is swallowed as the 4-position free acid and / or when the compound of formula I contains a free amino group, the compounds may be optionally converted into their pharmaceutically acceptable salts, as described above. by methods known per se.

The pharmaceutically acceptable salts of the compounds of Formula I are novel compounds and exhibit very good antibacterial activity by inhibiting the growth of a very broad range of both Gram-positive and Gram-negative bacteria; therefore they can be used as antibacterial agents.

To illustrate the activity of the compounds of the formula I, the mutant antimicrobial activity of various compounds in vitro is illustrated below.

Test compounds (I) 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color isomer) (2) 7- [2-ciklopcntiloxiimino-2- (5-amino-l, 2,4-thiadiazol-3-yl) acetamido | -3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3cefem- 4-Carboxylic acid (color isomer) (3) 7- [2- (2-cyclopenten-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cephem -4-Carboxylic acid (color isomer) (4) 7- (2- (2-cyclopenten-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1,3,4-Thiadiazol-2-yl) thiourethyl-3-cephem-4-carboxylic acid (color isomer) (5) 7- [2- (2-Cyclohexen-1-yl) oxyimino-2- ( 5-Amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (color isomer) (6) 7- (2- (4-klórfenoxümino) -2- (5-amino-l, 2,4-thiadiazol-3-yl) acetamido] -3- (l, 3,4-thiadiazol-2-yl) - thiomethyl-3 cephem-4-carboxylic acid (color isomer) (7) 7- [2-Allyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-allyl) -1H-Tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer) (8) 7- [2-Carbo ximethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (2-aminoethyl) -1H-tetrazol30-yl] -thiomethyl-3-cephem -4-Carboxylic acid (color isomer) (9) 7- (2- (1-carboxyethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- ( 3-Aminopropyl) -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer) (10) 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2), 4-Thia-35-diazol-3-yl) -acetamido] -3- (tetrazolo [1,5-b] pyridazin-6-yl) -methyl-3-cephem-4-carboxylic acid (color isomer) (II) N- [ 7- (2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido) -3-cephem-3-ylmethyl] -4-carbamoylpyridinium-4-carboxylate (color isomer )

Test method

The in vitro antibacterial activity of the above compounds was tested by a double agar dilution method. Mode 45 is described below. An overnight culture (10 ⁸ live cells / ml) of the tryptase soy medium of test strains was inoculated with a tiny amount of increasing concentrations of test compounds (HI-agar) and the minimum inhibitory concentration (MIC) in micrograms / ml. After incubation at 37 ° C for 20 hours. The test results are as follows:

55 Test organism Escherichia coli 0) 60 NIHJ JC-1 Klebsiella 0.39 pneumoniae 12 0.78 Proteus vulgaris 2 0.39 Pseudomonas aero- 65 ginosaNCTC 10490 3.13

MIC (Mg / ml) Test compound

(2) (3) (4) (5) (6) 0.78 0.39 0.78 3.13 3.13 3.13 0.78 1.56 3.13 3.13 3.13 0.39 1.56 3.13 3.13 1.56 1.56 3.13 3.13 3.13

-101

00 (,

Test MIC (Mg / ml) organism Test compound

(7) (8) (9) (10) (H) E. coli NIHJ JC-1 0.20 0.10 0.20 0.78 1.56 WHO. Prieure. 12 1:56 0.10 0.20 1.56 3.13 Ms. Vulg. 2 0.78 0.10 0.20 1.56 3.13 Ps. Aerog. NCTC 10490 3.13 1:56 3 13 12.5 6.25 therapeutic for application a lalálntány by

The compounds of Formula I may be used in the form of conventional pharmaceutical formulations containing the active ingredient in admixture with pharmaceutically acceptable carriers, such as organic or inorganic solid or liquid carriers, for oral, parenteral or external administration. The pharmaceutical compositions may be in solid form, such as capsules, tablets, dragees, ointments or suppositories, or in liquid forms, for example, in the form of solutions, suspensions or emulsions. If necessary, the above formulations may also contain additional excipients, stabilizers, wetting or emulsifying agents, buffers or other additives known per se.

Since the dosage of the compounds of the invention depends on the age, physical condition, nature of the infection, the compound of formula I, etc., the average single dose of the compounds of formula I may be 50 mg, 100 mg, 250 mg and 500 mg. . These doses were effective in treating infections caused by pathogenic bacteria.

Generally, a daily dose of between 5 and 3000 mg per day may be used or more.

The following Preparation Examples and Examples illustrate the process of the invention in detail.

Preparation Example 1 (1) A mixture of 8.15 g of N-hydroxyphthalimide, 5.05 g of triethylamine, 60 ml of Ν, Ν-dimethylformamide and 8.05 g of 1-bromo-2-cyclohexene is stirred at room temperature for 3.5 hours. . The reaction mixture was then poured into water (300 mL). The precipitated crystals were collected by filtration, washed successively with water and n-hexane, and after drying 9.8 g of N- (2-cyclohexen-1-yloxy) phthalimide, m.p. 87 ° C.

IR spectrum (Nujol). 1770, 1720, 1610 cm @ ⁵ .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, a): 1.50-2.17 (6H, m), 4.60-4.77 (1H, m), 5.73-6.27 (2H, m), 7. 90 (4H, s).

(2) A mixture of 52, hanging N-hydroxyphthalimide, 62.41 g of bromocycloheptane, 385 ml of dimethylsulfoxide and 44.16 g of potassium carbonate is stirred at 70 ° C for 74 hours. The reaction mixture was cooled using ice and added to 1.5 L of ice water. The precipitate was filtered off, washed twice with ice water and dried to give 63 g of N- (cycloheptyloxy) phthalimide, m.p. 100-112 ° C.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO,?): 1.57 (8H, m), 1.90 (4H, m), 4.20 (1H, m), 7.93 (4H, s).

(3) A mixture of 58.2 g of N-hydroxyphthalimyl, 36.9 g of l-chloro-2-cyclopentene and 53.9 g of 370 ml of acetonitrile was treated as described in (1) and (2) above.

56.5 g of N- (2-cyclopenten-1-yloxy) phthalimide are obtained.

IR (Nujol): 1780, 1730, 1610 cm ^- '.

NMR (d _é -DMSO, δ): 7.92 (411, s). 6.28 (1H, m), 6.00 (1H, m), 5.42 (til, m) 2.9-1.98, 14H. ml.

Production Example 2

A mixture of 2.59 g of N- (cycloheptyloxy) phthalimide, 0.45 g of hydrazine hydrate and 12 ml of ethanol is refluxed for 5 minutes. The reaction mixture was then cooled and filtered to give a filtrate containing cycloheptyloxyamine.

Preparation Example 3 (1) A mixture of 22.9 g of N- (2-cyclopenten-1-yloxy) phthalimide and 4.75 g of hydrazine hydrate in 115 ml of ethanol is refluxed for 5 minutes. The reaction mixture was then filtered and the filtrate containing 2- (2-cyclopenten-1-yl) oxyamine was added to an aqueous solution of 2- (5-formamido-1,2,4-thiadiazol-3-yl) glyoxylate (22.4 g). The pH of the mixture was adjusted to 2 with 10% hydrochloric acid, stirred for 2 hours and then concentrated. The concentrated solution was adjusted to pH 1 with 10% hydrochloric acid. The precipitate was collected by filtration and, after drying, 20.0 g of 2- (2-cyclopenten-1-yl) oxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (color isomer). m.p. 150 DEG C. (with decomposition).

IR (Nujol): 3400, 3100, 1720, 1690, 1540 cm @ -1.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, α): 1.80-200 (4H, m), 5.30-5.50 (1H, m), 5.83-6.30 (2H, m), δ , 90 (1H, s).

(2) A mixture of 7.29 g of N- (2-cyclohexen-1-yloxy) phthalimide and 1.5 g of hydrazine hydrate in 40 ml of ethanol is refluxed for 5 minutes. The reaction mixture was then cooled and filtered to give a filtrate containing (2-cyclohexen-1-yl) oxyamine (filtrate A). A solution of 6.93 g of S-methyl-2- (5-formamido-1,2,4-thiadiazol-3-yl) -thioglyoxylate in 90 ml of ΙΝ-aqueous sodium hydroxide solution is stirred for 30 minutes at room temperature. The reaction mixture containing the sodium salt of 2- (5-formamido-1,2,4-thiadiazol-3-yl) -glyoxylic acid was adjusted to pH 7 with 10% hydrochloric acid, then the filtrate A was added and the pH of the reaction mixture was adjusted to 10. with 3% hydrochloric acid. The reaction mixture was then stirred for 3 hours at room temperature, then evaporated and ebi acetate was added to the concentrated solution. The pH of the mixture was adjusted to 1 with 10% hydrochloric acid. The precipitate was collected by filtration to give 2.5 g of 2- (2-cyclohexen-1-yl) oxyimino-2- (5'-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer). ) we get. At the same time, the ethyl acetate layer was separated from the filtrate and evaporated. Trituration of the residue with diethyl ether gave an additional 1.5 g of the above product, 4.0 g, m.p. 190-192 ° C (with decomposition).

IR (Nujol): 3550, 3400, 3200, 2500, 1690, 1590, 1540 cm ^-1 .

1 H NMR (d 6 -DMSO,?): 1.5-2.3 (6H, m),

4.73-5.0 (1H, m), 5.76-6.23 (2H, m), 8.97 (1H, s), 13.60 (1H, broad s).

(3) To a solution of 11.2 g of sodium hydroxide in 140 ml of water is added 27 g of S -meryl-2- (5-formamido-1,2,4-thiadiazol-3-yl) thioxylate at 10 ° C and the mixture is stirred for 30 minutes. Stir at 20 ° C. THE

-111

The reaction mixture containing the sodium salt of 2- (5-formamido-1,2,4-thiadiazol-3-yl) -glyoxylal was cooled to pH 7 with 10% hydrochloric acid and 15.3 g of cyclopentyloxyamine in 150 ml of ethanol were added. solution. The pH of the mixture was adjusted to 3 with 10% hydrochloric acid and stirred for 1.5 hours. The reaction mixture was then adjusted to pH 7 with aqueous sodium bicarbonate solution and the ethanol was evaporated. The residue is washed with ethyl acetate, ethyl acetate is added to the aqueous phase, and the mixture is adjusted to pH 1 with 10% hydrochloric acid. The precipitate was collected by filtration to give 3.99 g of 2-cyclopentyloxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) -acetic acid <(color isomer). The filtrate was extracted with ethyl acetate and the extract was dried over magnesium sulfate and evaporated. The precipitate was filtered off and washed with diethyl ether to give an additional 8.1 g of the above product, total yield 12.09 g, m.p. 180-185 ° C (with decomposition).

IR (Nujol): 3130, 3040, 2680, 2610, 2520, 1620, 1690, 1660, 1550 cm ^-1 .

¹ H NMR (d ₆ -DMSO,?): 1.33-2.10 (811, m), 4.67-5.0 (1H, m), 8.88 (111, s), 13 , 50 (111, s).

(4) A 3 / 1-3 / 3. The following compound was prepared according to the methods described in the Preparation Examples.

2-Cycloheptyloxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer).

NMR (d _e -DMSO, a): 1.50 (8H, m), 1.80 (4H, m), 4.37 (IH, m), 8.81 (lH, s), 9, 88 (1H, s).

Production Example 4

20.0 g of 2- (2-cyclopenten-1-yl) oxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (color isomer) and 200 ml of 1N aqueous sodium hydroxide solution was stirred at 50-55 ° C for 1 hour. The reaction mixture was then cooled to pH 10 with hydrochloric acid. After adjusting to 7, ethyl acetate was added. The mixture was adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and evaporated. The residue is triturated with diisopropyl ether to give 2- (2-cyclopenten-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (color isomer), m.p. 150 ° C. (during decomposition).

IR (Nujol): 3300, 3150, 1710, 1620,

At a wave number of 1520 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO,?): 1.80-2.50 (4H, m), 5.30-5.50 (1H, m), 5.83-6.30 (2H, m) , 8.20 (2H, s).

Production Example 5

Following Preparation Example 4, the following compounds were prepared:

(1) 2- (2-Cyclohexen-1-yl) -oxymimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer), m.p. 173 ° C.

IR (Nujol) 3400, 3300, 3200, 1720, 1620, 1600, 1520 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, a): 1.50-2.17 (6H, m), 4.53-4.83 (1H, m), 5.57-6.13 (2H, m) , 8.18 (2H, s).

(2) 2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer), m.p. 160-165 ° C (with decomposition).

IR-spectroscopy (ntijolj: .mu.l.i. 3290, 320U, 2400, 1715, 1615, 1600, 1520 cm ^-1) .

Nuclear Magnetic Resonance Spectrum (d _r , -DMSO,?): 1.17-2.10 (811, ml, 4.60 4.97 (1H, m), 8.22 (211 s) (3) 2 -cycloheptyloxyimino-2- (5-amino-1,2,4-liadiazin-3-yl) -acetic acid (color isomer), m.p. 116-119 ° C (dec.).

IR (Nujol): 3250, 3200, 1650, 1600, 1520, 1400, 1260, 1150, 1000 ,, 820 720 ^cm-1 wavenumber.

Preparation Example 6 (1) A solution of 122.6 g of 4- (3-aminopropyl) morpholine in 520 ml of dioxane is added to a solution of 35.1 g of 97% sodium hydroxide in 420 ml of water at a temperature below 04.71. Carbon disulphide (g) was added dropwise over half an hour at 0-5 ° C. The mixture was stirred at the same temperature for an additional hour and then 120.65 g of methyl iodide was added over half an hour at 0-5 ° C. stirring at the same temperature. The precipitate was filtered off, washed twice with water and dried to give 4- [3- (N -methyl-thiocarbortyl) amino] -propyl] -morpholine as a pale yellow powder. Yield: 174.55 g

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO,?): 1.73 (2H, m), 2.3 (6H, m), 2.48 (3H, s), 3.2-3.9 (6H, m) ), 9.91 (1H, broad s).

(2) To a solution of 152 g of 4- {3- (N-methylthio- (thiocarbonyl) amino} propyl) morpholine in 430 ml of dioxane is added a solution of 42.25 g of sodium azide in 290 ml of water. The resulting mixture was refluxed for 2 hours. The reaction mixture was concentrated, adjusted to pH 8, and washed with diethyl ether. The aqueous phase was adjusted to pH 5 and cooled, and the precipitate was collected by filtration, washed twice with ice-water and dried to give 116 g of 1- (3-morpholinopropyl) -1H-tetrazol-5-thiol as a white crystalline solid, m.p. ° C (with decomposition).

IR (nujol): 3550, 3500, 2350, 1610, 1410, 1360, 1280, 1190 1130, 1090, 1050, 990, 880 825, 785 cm @ -1.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO,?): 2.14 (2H, m), 2.99 (2H, t, J = 7Hz), 3.09 (4H, m), 3.79 (4H, m) ), 4.24 (2H, t, J = 7Hz).

Example 7 producedPisi (1) A 6) 1. In the same manner as in Preparation Example I, the following compound was prepared:

[3- {N-methylthio (thiocarbonyl) amino} propyl] piperidine, white powder, m.p. 74-76 ° C.

IR (Nujol): 3450, 3150, 1670, 1560, 1410, 1340, 1315, 1255, 1030, 1000, 950, 880, 860,800, 750 cm &lt; -1 &gt;.

(2) A 6/2. In the same manner as in Preparation Example I, the following compound was prepared:

1- (3-piperidinopropyl) -1H-tetrazole-5-thiol, m.p. 142144 ° C (with decomposition).

IR (Nujol): 3500, 3350, 2450, 1635, 1360, 1280, 1200, 1185, 1120, 1100, 1085, 1070, 1000, 965, 950, 810 ^cm-1 wavenumber.

-121

183,006

NMR Spectrum Jin O-1JMSO, (a): 1.3 -1.9 (6H, in), 2.20 (211 m), 3.07 (2H, t, J = 7Hz), 1) 7 (411, m), 4, 24 (2H, t, J = 711z).

PREPARATION EXAMPLE (1) To a solution of 3.22 g of tea in a mixture of 300 ml of methyl chloride chloride was added 108.5 g of ethyl formate of chloroformate at -20 ° C. The resulting mixture was shaken for 1 minute at -13 ° C. The organic phase was separated off, dried over anhydrous magnesium sulfate and allowed to warm to room temperature. The methBenfewikis phase was separated by decantation and the ofdhaJatbin was washed with methylene chloride. The combined MRF phases, total volume 370 ml, were evaporated under pressure to give a solution containing 335 ml of ethyl cyanoformate, boiling at 42-117 ° C.

(2) A solution of 32.5 hydrochloric acid in ethanol (34.5 g) was cooled to -10 ° C. The reaction mixture is prepared by adding a cold-cooled ethyl formoformate to -10 ° C. The resulting solution was initiated hőmélsékleten between -5 and + 5 ° C for 6 hours, then cooled to ^-10 ° C and 400 ml of methylene chloride is given to it. A solution of triethylamine (85.8 g) in methylene chloride (80 ml) and water (200 ml) was added dropwise at -5 to 0 ° C. The ethylene chloride phase was separated, washed with water (2 x 200 ml), dried over anhydrous magnesium sulfate, and evaporated to give 12 g of product containing 78.8% of ethyl 2-immo-2-ethoxyacetate. The product was purified by distillation (bp = 80-88 ° C / 40 mm Hg) to give pure product.

(3) A mixture of 60 g of ethyl 5- imino-2-ethoxyacetate (78.8% purity), 17.4 g of ammonium chloride and 180 ml of methanol was stirred at room temperature for 3 hours and then cooled to -15 to -10 ° C. To the resulting mixture containing 1-methoxycarbonylformamide hydride

51.2 g of bromol are added dropwise over a period of 10 minutes, followed by 71.1 g of thyrosulfone in 30 minutes and a solution of 31.0 g of potassium thiocyanate in 150 ml of methanol are also added over 30 minutes. The resulting mixture was stirred at -10 to -5 ° C for 15 minutes and then at 0 to 5 ° C for an additional 1.5 hours. The precipitate was collected by filtration, washed with methanol and 200 mL of cold water was added. The mixture was stirred and the precipitate was collected by filtration, washed with cold water and dried to give 32.5 g of 5-amino-1,2,4-thiadiazole-3-carboxylate methyl ester.

(4) To a solution of ethyl cyanoformate (25.0 g) in methylene chloride (55 ml) was added a solution of hydrochloric acid (16.8 g, 43.5% in ethanol) at 3 ° C. The mixture was then stirred for 5 hours at 3 to 5 ° C and allowed to stand overnight at -5 to -3 ° C. To the resulting mixture was added 120 ml of methylene chloride at a temperature below 6 ° C, followed by a solution of 20.2 g of triethylamine in 20 ml of methylene chloride at a temperature below 6 ° C. The mixture was stirred for 40 minutes and then water (40 ml) was added at a temperature below 6 ° C. The resulting mixture was stirred for 3 minutes, then the methylene chloride phase was separated, dried over anhydrous magnesium sulfate and concentrated. To the residue is added 40 ml of diisopropyl ether, the insoluble material is filtered off and washed with 10 ml of diisopropyl ether. The filtrate and washings were combined to give, after evaporation, 26.2 g of ctyl-2-imino-2-ethoxyacelate as a pale yellow oil. A mixture of 26.2 g of the oil obtained above, 6.42 g of ammonium chloride and 90 ml of methanol is stirred for 2 hours at room temperature, and thereto is added 450 ml of diisopropyl. The mixture was cooled with ice and stirred for 30 minutes. The precipitate was collected by filtration to give 13.8 g of white powdered 1-methoxycarbonylformamide hydrochloride, m.p. 150-155 ° C (with decomposition).

IR (Nujol): 3350-3050, 1780, 1710, 1695, 1290, 1270, 1070, 980 and 800 ^cm-1 wavenumber.

NMR (d -DMSO _an a): 3.97 (3H, s), 9.8 (4H, sz.éles, s).

(5) To a solution of 7.6 g of 1-methoxycarbonylformamide hydrochloride in 55 ml of methanol is added 8.8 g of bromine over 5 minutes at -5 to -0 ° C. 11.1 g of triethylamine and 5.3 g of potassium thiocyanate (30 ml) are added over 10 minutes at -5 to 0 ° C. The mixture was then stirred at 0 to 5 ° C for 1.5 hours. The precipitate was collected by filtration, washed with methanol (11 mL) and water (15.5 mL) was added. After stirring for 30 minutes, the precipitate was collected by filtration, washed with water (3 x 5 mL) and dried to give 6.3 g of a white powder of 5-amino-1,2,4-thiadiazole-3-carboxylic acid methyl ester.

(6) A mixture of ethyl 2-imino-2-ethoxyacetate (36.2 g), ammonium bromide (21.2 g) and methanol (180 ml) was stirred at room temperature for 4 hours, then diisopropyl ether (400 ml) was added with stirring. The mixture was allowed to stand for 30 minutes and the precipitate was collected by filtration. 200 ml of diisopropyl ether were added to the filtrate and the mixture was allowed to stand for 10 minutes. The precipitate was collected by filtration to give 16.1 g of white powdery 1-methoxycarbonylformamidine hydrobromide. The filtrate was evaporated to a volume of 150 ml and 200 ml of diisopropyl ether were added to the concentrated solution and the mixture was allowed to stand for 30 minutes. The precipitate was further separated by filtration

II, 6 g of white powdery product is obtained, total yield 27.7 g.

IR (Nujol): 3350-3150, 1780, 1710, 1690, 1290, 1270, 1060, 980, 850, 800, 730 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO,?): 3.91 (3H, s), 11.0 (4H, broad s).

(7) A mixture of 18.1 g of ethyl 2-imino-2-ethoxyacetate, 5.5 g of ammonium chloride and 90 ml of ethanol is stirred for 6 hours at room temperature. Insoluble materials were filtered off and washed with ethanol. The filtrate and washings were combined and evaporated. To the resulting oil was added 50 ml of acetone. The precipitate was collected by filtration and washed with 2 x 10 mL of acetone to give 1.2 g of white powdered 1-ethoxycarbonylformamide hydrochloride. The filtrate and washings were combined and evaporated. The residue was triturated with acetone (30 mL), separated by filtration, washed successively with acetone, methylene chloride and diisopropyl ether to give 7.3 g of the above product as a white powder. Total yield 8.5 g.

IR (Nujol): 3400-3100, 1770, 17301680, 1650, 1300-1260, 1120, 1010,860,760 cm ^-1 .

-13183 006

Production Example 9

5-amino-1,2,4-thiadiazole-3-carboxylic acid methyl and 7.tcr.

To a solution of 16.6 g of 1-ethoxycarbonylformamldine hydrobromide in 84 ml of anhydrous methanol was added a solution of 1.93 g of sodium in 42 ml of anhydrous methanol at 0 ° C. To the mixture was then added 12.8 g of bromine, followed by

A solution of 1.93 g of Na'irin in 42 ml of anhydrous methanol was added at 0 ° C and 8 µl of potassium trocyanate was added to the suspension. 100 ml of anhydrous methanol was added. The reaction mixture was stirred at 0 ° C for 1 hour and then at room temperature for a further 6 hours. The mixture was filtered through cellulose powder and the filtrate evaporated to dryness. The residue was left in a mixture of ethyl acetate and water, and the ethyl acetate layer was separated and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue triturated with diethyl ether to give 9.0 g of the title compound, m.p. 202-205 ° C.

IR (Nujol): 3400, 3250, 3100, 1710, 1610, 1540 cm @ ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ 3.85 (3H, s), 8.25 (2H, s)).

Production Example 10

Preparation of 5-formamido-1,2,4-thiadiazole-3-carboxylic acid methyl ester.

To a mixture of formic acid (22 g) and acetic acid (22 g) was added 6.2 g of 5-amino-1,2,4-thiadiazole-3-carboxylic acid methyl ester and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure and the residue triturated with a mixture of diethyl ether and n-hexane.

7.2 g of the title compound are obtained, m.p.

IR (Nujol): 3100, 1720, 1680 cm @ -1.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, a): 3.90 (3H, s), 8.85 OH, s).

PREPARATION 11 Preparation of 5-formamido-3- (2-methylthio-2-methylsulfmiacetyl) 1,2,4-thiadiazole.

To a mixture of 9.2 g of 5-formamido-1,2,4-thiadiazole-3-carboxylic acid methyl ester and 6.1 g of methyl methylthiomethylsulfoxide in 100 ml of N-dimethylformamide was added 7.1 g of 50% sodium hydride. with cooling in an ice water bath. The mixture was stirred for 1 hour at room temperature and then for an additional 1 hour at 40 ° C. After cooling at room temperature, 30 µl of methylethylene chloride was added to the reaction mixture, and the resulting precipitate was collected by filtration and washed with methylene chloride. The precipitate was added to a mixture of 14.7 ml of hydrochloric acid, 200 ml of ice water and 200 ml of methylene chloride. The insoluble material is filtered off and the methylene chloride phase is separated from the filtrate. The solution was dried over anhydrous magnesium sulfate, concentrated and the residue triturated with diethyl ether to give 4.5 g of the title compound, m.p. 130-132 ° C.

IR (Nujol): 3100, 1680, 1670 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO,?): 2.22 and 2.28 (3H, 2s), 2.68 and 2.85 (2H, 2s), 5.70 and 5.80 (1H, 2s). , 8.86 (1H, s).

Production Example 12

Preparation of 5-methyl- (5-formamido-1,2,4-thiadiazol-3-yl) -thioglyoxylal.

A solution of 0.085 g of 5-formamido-3- (2-methylthio-2-methylsulfinylacetyl) -1,2,4-thiadiazole and 0.2 g of sodium hydroxide in 10 ml of glacial acetic acid is stirred at 70 ° C for 45 minutes. The reaction mixture was evaporated and the residue was dissolved in a mixture of ethyl acetate and water. The pH of the mixture was then adjusted to 7 with aqueous sodium bicarbonate solution and then treated with sodium thiosulfate. The organic layer was separated, dried over anhydrous magnesium sulfate and evaporated to dryness. Trituration of the residue with diethyl ether / petroleum ether gave 280 g of the title compound, m.p. 186-187 ° C.

IR (Nujol): 3100, 1680, 1660 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO .alpha.): 2.55 (3H, s), 8.95 (1H, s).

Production Example 13 A mixture of 5-formamido-3- (2-methylthio-2-metilszulfinilacetil) ₂₅ 1,2,4-thiadiazole and 2.0 g nátriumpeijodát mixture of 50 ml glacial acetic acid was stirred for 50 minutes at 70 ° C. The solvent was then evaporated and the residue was washed with n-hexane. To the residue was added 160 mL of 1N aqueous sodium hydroxide solution and the mixture was stirred for 1 hour at ₃ ° C. To the reaction mixture was added 4.31 g of O-allylhydroxylamine hydrochloride and the solution was adjusted to pH 3 to 4 with 10% hydrochloric acid and stirred for 1 hour at room temperature. The insoluble material was then filtered off, the filtrate was washed with ethyl acetate ( ₃ g), adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated with diethyl ether in diisopropyl ether

5.6 g of 2-alltloxrimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) are obtained, m.p. 169-172 ° C (with decomposition).

IR (Nujol): 3130, 2500, 1720, 1690, 1590, 1550 cm @ -1.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, a): 4.79 (2H, d, J = 6Hz), δ, 1-5.6 (2H, m), 5.8-6.4 (1H m), 8.88 (1H, s).

Production Example 14

By the method of Preparation Example 13, the following compounds 50 were prepared:

(1) 2-Benzyloxyimino-2- (5-formamido-1,2,4-tradiazol-3-yl) -acetic acid (color isomer), m.p. 90-95 ° C (dec.

IR (Nujol): 1720, 1680, 1590, 1550, 551530 cm ^-1 .

NMR (d -DMS0 _e, a), 5.28 (2H, s), 7.37 (5H, $), 8.83 (IH, s).

(2) 2- (2-Propynyloxyimino) -2- (5-formamido-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer), m.p. 150-155 ° C (with decomposition)

IR (Nujol): 3570, 3360, 3260, 3120, 1720, 1670, 1550, 1530 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO,?): 3.55 (1H, t, J = 2Hz), δ 4.88 (2H, d, J = 2Hz), 8.85 (1H, s).

-141

183 006 (3) 2- (2-Phenoxyethoxyimino) -2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (m.p. 147-150 ° C) (color isomer), (with decomposition) ).

IR (Nujol): 3200, 1740, 1720, 1640, 1590, 1530 cm ³ ,

Nuclear Magnetic Resonance Spectrum (d ₆ DMSO, a): 4.0-4.7 (4H, m), 6.7-7.5 (5H, m), 8.83 (1H, s).

(4) 2-Hydroxymethno-2- (5-formamido-2,4-thiadiazole, 3-yl) -acetic acid (color isomer), m.p. 240-241 ° C (with decomposition).

IR (Nujol) 3550, 3460, 1665, 1635,

150 cm ^{- at the} wave number.

Production Example 15

6.64 g of a solution of S-methyl- (5-formamido-1,2,4-thiadiazol-3-yl) -thioglyoxylate in 80 ml of aqueous sodium hydroxide solution are adjusted to pH 8.5 with 10% hydrochloric acid and Stir at room temperature for 30 minutes. At the same time, a mixture of 8.78 g of N- (2,2,2-trifluoroethoxy) phthalimide and 1.7 g of hydrazine hydrate in 40 ml of ethanol was refluxed for 5 minutes and then cooled in an ice bath. The resulting precipitate was filtered off and washed with ethanol. The filtrate and washings were combined and the combined solution containing O- (2,2,2-trifluoroethyl) hydroxylamine was added to the above aqueous solution. The pH of the mixture was adjusted to 3 and 10 with 10% hydrochloric acid and stirred at room temperature for 1.5 hours. The solution was then neutralized with aqueous sodium bicarbonate solution, evaporated to half volume in vacuo and washed with ethyl acetate. The aqueous solution was acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, evaporated to dryness and the residue triturated with diisopropyl ether.

2.46 g of 2- (2,2,2-trifluoroethoxyimino) -2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (color isomer) are obtained, m.p. 180-185 ° C. during decomposition).

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO,?): 4.80 and 5.7 (2H, ABq, J = 9Hz), 8.85 (1H, s).

Production Example 16

Preparation 15 The following compounds were prepared by the methods of Example.

(1) 2-methylthiomethoxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer), m.p. 146-148 ° C (with decomposition).

IR (Nujol): 3300, 2600, 2550, 1730, 1705, 1680, 1600, 1530 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, a): 2.23 (3H, s), 5.40 (2H, s), 8.87 (1H, s).

(2) 2- (2-methylthioethoxyimino) -2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer).

IR (Nujol): 3230, 1720, 1690, 1590, 1520 cm -1 .___

NMR (d -DMSO _an a): 2.17 (3H, s), 2.82 (2H, t, J = 7Hz), 4.42 (2H, t, J = 7Hz), ^v 8, 87 (1H, s).

(3) 2-Phenoxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer), m.p. 145-147 ° C (with decomposition).

IR (Nujol): 3130, 1720, 1690, 1S85, 1550 cm ^"1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, a); 7.0-7.6 (5H, m), 8.88 (1H, $).

(4) 2- (2- (2-Hexyloxy-ethoxy) -ethoxy) -nino] -2- (5-ol-amido-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer).

IR (CHCl3) 3420, 3180, 1740, 1700, 1600, 1530, 1460 cm @ -1 ^. wave number.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO,?): 0.87 (311, J = 5Hz), 0.87-1.73 (8H, m), 3.20-3.90 (8H, m), 4.23 -4.53 (211, m), 8.84 (131, s), 13.55 (111 broad).

(5) 2-Trityloxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) -acetic acid (anti-isomer), m.p. 188-190 ° C (with decomposition).

IR (Nujol): 3150, 1620, 1600, 1540 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (C 18 H-DMSO,?): 7.00 (15H, s). 8.92 (1H, s).

PREPARATIVE EXAMPLE 17 A solution of 5 g of S-methyl- (5-formamido-1,2,4-thiadiazol-3-yl) -thioglyoxylate and 4.2 g of sodium hydroxide in 50 ml of water was stirred at 50-55 ° C for 1 hour. . The mixture was then cooled to room temperature and adjusted to pH 7 with 10% hydrochloric acid. At the same time, a mixture of 12.9 g of N- (ethoxycarbonylmethoxy) phthalimide and 2.08 g of hydrazine hydrate in 60 ml of ethanol is refluxed for 5 minutes and then cooled in an ice bath. The resulting precipitate was filtered off and washed with ethanol. The filtrate and washings were combined and the combined solution containing O- (ethoxycarbonylmethyl) hydroxylamine was added to the above aqueous solution. The pH of the mixture was adjusted to 3 to 4 with 10% hydrochloric acid and stirred at room temperature for 1.5 hours. The solution was neutralized with aqueous sodium bicarbonate solution, concentrated to half volume in vacuo and washed with ethyl acetate. The aqueous solution was acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, evaporated to dryness and the residue triturated with diisopropyl ether (1.8 g).

2-Ethoxycarbonylmethoxyimino-2- (5-amino-1,2,4-thiadiazole-3'-U) -acetic acid, m.p. 135140 DEG C. (dec.).

IR (Nujol): 3500, 3330, 3210, 2670, 2550, 1740, 1610, 1540 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, a): 1.24 (3H, t, J = 7Hz),

4.14 (2H, q, J = 7Hz), 4.80 (2H, s),

8.15 (2H, broad).

Production Example 18

By the methods described in Preparation Example 17, the following compounds were prepared:

(1) 2-Cyanomethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer), m.p. 130-135 ° C (with decomposition).

IR (nujol): 3350, 3150, 1730, 1630, 1540 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO,?): 5.17 (2H, s), 8.28 (2H, broad s).

(2) 2- (1-Ethoxycarbonyl-1-methylethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer), m.p. 165-168 ° C. C ^(dec),! IR (Nujol): 3450, 3350, 3240, 1750, 1730, 163Q, 1530 ^cm-1 wavenumber.

IS

-15183 006

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO.r). 1J8 (3H, J = 711 /).

1.50 (6R s), 4.15 (211, q, J = 11z),

8.23 (2-1, wide).

(3) 2- (N, N-Diethylcarbamoylmethoxyquinoino) -2- (5-alkylthio-1,2,4-thiadiazot-3-yl) acetic acid (slant isomer), m.p. 150-155 ° C (rollover).

IR-spcktrum (nujol); 3400. 3150. 1745, 1635, 1610, / 595, 1535 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO,?): 3.03 (31 /, t, J = 7Hz), 1.10 (3H, t, J = 7 / delta 281411, q, J = 7Hz), 4.90 (2H, s, 8.23 (2H, s, broad s).

(4) 2-Mesylmethoxyimino-2- (5-amino-1,2,4-liadiazol-3-yl) -acetic acid (color isomer).

IR (Nujol) 3450. 3400, 3270, 2600, 2460, 1735, 1640, 1620, 1530 cm- ¹ .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO,?): 3.00 (3H, s), 5.38 (2H, s), 8.22 <2H, broad s).

19. Prefixing Example

By the methods of Preparation Example 4, the following compounds were prepared:

(1) 2-Alloxy-imino-2- (5-amyl-1,4-2,4-thiadiazol-3-yl) -acetic acid (color isomer), m.p. 93-95 ° C (with decomposition).

IR (Nujol): 3430, 3100, 1710, 1615, 1525 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, a): 4.72 (2H, d, J = 6Hz),

5.1-5.5 (2H, m), 5.7-6.3 (JH, m),

8.17 (1H, broad s).

(2) 2-Benzyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer), m.p. 158-160 ° C (with decomposition).

IR (Nujol): 3430, 3380, 3260, 1730, 1640, 1610, 1535 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO,?): 5.22 (2H, s), 7.33 (5H, s), 8.17 <2H, broad s).

(3) 2- (2-Propynyloxytmino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (color isomer), m.p. 155-157 ° C (with decomposition) .

ι IR (Nujol): 3500, 3310, 3160, 2600, 2480, 1745, 1610, 1535 ^cm-1 wavenumber.

NMR (d _é DMSO,): 3.53 (1H, t, J = 2Hz),

4.87 (2H, d, J = 2Hz), 8.23 (2H, broad s).

(4) 2- (2-Phenoxyethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer), m.p. 150-153 ° C (with decomposition) .

IR (Nujol): 3470, 3300, 3150, 2550, 1750, 1620, 1600,1540,1500 cm ^-1 hultámszámnál.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, a): 4.0-4.7 (4H, m),

6.7-7.5 (5H, m), 8.20 (2H, broad s).

(5) 2- (2 ', 2-Trifluoroethoxyindinyl) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), m.p. 140-143 ° C. during decomposition).

IR (Nujol): 3450, 3350, 3260, 1745, 1670, 1645, 1615, 1515 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ DMSO,?): 4.72 and 4.95 (2H, ABq, J = 9Hz), 8.25 (2H, bs).

(6) 2-methylthiomibtoimimethyl-2- (5-anino-1,2,4-thiadia-16-zol-3-yl) -acetic acid ("m-isomacr"), m.p. 140 143 '(' (with decomposition) .

IR spectrum (nujol): 3500, 3300, 3150. 2670, 2580, 1740, 1615, 1605, 1530 cm @ -1.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO,?): 2.22 (311, s), 5.33 (2H, s), 8.20 (211, broad s).

(7) 2- (2-methylthioethoxyimino) -2- (5-amino-1,2,4-thiazol-3-yl) -acetic acid (color isomer), m.p. 140-143 ° C (with decomposition).

IR (Nujol): 3430, 3340, 3230. 2650, 2450, 1720, 1610, 1520 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO,?): 2.08 (311 s), 2.72 (2H, t, J = 7Hz), 4.28 (2H, t, 1H-7Hz),

8.17 (2H, bs).

(8) 2-Phenoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (color isomer), m.p. 145-147 ° C (with decomposition).

IR (Nujol): 3350, 3170, 2500, 1730, 1710, 1645, 1630, 1595, 1535 ^cm-1 / wave number.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, a): 7.0-7.5 (5H, m). 8.30 (2H, bs).

(9) 2- {2- (2-hexyloxyethoxy) -ethoxyimino] -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer).

IR (CHC1 _3): 3350, 3230, 2600, 2500, 1730, 1620, 1520, 1460 ^cm-1 wavenumber.

NMR (d -DMSO _an a): 0.87 (3H, t, J = 5Hz), 0.87 to 1.73 (8H, m), 3.20-3.90 (8H, m) , 4.13-4.47 (2H, m), 8.17 (2H, broad s).

(10) 2-Trityloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (color isomer), m.p. 173-174 ° C (with decomposition).

IR (Nujol): 3450, 1735, 1620, 1540 ^cm-1 hulláinszámnál.

Nuclear Magnetic Resonance Spectrum (dec-DMSO,?): 7.35 (15H, s), 8.22 (2H, s).

(11) 2-Trityloxyimino-2- (5-amino-1 H -biathiazole-5-decacetic acid (anti-isomer), m.p. 170-171 ° C.

IR (Nujol): 3300, 3150, 1680, 1635, 1520 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d 6 -DMSO,?): 7.33 (15H, s), 8.13 (2H, s).

Production Example 20

A mixture of 3.3 g of 2-hydroxyimino-2- (5-formamido-1 ₎ 2,4-thiadiazol-3-yl) acetic acid (color isomer) and 9.0 g of dichloroacetyl chloride in 50 ml of methylene chloride was stirred for 6.5 hours. stirring at room temperature. The resulting precipitate was filtered off and dissolved in ethyl acetate. After removal of the insoluble matter by filtration, the filtrate is evaporated to dryness. Trituration of the residue with diisopropyl ether gives 2-dichloroacetoxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (color isomer) (2.3 g), m.p. 123 ° C.

IR (Nujol): 3150, 1790, 1690, 1550 cm ^-1 .

Production Example 21

To a mixture of 9.5 g of 2-hydroxymimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (color isomer) and 80 ml of dimethylformamide was stirred at room temperature, 22.8 g of trityl chloride, followed by 4.1 g. Triethylamine (g) was added gradually after stirring for 3 minutes. The resulting mixture was stirred for 10 minutes

-161

After stirring for 3 006, 250 ml of ethyl acetate were added. The mixture was washed three times with water and brine, dried over anhydrous magnesium sulfate and evaporated. To the residue were added 50 ml of aqueous sodium bicarbonate solution and 100 ml of diisopropyl ether. The precipitate was collected by filtration and the aqueous layer was separated. The resulting precipitate was suspended in the separated aqueous phase and ethyl acetate was added. The mixture was adjusted to pH 2 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was washed with hexane to give 17.1 g of 2-trityloxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer), m.p. 175-176 ° C (with decomposition).

IR (Nujol): 3180, 3070, 1700, 1600, 1540 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, a): 7.35 (1511, s). 8.83 (1H, s), 13.52 (1H, broad s).

Preparation Example 22 (1) A solution of 146 g of N- (3-aminopropyl) acetamide in 710 ml of dioxane was added to a solution of 52 g of 97% sodium hydroxide in 620 ml of water and 96 g of carbon disulphide were added dropwise over 35 minutes. 4 at 3 ° C. The mixture was then stirred at 0 to + 2 ° C for 1 hour. To the mixture containing N- (3-acetamidopropyl) -d) thiocarbamate was added dropwise 179 g of methyl iodide at 0-5 ° C over 35 minutes and the resulting mixture was stirred at the same temperature for 3 hours. The dioxane was then distilled off from the reaction mixture and the residue was extracted with 300 ml or 4 x 200 ml ethyl acetate. The extracts were dried over anhydrous magnesium sulfate and evaporated in vacuo to give 193.18 g of methyl N- (3-acetamidopropyl) dithiocarbamate as an oil (2) in a solution of 193 g of methyl N- (3-acetamidopropyl) dithiocarbamate in 610 mL of dioxane. and a solution of sodium azide (79.42 g) in water (500 ml) was heated to reflux for 4 hours with stirring. The dioxane was then evaporated and the remaining aqueous layer was washed with diethyl ether (2 x 150 mL), adjusted to pH 1 with 17.5% hydrochloric acid, and cooled in an ice bath. The precipitate was collected by filtration and, after washing with ice-water, 91.75 g of white powdered 1- (3-acetamidopropyl) -! H-tetrazole-5-thiol is obtained, m.p. 152-154 ° C.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 1.87 (3H, s), 1.97 (2H, m), 3.17 (2H, m), 4.28 (2H, t, J = 7Hz) ), 7.9 (1H, broad s), 15.0 (1H, broad s).

(3) A mixture of 85 g of 1- (3-acetaphnidopropyl) -1H-tetrazole-5-thiol and 116 N hydrochloric acid was heated to reflux for 75 minutes. The reaction mixture was then concentrated in vacuo and the precipitate was collected by filtration; followed by washing with hexane to give 67.15 g of 1- (3-aminopropyl) -1H-tetrazole-5-thiol hydrochloride.

Nuclear Magnetic Resonance Spectrum (D2O, a): 2.45 (2H, m), 3.23 (2H, t, J = 7Hz), 4.50 (2H, t, J = 7Hz).

(4) A solution of 12.3 g of 2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile in 30 ml of dioxane is added under ice-cooling, 9.78 g of 1- (3-aminopropyl) -1H-tetrazole-5-thiol hydrochloride and 11.1 g of triethylamine in 25 mL of dioxane and 25 mL of water and the resulting mixture

Stir at room temperature for 1.75 hours. The dioxane was then distilled off and diethyl ether and a small amount of water were added to the residue. After mixing with water, the aqueous phase is separated and the organic phase is extracted twice with 10% potassium carbonate solution. The extracts and the separated aqueous phase were combined and washed three times with diethyl ether and adjusted to pH 1 with hydrochloric acid and extracted with diethyl ether. The extract was washed with water, dried and concentrated in vacuo. The resultant oil (10.92 g) was triturated with diisopropyl ether to give 9.6 g of 1- [3- (N-tert-butoxycarbonylamino) propyl] -1H-tetrazol-5-thiol, m.p. 75-77 ° C.

IR (Nujol): 3380, 3260, 1650, 1530,

1170, 1050 cm @ ¹ .

Nuclear Magnetic Resonance Spectrum (CDCl3, a): 1.50 (9H, s), 2.14 (2H, m), 3.25 (2H, m), 4.39 (2H, t, JMHz), 4.9 -6.7 (1H, broad).

Example 1

To a cooled solution of 450 mg of phosphorus pentachloride in 10 ml of methylene chloride is added 650 mg of 2- (4-chlorophenoxyimino) 2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (color isomer) at -15 ° C. and the mixture was stirred at the same temperature for 30 minutes. At the same time, a mixture of 785 mg of 7-amino-3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid and 2.1 g of trimethylsilylacetamide in 10 ml of methylene chloride was heated to a clear solution and then -20 °. Cool to C. The solution was added to the above activated mixture at -20 ° C and the mixture was stirred for an additional 40 minutes at -15 ° C. The reaction mixture was then poured into 20 ml of cold aqueous sodium bicarbonate solution and stirred at room temperature for 30 minutes. The methylene chloride was distilled off and ethyl acetate was added to the remaining aqueous solution. The pH of the mixture was adjusted to 3 to 4 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was dried over magnesium sulfate, treated with activated carbon and evaporated to dryness. The residue was triturated with diethyl ether and precipitated again from a mixture of acetone and diethyl ether. The precipitate was dissolved in aqueous sodium bicarbonate solution and the pH of the solution was adjusted to 1 to 2 with 10% hydrochloric acid when a precipitate formed. The precipitate was collected by filtration and, after washing with water, 35 g of 7- (2- (4-chlorophenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido) -3- (1,3, 4-Thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (color isomer) is obtained, m.p. 150-155 ° C (with decomposition).

IR (nujol): 3300, 3200, 1770, 1670, 1620, 1520 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO,?): 3.67 (2H, bs).

4.27 and 4.50 (2H, ABq, JMHz).

5.17 (1H, d, J = 4Hz), 5.80 (1H, dd, J = 4 and 8Hz), 7.00-7.50 (4H, m), 8.22 (2H, s), 9.50 (1H, s), 9.80 (1H, d, J = 8Hz).

Example 2

To a cold solution of 1.04 g of phosphorus pentachloride in 25 ml of methylene chloride is added 1.4 g of 2- (4-fluorophenoxyimino) 2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (color isomer). 15 ° C and the mixture was stirred at the same temperature for 30 minutes. At the same time, 1.65 g of 7-amino-3 '(1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid and 5 g of trimethylsilylacetamide in 25 ml of methylene. ...... .... _n

-17i (ύ ΐ rif) 6Chloride was heated to a pure hour and then cooled to -15 ° C. and the resulting mixture was stirred at 0 to 5 T for 1 hour. The reaction mixture was concentrated and ethyl acetate and water were added to the residue. After filtering off the insoluble material, the ethyl acetate layer was poured into aqueous sodium bicarbonate solution. The aqueous layer was separated and the pH was adjusted to 4 with 10% hydrochloric acid after addition of ethyl acetate. followed by extraction with ethyl acetate. The extract 10 was dried over anhydrous magnesium sulfate and dried for ca. Evaporate to a volume of 10 ml. The precipitate was collected by filtration, washed with ethyl acetate and diethyl ether and, after drying, 1.2 g of 7-12- (4-fluorophenoxyimino) -2- (1,2,4-thiadiazol-3-yl) -acetamido-3 - (. 3,4-Thiadiazol-2-yl) -thiomethyl-15

3-cephem-4-carboxylic acid (color isomer) is obtained, m.p. 140-145 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1680, 1620, 1520 ^cm-1 wavenumber.

NMR (d -DMSO _é, a), 3.57 and 3.80 (211: 20 AB quartet, J = 18 Hz), 4.27 and 4.57 (2H, ABq, J = 13Hz), 5.20 (1H, d, J = 4Hz),

5.87 (1H, dd, J = 4 and 8Hz), 7.17-

7.3 (4H, in), 8.20 (2H, s), 9.50 (1H, s), 9.83 (1H, d, J = 8Hz). . 25

Example 3

For a cold solution of 2.08 g of phosphorus pentachloride in 50 ml of methylene chloride at -15 ° C, 2.64 g

2-Phenoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (color isomer) was added and the mixture was stirred at the same temperature for 30 minutes. However, 3.35 g

A solution of 4-nitrobenzyl-7-amino-3-cephem-4-carboxylate and 10 g of trimethylsilylacetamide in 50 ml of methylene chloride was heated to a clear solution and then cooled to -15 ° C. The solution was added to the above active mixture and the resulting mixture was added for 0.5 h. Stir at 0-5 ° C. The reaction mixture was cooled with 5.9 g of sodium bicarbonate in 100 ml of water. solution. The methylene chloride phase was dried over anhydrous magnesium sulfate and evaporated to dryness.

The residue was triturated with diethyl ether and the resulting powder was collected by filtration and dried over 5,17 g-1,2-phenoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cephem-4-carboxylic acid 4 The nitrobenzyl ester (color isomer) is obtained, m.p. 140-145 ° C (with decomposition).

IR (Nujol): 3300, 1775, 1720, 1680, 1625, 1600, 1590, 1520 cm @ -1. _5N

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.60 (2H, bs),

5.23 (1H, d, J = 4Hz), 5.42 (2H, s),

6.00 (1H, dd, J * 4 and 8Hz), 6.67 (1H, t, J = 4Hz), 7.0-7.50 (5H, m), 7.73 (2H, d, J = 8Hz), 8.27 ((2H, d, J = 8Hz), 8.30 (2H, s),

9.97 (1H, d, J = 8Hz).

Example 4

1.3, 5 and 7-12. The following compounds were prepared by the methods set forth in Examples 1 to 5:

(1) 7- [2-Phenoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-carboxymethyl-1H-tetrazol-5-yl) -thiomethyl-3 cephem-4-carboxylic acid (color isomer), m.p. 175-180 ° C (with decomposition). 65

IR spectrum (nujol): 3400, 3200, 1770, 1700.

1660, 1620. 1580, 1510 im at ¹ wave number.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.70 (211 broad s),

4.23 cs 4.50 (2H. ABq. 1 1413/1.

5.17 (1H, d, 1-411 /). 5.30 (2H, s), 5.89 (1H, dd .14 and 8Hz).

7.0-7.5 (511, m). 8.22 (111 s).

9.83 (III, dI SiI) (2) 7- [2-Phenoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetanoic] -3- (1-allyl-111) -tetrazol-5-yl) -thiomethyl-3-cepheyl-4-carboxylic acid (color isomer), m.p. 145-150 ° C (with decomposition).

IR (nujol) 3450, 3350, 3180, 1780,

1710, 1680, 1610,1590,1510 cm ^- 'wave number.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.70 (2H, bs),

4.28 and 4.45 (2H, ABq, J = 13Hz),

4.83-5.10 (2H, m), 5.18 (1H, d,

J = 4Hz), 5.20-5.43 (2H, m),

5.93 (1H, dd, J = 4 and 8Hz),

5.67-6.30 (1 H, m), 7.0 ... 7.57 (5 H, m), 8.30 (2 H, s), 9.92 (1 H, d, J = 5 ).

(3) 7- [2-Phenoxyimino-2- (5-amino], 2,4-thiadiazol-3-yl) acetanido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl -3-cephem-4-carboxylic acid (color isomer), m.p. 155-158 ° C (with decomposition).

IR (Nujol) 3400, 3300, 3200, 1770,

1720, 1680, 1620, 1590, 1520 cm '.

NMR (d _é -DMSO, δ): 3.77 (2H, br s);

3.95 (3H, s), 4.33 (2H, broad s),

5.27 (1H, d, J = 4Hz), 5.93 (1H, * dd, J = 4 and 8Hz), 7.0-7.67 (5H, m), 8.37 (2H, s) , 10.0 (1H, d, J = 8Hz).

(4) 7- [2-Phenoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -ceph-3-em-4-carboxylic acid (color isomer), m.p. :

150-155 ° C (with decomposition).

IR (Nujol) 3450, 3350, 3180, 1775,

1710, 1680, 1610, 1580, 1515 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 2.03 (3H, s), 3.62 (2H, broad s), 4.77 and 5.03 (2H,

ABq, J = 14Hz), 5.28 (1H, d,

J = 4Hz), 5.97 (1H, dd, J = 4 and 8Hz), 7.0-7.67 (5H, m), 8.37 (2H, s), 9.97 (1H, d) , J = 8Hz).

(5) 7- [2- (2-Methoxy-5-nitrophenoxyimino) -2- (5-amino-

1,2,4-thiadiazol-3-yl) -acetamido} -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p.

160-169 ° C (with decomposition).

IR (nujo): 3380, 3220, 3100, 1780,

1690, 1620, 1600, 1520, 1340,

1280, 1085, 1065, 820, 750 cm @ ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.71 (2H, m), 3.98 (3H, s), 4.25 and 4.66 (2H, ABq,

J = 14Hz), 5.23 (1H, d, J = 5Hz),

5.94 (1H, dd, J = 5 and 9Hz), 8.19 (1H, s), 8.34 (2H, broad s), 9.58 (1H, s). 9.87 (1H, d, J = 9Hz).

(6) 7- [2- (4-Fluorophenoxyimino) -2- (5-amino-1,2,4-thiazol-3-yl) acetamido) -3- (tetrazolo [1,5-b] pyridazine). 6-yl) -18I

183,006 thioinethyl-3-cephene-4-carboxylic acid (barin isomer). m.p .: 125-130 ° C (dec közből R (Nujol): .3300, 3190, 1770, 1670, 1615, 1570. 1495 ^cm-1 wavenumber.

1 H NMR (d ₆ -DMSO, _δ ): 3.80 (2 (1, bs),

4.30 and 4.05 (211, ABq.1.1 = 13Hz),

5.27 (IR d, J = 5tlz). 5.95 (1H, dd, J = 5 and 8 Hz), 7.25 (2H, s),

7.35 (2R s), 7.80 (111, d, J = 10 Hz), pH 8.37. wide s). 8.62 (1H, d, 1 =

10Hz) 9.92 (1H, d, J = 81k).

(7) 4-Nitobenzyl-7- [2- (4-fluorophenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -amide] | -3-Cephem-4-carboxylic acid 4-nitrobenzyl ester (color isomer), m.p. 135-140 ° C (with decomposition)

IR (stretching): 3300, 3200, 1770, 1720, 1680, 1625, 1605.1500, 1495 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₄ -DMSO, δ): 3.45-3.75 (2H, m),

5.35 (1H, d, J = 5Hz), 5.35 (211, s),

5.92 (1H, dd, J = 5 and 8Hz), 6.58 (3H, 1.1, J = 4Hz), 7.08 (2H, s), 7.18 (2H, s), 7.60 (2H, d, J = 8Hz), 8.13 (2H, d, J = 8Hz), 8.17 (2H, broad s), 9.75 (1H, d, J = 8Hz).

(8) 7- [2- (4-Chloro-phenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (5-hydroxymethyl-1,3,4) -thiazol-2-yl) -thiomethyl-3-cephem-4-caffonic acid (syn isomer), m.p.

135-140 ° C (with decomposition).

IR (Nujol): 3450, 3280, 3180, 1760, 1720, 1660, 1620, 1580, 1520, 1480 4 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.72 (2H, bs),

4.27 and 4.55 (2H, ABq, 3 = 13Hz), 4.80 (2H, s), 5.22 (1H, d, J = 5Hz), 5.88 (1H, dd, J = 5 and 8Hz) ), 7.25 (2H, d, J = 9Hz), 7.42 (2H, d, J = 9Hz), 8.23 (2H, broad s), 9.85 (1H, d, J = 8Hz) ).

* (9) 7- [2- (4-Chlorophenoxyimino) -2- (5-amino], 2,4-thiadiazol-3-yl) -acetamido] -3- (1-carboxymethyl-1H-tetrazole-5) -yl) thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 135-140 ° C (with decomposition).

IR (Nujol): 3400, 3250, 3170, 1765, 1700, 1680, 1650, 1615, 1580, 1510, 1480 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.70 (2H, sharp s), 4.27 and 4.48 (2H, ABq, J = 13Hz), 5.22 (1H, d, J = 5Hz), 5.30 (2H, s),

5.93 (1H, dd, J = 5 and 8Hz), 7.35 (2H, d, J = 9Hz), 7.48 (2H, d, J = 9Hz), 8.37 (2H, broad s), 9.97 (1H, d, J = 8Hz (10)) 7- [2- (4-Chloro-phenoxyimino> 2- (5-amino-1,2,4-thia-diazol-3-yl) -acetamido] -2- methyl 3-cephem-4-carboxylic acid ^v (color isomer), m.p. 150-155 ° C (with decomposition).

IR (nujol) 3400, 3270, 3180, 1770, 1620, 1580, 1520, 1480 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ DMSO, δ): 1.45 (3H, d, J = 7Hz), 3.60-4.10 (1H, m), 5.20 (1H, d, J = 5Hz), 5.80 (1H, dd, J = 5 and 8Hz), 6.62 (1H, d, J = 6Hz), 7.35 (2H, d, J = 9Hz), 7.48 (2H, d, J) = 9Hz, 8.03-8.73 (2. M), 9.97 (1H.d, J = 8Hz).

(11) 4-Nitrobenzyl-7- [2- (4-chlorophenoxumino> 2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamide] -3-ecphem-4-carboxylic acid (color) m.p. 155-160 ° C (with decomposition).

IR (Nujol): 3300. 3180. P70. 1720th

1680, 1625, 1600. 1580, 1520. 1480 cm ^-1 hullámszáinnál.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.62 (211, wind s),

5.18 (1H, d, .1511 /). 5.38 (2H, s),

5.95 (111, dd .1 = 5 and 8Hz), 6.63 (1H, t. J = 4Hz), 7.25 (211, d, J = 9Hz), 7.38 (211d, J = Slfc)

8.23 (2H, bs). 9.85 (1H, d J = 8Hz) (12) 7- (2- (4-k) Orphenoxyimino) -2- (5-antino-1,2,4-thia-diazol-3-yl) -acetanedio-3 -I- (2-hydroxyethyl) -1H-telr: 17,5'-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 120-125 ° C (with decomposition).

IR (Nujol) 3400, 3300, 3180, 1765.

1670, 1615, 1580, 1520, 1480 cm ''.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.50-3.93 (4H, in), 4.12-4.48 (4H, m), 5.18 (1H, d, J = 5Hz) , 5.88 (1H, dd, J = 5 and 8Hz),

7.28 (2H, d, J = 9Hz), 7.45 (2H, d, J = 9Hz), 8.30 (2H, broad s), 9.94 (111, d, J = 8Hz).

(13) 7- (2- (3,4-dichlorophenoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido) -3-cephem-4-carboxylic acid (color isomer), dec. ° C.

IR (Nujol): 3600, 3400, 1770, 1720, 1680, 1530, 1250, 1120, 970 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 2.03 (3H, s), 3.60 (2H, m), 4.65 and 5.05 (2H, ABq, J = 15Hz), δ, 27 (1H, d, J = 5Hz), 5.97 (1H, dd, J = 5 and 8Hz), 7.13-7.77 (3H, m), 8.35 (2H, m), 9, 90 (1H, d, J = 8Hz).

(14) 7- (2- (3,4-dichloro-phenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1,3,4-thiadiazol-2-one). il) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 160 ° C.

IR (Nujol): 3300, 3200, 1770, 1680, 1620, 1520, 1250,1205,1060 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.77 (2H, m), 4.28 and

4.68 (2H, ABq, J = 14Hz), 5.37 (1H, d, J = 5Hz), 5.97 (1H, dd, J = 5 and 8Hz), 7.16-7.80 (3H , m), 8.36 (2H, s), 9.60 (1H, s), 9.93 (1H, d, J = 810) (15) 7- (2- (3-trifluoromethyl-tenoximino)) -2- (5-aminol, 2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid 4-nitro-benzyl ester (color isomer), m.p. 136-140 ° C (with decomposition).

IR (Nujol): 3370, 3200, 1780, 1730, 1690, 1680, 1630, 1610, 1520, 1450, 1325, 1280, 1160,1125,975, "50, 740 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.7 (2H, m), 5.22 (1H, d, δ = 5Hz), 5.37 (2H, s), 5.99 (1H, dd) , J = 5 and 8Hz), 6.63 (1H, m),

7.50 (4H, broad s), 7.66 (2H, d. J =

-19183 006 = 911 (,), 8.20 (2Η, d, J = 9Hz). 9.89 (1H, d, J = 8Hz).

(16) 7- [2- (3-Trifluoroethyl-phenoxyimino) -2-15-amino-1,2,4-thiadiazol-3-yl] -acetamido] -3- (1,3,4-thiadiazol-2-yl) -thiomethyl-3- cephem-4-carboxylic acid (color isomer), m.p. 164 ° C.

IR (Nujol): 3300, 3180, 1765, 1670, 16) 0, 3520, 3320, 1165, 1120, 1060, 930, 790, 700 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.73 (211, m). 4.23 and 5.63 (2H, ABq, J = 14Hz), 5.27 (1H, d, J = 5Hz), 5.93 (1H, dd).

J = 5 and 8Hz), 7.55 (4H, broad s),

8.34 (2H, bs). 9.60 (1H, s), δ 9.99 (1H, d, J = 8Hz).

(17) 7- (2- (3-Ethoxycarbonyl-phenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1,3,4-thiadiazol-2-yl) -thiomethyl- 3-cephem-4-carboxylic acid (color isomer), m.p. 162 DEG C. 20

IR (Nujol): 3350-3150, 1770, 1720 1660, 1620, 1520, 1290, 1270 1100, 1060, 900, 760 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 1.32 (3H, t, J = 7Hz)

3.71 (2H, m), 4.25 and 4.60 (2H, ABq.).

J = 14Hz), 4.32 (2H, q, J = 7Hz).

5.23 (1H, d, J = 5Hz), 5.73 (1H, dd,

J = 5 and 8Hz), 7.40-7.95 (4H, m), 8.67 (2H, broad s), 9.59 (1H, s), 30

9.98 (1H, d, J = 8Hz).

(18) 7- [2- (4-Fluorophenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [1- (2-hydroxyethyl) -1 H -tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p.

145-150 ° C (with decomposition). 35 IR (nujol): 3300, 3200, 1770, 1670, 1610, 1520 cm ^-1 . Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.50-3.83 (4H, m), 4.0-4.53 (4H, m), 5.13 (1H, d,

J = 4Hz), 5.83 (1H, dd, J = 4 and 40 8Hz), 7.12 (2H, s), 7.23 (2H, s),

8.18 (2H, s), 9.77 (1H, d, J = 8Hz).

(19) 7- [2- (4-Fluorophenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-carboxymethyl-1H-tetrazol-5-yl) ) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p.

150-155 ⁰ C (dec).

IR (Nujol): 3300, 3200, 1770, 1720, 1670, 1620, 1520, 1500 cm @ ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.57 (2H, bs),

4.27 and 4213 (2H, ABq, J = 14Hz).

5.23 (1H, d, J = 8Hz), 5.37 (2H, s).

5.93 (1H, dd, J = 4 and 8Hz), 7.25 (2H, s), 7.37 (2H, s), 8.32 (2H, s), 9.92 (1H, d, J = 8I * (20) 7- {2- (4-Fluorophenoxyimino) -2 (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (2-carboxymethyl-3-oxo) -2,3-dihydro-1,2,4-triazolo [4,3-b] pyridazin-6-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 165-170 ° C. C (decomposition intermediate '

IR (Nujol): 3300, 3200, 1770, 1710, 1620, 1540, 1520, 1500 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.67 and 3.90 (2H,

ABq, J = 18Hz), 4.13 and 4.37 (2H, θ *

ABq, J = 3Hz), 4.73 (211, s. 5.23 (1H, d, J = 4Hz). 5.90 (1H, dd, J = 4 and 8Hz), 7.08 (1H , d, J = 10.18z), 7.17 (2H, s), 7.28 (211, s), 7.72 (111 d. 5 J = 1011 /), 8.23 (2H, ss, 9.83). (111, d, J = 8Hz).

(21) 7- [2- (4-Fluorophenoxyimino) -2- (5-amino-1,2,4-thiaza -azol-3-yl) -acetamido] -3- [1- (2-carboxyethyl) -1 H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p.

140-145 ° C (with decomposition).

IR (Nujol): 3300, 3200. 1770, 1700 1620, 1520, 1500 ^cm-1 BULL number.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSQ, δ): 2.90 (211, ι, J-611z).

3.70 (211, broad x), 4.40 (2H, t, J = 61). 4.27 and 4.47 (211, ABq, J = 13Hz), 5.17 (1H, d, J = 411). 5.87 (111, dd, J = 4 and 81). 7.15 (2H, s), 7.25 (2H, s), 8.22 (2H, s), 9.83 (1H, d, J = 8Hz).

(22) 7- [2- (4-Fluorophenoxyimino) -2- (5-amino-1,2,4-thia-diazol-3-yl) -acetatnido] -3- (1-allyl-1H-tet) Razol-5-yl) -thiomethyl 3-cephem-4-carboxylic acid (color isomer), m.p. 145-150 ° C (with decomposition) (N-ol): 3450, 3350, 3150, 1780, 1705; 1670, 1610, 1510 cm @ ¹ .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.66 and 3.84 (2H, Bq, J = 18Hz), 4.30 and 4.50 (2H, ABq, J = 14Hz), δ, 00 (2H, d, J = 5Hz), 5.24 (1H, d, J = 4Hz), 5.20-5.40 (2H, m), 5.96 (1H, dd, J = 4 and 8Hz), 5.80-6.20 (1H, m), 7.28 (2H, s), 7.34 (2H, s), 8.32 (2H, s), 9.96 (1H, d) , J = 8Hz).

(23) 7- {2- (4-trifluorophenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -azoethamkdo] -3-cephem-4-carboxylic acid (color isomer), m.p. 156-161 ° C (with decomposition).

Snektrum IR (Nujol): 3450, 3300, 3200, 1770, 1730, 1680, 1610, 1510.1500 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 2.04 (3H, s), 3.52 and 3.68 (2H, ABq, J = 18Hz), 4.74 and 5.02 (2H, ABq). J = 14Hz), 5.26 (1H, d, J = 4Hz), 5.94 (1H, dd, J-4 and 8Hz), 7.26 (2H, s), 7.34 (2H, s) ,. 8.30 (211, s), 9.94 (1H, d, J = 8Hz).

(24) 7- [2-Phenoxy-imino-2-yl-1,2,3-thiadiazol-3-yl] -acetimidoyl] -3- (tetrazolo [1,5-b] pyridazin-6-yl) -thiomethyl -350 cephem-4-carboxylic acid (color isomer), m.p. 175-180 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1775, 1680, 1615, 1585, 1520 ^cm-1 wavenumber.

(25) 7- [2-Phenoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- {2- (Nt-thyloxycarbonylamino) -ethyl) -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 150-155 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1680,

1620, 1590, 1520 cm ^-1 .

(26) 7- [2- (3-Trifluoromethyl-phenoxyimino) -2- (5-amino-1,2,4-thiadlazol-3-yl) -acetamido] -3-cephem-4-carbonazole (color isomer), decomposition point : 193 ° C.

IR (Nujol) 3450, 3320, 3200, 1770,

-20!

185 00 (,

1710. 1665. Κ, 30. 1560. 1515. 1325. 1170. II10. 940 cm ' ^{1 in a} wave.

(27) 7- [2-fenoxiimino-2- (5-amino-1,2,4-tiadiazoI3-yl) acetamido] -3-ccfein-4-carboxylic acid (syn isomer), mp .: 168-170 ° ^B C (during decomposition).

IR (Nujol): 3400-3200. 1780. 1660.

1620. 1600. 1590, 1540 cm ' ¹ corral.

(28) 7- [2- (4-Chloro-phenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido) -3-cephene-4-carboxylic acid (sine isomer) ) m.p .: 145 to 150 ^O C (dec).

(R spectrum (nujol): 3400, 3260, 3180, 1775,

1675, 1625, 1600, 1520, 1480 cnf at ₁₅ wave numbers.

(29) 7- [2- (4-Fluorophenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color isomer), m.p. 130-135 T (dec.).

IR (Nujol): 3400, 3270, 3J80, 1765, 0 ₂ 1675, 1605, 1500 ^cm-1 wavenumber.

(30) 7- [2-Phenoxyquinoino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-11- (2-aminoethyl) -111-tetrazole- 5-yl] thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. ^180-2255 ° C (with decomposition).

IR (Nujol): 3300, 3250, 1760, 1670, 1620, 1590, 1520 ^cm-1 wavenumber.

Example 5

To a cooled solution of 2.08 g of phosphorus pentachloride in 45 ml of methylene chloride was added 2.51 g of 2- (tert-butoxycarbonyl-35-methoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (color). (isomer) was added at -17 ° C and the mixture was stirred at the same temperature for 50 minutes. At the same time, a mixture of 3.34 g of 7-amino-3- (tetrazolo] 1,5-b] pyridazin-6-yl) thiomethyl-3-cephem-4-carboxylic acid and 12 g of trimethyl 40 silylacetamide in 45 ml of methylene chloride is heated, to a clear solution and then cooled to -20 ° C. The solution was then added to the above activated mixture and the mixture was stirred at -10 to -15 ° C for 1 hour. The reaction mixture was evaporated and ethyl acetate and aqueous sodium bicarbonate solution were added to the residue. The aqueous phase was separated, the pH was adjusted to 3 to 4 with 10% hydrochloric acid and then extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated under reduced pressure. Trituration of the residue with diethyl ether gave 2.4 g of 7- [2- (tert-butoxycarbonylmethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3 ^: (tetrazolo [1,5-b]). of pyridazin-6-yl) thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 125-130 ° C (with decomposition). 55

IR (Nujol): 3400, 3300, 3180, 1770, 1720, 1680, 1620, 1525 cm @ -1.

NMR (d _é -DMSO, δ): 1.47 (911, s), 3.73 (2H, br s), 4.28 and 4.60 (2H, ABq, 60 J = 13Hz), 4 , 65 (2H, s), 5.18 (111, d,

J = 5Hz), 5.87 (111, dd, J = 5 and 8Hz),

7.78 (1H, d, J = 1011z), 8.17 (2H, broad s), 8.62 (1H, d, J = 1011z), 9.55 (111, d, J = 8Hz). 65

6. pcida

In Examples 3, 5, and 12, the following compounds were prepared:

(1) 7-12 · {3- (N-Icc-Bu-oxy-carbolyl) -ptopoxlimino) -2- (5-αιηίιιο-1,2,4-thiadia / .ol-3-yl) avetainido] -3-methyl-3-cis-fem-4-carboxylic acid (syn), m.p. 114-119 ° C (with decomposition).

Nuclear Magnetic Resonance Spectrum (d < -1) MSO. δ): 1.40 (<Ί | _s ), 174 (311, s), 1.80 (211, m), 3.00 (411, in),

4.14 (211 ni), 5.10 (III, d, J = 51),

5.72 (111, dd, J = 5 and 8lz), 6.70, (111, broad s), 8.10 (211, broad s), 9.44 (111d, J - Sllz). ).

(2) 7- [2- {3- (N-tert -carboxycarbonylamino) -propoxynino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-chloro M.p. 91-100 DEG C. (decomposition) -3-cephene-4-carboxylic acid 4-nitrobenzenesulfonate (syn isomer).

Nuclear Magnetic Resonance Spectrum (d 6 -DMSO + D 6 O, δ): 1.38 (9, s, s),

1.80 (2H, ni), 3.06 (211 m). 3.7 4.3 (411, tn), 5.33 (111, d, J = 511z), 5.49 (2.1, s), 5.95 (111, d, J = 511z), 7.74 (211 , d, J = 9llz), 8.92 (211, d, J = 9llz).

(3) 7- [2- {3- (N-tert-Butoxycarbonylamino) propoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido) -3- [1 ( 2- (N-tert-butoxycarbonylamino) ethyl) -II-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p.

107-112 ° C (with decomposition).

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO + D ₂ O, δ): 1.32 (9H, s), 1.34 (911, s), 1.80 (211, ni), 3.10 (211, in) ), 3.30 (211, in), 3.70 (211, in), 4.0 4.5 (611, m), 5.13 (1H, d, J = 5Hz), 5.83 (1H , d, J = 5Hz).

(4) 7- [2-Allyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cephem-4-carboxylic acid 4-nitrobenzyl ester (color isomer), m.p. 125-130 ° C (with decomposition).

IR (Nujol): 3300, 1770, 1720, 1680, 1630, 1610, 1520 ^cm-1 wave number,

Nuclear Magnetic Resonance Spectrum (d 6 -DMSO, δ): 3.60 (211, bs), 4.57-4.83 (211, m), 5.17 (111, d, J = 4Hz), δ, 0-5.35 (211, ni), 5.40 (2H, s), 5.93 (1Η, dd, J = 4 and 8Hz), 5.87-6.17 (1H, in), 6, 63 (1H, t, J = 3Hz), 7.70 (2H, d, J = 9Hz), 8.10 (2H, s) 8.23 (211, d, J = 9Hz), 9.57 (1H , d, J = 8Hz).

(5) 7- [2- (2,2,2-Trifluoroethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cephem-4-carboxylic acid (color isomer) 185-195 ° C (with decomposition).

IR (Nujol): 3470, 3330, 3210, 3060, 1770,1735,1700, 1670, 1620, 1555, 1520 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 2.00 (311, s), 3.53 (211, broad s), 4.65 and 4.87 (2H, ABq, J = 9Hz), 4, 70 and 4.93 (211, ABq, J = 13Hz), 5.12 (1H, d, J = 5Hz),

5.78 (1H, dd. J = 5 and 81 flavors), 8.12 (2H, broad s), 9.62 (111, d, J = 81 flavors).

(6) 7-] 2- (2,2,2-trifluoroethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-allyl-11'-tetrazole) -5-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 125-130 ° C (with decomposition).

-21183 006

IR (Nujol): 3300, 3200, 1770, 1680, 1620, 1520 cm @ ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.68 (211, bs), 4.30 and 4.40 (211, ABq, J = 13Hz),

4.68 and 4.92 (2H, ABq, J = 9Hz),

4.87 5.10 (2H, in), 5.15 (1H, d, J-5H /.), 5.17-5.47 (2H, m). 5.83 (1H, dd, J = 5 and 8Hz), 5.67-6.27 (1H, m), 8.25 (2H, bs), 9.77 (1H.d, J = 8Hz). .

(7) 7- [2- (2,2,2-Trinouroroethoxyimino) -2- (5-amino-1,2,4-thiazol-3-yl) acetamido] -3- (1-methyl-1 H -tetrazole -5-yl) thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 145-150 ° C (with decomposition).

IR (Nujol): 3300. 3200, 1770, 1680, 1620, 1525 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.70 (2H, bs),

3.95 (3H, s), 4.32 (2H, broad s),

4.68 and 4.92 (2H, ABq, J = 9Hz),

5.15 (1H, d, J = 5Hz), 5.85 (1H, dd, J = 5 and 8Hz), 8.25 (2H, broad s), 9.75 (1H.d, J = 8Hz) .

(8) 7- [2- {2- (N-tert-Butoxycarbonylamino) -ethoxyimino} -2 (5-amino-1,2,4-thiothiazol-3-yl) -acetamido] -2-methyl-3 - cephem-4-carboxylic acid (color isomer), m.p. 215-220 ° C (with decomposition).

IR (Nujol): 3230, 3150, 1775, 1680, 1620, 1525 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO + D ₂ O, a): 1.37 (9H, s), 1.43 (3H, d, J = 7Hz), 3.0-3.5 (2H, m) , 4.0-4.4 (2H, m), 5.10 (1H, d, J = 4.5Hz), 5.8-6.1 (1H, m), 6.53 (1H, d, J = 6.9 Hz).

(9) 7 -12- {2- (N-tert-butoxycarbonylamino) -ethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamide] -3 [1- { 2- (N-tert-butoxycarbonylamino) -ethyl} -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 181-186 ° C (with decomposition).

IR (Nujol): 3320, 1780, 1680, 1620, 1520, 1165 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO + D ₂ O, a): 1.32 (18H, s), 3.07-3.52 (4H, m), 3.7 (2H, broad s), 4, 0-4.5 (6H, m), 5.15 (1H, d, J = 4.5Hz), 5.85 (1H, d, J = 4.5Hz),

8.23 (2H, broad sl (10) 7- [2-trityloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (5-methyl-1,3), 4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid (syn isomer), m.p. 147-161 ° C (with decomposition).

IR spectrum (nujol): 3420, 1780, 1680, 1615, 1525 cm @ ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO + D ₂ O, a): 2.72 (3H, s),

3.73 (2H, broad s), 4.30 and 4.67 (2H, ABq, J = 14Hz), 5.35 (1H, d, J = 5.0Hz), 7.50 (15H, s) .

(11) 7-12 - {(N-tert-Butoxycarbonylamino) -ethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] 3- (1-carboxymethyl-1H) -tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 105 ° C (with decomposition).

IR (nujol): 3305, 3160, 1770, 1670, 1520, 1245 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO + D ₂ O, a): 1.37 (9H, s), 3.0-3.5 (2H, m), 3.72 (2H, bs), 3; 9-4.3 (2H, m), 4.1-4.6 (2H, m),

5.15 (III, d, J 11 lz). 5.33 (211, s). 5.7 6.0 (111, ni).

(12) 7- (2- tert -butoxycarbonylcarboxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3,11,3,4-thiadiazol-5-yl) thiomethyl-3 -cfem-4-carboxylic acid (color isomer). 140-145 ° C (with decomposition).

IR (Nujol): 3300, 3175, 1770, 1720, 1680, 1620, 1520 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d 6 -DMSO,?): 1.50 (911, s), 3.73 (2H, broad), 4.65 (2H, s), 5.17 (1H, d, J = 4Hz). , 5.85 (111, dd, J = 4 and 8Hz), 8.18 (211, s), 9.50 (111, d, J = 8Hz), 9.53 (1H, s).

(13) 7- [2- (tert-Butoxycarbonylmethoxyimino) 2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color isomer), m.p. -130 ° C (during bonding)

IR spectrum (nujol): 3300, 3200, 1770, 1720, 1680, 1620, 1520 cm @ -1.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO,?): 1.50 (911, s), 2.10 (3H, s), 3.62 (2H, broad s), 4.68 (211, s), 4 , 77 and 5.03 (2H, ABq, J = 131 flavors). 5.20 (1H, d, J = 4Hz), 5.88 (III, dd,

J = 4 and 8Hz), 8.18 (211, s). 9.55 (1II.

d, J = 8Hz).

(14) 7- [2- (tert-Butoxycarbonyl) methoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamide] -3- (1-allyl-111-tetrazol-5-yl) ) -thiomethyl-3-cephem-4-carboxylic acid (color isomer) m.p. 130-135 ° C (dec.).

IR (Nujol) 3400, 3280, 3180, 1770.

1720, 1680, 1620, 1520 cm @ ¹ lm).

NMR (d -DMSO _an a): 1.42 (9H, s), 3.67 35 (2H, br s), 4.27 and 4.43 (2H, AB q.

J = 13Hz), 4.62 (2H, s), 4.87-5.07 (2H, m), 5.10 (1H, d, J = 5Hz), 5.13-5.43 (2H, m) , 5.82 (1H, dd, J = 5 and 8Hz), 5.60-6.20 (1H, m),

8.10 (2H, bs), 9.47 (111, d,

J = 8Hz).

(15) 7- [2- (tert-Butoxycarbonylmethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [1 - {(2- (N-tert-butoxycarbonylamino)) (ethyl) -1H-tetrazol-5-yl] -thiomethyl 45 3-cephem-4-carboxylic acid (color isomer), m.p. 110-115 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1775, 1680, 1620, 1520 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMS.j, a): 1.32 (9H, s). 1.42 50 (9H, s), 3.33 (2H, broad s), 3.533.80 (2H, m), 4.13-4.47 (4H, m), 4.58 (2H, s) , 5.08 (1H, d, J = 5Hz),

5.78 (1H, dd, J = 5 and 8Hz), 8.07 (2H, broad s), 9.45 (1H, d, J = 8Hz).

(16) 7- [2- (tert-Butoxycarbonylmethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-phenyl-1H-tetrazol-5-yl) -thiomethyl- 3-α-fem-4-carboxylic acid (color isomer), m.p. 135-140 ° C (with decomposition).

IR (Nujol) 3400, 3300, 3200, 1775,

1720, 1685, 1620, 1525, 1500 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO,?): 1.43 (9H, s), 3.70 (2H, bs), 4.32 and 4.57 (2H, ABq, J = 13Hz), 4, 65 (2H, s), 5.12 (1H, d,

J = 5Hz), 5.85 (1H, dd, J = 5 and 8Hz),

-22183 (Clone

7.67 (5Π, s), 8.17 (211, broad s), 9.50 (1H, d, J-8H /).

(17) 7- [2- {3- (N-tert-Butoxycarbonylamino) -propoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -2-ethyl-3 -cephene-4-carboxylic acid (color isoiner), m.p. 133 146 C 5 (with decomposition).

IR (Nujol): 3280, 3170, 1775, 1685, 1670, 1625, 1520 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO + D ₂ O, a): 1.40 (911, s), δ

1.46 (3H, d, J = 7Hz), 1.56 2.06 (2H, m), 3.03 (2H, t), J = 7Hz), 3.1-4.1 (1H, in ), 4.23 (2H, t, J = 7Hz), 5.13 (1H, d, J = 5Hz),

5.97 (1H, d, J = 5Hz), 6.65 (1H, d, 15 J = 6Hz).

(18) 7- [2-Allyloxyquino-2- (5-anino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-allyl-η 5 -tetrazol-5-yl) -thiomethyl -3-cephem-4-carboxylic acid (color isomer), m.p. 150-155 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1775, 1670, 1620, 1520 ^cm-1 wavenumber.

(19) 7- [2-Allyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (tetrazolo [1,5-b] pyridazin-6-yl) -thiomethyl -3-cephem-4-carboxylic acid (color isomer), m.p. 180185 ° C (with decomposition).

IR spectrum (nujol); 3300, 3200, 1770, 1670, 1620, 1525 ^cm-1 wavenumber.

(20) 7- [2- (2,2,2-Trifluoroethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- {2- (N-tert- butoxycarbonylamino) ethyl) -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), powder.

(21) 7- [2- (2,2,2-trifluoroethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (5-aminomethyl-1,3,4- 35 thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 150-155 ° C (with decomposition).

IR (Nujol): 3300, 3180, 1760, 1670, 1610, 1520 cm ^-1 .

(22) 7- (2- (2,2,2-trifluoroethoxyimino) -2- (5-amino-40

1,2,4-Thiadiazol-3-yl) -acetamido] -3- (tetrazolo [1,5-b] pyridazin-6-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 165-170 ° C (with decomposition).

IR spectrum (nujol): 3420, 3300, 3190, 1770,

1705, 1670, 16-20, 1525 cm < ^-1 >.

(23) 7- [2- {3- (N-tert-butoxycarbonylamino) -propoxyimino} -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-chloro: 3 -cephem-4-carboxylic acid (color isomer), m.p. 111-115 ° C (with decomposition). 50

IR (Nujol): 3300-3100, 1780, 16901660, 1520, 1270 ^cm-1 wavenumber.

(24) 7- [2-Allyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color isomer), m.p. 165 ° C (with decomposition).

(25) 7- [2- (3-Amino-propoxyimino) -2- (5-amino-1,2,4-thiazol-3-yl) -acetamido] -3- [1- (2-amino-ethyl) -1H-tetrazol-5-one. yl] thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 184-196 ° C (with decomposition). 60

IR (Nujol): 3400-3100, 1760, 1660, 1610, 1520, 1170, 1060, 1010 cm ^-1 .

(26) 7- (2- (2-Aminoethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-carboxymethyl-1H-tetrazole-55)

5-yl) -thiomethyl-3-cephem-4-carboxylic acid (colorless). np .:

J 90 -198 ° C (with decomposition).

IR (Nujol): 3250, 3160, 1760, 1650,

1615, 1522, 1020 ^cm-1 wavenumber.

(27) 7- (2-Carboxymethoxyimino-2- (5-amino-1,2,4-diazol-3-yl) -acetamido] -3- (1,3,4-thiadiazol-2-yl) - thiomethyl 3-cephem-4-carboxylic acid (color isomer), m.p. 170-175 ° C (with decomposition).

IR (Nujol): 3250, 3150, 1770, 1710, 1680, 1610, 1520 ^cm-1 wavenumber.

(28) 7- [2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-allyl-1H-tetrazol-5-yl) - thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 145-150 ° C (with decomposition).

IR (Nujol): 3400, 3300, 3200, 1765, 1720, 1680, 1620, 1520 ^cm-1 wavenumber.

(29) 7- [2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color isomer), 160-165 ° C (during decomposition).

IR (Nujol): 3300, 3_200, 1770, 1720, 1680, 1520 ^cm-1 wavenumber.

(30) 7- [2- (2-Aminoethoxylamino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -2-methyl-3-cephem-4-carboxylic acid (colorless) m.p. 190-195 ° C (with decomposition).

IR (Nujol): 3300, 3150, 1760, 1660.

1575, 1520, 1400 ^cm-1 wavenumber.

(31) 7- [2- (3-Aminopropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -2-methyl-3-cephem-4-carboxylic acid (color isomer) 182-187 ° C (with decomposition).

IR (Nujol): 3260, 3150, 1758, 1660,

1616, 1575, 1520, 1400 'cm ^-1 .

(32) 7- [2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (tetrazolol, 5-b] pyridazin-6-yl) thiomethyl- 3-cephem-4-carboxylic acid (color isomer), m.p. 170-175 ° C (with decomposition).

IR (Nujol): 3400, 3300, 3180, 1765, 1720, 1680, 1615, 1520 ^cm-1 wavenumber.

(33) 7- [2- (3-Aminopropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-methyl-3-cephem-4-carboxylic acid (color isomer) 175-195 ° C (with decomposition).

IR (Nujol): 3300-3100, 1770-1740, 1660, 1620, 1570, 1520, 1280, 1170, 1060, 1020 ^cm-1 wavenumber.

(34) 7- [2- (3-Aminopropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-chloro-3-cephem-4-carboxylic acid (color isomer) 190-205 ° C (with decomposition).

IR (nujol) 3400-3150, 1760, 1660, 1630-1590, 1520, 1340, 1170,

1030 cm at wave number ¹ .

(35) 7- (2- (2-aminoethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [1- (2-aminoethyl) -1H- tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 182-187 ° C (with decomposition).

IR (Nujol): 3350, 3150, 1760, 1660, 1625, 1565, 1520 cm ^-1 . (36) 7- [2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (2-aminoethyl) -1H-tetrazole23

-23IK? NNO

7.67 (5H, s), 8.17 (211, broad s),

9.50 (1H, d, J-811Z).

(17) 7- [2- {3- (N-tert-Butoxycarbonylamino) -propoxyimino} -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -2-methyl-3-cephem -4-carboxylic acid (color isomer), m.p. 133-146 ° C (dec.).

IR (Nujol): 3280, 3170, 1775, 1685, 1670, 1625, 1520 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO + D ₂ O, a): 1.40 (9H, s), δ

1.46 (3H, d, J-7lz), 1.56-2.06 (2H, m), 3.03 (2H, t), J = 7Hz),

3.1 4.1 (111, in), 4.23 (2H, t,

J = 7Hz), 5.13 (1H, d, J = 5Hz),

5.97 (1H, d, J = 5Hz), 6.65 (1H, d, 15 J = 6Hz).

(18) 7- [2-Allyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-allyl-1H-tc-trazol-5-yl) -thiomethyl-3-cephem -4-carboxylic acid (color isomer), m.p. 150-155 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1775, 1670, 1620, 1520 cm ^-1 .

(19) 7- [2-Allyloxy-amino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (tetrazolo [1,5-b] pyridazin-6-yl) -thiomethyl -3-cephem-4-carboxylic acid (color isomer), m.p. 180185 ° C (with decomposition).

IR spectrum (nujol); 3300, 3200, 1770, 1670, 1620, 1525 cm ^- 'wave number.

(20) 7- (2- (2,2,2-Trininoethoxyimino) -2- (5-amino-βθ)

1.2.4-Thiadiazol-3-yl) -acetamido] -3- (1- {2- (N-tert-butoxycarbonylamino) -ethyl} -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid ( color isomer), powder.

(21) 7- (2- (2,2,2-trifluoroethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (5-aminomethyl-1,3,4- 35 thiadiazol-2-yl) thiomethyl-3-cefcm-4-carboxylic acid (color isomer), m.p. 150-155 ° C (with decomposition).

IR (Nujol): 3300, 3180, 1760, 1670, 1610, 1520 ^cm-1 wavenumber.

(22) 7- (2- (2,2,2-trifluoroethoxyimino) -2- (5-amino-40

1.2.4-Thiadiazol-3-yl) -acetamido] -3- (tetrazolo (1,5-b] pyridazin-6-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 165-170 ° C (with decomposition).

IR spectrum (nujol): 3420, 3300, 3190, 1770,

1705, 1670, 16-20, .1525 cm &^lt; -1 &gt;

(23) 7- (2- {3- (N-tert-Butoxycarbonylamino) -propoxyimino} -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-chloro-3-cephem -4-carboxylic acid (color isomer), m.p. 111-115 ° C (with decomposition)

IR (Nujol): 3300-3100, 1780, 16901660, 1520, 1270 cm ^-1 .

(24) 7- [2-Allyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color isomer), m.p. 165 ° C (with decomposition).

(25) 7- (2- (3-Aminopropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [1- (2-aminoethyl) -1H-tetrazole -yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 184-196 ° C (with decomposition).

IR (Nujol): 3400-3100, 1760, 1660, 1610, 1520, 1170, 1060, 1010 cm ^-1 .

(26) 7- (2- (2-Aminoethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-carboxymethyl-1H-tetrazole-65)

5-yl) methyl-3-cefcm-4-carbolic acid (color isomers). 190-198 ° C (with decomposition).

IR (Nujol): 3250, 3160, 1760, 165 (1,

1615, 1522, 1020 ^cm-1 wavenumber.

(27) 7- [2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiazol-3-yl) -acetamido] -3- (1,3,4-thiadiazol-2-yl) - thiomethyl 3-cephem-4-carboxylic acid (color isomer), m.p. 170-175 ° C (with decomposition).

IR (Nujol): 3250, 3150, 1770, 1710, 1680, 1610, 1520 cm ^-1 .

(28) 7- [2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-allyl-1H-tetrazol-5-yl) - thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 145-150 ° C (with decomposition).

IR (Nujol): 3400, 3300, 3200, 1765, 1720, 1680, 1620, 1520 cm ^-1 .

(29) 7- [2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color isomer), 160-165 ° C (during decomposition).

IR (Nujol): 3300, 3200, 1770, 1720, 1680, 1520 cm ^-1 .

(30) 7- [2- (2-Aminoethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -2-methyl-3-cephem-4-carboxylic acid (color isomer 190-195 ° C (with decomposition).

IR (Nujol): 3300, 3150, 1760, 1660.

1575, 1520, 1400 cm ^-1 .

(31) 7- [2- (3-Aminopropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -2-methyl-3-cephem-4-carboxylic acid (color isomer) 182-187 ° C (with decomposition).

IR (Nujol): 3260, 3150, 1758, 1660,

1616, 1575, 1520, 1400 'cm ^-1 .

(32) 7- [2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (tetrazolo [1,5-b] pyridazin-6-yl) thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 170-175 ° C (with decomposition).

IR (Nujol): 3400, 3300, 3180, 1765, 1720, 1680, 1615, 1520 cm ^-1 .

(33) 742- (3-Aminopropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-methyl-3-cephem-4-carboxylic acid (color isomer), m.p. 175-195 ° C (with decomposition).

IR (Nujol): 3300-3100, 1770-1740, 1660, 1620, 1570, 1520, 1280, 1170, 1060, 1020 ^cm-1 wavenumber.

(34) 7- [2- (3-Aminopropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-chloro-3-cephem-4-carboxylic acid (color isomer) 190-205 ° C (with decomposition).

IR (nujol) 3400-3150, 1760, 1660, 1630-1590, 1520, 1340, 1170,

1030 cm at wave number ¹ .

(35) 7- [2- (2-Aminoethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1- (2-aminoethyl) -1 H -tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 182-187 ° C (with decomposition).

IR (Nujol): 3350, 3150, 1760, 1660, 1625, 1565, 1520 cm ^-1 . (36) 7- [2-Carboxymethoxylmino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-yl- (2-aminoethyl) -1H-tetrazole23

-24183 006

Ί.

The pI of the mixture was adjusted to 4 with 10% hydrochloric acid and then extracted with ethyl acelate. The crude product was dried over magnesium sulfate and evaporated to dryness. Triturate the residue with diethyl ether. the solid was collected by filtration after drying to give 400 mg of crude product. This product was dissolved in aqueous sodium bicarbonate solution and adjusted to pH 2 with hydrochloric acid. The precipitate was collected by filtration, washed with water and after drying 250 mg of 7- [2- (2-cyclohexcn-1-yl) oxyimino-2- (5-amino-1,2.4-thiadiazol-3-yl) acetanido] - 3- (1,3,4-Thiadiazol-2-yl) -thiomethyl-3-cfem-4-carboxylic acid (color isomer) is obtained. mp 150-155 ° C (with decomposition).

IR (Nujol): 3300, 3180, 1770, 1660, 1620, 1520 ^cm-1 lmllámszámnál.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO,?): 1.50 2.17 (6H, ni),

3.70 (broad s. 211), 4.33 and 4.58 (2H, ABq, J = 14 Hz). 5.83 (1H, dd, J = 4 and 8 Hz), 5.60 6.12 (2H, m).

8.15 (2H, s), 9.53 (111, d, J = 8Hz),

9.93 (1H, s).

Example 10

To a cold solution of 1.50 g of phosphorus pentachloride in 30 ml of methylene chloride is 1.61 g of 2- (2-cyclohexen-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (color isomer) at -15 ° C. After stirring for 30 minutes at 13 and -10 ° C, the mixture was evaporated and tetrahydrofuran (20 ml) was added to the residue. At the same time, 2.86 g of 7-amino-3- (tetrazoloyl, 5-b] pyridazin-6-yl) -thiomethyl-3-cephem-4-carboxylic acid was 2.52 g of sodium bicarbonate, 80 ml of water and 45 ml the acetone mixture was cooled to 5-10 ° C. The solution is added to the above activated mixture. The mixture was stirred for 20 minutes at 5 to 10 ° C, then allowed to rise to room temperature and then evaporated. Ethyl acetate was added to the residue, and the mixture was adjusted to pH 2 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was treated with 0.5 g of activated carbon, dried over magnesium sulfate and evaporated. The residue was triturated with diethyl ether and the crude product (2.37 g) was collected by filtration. This product was dissolved in aqueous sodium bicarbonate solution and adjusted to pH 2 with hydrochloric acid. The precipitate was collected by filtration, 2.28 g of 7- [2- (2-cyclohexen-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (tetrazolo [1,5-b] pyridazin-6-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 170-175 ° C (with decomposition).

IR (Nujol): 3400, 3300, 3180, 1670, 1620, 1520 ^cm-first

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, a): 1.40-2.20 (6H, m),

3.73 (2H, bs), 4.27 and 4.65 (2H, ABq, J = 13Hz), 4.65-4.88 (1H, m),

5.18 (1H, d, J = 5Hz), 5.80 (1H, dd, J = 5 and 8Hz), 5.78-6.02 (2H, m),

7.80 (1H, d, J = 10Hz), 8.17 (2H, broad s), 8.60 (1H, d, J = 10Hz), 9.55 (1H, d, J = 8Hz).

Example 11

To a cold solution of 1.5 g of phosphorus pentachloride in 30 ml of methylene chloride is added 1.37 g of 2-cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer). The mixture was stirred at 15 ° C and stirred for 30 minutes at -13 ° C to 10 ° C. At the same time, 2.18 g of a solution of 7-amino-3- (1,3,4 thiadia / ol 2-yl) -methyl 3-cis-4-carboxylic acid and 6 g of trimethylsilyl acelamide in 30 ml of methylene chloride were purified The solution was added to the above activated mixture and the crpol mixture was stirred for half an hour at 10 ° C. The reaction mixture was then treated with 60 ml of cold saturated aqueous sodium bicarbonate. The aqueous phase was separated, added to ethyl acetate, adjusted to pH = 2 with pH 3 with 10% hydrochloric acid, extracted with ethyl acetate, dried over magnesium sulfate and evaporated to dryness. Wash the residue with diethyl edge

2.62 g of crude product are obtained. This product was dissolved in aqueous sodium bicarbonate solution and adjusted to pH 2 with 2N hydrochloric acid. The precipitate was collected by filtration (2.22 g) of 7- [2-cyclopentyloxyquinoino-2- (5-amine).

1,2,4-Thiadiazol-3-yl) -acetamido] -3- (1,3,4-thiadiazole-141) thiomethyl-3-cephem-4-carboxylic acid (color isomer) is obtained. having a melting point of 140-145 ° C (with decomposition)

IR (Nujol) 3400, 3300, 3200, 1770.

1670, 1620, 1525 cin 'bullion.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, a): 1.33 2.10 (811, in).

3.72 (211, broad s), 4.33 and 4.58 (21, ABq, J = 13 Hz), 4.60 4.90 (1H, m). 5.17 (1H, d, J = 5Hz), 5.82 (111, dd.

J = 5 and 8Hz). 8.15 (2 H, s). 9.52 (111d, J = 8Hz), 9.58 (1H, s).

Example 12

To a cooled solution of 1.25 g of phosphorus pentachloride in 25 ml of methylene chloride is added 1.28 g of 2-cyclopentylimino 2- (5-amino-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer 1). The mixture was stirred at 15 ° C and stirred for 30 minutes at -13 ° C and -10 ° C. At the same time 1.1 g of 7-amino-3-cephem-4-carboxylic acid and 5.5 g of trimethylsilylacetamide in 25 ml of methylene Chloride was heated to a clear solution and cooled to -15 ° C. The resulting solution was added to the above mixture and stirred at -10 ° C for half an hour. The reaction mixture was poured into sodium bicarbonate solution and stirred at room temperature for 30 minutes, then the methylene chloride was evaporated, the residue was washed with ethyl acetate and ethyl acetate was added to the aqueous phase, the pH was adjusted to 3 with 10% hydrochloric acid and Extract it The extract was dried over magnesium sulfate, treated with 1.0 g of activated carbon and evaporated. The residue was washed with diethyl ether to give 1.03 g of crude product. This product was dissolved in aqueous sodium bicarbonate solution and adjusted to pH 3 with 10% hydrochloric acid. The precipitate was collected by filtration to give 860 mg of 7- [2-cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cephem-4-carboxylic acid (color isomer). mp 170-175 ° C.

IR (Nujol): 3520, 3420, 3320, 3220, 3160, 1770, 1685, 1655, 1635, 1625, Γ57Ο, 1505 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, a): 1.33-2.07 (8H, m), δ

-25183 006

3.43 3.77 (2Η, m), 4.60 4.93 (111, m), 5.15 (111, d, J = 5Hz), 5.90 (111, dd, J = 5 and 8Hz) ), 6.43-6.67 (1H, m).

8.23 (211, broad s), 9.63 (1H, d,

J = 8Hz). 5

Example 13

13, 5 and 7-12. In the same manner as in Examples 1 to 9, the following compounds were prepared: 10 (1) 7- [2- (2-Cyclopenten-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cephem-4-carboxylic acid (color isomer), m.p. 154-159 ° C (with decomposition).

IR (Nujol): 3300, 1770, 1720, 1670,

At a wave number of 1620, 1520 cm ^-1 . 15

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO,?): 2.0 (3H, s), 2.0 2.40 (411, m), 3.52 (2H, bs), 4.70 and

4.97 (2H, ABq, J = 14Hz), 5.12 (1H, d, J = 4Hz), 5.27-5.40 (1H, m), 5.82 (1H, dd, J = 4 and 8Hz) ), 5.83-6.17 δ (211, m), 8.13 (2H, s), 9.50 (1H, d, J = 8Hz).

(2) 7- [2- (2-cyclopenten-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamide] 3- (1-methyl-1H-tetrazol-5-yl) ) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p.

155-160 ° C (with decomposition).

IR (Nujol): 3333, 1770, 1670, 1620,

1520 cm at wave number ¹ .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, a): 1.90-2.30 (4H, m),

3.62 (2H, broad s), 3.88 (3H, s), 4.25 (2H, broad s), 5.07 (1H, d, J = 4Hz), 5.20-5.40 (1H, m), 5.80 (1H, dd, J = 4 and 8Hz), 5.83-6.17 (2H, m), 8.08 (2H, s), 9.47 (1H, d) , J = 8Hz). 35 (3) 7- [2- (2-cyclopenten-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- {1-carboxymethyl-1H-tetrazole-5 -yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 155-160 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1720, 401670, 1620, 1520 cm @ -1.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, a): 1.83-2.50 (4H, m),

3.67 (2H, broad s), 4.27 and 4.48 (2H, ABq, J = 14Hz), 5.17 (1H, d, 45 J = 4Hz), 5.30 (2H, s), 5.27-5.50 (1H, m), 5.82 (2H, dd, J = 4 and 8Hz), 5.83-6.20 (2H, m), 8.17 (2H, s),

9.50 (1H, d, J = 8Hz).

(4) 7- [2- (2-Cyclopenten-1-yl) oxyimino-2- (5-amino-

1.2.4-Thiadiazol-3-yl) -acetamido] -3- [1- (2-carboxyethyl) -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 150-155 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1720,

1670, 1620, 1520 cm ^{-1 at} wave number 55.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 1.90-2.50 (4H, m),

2.97 (2H, t, J = 6Hz), 3.73 (2H, broad s), 4.30 and 4.50 (2H, ABq,

J = 14Hz), 4.52 (2H, 5, J = 6Hz), 60 ', 5.20 (1H, d, J = 4Hz), 5.30-5.57 (1H, m), 5.90 ( 1H, dd, J = 4 and 8Hz), 5.93-6.33 (2H, m), 8.33 (2H, s),

9.77 (1H, d, J = 8Hz).

65) 7- (2- (2-cyclopenten-1-yl) oxyimino-2- (5-amino)

1.2.4-Thiadiazol-3-yl) -acc (amido 1-3- (1-allyl-1H-thiazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. :

160-165 ° C (with decomposition).

IR spectrum (nujol): 3300, 1770, 1670, 1620, 1520 cm @ ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 1.93-2.33 (4H, m),

3.60 (2H, bs), 4.22 and 4.37 (2H, ABq, J = 13Hz, 4.83-5.0 (2H, m), 5.0 -5.40 (4H, m) ), 5.60-6.17 (411, m), 8.07 (211, s), 9.47 (1H, d, J = 8Hz).

(6) 7- [2- (2-Cyclopenten-1-yl) oxyimino-2- (5-anino-1,2,4-thiadiazol-3-yl) -acetamido-3-tetrazolo [1,5-b] pyridazine -6-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 170-175 ° C (with decomposition).

IR (nujol): 3400, 3300, 3190, 1770, 1670, 1615, 1520 cm @ ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 1.90-2.43 (4H, m),

3.68 (2H, bs), 4.22 and 4.58 (2H, ABq, J = 13Hz), 5.10 (1H, d,

J = 5Hz), 5.20-5.47 (1H, m), 5.78 (1H, dd, J = 5 and 8Hz), 5.80-6.20 (2H, m), 7.75 ( 1H, d, J = 10 (lz).

8.13 (2H, bs), 8.55 (1H, d,

J = 10Hz), 9.52 (1H, d, J = 8Hz).

(7) 7- [2- (2-Cyclopenten-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamide] -3- [1- (2- (N tert-butoxycarbonylamino) ethyl} -1H-tetrazol-5-yl] thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 95-100 ° C (with decomposition).

IR (Nujol): 3300, 3190, 1770, 1680, 1620, 1520 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 1.40 (9H, s), 2.072.50 (4H, m), 3.30-3.57 (2H] m),

3.67-3.87 (2H, m), 4.27-4.57 (4H, m), 5.17 (1H, d, J = 5Hz), 5.23 5.57 (1H, m), δ , 70-6.30 (3H, m), 8.17 (2H, broad s), 9.53 (1H, d, J = 8Hz).

(8) 7- [2- (2-Cyclohexen-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazole-3 -) acetamido] -3-cephem-4-carboxylic acid (color isomer), m.p. 175-180 ° C (with decomposition).

IR (nujol): 3300, 3200, 1770, 1670, 1630, 1520 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 1.50-2.13 (6H, m),

3.63 (2H, bs), 4.60-4.83 (1H, m), 5.12 (1H, d, J = 4Hz), 5.77-6.00 (3H, m), δ , 50 (1H, t, J = 3Hz), 8.15 (2H, s), 9.55 (1H, d, J = 8Hz).

(9) 7- [2- (2-Cyclohexen-1-yl) oxyimino-2- (5-amino-2,4-thiadiazol-3-yl) acetamido] -3-cephem-4-carboxylic acid (color isomer 160-165 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1775, 1720, 1670, 1620, 1520 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 1.50-2.10 (6H, m), 2.07 (3H, s), 3.60 (2H, broad s),

4.67-4.83 (1H, m), 4.77 and 5.03 (2H, ABq, J = 14Hz), 5.17 (1H, d, J = 4Hz), 5.77-6.10 ( 3H, m), 8.17 (2H, s), 9.60 (1H, d, J = 8Hz).

(10) 7- [2- (2-Cyclohexen-1-yl) -oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-methyl-1H-tetrazol-5-yl) ) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 170-173 ° C (with decomposition).

-261

183,006

IR (Nujol): 3350, 3250, 1780, 1680, 1620, 1520 ^cm-1 hullámszámnáí.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 1.50 -2.17 (6H, m),

3.16 (2H, broad s), 3.93 (3H, s), 4.30 (2H, broad s), 4.55 4.80 (1H, m), 5.10 (1H, d, J = 4Hz). 5.80 (1H, dd, J = 4 and 8Hz), 5.80-5.93 (2H, m), 8.08 (2H, s), 9.50 (1H, d, J = 8Hz) (11) 7-L2- (2-cyclohexen-l-yl) oxyimino-2- (5-amino

1.2.4-Thiadiazol-3-yl) -acetamido] -3- (1-carboxymethyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 170-175 ° C. C (decomposition with).

IR spectrum (nujol): 3300, 3200, 1770, 1720, 1650, 1620, 1520 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 1.50-2.27 (6H, m) 3.75 (2H, bs), 4.30 and 4.55 (2H, ABq, J = 14Hz). , 4.67-4.83 (1H, m), 5.17 (1H, d, J = 4Hz). 5.37 (2H, s), 6.17-6.77 (3H, m)

8.18 (2H, s), 9.57 1H, d, J = 8Hz) (12) 7- [2- (2-Cyclohexen-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazole) -3-yl) -acetamido] -3- [1- (2-carboxyethyl) -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 165-170 ° C. .

IR (Nujol): 3300, 3200, 1770, 1720, 1670, 1620, 1520 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 1.50-2.17 (611, m),

3.77 (2H, broad s), 4.37 and 4.50 (2H, ABq, J = 14Hz), 4.53 (2H, t, J = 6Hz), 4.67-4.93 (1H, m), 5.23 (1H, d, J = 4Hz), 5.93 (1H, dd, J = 4 and 8Hz), 5.97-6.17 (2H, m),

8.70 (2H, s), 9.80 (1H, d, J = 8Hz).

(13) 7- [2- (2-Cyclohexen-1-yl) -oxyimino-2- (5-amino-1,2,4-thiadiazol-5-yl) -acetamido] -3- (1-allyl-1H-tetrazole) -yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 160-165 ° C (with decomposition).

IR (nujol): 3300, 3200, 1780, 1680, 1620, 1520 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 1.50-2.16 (6H, m), 3.66 (2H, bs), 4.25 and 4.43 (2H, ABq, J = 14Hz ), 4.55-4.80 (1H, m), 4.93-5.00 (2H, m), 5.10 (1H, d, J = 4Hz), 5.20-5.37 (2H) , m),

5.67-6.20 (4H, m), 8.08 (2H, s), ^OC 0 (1H 'J = 8Hz).

(14) 7- [2- (2-Cyclohexen-1-yl) -oxyimino-2- (5-amino-2,4-thiadiazol-3-yl) -acetamide] -3- [1- {3- (N- tert-butoxycarbomylamino) -propyl} -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 100-105 ° C (with decomposition).

IR (nujol): 3300, 3170, 1770, 1670, 1620, 1520 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO,?): 1.37 (9H, s), 1.502.20 (8H, m), 2.92 (2H, t, J = 6Hz),

3.68 (2H, bs), 4.07-4.47 (4H, m), 4.53-4.83 (1H, m), 5.10 (1H, d, J = 5Hz), δ , 80 (1H, dd, J = 5 and 8Hz), 5.70-5.93 (2H, m), 8.10 (2H, broad s), 9.47 (1H, d, J = 8Hz).

(15) 7- [2-Cyclopentylloxyimino-2- (5-allyl) -1,2,4-thiadiazol-3-yl] -acetamidol-3α-cm-4-carboxylic acid (color isomer), m.p. 140-145 ° C (with decomposition).

IR spectrum (nujol): 3480, 3370, 3250, 1785, 1730, 1680, 1630, 1530 cm -1.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO,?): 1.33 2.17 (811, m), 2.03 (311, s), 3.57 (211, broad s),

4.60 4.90 (111, in), 4.73 and 4.97 (2H, ABq, J = 13Hz). 5.15 (111, d, J = 5Hz), 5.80 (111, dd, J = 5 and 8Hz), 8.10 (211, broad s), 9.47 (III, d, J = 8Hz) .

(16) 7-12-Cyclopentyloxy-amino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl -3-cephem-4-carboxylic acid (color isomer), m.p. 145-150 ° C (with decomposition).

IR (Nujol): 3400, 3290, 3180, 1770, 1670, 1620, 1520 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, a): 1.33-2.07 (8H, ni),

3.70 (2H, broad s), 3.93 (3H, s), 4.32 (211, broad s), 4.10 4.90 (1H, m). 5.12 (1H, d, J = 5Hz), 5.78 (1H, dd, J = 5 and 8Hz), 8.10 (2H, broad s),

9.47 (1H, d, J = 8Hz).

(17) 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-carboxymethyl-1H-tetrazol-5-yl) -thiomethyl-3- cephem-4-carboxylic acid (color isomer), m.p. 155-160 ° C (with decomposition).

IR (Nujol): 3400, 3290, 3180, 1765, 1720, 1670, 1620, 1520 cm @ -1.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, a): 1.27-2.07 (8H, m),

3.70 (2H, broad s), 4.28 and 4.53 (2H, ABq, J = 13Hz), 4.70-4.93 (1H, m), 5.17 (1H, d, J = 5Hz), 5.33 (2H, s), 5.85 (1H, dd, J = 5 and 8Hz), 8.23 (2H, broad s), 9.60 (1H, d, J = 8Hz).

(18) 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-allyl-1 H -tetrazol-5-yl) -1-methyl o-methyl-3-cephem-4-carboxylic acid (color isomer), m.p.

135-140 ° C (with decomposition).

IR (Nujol): 3400, 3300, 3190, 1770, 1670, 1620, 1520 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, a): 1.30-2.10 (8H, m),

3.73 (2H, bs), 4.32 and 4.50 (2H, ABq, J = 13Hz), 4.60-4.90 (1H, m), 4.83-5.17 (2H, m), 5.17 (1H, d, J = 5Hz), 5.17-5.50 (2H, m), 5.87 (1H, dd, J = 5 and 8Hz),

5.67-6.33 (1H, m), 8.20 (2H, broad s), 9.60 (1H, d, J = 8Hz).

(19) 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (tetrazolo [1,5-b] pyridazin-6-yl) thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 160-165 ° C (with decomposition).

IR (nujol): 3570, 3440, 3320, 3180, 1775, 1710, 1660, 1620, 1580, 1540, 1520 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, a): 1.40-2.30 (8H, m),

3.78 (2H, bs), 4.27 and 4.65 (2H, ABq, J = 13Hz), 4.67-4.93

-27183006 (111, m), 5.20 (1H, d, J = 5Hz), 5.87 (1H, dd, J = 5 and 8Hz). 7.78 (III, d, J = 10Hz), 8.15 (2H, broad s), 8.58 (1H, d, J = 10Hz), 9.53 (1H, d, J = 8Hz), ( 20) 7- [2-cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-12-methoxycarbonyl-ethyl) -1H-tetrazol-5-yl] -thiomethyl-3- cephem-4-carboxylic acid (color isomer), m.p. 125-130 ° C.

IR (Nujol): 3480, 3370, 3250, 1780, 1740, 1685, 1625, 1530 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, a): 1.30-2.07 (8H, m),

2.80 - 3.20 (2H, m), 3.58 (3H, s),

3.67 (2H, bs), 4.20-4.70 (411, m), 4.60-4.90 (1H, m), 5.12 (JH, d, J = 5Hz), δ , 78 (1H, dd, J = 5 and 8Hz), 8.07 (2H, broad s), 9.43 (1H, d, J = 8Hz).

(21) 7- [2-cyclopentyloxyimino-2- (5-anino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (4-methyl-5-oxo-6-hydroxy-4), 5-Dihydro-1,2,4-triazin-3-yl) -thioethyl-3-cephem-4-carboxylic acid (color isomer), pale yellow powder, m.p. 195-199 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1710 1670, 1590, 1520, 1240, 1170, 1090, 1000, 720, cin ¹ .

(22) 7- (2-Cycloheptyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido) -3- (1,3,4-thiadiazol-2-yl) -thiomethyl-3 cephem-4-carboxylic acid (color isomer), white powder, m.p.

150-154 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1670, 1620, 1520, 1400, 1240, 1160, 1060, 1000 cm @ ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO,?): 1.50 (8H, m), 1.82 (4H, m), 3.54 and 3.76 (2H, ABq, J = 20Hz), 4.32 (1H, m), 4.24 and

4.60 (2H, ABq, J = 14Hz), 5.10 (1H, d, J = 5Hz), 5.74 (111, dd, J = 5 and 8Hz), 8.02 (2H, m) , 9.48 (1H, s), 9.38 (1H, d, J = 8Hz).

(23) 7- [2-Cycloheptyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color isomer), white powder, m.p. 170-175 ° <22 (dec.).

IR (Nujol): 3400, 3300, 3200, 1770, 1670, 1620, 1520, 1280, 1240, 1160, 1000, 980, 730 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO,?): 1.50 (8H, m), 1.85 (4H, m), 3.60 (2H, m), 4.0-4.50 (1H, m) ), 5.13 (1H, d, J = 5Hz),

5.87 (1H, dd, J = 5 and 8Hz), 6.50 (1H, m), 8.13 (2H, m), 9.37 (1H, d, J = 8Hz).

(24) N- [7- {2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido} -3-cc-metal -3-yl) methyl] -4 * -carbamoylpyridium 4-carboxylate (color isomer), m.p. 230-235 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1680, 1610, 1560, 1520, 1510 ^cm-1 wavenumber.

(25) 7- [2-Cyclopentyloxy-nitro-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (3- (N-tert-butoxycarbonylamino) -propyl] -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (syn-isomer), pale yellow powder.

IR spectrum (nujol). 3300. 1770, lu70, 1520, 1240, 1160, 1000 cm ^"1 wavenumber.

(26) 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thia-diazol-3-yl) -acetamido] -3- (1,2,4-thiadiazol-3-yl) -thiomycl 3 -cephem 4-carboxylic acid (syn isomer). mp 175-178 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1775, 1680, 1620, 1525 cm &lt; -1 &gt;.

(27) 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2.4-thiadiazol-3-yl) -acetamido] -3- [1- (3-norpholinopropyl) -1H-tetrazol-5-yl] thiomethyl 3-cefcm-4-carboxylic acid (color isomer), m.p. 183-188 ° C (with decomposition).

IR (Nujol) 3300, 3150, 1770, 1670,

1610, 1530 cm * ^{1 at} wave number.

(28) 7- [2- (2-Cyclopenten-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetanido] -3-11- (2-aminoctyl) - 1 Htetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 175-180 ° C (with decomposition).

IR (Nujol): 3400, 3300, 3170, 1760, 1665, 1610, 1520 ^cm-1 hullámizámnál.

(29) 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (3-aminopropyl) -1H-tetrazol-25-yl] - thiomethyl-3-cephem-4-carboxylic acid (color isomer), white powder, m.p. 195-199 ° C (with decomposition).

IR (Nujol): 3300, 3150, 1760, 1660, 1620.1520, 1280.1180, 1000 ^cm-1 wavenumber.

(30) 7- (2- (2-Cyclohexen-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamide) -3-11- (3-aminopropyl) - 111-Tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 185-190 ° C (with decomposition).

IR (nujol): 3280, 3150, 1760, 1665, 351620, 1520 cm ^-1 . wave number.

(31) 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (3-piperidinopropyl) -111-tetrazol-5-yl ] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 230 DEG C. (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1670, 1600, 1520 ^cm-1 wavenumber.

Example 14

3.5 g 7- (2-Phenoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cephem-4-carboxylic acid (color isomer), 1.35 g tetrazole A solution of [1,5-b] pyridazine-6-thiol and 1.1 g of sodium bicarbonate in 130 ml of pH 6.8 phosphate buffer is stirred for 2 hours at 70 [deg.] C. The reaction mixture is cooled in an ice bath, stirred with ethyl acetate and The pH was adjusted to 3 with 10% hydrochloric acid, the insoluble material was filtered off, and the filtrate was extracted with ethyl acetate, dried over magnesium sulfate and evaporated to dryness, triturated with diethyl ether.

0.7 g of 7- [2-phenoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (tetrazolo [1,5-b] pyridazin-6-yl) of thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 175-180 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1775, 1680,

1615, 1585, 1520 cm * ^{1 at} wave number.

NMK spectrum (d -DMSO _an a): 3.77 (2H, br s);

4.23 and 4.63 (2H, ABq, J = 13Hz),

5.23 (1H, d, J = 4Hz), 5.93 (1H, dd,

J = 4 and 8Hz), 7.00-7.50 (5H, m).

-28183OOÓ

7.77 (111 d, J 1011 /), 8.30 (2H, s). 8.60 (111. d. J 1011 /) 9.85 (111, d, J = 811 /).

15. pckla

4.0 g of 7- [2-phenoxyimino-2- (5-amino-1,2.4-tindiaol-3-yl) -acetamidol-3-cephin-4-carboxylic acid (color isomer),

A solution of 2.45 g of 1- [2- (N-tert-butoxycarbonylamino) ethyl] -1H-rasazol-5-thiol and 1.3 g of sodium bicarbonate in 150 ml of pH 6.8 phosphate buffer is added.

Stir at 70 ° C for 1.5 hours. The reaction mixture was then cooled in an ice bath, stirred with ethyl acetate and adjusted to pH 3 with 10% hydrochloric acid. The insoluble material was filtered off and the filtrate was extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated to dryness. Trituration of the residue with diethyl ether gave 1.4 g of 7- [2-phenoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-11- {2- (N-tert-butoxycarbonylamino). -ethyl} -1,11-tetrazol-5-yl] -thioethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 150-155 ° C (dec.).

IR spectrum (nujol): 3300, 3200, 1770, 1680, 1620, 1590, 1520 cm @ ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO,?): 1.27 (911, s), 3.3, 3.5 (211, ni), 3.70 (211, wind s), 4.3, 4.6 ( 4H, m), 5.18 (1H, d, J = 4Hz), 5.90 (III, dd, J = 4 and 811z), 7.0-7.5 (5H, m). 8.28 (211, s), 9.88 (1H, d, J = 8Hz).

Example 16

3.3 g 7- [2-Allyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetanido] -3-eephem-4-carboxylic acid (color isomer), 1.4 g l A solution of allyl-1H-tetrazol-5-thiol and 1.3 g of sodium bicarbonate in 210 ml of phosphate buffer pH 6.8 is stirred for 2 hours at 70 ° C. The reaction mixture was cooled in an ice bath, mixed with ethyl acetate and adjusted to pH 2 with 10% HCl. The insoluble material was filtered off and the filtrate was extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated to dryness. The residue was triturated with diethyl ether to give 2.1 g of 7- [2-alloyloximino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamide] -3- (1-allyl-1H-tetrazole). m.p. 150-155 ° C (with decomposition). -yl) thiomethyl-3-cfem-4-carboxylic acid (color isomer).

IR spectrum (nujol): 3300, 3200, 1775, 1670, 1620, 1520 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO,?): 3.68 (2H, bs), 4.28 and 4.45 (2H, ABq, J = 13Hz),

4.60 4.83 (2H, m), 4.93 5.07 (2H, m), 5.12 (1H, d, J = 4Hz), 5.17-5.57 (4H, m), 5.83 (1H, dd, J = 4 and 8Hz), 5.77-6.37 (2H, m), 8.22 (2H, s),

9.67 (1H, d, J = 8Hz).

Example 17

5.1 g 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color isomer), 840 l of sodium hydrogen carbonate, 50 ml water, 24.3 g potassium thiocyanate and 1.83 g isonicotinamide are stirred for 22 hours at 50-55 ° C. The reaction mixture was cooled and added to ethyl acetate. The mixture was adjusted to 2-rc with 10% hydrochloric acid in p1C1 and filtered. The aqueous phase was separated from the filtrates, washed with ethyl acetate and evaporated. The residue was subjected to column chromatography (non-ionic adsorption resin, Diaion IIP20, Mitsubishi Chemical Indus- trial factory), the column was washed with 0.7 L of water and eluted with 11.7 L of 30% aqueous methanol. The eluate containing the desired product was collected, washed with ethyl acetate and evaporated. The residue was lyophilized to give 1.0 g of N- [7- {2-cyclopentyloxyquinoino-2- (5-amino-1,2,4-thiadiazol-3-ylacetamido) -3-cephein-3-ylmethyl] -4'- Carbamoyl pyridine-4-carboxylate (syn isomer) is obtained, m.p. 230-235 ° C (with decomposition).

IR spectrum (nujol): 3300, 3200. 1770, 1680, 1610, 1560, 1520, 1510, 1580, 1510, 1120.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 1.30 1.95 (8H, ni),

3.15 and 3.50 (2H, ABq, J = 18Hz).

5.60-5.75 (111, ni), 5.06 (111, d, J = 4Hz), 5.30 cs 5.65 (211, ABq, J = 14Hz), 5.70 (III, dd, J) = 4 and 8Hz), 8.12 (2H, s), 8.45 (211, d, J = 6Hz), 9.42 (2H, d, .1611 / 1. 9.50 (111, d, J) = 8 Hz).

Example 18

14-17. Following the procedures of Examples 1 to 4, the following compounds were prepared:

(1) 7- [2-Allyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (tetrazolo [1,5-b] pyridazin-6-yl) -thiomethyl -3-cephem-4-carboxylic acid (color isomer), m.p. 180-185 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1670, 1620, 1525 ^cm-1 hullámszárnnál.

NMR (d _é -DMSO, δ): 3.73 (2H, br s), 4.27 and 4.63 (2H, ABq, J = 14Hz).

4.60-4.83 (2H, m), 5.18 (111, d, J = 4Hz), 5.23-5.53 (2H, m), 5.83 (1H, dd, J = 4 and 8Hz) ), 5.87-6.33 (1H, m), 7.82 (1H, d, J = 1011z),

8.20 (2H, s), 8.68 (1H, d, J = 10Hz).

9.68 (1H, d, J = 8Hz).

(2) 7- [2- (2,2,2-trifluoroethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [1- {2- (N- tert-Butoxycarbonylamino) ethyl} -1H-tetrazol-5-yl] thiomethyl-3-cephem-4-carboxylic acid (color isomer), powder.

(3) 7- [2- (2,2,2-trifluoroethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (5-aminomethyl-1,3), 4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 150-155 ° C (with decomposition).

IR (Nujol): 3300, 3180, 1760, 1670, 1610, 1520 cm @ ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.60 (2H, bs), 4.05 and 4.28 (2H, ABq, J = 13Hz), 4.57 (2H, s), 4, 73 and 4.95 (2H, ABq, J = 9Hz), 5.07 (1H, d, J = 5 and 8Hz), 8.17 (211, broad s), 9.63 (1H, d, J = 8Hz).

(4) 7- [2- (2,2,2-Trifluoroethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (tetrazolo [1,5-b] pyridazin-6-yl) thiomethyl-3-cephem-4-carboxylic acid (color isoiner), m.p. 165-170 ° C (with decomposition).

IR (Nujol): 3420, 3300, 3190, 1770, 1705, 1670, 1620, 1525 cm ^-1 .

-29183 006

NMR (d _f, -I> MSO, O): 3.60 and 3.80 (2H, ABq, ISII .1 '.), 4.23 cs 4:58 (2H, ABq J 1311 /..). 4.67 4.87 (211, ABq .1 Ullz). 5.13 (III, d. J 5llz). 5.82 (IIIdd, .15c 8Hz), 7.72 (IIId. J - 101 taste), 8.17 (211, broad s), 8.55 (IIId, .1-101 Iz), 9.68 (1H, d,

J 8 Hz).

(5) 7- [2-Cyclopaeyl] ximino-2- (5-yne () -1,2,4-thiadia · [(1-3-yl) -acetamido] -3- {1- {3- (N-lcrc-Biotoxycarbonylamine-1-yl) propyl} 11,11-telrazol-5-yl] -thionyl-3-cefcn-4-carboxylic acid (color isomer), pale brown powder.

IR spcktinm (nujol): 3300, 1770, 1670, 1520, 1240, 1160, 1000 cin waves / anam. . 1

NMR (d -1) MSO. δ): 1.33 (911, s), 1.40 2.07 (1011, m). 2.95 (211, ni), 3.63 (211, nr), 4.0 4.43 (4H, ni), 4.70 (1H, ni), 5.07 (1H, d, J = 5Hz) )

5.73 (III, dd, J-5 and 8Hz). 6.80 (111, m), 8.07 (2H, ni), 9.89 (1H, d, J = 81).

(6) 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1,2,4-thiadiazol-5-yl) -thiomelyl- 3-cefcine-4-carboxylic acid (color isomer), m.p. 175-178 ° C (decomp. In IR): 3300, 3200, 1775, Jo80, 1620, 1525 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 1.50 2.00 (8H, m),

3.67 (2H, bs), 4.34 and 4.60 (2H, ABq. J = 14Hz), 4.67-4.83 (1H, m), 5.17 (III, d, J = 4Hz), 5.82 (1H, dd, J = 4 and 8Hz), 8.12 (2H, s), 8.73 (111, s), 9.50 (1H, d, J = 8Hz).

(7) 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (3-fluoro-pyrrolopropyr) -1H-te] Trazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 183-188 ° C (with decomposition).

IR (Nujol): 3300, 3150, 1770, 1670, 1160, 1530 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, _δ ): 1.50-1.90 (8H, m), 2.00-2.27 (2H, m), 2.50-2.83 (6H, m) , 3.50-3.83 (6H, m), 4.23-4.53 (4H, m), 4.70-4.86 (1H, m), 5.13 (1H, d, J = 4Hz), 5.80 (1H, dd, J = 4 and 8Hz), 8.13 (2H, s), 9.50 (1H, d, (= 8Hz)).

(8) 7- [2- (2-Cyclopenten-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamide] -3- (1,3,4-thiadiazole); 2-yl) thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p.

155-160 ° C, yield 1.4 g (dec.).

IR spectrum (nujol): 3300, 3200, 1770, 1670, imn isin-m ^-1 .

(9) 7- [2- (2-cyclopenten-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] 3- (1-methyl-1H-thiazol-5-yl) ) -thiomethyl-3-cfem-4-carboxylic acid (color isomer), m.p.

155-160 ° C (with decomposition).

IR (Nujol): 3300, 1770, 1670, 1620, 1520 ^cm-1 wavenumber.

(10) 7- [2- (2-Cyclopenten-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamide] -3- [1- (2-carboxyethyl) - 1H-Tetrazol-5-yl] -thiomethyl-3-cfem-4-carboxylic acid (color isomer), m.p. 155-16 ° C (with decomposition).

IR spectra (nujol): 3300, 3200. 1770, 1720.

1970, 1620, 1520 cin ' ¹ wave number.

(II) 7- [2- (2-Cyclopenten-1-yl) oxyimino-2- (5-amino-1,2,4-thiaiazol-3-yl) acetamido] -3-11- (2-carboxylyl) -1 H-tetrazole; 5-yl] -thiomethyl-3-cis-c-4-carboxylic acid (color isomer), m.p. 150-155 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1720.

1670, 1620, 1520 cnf ¹ bull at number 0.

(12) 7- [2- (2-Cyclopenten-1-yl) -oxynino-2- (5-allyl)

1.2.4-Thiaziazol-3-yl) -acetamido] -3- (1-allyl-111-tetrazot5-yl) -thioethyl-3-cephrel-4-carboxylic acid (color isomer), m.p. 160-165 ° C. C (during decomposition).

IR (nujol): 3300, 1770, 1670. 1620.

1520 cm at wave number ¹ .

(13) 7- [2- (2-Cyclopenten-1-yl) -oxyquinoino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-tetrazolo [1,5-b] pyridazin-6-yl) -thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

mp 170-175 ° C (with decomposition).

IR (Nujol): 3400, 3300, 3190, 1770, 1670, 1615, 1520 ^cm-1 wavenumber.

(14) 7- [2- (2-cyclopentn-1-yl) oxyimino-2- (5-antino-1,2,4-thiadiazol-3-yl) -acetamide] 3 - [ 1- {2- (N-tert-butoxycarbonylamino) -ethyl} -1H-tetrazol-5-yl] -thiomethyl-3-cis-cm-4-carboxylic acid (color isomer), m.p. 95-100 ° C (dec.) ).

IR (Nujol): 3300, 3190, 1770, 1680, 0 1620, 1520 ^cm-1 hullámszátnnál.

(15) 7- [2- (2-Cyclopenten-1-yl) -oxyquinoino-2- (5-anrino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (2-aminoethyl) -1H-tetrazole -5-yl] -thioethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 175-180 ° C.

IR (Nujol): 3400, 3300, 3170, 1760, 1665, 1610, 1520 ^cm-1 wavenumber.

(16) 7- [2- (2-Cyclohexen-1-yl) -oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetanrido] -3- (1,3,4-thiadiazole- 2-yl) thiomycti-3-cephem-4-carboxylic acid (color isomer), m.p. 150-155 ° C (with decomposition).

IR (nujol): 3300, 3180, 1770, 1660, 1620, 1520 cm ^-1 .

(17) 7- [2- (2-Cyclohexen-1-yl) -oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (tetrazolo [1,5-b] pyridazin-6-yl) thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 170-175 ° C (with decomposition).

IR (Nujol): 3400, 3300, 3180, 1670, 5q 1620, 1520 ^cm-1 hullámszámnát.

(18) 7- [2- (2-Cyclohexac-1-yl) -oxyimino-2- (5-amino-1,2,4-iadiazol-3-yl) -acetamido] -3- (1-methyl-1) M.p. 170-173 ° C (with decomposition). H-tertrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (color isomer).

IR (Nujol): 3350, 3250, 1780, 1680, 1620, 1520 ^ETN-1 wavenumber. tert -is- (γ-cyano-hexen-1-yl) -oxyimino-2- (5-aminol).

1.2.4-Thiadiazol-3-yl) -acetamido] -3- (1-carboxymethyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 175 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1720, 1650, 1620, 1520 ^cm-1 wavenumber.

(20) 7- [2- (2-Cyclohexen-1-yl) -oxyimino-2- (5-amino-1,2,4-thiazol-3-yl) -acetamido] -3- {1- ( 2-Carboxyethyl) -1H-30183 006Ta trazol-5-yl} -thiomethyl-3-cephen-4-carboxylic acid (silyl isomer), m.p. 165-170 ° C.

IR (Nujol): 3300, 3200, 1770, 1720, 1670, 1620, 1520 cm @ -1.

(21) 7- [2- (2-Cycloxyxen-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-allyl-1H-tetrazole) -5yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 160-165 ° C (dec.).

IR (Nujol): 3300, 3200, 1780, 1680 1620, 1520 ^cm-1 wave number (22) 7- [2- (2-cyclohexen-l-yl) oxyimino-2- (5-thiadiazol amino1.2.4- -3-yl) -acetamido] -3- [1- {3- (N-tert-butoxycarbonylamino) -propyl} -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 100-105 ° C (with decomposition).

IR (Nujol): 3300, 3170, 1770, 1670, 1620, 1520 ^cm-1 wavenumber.

(23) 7- [2- (2-Cyclohexen-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [1- (3-aminopropyl) -1 H-tetrazole -5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 185-190 ° C (with decomposition).

IR (nujol): 3280, 3150, 1760, 1665, 1620, 1520 cm ^-1 .

(24) 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1,3,4-thiadiazol-2-yl) - thiomethyl 3-cephem-4-carboxylic acid (color isomer), m.p. 140-145 ° C (with decomposition).

IR (Nujol): 3400, 3300, 3200, 1770, 1670, 1620, 1525 ^cm-1 wavenumber.

(25) 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl -3-cephem-4-carboxylic acid (syn isomer), 145-150%; gg (during decomposition).

IR (Nujol): 3400, 3290, 3180, 1770, 1670, 1620, 1520 cm ^-1 .

(26) 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thia- ₄ g of diazol-3-yl) -acetamido] -3- (1-carboxymethyl-1H-tetrazol-5-yl) ) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 155-160 ° C (with decomposition).

IR (Nujol): 340, 3290, 3180, 1765,

1720, 1670, 1620, 1520 cm at ¹ ₄₅ .

(27) 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-allyl-1H-tetrazol-5-yl) - thiomethyl-3-cephem-4-carboxylic acid (color isomer), mp 135-140 ° C (with decomposition). . 50

IR (nujol) 3400, 3300, 3190, 1770, 1670, 1620, 1520 cm @ -1.

(28) 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (tetrazolo [1,5-b] pyridazin-6-yl) _55- thiomethyl-3-cephem-4-carboxylic acid (syn isomer), m.p. 160-165 ° C (with decomposition).

IR spectrum (nujol): 3570, 3440, 3320, 3180, 1775, 1710, 1660, 1620, 1580, 1540, 1520 cm ^-1 , θθ (29) 7- (2-cyclopentyloxymethyl-2- (5-amino) -1,2,4-thiadiazol-3-yl) -acetaldido] -3-11- (3-aminopropyl) -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), white powder, m.p. 195-199 ° C (with decomposition).

IR (Nujol) 3300, 3150, 1760, 1660,

1620, 1520, 1280.1 ISO at 1000 cm @ ¹ .

(30) 7- [2-Cyclopentyloxyl-amino-2- (5-amino-1,2,4-badiazol-3-yl) -acetamido] -3- [1- (2-methoxy-carbonyl) -1,115-tetrazol-5-yl. ] -thiomethyl-3-cephem-4-carboxylic acid (colorless), m.p. 125-13 ° C (with decomposition).

IR (Nujol): 3480, 3370, 3250, 1780, 1740, 1685, 1625, 1530 cin ^- 'wavenumber.

(31) 7- (2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (4-methyl-5-oxo-6-hydroxy-4,5-dihydro) -1,2,4-Triazin-3-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), yellow powder, m.p. 195-199 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 17101670, 1590, 1520, 1240, 1170, 1090, 1000 ^cm-1 wavenumber. Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 1.3-2.1 (8H, m), 3.32 (3H, s), 3.66 (2H, m), 4.11 (2H, m) ), 4.76 (1H, m), 5.16 (1H, d, J = 5Hz). 5.83 (111, dd, J = 5 and 8Hz), 8.13 (2H, broad s), 9.50 (1H, d, J = 8Hz), 12.50 (1H, broad s).

(32) 7- (2-Cycloheptyloxyimino-2- (5-atnino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1,3,4 -1-adiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), white powder, m.p. 150-154 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1670, 1620, 1520, 1400, 1240, 1160, 1060, 1000 ^cm-1 wavenumber.

(33) 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (3-piperidinopropyl) -1H-tetrazol-5-yl]. -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 230 DEG C. (with decomposition).

IR (nujol): 3300, 3200, 1770, 1670, 1600, 1520 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 1.3-2.0 (6H, m), 2.10-2.3 (2H, m), 2.73-3.10 (6H, m) , 3.57 (2H, bs), 4.10-4.50 (4H, m), 4.60-4.80 (1H, m), 5.00 (1H, d, J = 4Hz) , 5.67 (1H, dd, J = 4 and 8Hz), 9.06 (2H, s), 9.37 (1H, d, J = 8Hz).

Example 19

4.4 g 7-N- [3- (3-Trifluoromethyl-phenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid 4-nitrobenzyl ester (color isomer ) In a solution of 80 ml of tetrahydrofuran in 50 ml of water and 4.4 ml of acetic acid

Hydrogenation (2.2 g, 10% palladium on carbon) at ambient temperature for 3 hours at room temperature. The catalyst is then filtered off and washed with tetrahydrofuran. The filtrate and washings were combined and evaporated. To the residue was added ethyl acetate followed by aqueous sodium bicarbonate solution to bring the pH to 8. The aqueous phase was separated, adjusted to pH 1-2 and extracted with ethyl acetate. The extract was washed successively with water and brine, treated with activated charcoal, dried over magnesium sulfate and evaporated. The residue was washed with diethyl ether to give 1.0 g of a yellow powder. To this crude product was added water (10 mL) and the mixture was stirred for 30 minutes. The precipitate was filtered off, washed with water and reduced

Dried under pressure of -31183 006, 1.0 g of yellow powder of 7- [2- (3-trifluoromethyl-phenoxyimino) -2- (5-arorno-1,2,4-thiazolazol-3-yl) -acetainido] -3-cephem-4- of carbot »3vat (color isomer) having a decomposition point of 193 C.

IR spectrum (nujol): 3450. 3320, 3200, 1770, 1710, 665, 1630, 1560, 1515,

1325, 1170.3110, 940 cin at wave number ¹ .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.63 (2H, in) 5.21 (H 1, d, J = 5 µz), 5.94 (10U, Ud, J = 5 and 8 Hz), 6.48 ( H, m), 7.53 (411, broad s), 8.27 (2H, broad s), 9.87 (1H, d, J = 8Hz).

Example 20

4.5 g of 7- [2-phenoxy] imino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cephem-4-carboxylic acid 4-nylrobenzyl ester (color isomer) in 45 ml A solution of lithium hydrogen chloride in water (20 mL) was hydrogenated at room temperature under atmospheric pressure for 2.5 hours in the presence of 2.5 g of 10% palladium on carbon. The catalyst is then filtered off and the filtrate is evaporated. Ethyl acetate is added to the residue and the mixture is adjusted to pH 8 with aqueous sodium bicarbonate. The aqueous layer was separated and ethyl acetate was added and the pH of the mixture was adjusted to 3 with hydrochloric acid. The resulting mixture was extracted with ethyl acetate and the extract was washed with water, dried over magnesium sulfate and then concentrated by evaporation to give 1.4 g of 7- [2-phenoxy-imino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamide]. ] -3-cephem-4-carboxylic acid (color isomer), m.p. 168-170 ° C (with decomposition).

Spcktrum IR (Nujol): 3400, 3200, 1780, 1660, 1620, 1600, 1590, 1540 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.58 (211, broad s),

5.15 (111, dJ = 4Hz), 5.90 (111, dd, J = 4 and 8Hz), 6.47 (1H, t, J = 3llz), 6.97 -7.60 (511, m ), 8.27 (211, s), 9.92 (1H, 4J = 8Hz).

Example 27

By the methods described in Examples 19 and 20, the following compounds were prepared:

(1) 7- [2- (3- (N-tert-Butoxycarbonylamino) -propoxtimino) -2- (5-amino-1,2,4-thiadtazol-3-yl) -acetamido] -3-chloro-3-cephem -4-carboxylic acid (syn isomer).

IR (Nujol): 3300-3100, 1780, 16901660, 1520, 1270 ^cm-1 wavenumber.

(2) 7- [2- (4-chlorophenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cephem-4-carboxylic acid (color isomer), 145-150 ° C (with decomposition).

•] R (Nujol): 3400, 3260, 3180, 1775, 1675, 1625, 1600.1520, 1480 ^cm-1 wavenumber.

NMR (d _é -DMSO, δ): 3.63 (211, br);

5.20 (1H, d, J = 510 :), 5.93 (111, dd, J-5 and 8Hz), 6.52 (1H, t, J = 4Hz), 7.33 (211, d, J = 91 | z), 7.47 (211, d, J = 9Hz), 8.32 (211, broad s), 9.90 (111, d, 1 = 811).

(3) 7- [2- (4-Fluorophenoxyquinoino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamethyl] -3-cephem-4-carboxylic acid (color isomer), 130-135 ° C (with decomposition).

IR spectra (nujol): 3400, 3270, .31. 1765,

1675, 1605, 1500 cin at wave number ¹ .

Nuclear Magnetic Resonance Spectrum (d ₆ -MSMSO, δ): 3.63 (211, broad s) 5.22 (111, d, J = 51). 5.97 (HI, dd J = 5 and 8 µz). 6.53 (IU.1.1, j = 4Hz) 7.25 (211, s), 7.37 (211, s), 8.30 (211 broad s), 9.90 (111, d, J = 8Hz) ).

(4) 7-1,2-Allyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color isomer), m.p. 160-165 ° C (with decomposition).

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.53 (2H, d, J = 4Hz),

4.60-4.77 (2H, m), 5.07 (1H, d, J = 4Hz), 5.0-5.50 (2H, m), 5.83 (1H, dd, J = 4 and 8Hz), 5.70-6.23 (1H, m), 6.45 (1H, t, 3-4Hz), 8.13 (2H, s), 9.57 (1H, d, J = 8Hz). ).

(5) 7- (2- (2-cyclopenten-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1,3,4-thiadiazole); 2-yl) thiomethyl-3-cephem-4-carboxylic acid (color isomer), mp 155-160 ° C.

Spcktrum IR (Nujol): 3300, 3200, 1770, 1670, 1620, 1520 ^cm-1 wave number, (6) 7- [2- (2-cyclopenten-1-yl) oxyimino-2- (5-amino1.2.4 - thiadiazol-3-yl) -acetamide <1> -3-cephem-4-carboxylic acid (color isomer), m.p. 180-185 [deg.] C. (dec.).

IR (Nujol): 3500, 3430, 3300, 3200 1770, 1690, 1660, 1640, 1620 1580, 1510 ^cm-1 wave number (7) 7- [2- (2-cyclopenta-l-yl) oxyimino-2 - (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color isomer), m.p. 154-159 ° C (with decomposition).

IR (Nujol): 3300, 1770, 1720, 1670 1620, 1520 cm ^{-1 at} (8) 7- {2- (2-cyclopenten-1-yl) oxyimino-2- (5-amino-1,2,4- thiadiazol-3-yl) -acetamido] -3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 155-160 ° C (dec.).

IR (Nujol): 3300, 1770, 1670, 1620 at 1520 cm ^-1 .

(9) 7- (2- (2-cyclopenten-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-carboxymethyl-1H-tetrazol-5-yl) ) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 155-160 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1720, 1670, 1620, 1520 ^cm-1 wavenumber.

(10) 7- [2- (2-Cyclopentenyl-11) -oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (2-carboxyethyl) -111-tetrazole -5-yl] -thiomethyl-3-cephein-4-carboxylic acid (color isomer), m.p. 150-155 ° C (with decomposition).

IR (nujol): 3300, 3200, 1770, 1720, 1670, 1620, 1520 cm ^-1 .

(11) 7-] 2- (2-cyclopenten-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetam} do] -3- (1-allyl-1) H-tetrazol-5-yl) -thiomethyl-3-cephem-4-cialic acid (color isomer), m.p. 160-165 ° C (with decomposition).

IR (Nujol): 3300, 1770, 1670, 1620, 1520 cm ^-1 .

(12) 7- [2- (2-Cyclopenten-1-yl) oxyimino-2- (5-anilineO '

1.2.4-Thiadiazol-3-yl) -acetamido] -3- (tetrazolo [1,5-b] pentazin-6-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. . 170-175 ° C (with decomposition).

IR spectrum (nujol): 3400,? 100,? 19, 1770.

-321

183,006

1670, 1615, 1520 cm ^-1 .

(13) 7- [2- (2-Cyclopenten-1-yl) -oxyquinoino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (2- (N- tert-butoxycarbonylamino) ethyl} -1H-tetrazol-5-yl] thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 95-100 ° C (with decomposition).

IR (Nujol): 3300, 3190, 1770, 1680, 1620, 1520 cm ^-1 .

(14) 7- {2- (2-Cyclopenten-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamide] -3- [1- (2-aminoethyl) -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 175-180 ° C (with decomposition).

) IR (Nujol): 3400, 3300, 3170, 1760, 1665, 1610, 1520 ^cm-1 wavenumber.

(15) 7- [2- (2-Cyclohexen-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamide] -3- (1,3,4-thiadiazole) -2-yl) thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p.

150-155 ° C (with decomposition).

IR (nujol): 3300, 3180, 1770, 1660, 1620, 1520 cm ^-1 .

(16) 7- [2- (2-Cyclohexcn-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer) 175-180 ° C (with decomposition).

IR (nujol): 3300, 3200, 1770, 1670, 1630, 1520 cm ^-1 .

(17) 7- [2- (2-Cyclohexen-1-yl) -oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamide] -3- (tetrazolo [1,5-b] pyridazin-6-yl) thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 170-175 ° C.

IR spectrum (nujol): 3400, 3300, 3180, 1670, 1620, 1520 cm ^-1 .

(18) 7- [2- (2-Cyclohexen-1-yl) -oximino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color isomer), m.p. 160-165 ° C (with decomposition).

IR (nujol): 3300, 3200, 1775, 1720, 1670, 1620, 1520 cm ^-1 .

(19) 7- [2- (2-Cyclohexen-1-yl) -oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-methyl-1H-tetrazole) 5-yl) thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 170-173 ° C (with decomposition).

IR (Nujol): 3350, 3250, 1780, 1680, 1620, 1520 cm ^-1 .

(2 H) 7- (2- (2-Cyclohexen-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-carboxymethyl-1 H -tetrazol-5-one) yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 170-175 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1720, 1650, 1620, 1520 ^cm-1 wavenumber.

(21) 7- [2- (2-Cyclolexen-1-yl) -oximino] -2- (5-amino-1,2,4-thiadia) -ol-3-yl) -acetamide] -3- [1- (2-) carboxyethyl) -1H-tetrazol-5-yl] -thiomethyl-3-phenylene-4-carboxylic acid (color isomer), m.p. 165-170 ° C.

IR (nujol): 3300, 3200, 1770, 1720, 1670, 1620, 1520 cm @ -1.

(22) 7- [2- (2-Cyclohexen-1-yl) -oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-allyl-1H-tetrazole -5yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p.

160-165 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1780, 1680, 1620, 1520 ^cm-1 wavenumber.

(23) 7- [2- (2-Cyclohexen-1-yl) -oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- {3- (N- tert-butoxycarbonylamino) propyl} _{-lH-tetrazole-5-il]} -tiomelil-3-cephem-4-carboxylic acid (syn isomer), mp .: 100-105 ° C (dec).

IR (Nujol): 3300, 3170, 1770, 1670 1620, 1520 ^cm-1 wave number (24) 7- [2- (2-cyclohexen-l-yl) oxyimino-2- (5-thiadiazol amino1.2.4- -3-yl) -acetamido] -3- [1- (3-aminopropyl) -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 185-190 ° C. (during decomposition).

IR (Nujol): 3280, 3150, 1760, 1665 1620, 1520 ^cm-1 wave number (25) 7- [2-cyclopentyloxyimino-2- (5-amino-l, 2,4-thiadiazol-3-yl) - acetamido] -3- (1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 140-145 ° C (with decomposition).

IR (Nujol): 3400, 3300, 3200, 1770, 1670, 1620, 1525 ^cm-1 wavenumber.

(26) 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color isomer), m.p. -175 ° C.

IR (Nujol): 3520, 3420, 3320, 3220, 3160, 1770, 1685, 1655, 1635, 1625, 1570, 1505 ^cm-1 wavenumber.

(27) 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color isomer), m.p. 140 -145 ° C (with decomposition).

IR (Nujol): 3480, 3370, 3250, 1785, 1730, 1680, 1630, 1530 ^cm-1 wavenumber.

(28) 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido} -3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p.

145-150 ° C (with decomposition).

IR spectrum. (Nujol); 3400, 3290, 3180, 1770, 1670, 1620, 1520 cm- ¹ .

(29) 7- {2-cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-carboxymethyl-1H-tetrazol-5-yl) -thiomethyl -3-cephem-4-carboxylic acid (color isomer), m.p. 155-160 ° C (with decomposition).

IR (Nujol): 3400, 3290, 3180, 1765, 1720, 1670, 1620, 1520 cm-1.

(30) 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 135-140 ° C (with decomposition).

IR (Nujol): 3400, 3300, 3190, 1770, 1670, 1620, 1520 ^cm-1 wavenumber.

(31) 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (tetrazolo [1,5-b] pyridazin-6-yl). thiomethyl-3-cfem-4-carboxylic acid (syn isomer), m.p. 160-165 ° C (with decomposition).

IR (Nujol): 3570, 3440, 3320, 3180, 1775, 1710, 1660, 1620, 1580, 1540, 1520 ^cm-1 wavenumber.

(32) 7- [2-Cyclopentyloxy] -mino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- {3- (N-tert-butoxycarbonylamino) -propyl } -1,11-tetrazole-541] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), light brown powder.

-33183 006

IR spectrum (nujol). 3300, 1770, 1670, 1520,

I 240, 1160, 1000 cm '.

(33) 7-12-Cyclopentyloxyquinoino-2- (5-amino-1,2,4-thialazol-3-yl) -acetamidol -3-11 (3-aminopropyl) -111-triazol-5-yl]. 4omelyl-3-cis-cinic-4-carboxylic acid (color isomer), white powder, m.p. 195-199 ° C (with decomposition).

IR (Nujol): 3300, 3150, 1760, 1660, 1620, 1520, 1280, 1180.1000 ^cm-1 wavenumber.

(34) 7- [2-Cyclopentyloxyquinoino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [N- (2-methoxycarbonyl-ethyl) -1H-tetrazol-5-yl] lioinctil-3-α-cm-4-carboxylic acid (color isomer), m.p. 125-130 ° C (with decomposition).

IR (Nujol): 3480, 3370, 3250, 1780, 1740, 1685, 1625, 1530 ^cm-1 wavenumber.

(35) 7- [2-Cyclopentyloxy] imo-2- (5-anrin-1,2,4-thiadiazol-3-yl) -acelamido] -3- (4-methyl- (5-oxo-6-hydroxy-4), 5-Dihydro-1,2,4-triazin-3-yl) -thionyl-3-cphenr-4-carboxylic acid (color isomer), yellow powder, m.p. 195-199 ° C (with decomposition).

IRspcktrum (nujol): 3300, 3200, 1770, 17101670, 1590, 1520, 1240, 1170, 1090, 1000, 720 cm ^-1 .

(36) N- [7- {2-Cyclopentyloxyimino-2- (5-amino-1,2,4-diazol-3-yl) -acetamido} -3-cephein-3-ylmethyl] -4'-carbamoylpyridinyl-4- carboxylate (syn isomer), m.p.

230-235 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1680, 1610, 1560, 1520, 1510 ^cm-1 wavenumber.

(37) 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1,2,4-thiadiazol-5-yl) -thiomethyl -3-cephem-4-carboxylic acid (color isomer), m.p. 175-180 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1775, 1680, 1620, 1525 ^cm-1 wavenumber.

(38) 7- [2- (Pentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [1- (3-morpholinopropyl) -1H-tetrazole -5-yl] -thioethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 83-188 ° C (with decomposition).

IR (Nujol): 3300, 3150, 1770, 1670, 1610, 1530 ^cm-1 wavenumber.

(39) 7-1,2-Cycloheptyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1,3,4-thiadiazol-2-yl) -thiomethyl- 3cefem-4-carboxylic acid (color isomer), white powder, m.p. 150-154 ° C (with decomposition).

IR (Nujol) 3300, 3200, 1770, 1670, 1620, 1520, 1400, 1240, 1160, 1060, 1000 cm ^-1 .

(40) 7- (2-Cycloheptyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color isomer), white powder, m.p. : (70-175 ° C (with decomposition).

IR (Nujol): 3400, 3300, 3200, 1770, 1670, 1620, 1520, 1280, 1240, 1160, 1000, 980, 730 ^cm-1 wavenumber.

(41) 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (3-piperidinopropyl) -1H-tetrazole-5 -yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 230 DEG C. (with decomposition).

IR (nujol): 3300, 3200, 1770, 1670, 1600, 1520 cm ^-1 .

22. pclda

1.4 g 7- [2-Phenoxyquinoino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [1- {2- (N-tert-butoxycarbonylanino) ethyl) -11- A solution of tlrazol-5-yl] -thionictyl-3-cefcin-4-carboxylic acid (color isomer) in formic acid (14 ml) was stirred at room temperature for 3 hours and then evaporated to dryness. The residue was dissolved in a mixture of ethyl acetate and aqueous sodium bicarbonate, and the pI was adjusted to 2 with 10% hydrochloric acid. The aqueous phase was separated, washed with ethyl acetate and the ethyl acetate was evaporated. The aqueous solution was subjected to column chromatography, Diaion. IIP-20 resin (manufactured by Mitsubishi Chemical Industries Ltd.). After washing the column with water, the reaction mixture was treated with 50% aqueous methanol. The eluent was then evaporated to remove the methanol by evaporation under reduced pressure and the residual aqueous solution lyophilized to give 0.3 g of 7 - [- phenoxylino-2- (5-amino-1,2,4-liadiazol-3-yl) -acetamido]. 3- (1- (2-aminoethyl) -1H-tetrazol-5-yl) thio methyl 3-cephem-4-carboxylic acid (color isomer) is obtained, m.p. 180-185 ° C (with decomposition).

IR (Nujol): 3300, 3250, 1760, 1670, 1620, 1590, 1520 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.40 (211, broad s),

3.60 (2H, broad s), 4.23 (211, broad s), 4.60 (2H, broad s), 5.13 (111, d. J = 4Hz), 5.83 (111, dd) , J = 4 and 811 /) 7.0-7.5 (511, ni), 8.33 (211, s),% 90 (III, d, J = 8Hz).

23. pclda

4.0 g of 7- [2- {3- (N-tert-butoxycarbonylamino) -propoximino} -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-yl {2 - A solution of (N-tert-butoxycarbonylamino) -ctyl} -yl-tetrazol-5-yl] thiomethyl 3-cefcm-4-carboxylic acid (color isomer) in 40 ml of acetic acid was stirred for 2.5 hours at room temperature. The reaction mixture was concentrated and dried under reduced pressure to give an oil. To the oil was added 40 mL of water and 5 mL of IN hydrochloric acid to form a clear solution. The solution was subjected to column chromatography using Diaion HP-20 resin (manufactured by Mitsubishi Chemical Industries Ltd.) followed by elution with water followed by 5% aqueous methanol.

7- (2- (3aminopropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido} -3- {1- (2-aminoethyl) -1H-tetrazol-5-yl} of thiomethyl-3α-fem-4-carboxylic acid (color isomer), m.p. 184-196 ° C (with decomposition).

IR spectrum (nujol): 3400-3100, 1760, 1660, 1610, 1520, 1170, 1060, 1010 cm @ ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO + D ₂ O, δ): 1.9 (211, m),

2.8 (2H, m), 3.3 (2H, m), 3.5 (2H, m), 4.1 (4H, m), 4.5 (2H, m), 4.90 (1H , d, J = 5Hz), 5.56 (111, d, J = 5Hz).

Example 24

1.9 g 7- [2- {2- (N-tert-butoxycarbonylamino) thiovimino} -2- (5-amino-1,2,4-thiadiazol-3-yl] -acetamido] -3- (icarboxymethyl-1H-tetrazole) -5-yl) -thionichl-3-cephem 4-protic acid (color isomer) was mixed with 28 ml of formic acid and stirred for 2 hours at room temperature.

-34Λί

183 00 (.

7-] 2- (2-Methoxyethoxymino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-carboxymethyl-1 H -tetrazol-5-yl) - of thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 190-198 ° C (with decomposition).

IR (Nujol): 3250, 3160, 1760, 1650, 1615, 1522, 1020 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (DCI, δ): 3.11 (2H, bs), 3.28 3.65 (2H, m), 4.35 (211, bs), 4.48-4.78 (2H) , m), 5.25 (1H, d, J = 4.5Hz), 5.42 (2H, s), 5.88 (1H, d, J = 4.5Hz).

Example 25

3.5 g 7- [2- (2-Cyclopenten-1-yl) -oxyrimino-2- (5-amino-1,2,4-thiazol-3-yl) -acetamido] -3- [1- { A mixture of 2- (N-tert-butoxycarbonylaminoctyl) -1H-tetrazol-5-yl] thiomethyl-3-cephem-4-carboxylic acid (s.isomer) and 35 mL of formic acid was stirred at room temperature for 2 hours. The reaction mixture was evaporated and the residue was washed successively with diethyl ether and acetone. The washed residue (2.65 g) was added to 60 ml of aqueous sodium hydrogen b.unonate solution. The mixture was stirred and the insoluble material was filtered off. Ethyl acetate was added to the filtrate, and the mixture was adjusted to 3 with 3% salt v / v and then the aqueous phase was separated. At the same time, water and ethyl acetate are added to the obtained and filtered material. The pH of the mixture was adjusted to 3 with 10% hydrochloric acid and the aqueous phase was separated. The separated aqueous phases were combined, adjusted to pH 2 with 10% hydrochloric acid, washed with ethyl acetate and evaporated to remove the ethyl acetate. The residue was subjected to column chromatography (nonionic absorption resin, Diaion IIP-20, manufactured by Mitsubishi Chemical Industries), eluted with water, then eluted with 30%, 50% and 100% methanol. Fractions containing the target compound were combined, evaporated, and after lyophilization, 580 mg of 7- [2- (2-cyclopenten-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] - 3- (1- (2-aminoethyl) -1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer) is obtained, m.p. 175-180 ° C (with decomposition).

IR (Nujol): 3400, 3300, 3170, 1760, 1665, 1610, 1520 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 1.87-2.52 (4H, m), 3.27-3.73 (4H, m), 4.13-4.37 (2H, m) , 4.57-4.80 (2H, m), 5.03 (1H, d, J = 5Hz), 5.27-5.53 (1H, m), 5.70 (1H, d, J = 5Hz), 5.85-6.27 (2H, m).

Example 26

22-25. The following compounds were prepared by the methods described in Examples 1 to 5:

(1) 7- {2- (2-Aminoethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -2-methyl-3-cephem-4-carboxylic acid (color isomer 190-195 ° C (with decomposition).

JR (Nujol): 3300, 3150, 1760, 1660, 1575, 1520, 1400 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (D ₂ O + DC 1, δ): 1.55 (3H, d, J = 7Hz),

3.5 (2H, t, J = 4.6Hz), 3.7-4.2 (1H, m), 4.67 (2H, t, J = 4.6Hz), 5.27 (1H, d, J = 4.5Hz), 6.03 (1H, d, J = 4.5Hz), 6.90 (1H, d, J = 6Hz).

(2) 7- [2- (3-aminopropoxyimino) -2- (5-amino-1,2,4'iadiazol-3-yl) -acetamido-2-methyl-3-c-cin-4-yloxanoic acid (color) isomer), m.p. 182-187 (with decomposition).

IR spectrum (nujol): 3260, 3150, 1758, 1660, δ 1616, 1575, 1520, 1400 cin ^-1 .

Nuclear Magnetic Resonance Spectrum (DCl + U ₂ O, δ): 1.55 (311, d,

J = 6.5Hz), 1.93 -2.50 (211, in), 3.25 (2H, t, J = 7Hz), 3.70-4.15 (III, int.

4.5 (211, t, J = 6Hz), 5.23 (III, d,

J = 4.5Hz), 6.05 (1H, d, J = 4.5ltz),

6.88 (1H, d, J = 611z).

(3) 7- [2- (3-Aminopropoxyimino) -2- (5-amino-1,2,4-iiadiazol-3-yl) acetamido] -3-methyl-3-cephem-4-carboxylic acid (colorless) 175-195 ° C (with decomposition).

IR (Nujol): 3300-3100, 1770, 1740,

1660, 1620, 1570, 1520, 1280, 1170, 1060, 1020 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ DMSO + ϋ ₂ Ο, δ): 1.87 (3H, s), 1.9 (2H, m), 2.9 (2H, m), 3.2 (2H, m) , 4.2 (2H, m), 4.93 (1H, d, J = 5Hz),

5.60 (1H, d, J = 5Hz).

(4) 7- [2- (3-Aminopropoxyimino) -2- (5-amino-1,2,425-thiadiazol-3-yl) -acetamido] -3-chloro-3-cephem-4-carboxylic acid (color isomer) m.p. 190-205 ° C (with decomposition).

IR (nujol): 3400-3150, 1760, 1660,

1630-1590, 1520, 1340, 1170,

1030 cm at wave number ¹ .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 2.00 (2H, m), 2.90 (2H, m), 3.33 and 3.83 (2H, ABq, J = 16Hz), 4.20 (2H, m), 5.09 (1H, d, J = 5Hz), 5.60 (1H, m), 8.15 (2H, m), 9.50 (1H, m).

(5) 7- [2- (2-Aminoethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [1- (2-aminoethyl) -1 H -tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 182-187 ° C (with decomposition).

IR (Nujol): 3350, 3150, 1760, 1660,

1625, 1565, 1520 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.2-3.9 (611, m), 4.05-4.32 (2H, ABq, J = 14Hz),

4.4-5.0 (4H, m), 5.22 (UH, d,

J = 4.5Hz).

(6) 7- (2- (2,2,2-trifluoroethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [1- (2-aminoethyl) - 1H-Tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 185-190 ° C (with decomposition).

5θ IR (nujol): 3300, 3170, 1760, 1670,

1615, 1500 cm ^{- at the} wave number,

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.17-3.83 (4H, m) 4.28 (2H, bs), 4.47-4.93 (4H, m), 5.10 (1H, d, J = 5Hz), 5.73 (1H, dd, J = 5 and 8Hz), 8.20 (211, broad s),

9.65 (1H, d, J = 8Hz).

(7) 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1- (3-aminopropyl) -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), white powder, m.p. 195-199 ° C (with decomposition).

IR (Nujol): 3300, 3150, 17ü0, 1660, 1620, 1520, 1280,1180,1000 ^cm-1 luillámszámnál.

NMR (d _e -DMSO, δ): 1.70 (8H, m), 2.20 55 (2H, m), 2.87 (2H, m), 3.57 (2H, m);

-35183 006

4.03 4.60 (411, in), 4.70 (III, ni), 5.00 (1II, d. 1-511 /), 5.63 (III, dd, J = 5cs, 8Hz) , 8.10 (211m), 9.40 (1H, d, J = 8Hz).

(8) 7- [2- (2-Cyclohexen-1-yl) -oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (3-aninopropyl) 1H-Tetrazol-5-yl] -methyl-3 eephem-4-carboxylic acid (color isomer), m.p. 185-190 ° C (with decomposition).

IR (Nujol): 3280, 3150, 1760, 1665, 1620, 1520 ^cm-1 hulláinszámnál.

Nuclear Magnetic Resonance Spectrum (d ₆ -I) MSO, δ: 1.47-2.30 (811, m),

2.73 3.13 (211, in), 3.63 (2H, bs), 4.17 4.60 (411, ni), 4.60 4.90 (HI, m), 5.03 (111, d, J = 5Hz),

5.73 (111, dd, J-5 and 8Hz), 5.75 5.99 (211, in), 8.13 (211, broad s), 9.43 (III, d, .1 = 811).

Example 27

1.6 g of 7- [2-tert-butoxycarbonylmethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) n-acetamidyl 3- (1,3,4-thiadiazol-2-yl) thioethyl- A mixture of 3-cefcm-4-carboxylic acid (color isomer), 10 ml of trifluoroacetic acid and 2 ml of anisole was stirred for 30 minutes at room temperature. The reaction mixture was evaporated and the residue was dotted with diethyl ether, filtered off and dried. The resulting product, weighed 1.6 g in aqueous sodium bicarbonate solution, was washed with ethyl acetate and added to ethyl acetate. The mixture was adjusted to pH 2 with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. The residue was triturated with diethyl ether, filtered off, and dried to give 0.52 g of 7- [2-carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1,3). (4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 170-175 ° C (with decomposition).

IR (Nujol): 3250, 3150, 1770, 1710, 1680, 1610, 1520 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.67 (2H, bs), 4.55 (211, ABq, J = 13Hz), 4.63 (211, s), 5.12 (1H, d, J = 4Hz, 5.80 (1H, dd, J = 4 and 8Hz), 8.15 (2H, s), 9.55 (1H, d, J = 8Hz), 9.58 (1H, s).

Example 28

Following the procedure described in Example 27, the following compounds were prepared:

(1) 7- [2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazzd-3-yl) -acetamido] -3- (1-allyl-1H-tetrazol-5-yl) -thiomethyl3 α-fem-4-carboxylic acid (syn isomer), m.p. 145-150 ° C (with decomposition).

Spcktrum IR (Nujol): 3400, 3300, 3200, 1765, 1720, 1680, 1620, 1520 ^cm-1 hulláinszámnál.

Nuclear Magnetic Resonance Spectrum Im (d ₆ -DMSO, δ): 3.70 (2H, bs), 4.30 and 4.47 (2H, ABq, J = 13Hz),

4.68 (2H, s), 4.83-5.15 (2H, m),

5.15 (1H, d, J = 5Hz), 5.17-5.50 (211, m), 5.85 (1H, dd, J = 5 and 8Hz),

5.60-6.20 (1H, m), 4.13 (2H, bs), 9.53 (1H, d, J = 8Hz).

(2) 7- [2-Carboxyethoxyimino-2- (5-amino-1,2,4-thia-36-diazol-3-yl) -acetamido] -cralosporanoic acid (color isomers), m.p. 160-165 ° C (dec.) while).

IR (Nujol): 3300, 3200, 1770, 1720, 1680, 1520 ^cm-1 hulláms / ámnál.

NMR Spectrum (d ₆ -1) MSO, δ): 2.10 (311, s). 3.60 (2H, s / cles s), 4.70 (211, s), 4.7] and 5.03 (211 ABq, J 1 H 1 /). 5.20 (1H, d, J = 411 /). 5.88 (lH, dd, J = 4 and 8Hz), 8.18 (211, s), 9.57 ₁₀ (111, d, J = 8Hz).

(3) 7- [2-Carboxymethoxy-quinoino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (tetra -olo (1,5-b) pyrazin-6-yl) thioethyl -3-Cephene-4-carboxylic acid (color isomer), m.p. 170-175 ° C (with decomposition).

Spcktrum IR (Nujol): 3400, 3300, 3180, 1765, 1720, 1680, 1615, 152 (1 cin ^- 'wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.75 (2H, bs).

4.28 cs 4.60 (211, ABq, J = 13 Hz),

4.67 (211, s), 5.17 (111, d, J-5H /).

5.87 (III, dd, J = 5 and 811z), 7.7 / (111, d, J = 10Hz), 8.17 (211, broad s).

8.60 (111, d, J = 1011 /), 9.57 (III, d, J = 811z).

(4) 7- [2-Carboxymethoxylamino-2- (5-amino-1,2,4-yl-diazol-3-yl) -acetamido] -3- (1 (2-aminoaminoethyl) -111-te 5-yl] -thiolethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 185-190 ° C (with decomposition).

(5) IR-Spctrum (nujol): 3250.1755, 1660, 1590,

At a wave number of 1520 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.23 3.67 (411, in), 4.07 and 4.35 (211, ABq, J = 131 lz), 4.23-4.80 (411, m) ). 5.03 (III, d, J = 5llz), 5.70 (1H, dd, J = 5 and 8IIz), 8.15 (211, broad s), 11.03 (111, d, J = 8Hz) .

7- [2-Carboxymeloxinoino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetatnido] -3- (1-phenyl-11'-tetrazol-5-yl) -thiomethyl-3-cephem- 4-carboxylic acid (color isomer), m.p. 155-160 ° C (with decomposition).

IR (Nujol): 3400, 3300, 3180, 1765, 1720, 1680, 1615.1520, 1495 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.65 (211, broad s), δ 4.28 and 4.52 (2H, ABq. J = 13Hz),

4.63 (2H, s), 5.07 (1H, d, J = 5Hz),

5.80 (111, dd, J = 5 and 8Hz), 7.63 (5H, s), 8.10 (2H, broad s), 9.47 (1H, d, J-8Hz).

Example 29

4.5 g 7- [2-Trityloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (5-methyl-1,3,4-thiadiazol-2-yl) ) -thioelinyl-355 cephem-4 carboxylic acid (color isomer), 4.5 ml of concentrated hydrochloric acid and 45 ml of methanol are stirred for 7 hours at room temperature. The methanol was then removed from the reaction mixture and the pH of the residue was adjusted to 5 by addition of ethyl acetate and aqueous sodium bicarbonate solution. Ethyl acetate was added to the separated aqueous phase and the pH of the mixture was adjusted to 2 by addition of 10% hydrochloric acid. The separated ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to 10 ml. The precipitate was collected by filtration, washed with ethyl acetate and treated with diethyl ether.

After drying -36183 006, 1.4 g of 7- {2-hydroxyimino-2- (5-amino-1,2,4-thiazol-3-yl) acetamido] -3- (5-methyl-1,3,4- thiadiazol-2-yl) thiomethyl-3-cephene-4-carboxylic acid (color isomer), m.p. 153-162 ° C (dec.). IR (Nujol): 3260, 3160, 1763, 1665, 1608, 1520 ^cm-1 wavenumber. NMR (d _é -DMSO, δ): 2.67 (311, s), 3.67 (211, br s), 4.23 and 4.53 (211, ABq, J = I3Ilz), 5, 12 (1H, d, J = 4.5Hz), 5.82 (1H, dd, J = 4.5 and 8.5Hz), 7.98 (211, broad s), 9.37 (1H, d, J = 8.5Hz).

Example 30

257.3 mg 7- [2-Hydroxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (5-methyl, 3,4-thiadiazol-2) -yl) thiomethyl] -3-cephem-4-carboxylic acid (color isomer) and 42 mg of sodium bicarbonate in 10 ml of water are lyophilized. The product obtained is dissolved in 5 ml of N, N-dimethylformamide and a solution of 142.5 mg of iodomethyl pivalate in 1 ml of N, N-dimethylformamide is added with stirring and stirring is continued for a further 20 minutes. The reaction mixture was washed three times with water, dried over anhydrous magnesium sulfate and evaporated. The residue was triturated with diethyl ether to give 240 mg of 7- [2-hydroxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (5-methyl-1,3,4-thiadiazole). -2-yl) -thiomethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (color isomer), m.p. 132-135 ° C (with decomposition).

IR (Nujol): 3270, 3160, 1775, 1745, 1675, 1610, 1520, 1115 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 1.09 (9H, s), 2.70 (3H, s), 3.66 and 3.83 (2H, ABq, J = 15Hz), 4.18 and 4.58 (2H, ABq, J = 14Hz), 5.20 (1H, d, J = 4.5Hz), 5.80, 6.02 (3 ', m), 8.04 (2H, broad s), 9.47 (1H, d, J = 7.5Hz).

Example 31

Following the procedure described in Example 30, the following compounds were prepared:

(1) 7- (2- (4-Chlorophenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido} -3-cephem-4-carboxylic acid 4-nitrobenzyl ester (color) 155-160 ° C (with decomposition).

IR (Nujol): 3300, 3180, 1770, 1720, 1680, 1625, 1600, 1580, 1520, 1480 ^cm-1 wavenumber.

(2) 7- [2-Phenoxyimino-2- (5-amino-1,2,4-thiadiazole-3-U) -acetamido] -3-cephem-4-carboxylic acid 4-yltrobenzyl ester (color isomer), m.p. 140-145 ° C (with decomposition).

IR (Nujol): 3300, 1775, 1720, 1680, 1625, 1600, 1590, 1520 cm ^-1 .

(3) 7- (2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido) -3-cephem-4-carboxylic acid 4-nitrobenzyl ester (color isomer), m.p. 136-140 ° C (with decomposition).

IR spectrum (nujol): 3370, 3200, 1780, 1730,

1690, 1680, 1630, 1610, 1520,

1450, 1325, 1280, 1160, 1125,

975, 850, 740 em ¹ .

(4) 7- [2- (4-Fluorophenoxyimino) - {2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid 4-nitrobenzyl ester (color) isomer), m.p. 135-140 ° C (during boom).

IR (Nujol): 3300, 3200, 1770, 1720, 1680, 1625, 1605.1500, 1495 ^cm-1 wavenumber.

(5) 7- [2- {3- (N-tert-Butoxycarbonylamino) -propoxyimino} -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetanido] -3-chloro-3- cephem-4-carboxylic acid 4-nitrobenzyl ester (color isomer), m.p. 91-100 ° C (with decomposition).

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO + D ₂ O, δ): 1.38 (9H, s),

1.80 (211, m), 3.06 (2H, m), 3.74.3 (4H, m), 5.33 (1H, d, J = 5Hz), 5.49 (2H, s) , 5.95 (111, d, J-51Iz).

7.74 (2H, d, J = 9Hz), 8.92 (211, d, J = 9Hz).

(6) 7- [2-Alloyloxylmino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cephem-4-carboxylic acid 4-nitrobenzyl ester (color isomer), m.p. 125-130 ° C (with decomposition).

IR (Nujol): 3300, 1770, 1720, 1680, 1630, 1610, 1520 ^cm-1 wavenumber.

Example 32

A mixture of 1.37 g of 2-alphaloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid and 3.67 g of phosphorus oxychloride in 30 ml of methylene chloride is stirred for 2 hours at room temperature and then -12 to 15 minutes. Cool to <RTI ID = 0.0> C </RTI>. To the cold mixture was added 2.4 ml of dimethylformamide and the mixture was stirred at -8 to -10 ° C for 45 minutes. However, a mixture of 2.9 g of 7-amino-3- (1,3,4-thiadiazol-2-yl) thio-methyl-3-cephem-4-carboxylic acid and 8 g of trimethylsilylacetamide in 40 ml of methylene chloride was heat until a solution is formed. The solution was cooled to -25 ° C and added to the above activated mixture. The reaction mixture was stirred at -8-10 ° C for 30 minutes and then poured into cold aqueous sodium bicarbonate solution. The mixture was stirred for 30 minutes at room temperature and the aqueous phase was separated. The aqueous solution was adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated to dryness. Trituration of the residue with diethyl ether gave 2.1 g of crude 7- [2-allyloxy-imino-2- (5-amino-1,2,4-thiadiazole-3-U) -acetamido] -3- (1,3,4-thiadiazol-2). -i]) - thiomethyl-3-cephem-4-carboxylic acid (color isomer) is obtained. The crude product was dissolved in aqueous sodium hldrogén carbonate solution and 10% hydrochloric acid was added again precipitating 1.15 g of product having a melting point of 138 to 140 ^e C (dec);

IR (Nujol): 3350, 3230, 1780, 1680, 1620, 1530 cm ^-1 .

NMR (d _é -DMSO, δ): 3.63 (2H, br s), 4.27 and 4.52 (2H, ABq, J = 14Hz), 4.5-4.8 (2H, m ), 5.10 (1H, d, J = 5Hz), 5.0-5.5 (2H, m), 5.78 (1H, dd, J = 5 and 9Hz), 5.7-6.3 (1H, m), 8.09 (2H, bs), 9.48 (1H, s), 9.53 (1H, d, J = 9Hz).

Example 33

A mixture of 1.62 g of 2- (2,2,2-trifluoroethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) and 3.67 g of phosphorus oxychloride in 30 ml of methylene chloride was stirred at room temperature for 1.5 hours and then cooled to -12-15 ° C. To the cold mixture 2.4 ntl dimethyl · 37

-37183 00 (formamide was added and the mixture was stirred for 45 minutes at -8 to -10 ° C.) At the same time, 2.9 g of 7-amino-3- (1,3,4-thiadiazol-2-yl) -thiethyl-3-α-cm-4 A solution of 8-carboxylic acid and 8 g of trimethylsilyl accainide in 40 ml of methylene chloride was heated to a clear side, cooled to -25 DEG C. and added to the above activated mixture. The reaction mixture was poured into cold aqueous sodium bicarbonate solution, stirred at room temperature for 30 minutes, the aqueous phase was separated, the pH of the aqueous solution was adjusted to 2 by addition of 10% hydrochloric acid, and the extract was anhydrous. After drying over magnesium sulfate and evaporation to dryness, the residue was triturated with diethyl ether to give 2.45 g of crude 7- [2- (2,2,2-trifluoroethoxyimino) 2- (5-anino-1,2,4-liadiazole-3-). yl) -acetanido] -3- (1,3,4-thiadiazol-2-yl) -thiomelyl-3-ethene-4-carbonic acid (color) The crude product was dissolved in aqueous sodium hydrogencarbonate solution and precipitated again by the addition of 10% hydrochloric acid; 1.42 g of pure product are obtained, m.p. 153-158 ° C (with decomposition).

IR-spcktrum (nujol). 3350, 3250, 1780, 1680, 1625 cm ^-1 .

NMR (d _ft -DMSU, δ): 3.70 (211, br s), 4.33 and 4.58 (2H, AB q, J = 13llz), 4.70 cs 4.92 (2H, ABq , I = 9llz).

5.17 (111, d, J = 5Hz), 5.82 (III, dd, J = 5 and 81 flavors), 8.18 (211, broad s), 9.55 (111, s), 9, 70 (1H, d, J = 8Hz).

34 ml of a mixture of dimethylformamide and 918 mg of phosphorus oxychloride was stirred for 30 minutes at room temperature. To the mixture was added 6 ml of methylene chloride, followed by addition of 1.6 g.

2-Dichloroacetoxyimino-2- (5-formamido-1,2,4'-thiazol-3'-yl) -acetic acid (color isomer) at 20-2 ° C. The mixture was stirred at 10 C for 30 minutes to 15 ^n, and the resulting mixture was 10 - at -I5 DEG C. 2.0 g of 7-amino-3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4 carboxylic acid and 6 g of trimethylsilyl acetate in 30 ml of methylene chloride, and the mixture is stirred for 30 minutes at -5 to 15 ° C. Λ A mixture of 7-β-dichloroacetoxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thi 3-eephem-4-carboxylic acid (color isomer) is obtained, adjusted to p1 = 5 by addition of aqueous sodium bicarbonate. The aqueous phase was separated and ethyl acetate was added. The mixture was pll-fold by adding 10% hydrochloric acid

Set to 2 and insoluble material is filtered off. The filtrate was extracted with 3 X ethyl acetate. The extracts were dried over magnesium sulfate and evaporated. The residue was triturated with diethyl ether and the precipitate was collected by filtration and washed with diethyl ether to give 0.9 g of 7- (2-hydroxyquinoino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetanido]. 3- (1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer) is obtained, m.p. 155-160 ° C (with decomposition).

IR spectrum (nujol): 3200,1780,1680,1620 cm ^-1 ,

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ); 3.67 (211, wide s),

4.27 and 4.73 (211, ABq, 1 = 13Hz),

5.13 (111, d, J-411 /), 5.83 (HI, dd, J-4 and 81), 8.80 (III, s), 9.50 (1H, d, J = 811). ), 9.53 (III, s), 12.22 (1H, s)

Example 35

Following the procedures described in Examples 3234, the following compounds were prepared:

(1) 7- (2- (2-Propynyloxyimino) -2 (5-atnino-1,2,4-thiadiazol-3-yl) -acetainido) -3- (1,3,4-thiadiazol-2-one) il) thioethyl-3-cfem-4 carboxylic acid (color isomer), m.p. 140-145 ° C (at rupture).

IR (Nujol): 3330, 3250, 1780, 1680, 1620, 1530 ^cm-1 wave number,

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.47 (1H, 1.1 J -2Hz).

3.67 (211, broad s), 4.28 and 4.53 (211, ABq, 1 = 1311 /), 4.77 (211, d, J = 2Hz), 5.12 (111, d,). 1 = 511 (), 5.78 (III, dd, 1 = 5 and 8), 8.13 (2H, broad s), 9.55 (111, s), 9.67 (1H, d) .J = 8Hz).

(2) 7- [2-Benzyloxy-yno-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1,3,4-thiadiazol-2-yl) -thiomelyl-3-cefcin

4-carboxylic acid (color isomer), m.p. 130-135 ° C (with decomposition).

Spektrutn IR (Nujol): 3360, 3250, 1780, 1680, 1625, 1530 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.63 (2H, br s), 4.35 cs 4.58 (2H, ABq, J = 13 Hz),

5.13 (III, d, 1-511 /), 5.23 (211, s),

5.80 (111, dd, 15 and 8Hz), 7.38 (511, s), 8.13 (2H, broad s), 9.57 (1H, s), 9.63 (1H, d, l) = 8Hz).

(3) 7- [2- (2-Phenoxyethoxyimino) -2- (5-amino-1,2,4-thiadlazol-3-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem 4-carboxylic acid (color isomer), m.p. 163. 167 ° C (with decomposition),

IR (Nujol): 3350, 3250, 1780, 1680, 1630, 1600, 1530, 1500 cm @ ^-1 ,

NMR (d -DMS0 _ft, δ): 3.30 and 3.60 (2H, AB q, 1 = 1811 /), 4.0 4.70 (6H, m);

5.10 (III, d, J = 4IIz), 5.93 (1H, dd, J = 4 and 8Hz), 6.7-7.5 (5H, ni), 8.13 (211, s). 9.50 (111, s), 9.57 (111, d, 1 = 81).

(4) 7- [2-Methyl-thiomethoxy-imino-2- (5-amino, 2,4-thiadiazol-3-yl) -acetamido] -3- (S, N-thiadiazol-4-yl) -thiomethyl-5-cimethyl-carboxylic acid (colorless) isomer), mp .: 168 -170 ^c C (dec).

IR (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm ^"1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 2.17 (3H, s), 3.65 (2H, broad s), 4.30 and 4.57 (2H, ABo, J = 14Hz), δ, 12 (1H, d, J = 4Hz), 5.20 (211, s), 5.80 (1H, dd, J = 4 and 8Hz), 8.17 (2H, s), 9.53 (111, s);

9.62 (1H, d, J = 8Hz).

(5) 7- [2- (2-Methylthioethoxyethoxy) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetanido] -3- (1,3 _s 4-thiadiazol-2) -yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 125-130 ° C (with decomposition).

IR (Nujol): 3350, 3250, 1780, 1680, 1625, 1530 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 2.08 (311, s), 2.72

-381

183,006 (2Η, t, J = 7Hz), 3.68 (2H, broad s),

4.28 (2H, t, J = 7Hz), 4.30 and 4.55 (2H, ABq, J = 13Hz), 5.13 (1H, d, J = 5Hz), 5.82 (1H, dd) , J = 5 and 8Hz), 9.53 (1H, s).

(6) 7- [2-Phenoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl- 3-cephem-4-carboxylic acid (color isomer), m.p. 145-350 ° C (with decomposition).

IR (Nujol): 3350, 3230, 1780, 1680, 1620, 1590, 1530 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, _δ ): 3.70 (2H, bs),

4.30 and 4.60 (2H, ABq, J = 14Hz),

5.23 (1H, d, J = 5Hz), 5.92 (1H, dd, J = 5 and 8Hz), 7.0-7.6 (5H, m),

8.30 (2H, broad s), 9.52 (1H, s),

9.83 (1H, d, J = 8Hz).

(7) 7- [2-Cu, Iloxyquinoino-2- (5-amino-1,2,4-thiadiazol-3: 1) -acetamido] -3- (1,3,4-thiadiazol-2-one). m.p. 105-110 [deg.] C. (decomposition).

IR (nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (d 6 -DMSO, δ): 3.6 and 3.76 (2H, ABq, J-18Hz), 4.3 and 4.56 (2H, ABq, J = 13Hz), 5.12 ( 2H, s), 5.14 (111, d, J = 5Hz), 5.80 (1H, dd, J = 5 and 8Hz), 8.20 (2H, broad s), 9.52 (1H, s) )

9.78 (1H, d, J = 8Hz).

(8) 7- (2- (N, N-Diethylcarbamoyl) -methoxyimino-2- (5-amiflo-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1,3,4-thiadiazol-2-one) yl) -thiomethyl-3-eephern-4-carboxylic acid (color isomer), m.p. 175-180 ° C (with decomposition).

IR (Nujol): 3480, 3310, 3200, 1775, 1740, 1680, 1630, 1610, 1515 cm ^-1 .

NMR (d _é -DMSO, 8): 1.00 _(s 3H, t, J = 7Hz), 1.08 (3H, t, J = 7Hz), 3.27 (4H, q, J = 7Hz) , 3.62 and 3.72 (2H, ABq, J = 18Hz), 4.33 and 405 (2H, ABq, J = 14Hz), 4.88 (2H, s), 5.15 (1H, d, J = 5Hz), 5.83 (1H, dd, J = 5 and 9Hz), 8.13 (2H, bs), 9.55 (1H, $), 9.62 (1H, d, J = 9Hz) ).

(9) 7- [2- (1-Ethoxycarbonyl-1-methylethoxyimino) -2- (5-amino-1,2,4-thiadiazole-3-11) -acetamide; -3- (1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-A-carboxylic acid (color isomer), m.p. 130-135 ° C (with decomposition).

IR (nujol): 3360, 3240, 1780, 1730, 1690, 1630, 1530 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 1.18 (3H, t, J = 7Hz), 100 (6H, s), 3.72 (2H, bs), 4.13 (2H, q, J-7Hz), 403 and 408 (2Y ABq, J = 13Hz), 5.18 (1H, d, J = 5Hz),

5.85 (1H, dd, J = 5 and 8Hz), 8.18 (2H, broad s), 9.48 (1H, d, J = 8Hz), 907 (1Ή, s).

(10) 7- [2-Etho-carbonylmethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamide! -3- (1,3,4-thiadiazol-2-yl) · tlomethyl-3-cephem-4-carboxylic acid (color isomer), m.p.

120-125 ° C (with decomposition).

IR (nujol): 3370, 3250, 1780, 1690, 2625, 1530 cm @ -1.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 1.23 (3H, t, J = 7Hz),

3.72 (2H, bs), 4.20 (211, q, J = 7Hz), 4.35 and 408 (2H, ABq,

J = 13Hz), 4.78 (2H, s), 5.17 (1H, d, J = 5Hz), 5.83 (1H, dd, J = 5 and 8Hz), 8.20 (2H, broad s) ), 9.58 (III, d, J = 8Hz), 9.60 (1H, s).

(11) 7-t2-Hydroxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) -acetamidol-3- (1,3,4-thiadiazol-2-yl) -thiomethyl-3 -cephem-4-carboxylic acid (color isomer), m.p. 155-16 ° C (with decomposition).

IR (Nujol): 3220, 1780, 1680, 1620 ^cm-1 wavenumber.

(12) 7- [2- {2- {2-hexyloxyethoxy) -ethoxyimino} -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (l-0.4) -thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 100-105 ° C (with decomposition).

IR (Nujol): 3340, 3210, 1785, 1685, 1620, 1525 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 0.87 (3H, t, J = 5Hz), 0.87-1.73 (8H, m), 3.10-3.93 (10H, m) ), 4.10-4.47 (2H, m), 4.30 and 4.58 (2H, ABq, J = 13Hz), 5.17 (1H, d, J = 5Hz), 5.83 (1H , dd, J = 5 and 8Hz),

8.12 (2H, bs), 9.55 (1H, d, J = 8Hz), 907 (1H, s).

(13) 7- (2-Mesylmethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1,3,4-thiadiazol-2-yl) -thiomethyl -3-cephemA carboxylic acid (color isomer), m.p. 164-167 ° C (with decomposition).

IR (Nujol): 3360, 3230, 1780, 1690, 1620, 1530 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.20 (3H, s), 3.72 (2H, broad s), 4.33 and 4.57 (2H, ABq, J = 13Hz, 5.15 (1H, d, J = 5Hz), 50O (2H, s), 5.83 (1H, dd, J = 5 and 8Hz), 8.20 (2H, broad s), 9.55 (1H, s) , 9.78 (1H, d, J = 8Hz).

(14) 7- [2-Tritloximino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl- 3cefemA-carboxylic acid (color isomer), m.p. 163-167 ° C

I rwxtnlae and <v7rkAn ι

IR (Nujol): 3480, 3350, 3250, 1785, 1690, 1620.1530 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.64 and 3.72 (2H, ABq, J = 18Hz), 3.90 (3H, s), 4.24 and 408 (2H, ABq, J = 14Hz), 5.18 (1H, d, J = 4IIz), 5.98 (1H, dd, J = 4 and 8Hz), 7.30 (15H, s), 8.08 (2H, s),

9.84 (1H, d, J = 8Hz).

(15) 7- [2-Trityloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (10,4-thiadiazol-2-yl) -thiomethyl-3-cephem -4-carboxylic acid (color isomer), m.p. 175-178 ° C (with decomposition).

IR (Nujol): 3450, 3350, 3200, 1790, 1690, 1620, 1530 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.73 (2H, bs), 403 and 4.63 (2H, ABq, J = 13Hz),

5.10 (1H, d, J = 4Hz), 6.03 (1H, dd, J = 4 and 8Hz), 707 (15H, s), 8.13 (2H, s), 9.60 (1H. s), 9.87 (1H, J = 8Hz).

(16) 7- [2-Allyloxyimino-2- (5-amino-1,2,4-thiadiazole-339).

-39183 006 il) -acetamido] -cephalosporanic acid (color isomer), m.p.

131-133 ° C (with decomposition).

IR (Nujol): 3350, 3240, 1780, 1730, 1680, 1530, 1240 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 2.07 (3H, s), 3.57 (211, broad s), 4.5-5.1 (2H, m), 4.7 (211, broad s), 5.1-5.6 (2H, m),

5.15 (1H, d, J = 4Hz), 5.6-6.4 (1H, m). 5.84 (1Η, dd, J = 4.5 and 9Hz),

8.13 (2H, bs), 9.67 (1H, d, J = 9Hz).

(17) 7- [2-Alloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3 -cephem-4-carboxylic acid (color isomer), m.p. 154-156 ° C (with decomposition).

IR (Nujol): 3380, 3245, 1780, 1680, 1625, 1527 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.53 and 3.77 (2H, ABq, J = 14Hz), 3.90 (3H, s), 4.27 (2H, broad s), 4, 5-4.8 (2H, m), 5.0-5.6 (2H, m), 5.15 (1H, d, J = 4.5Hz), 5.6-6.3 (111, m) ), 5.85 (1H, dd, J = 4.5 and 9Hz), 7.23 (2H, broad s), 9.77 (1H, d,

J = 9Hz).

(18) 7- [2-Trityloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1,3,4-thiadiazol-2-yl) -thiomethyl-3 -acephem-4-carboxylic acid (anti-isomer), m.p. 165-170 ° C (dec.).

IR (Nujol): 3350, 3200, 1785, 1690, 1620, 1515 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.70 (2H, bs), 4.33 and 4.60 (2H, ABq, J = 13Hz),

5.10 (1H, d, J = 4Hz), 5.73 (1H, dd, J = 4 and 8Hz), 7.33 (15H, s), 8.17 (1H, d, J = 8Hz), 8.23 (2H, s), 9.60 (1H, s).

(19) 7- [2-Allyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (5-aminomethyl-1,3,4-thiothiazol-2) -yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p.

161-164 ° C (with decomposition).

IR (Nujol): 3350, 3220, 1770, 1670, 1620, 1525 cm ^"1 wavenumber.

(20) 7- [2-Allyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- {2- (N-tert-butoxycarbonylamino) -ethyl} - 1H-Tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), powder.

(21) 7- [2-Allyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (2-aminoethyl) -1H-tetrazol-5-yl ] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p.

165-169 ° C (with decomposition).

Spektruni IR (Nujol): 3350, 3200, 1768, 1670, 1610, 1522 cm ^"1 wavenumber.

(22) 7- [2-Hydroxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl- 3cefem-4-carboxylic acid (color isomer), m.p. 165-170 ° C (with decomposition).

IR (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm ^"1 wavenumber.

(23) 7- [2-Hydroxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1,3,4-thiadiazol-2-yl) -thiomethyl-3 -acephem-4-carboxylic acid (color isomer), m.p. 170-175 ° C (with decomposition).

IR (Nujol): 3480, 3350, 1770, 1690, 1620, 1530 ^cm-1 wavenumber.

(24) 7- [2-Hydroxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1,3,4-thiadiazol-2-yl) -thiomethyl-3 -cefcm 4 -carboxylic acid (anti-isomer), mp 155-160 ° C (with decomposition).

IR (Nujol): 3350, 3250, 1780, 1680, 1620, 1520 ^cm-1 wavenumber.

Example 36

14-17. In the same manner as in Examples 1 to 4, the following compounds were prepared:

(1) 7- [2-Hydroxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1,3,4-thiadiazol-2-yl) -thiomethyl -3-cephem-4-carboxylic acid (color isomer), m.p. 155-160 ° C (with decomposition).

IR (Nujol): 3200, 1780, 1680, 1620 ^cm-1 wavenumber.

(2) 7- [2-Allyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl- 3-cephem-4-carboxylic acid (color isomer), m.p. 138-140 ° C (with decomposition).

IR (Nujol): 3350, 3230, 1780, 1680, 1620, 1530 ^cm-1 wavenumber.

(3) 7- [2- (2,2,2-Trifluoroethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamidol-3- (1,3,4-thiadiazol-2) -yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 153-158 ° C.

• IR (Nujol): 3350, 3250, 1780, 1680, 1625 cm ^"1 wavenumber.

(4) 7- {2- (2-Propynyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1,3,4-thiadiazole-2- yl) -thiomethyl-3 cephem-4-carboxylic acid (color isomer), m.p. 140-145 ° C (with decomposition).

IR (Nujol): 3330, 3250, 1780, 1680, 1620, 1530 ^cm-1 wavenumber.

(5) 7- [2-Benzyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1,3,4-thiadiazol-2-yl) -thiomethyl-3 -acephem-4-carboxylic acid (color isomer), m.p. 130-135 ° C (with decomposition).

IR (Nujol): 3360, 3250, 1780, 1680, 1625, 1530 cm ^-1 .

(6) 7- [2- (2-Phenoxyethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1,3,4-thiadiazol-2) -yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 163-167 ° C (dec.).

IR (Nujol): 3350, 3250, 1780, 1680, 1630, 1600, 1530, 1500 cm @ ^-1 .

(7) 7- [2-Methylthiomethoxyimino-2- (5-amino-1,2,4-thiadiazcl-3-yl) -acetamido} -3- (1,3,4-thiadiazol-2-yl) -thiomethyl-3 -cephem-4-carboxylic acid (color isomer), m.p. 168-170 ° C (with decomposition).

IR (Nujol): 3350, 3250, 1780, 1680, 1620.1530 ^cm-1 wavenumber.

(8) 7- [2- (2-Methylthio-thioxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1,3,4-thiadiazol-2-one). yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 125-130 ° C (with decomposition).

IR (Nujol): 3350, 3250, 1780, 1680, 1625, 1530 cm ^"1 wavenumber.

(9) 7- [2-Phenoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl- 3-cephem-4-carboxylic acid (color isomer), m.p. 145-150 ° C (with decomposition).

-40183 006

IR spectra (nujol): 3350, 3230, 1780, 1680, 1620, 1590, 1530 cm &lt; -1 &gt;.

(10) 7- [2-Cyanomethoxy-nitro-2- (5-amino-1,2,4-thiadtazol-3-yl) -acetamido] -3- (1,3,4-thiadiazol-2-yl) -thiomethyl- M.p. 105-110 ° C (with decomposition). 3- (cephem-4-carboxylic acid).

IR (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 ^cm-1 wavenumber.

(11) 7- (2- (N, N-Diethylcarbamoyl) -methoxyimino-2- 10 (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1,3,4) -iadiadiazol-2-yl) -thiomethyl-3-cephem-carboxylic acid (color isomer), m.p.

175-180 ° C (with decomposition).

IR (Nujol) 3480, 3310, 3200, 1775,

1740, 1680, 3630, 1610, 1515 cm ^{-1 at} 15.

(12) 7- (2- (1-Ethoxycarbonyl-1-methylethoxyimino) -2 (5-amino-1,2,4-thiazol-3-yl) acetamide) -3- (1,3,4-thiadiazole) -2-yl) -thiomelyl-3-cephem-4-carboxylic acid (color isomer), m.p.

130-135 ° C (with decomposition). 20

IR (Nujol): 3360th 3240, 1780, 1730, 1690, 1630, 1530 ^cm-1 wavenumber.

(13) 7-12-Ethoxycarbomylmethoxyimino-2- (5-amino-1,2,4-thiadiazol-2-yl) -thiomethyl-3-cfem-4-carboxylic acid (color isomer), m.p. C (decomposition).

IR (Nujol): 3370, 3250, 1780, 1690, 1625, 1530 ^cm-1 wavenumber.

(14) 7- [2- {2- (2-hexyloxyethoxy) -ethoxyimino} 2- (5-amino-1,2,4-tradthiazol-3-yl) -acetamido] -3- (1,3,4) -thiadiazole-2-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p.

100-105 ° C (with decomposition).

IR (Nujol): 3340, 3210, 1785, 1685, 1620, 1525 cm ^-1 .

(15) 7- [2-Mesylmethoxymethyl] -2- (5-amino-1,2,4-thiadia-3S-zol-3-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) ) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 164-167 ° C (with decomposition).

IR (Nujol): 3360, 3230, 1780, 1690,

162Ό at 1530 cm ^-1 . 40 (6) 7- [2-Trityloxy-amino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl -3-cephem-4-carboxylic acid (color isomer), m.p. 163-167 ° C (with decomposition).

IR (nujol): 3480, 3350, 3250, 1785, 451690, 1620, 1530 cm ^-1 .

(17) 7-t2-trityloxylmino-2- (5-anuno-1,2,4-thiadiazole ·

3-yl) -acetamido] -3- (1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), (m.p. 175-178 ° C (dec. At 6θ) ).

IR (Nujol): 3450, 3350, 3200, 1790, 1690, 1620, 1530 ^cm-1 wavenumber.

(18) 7- [2-Allyloxylmino-2- (5-amino-1,2,4-thiadiazol-55 3-yl) -acetamido] -3- (1-methyl-1H-tetrazol-5-yl) - thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 154-156 ° C (with decomposition).

IR (nujol) 3380, 3245, 1780, 1680,

1625, at 1527 cm ^-1 , θθ (19) 7-1,2-trityloxylmino-2, 5-amino-1,2,4-thiadiazol-3J) -acetamido] -3- (1,3,4-thiadiazol-2) -yl) -thiomethyl-3-cephem-4-carboxylic acid (anti-isomer), m.p. 165-170 ° C (with decomposition). , ....

IR (Nujol): 3350, 3200, 1785, 1690,

At 1620, 1515 cm ^-1 .

IR (Nujol): 3350, 3200, 1785, 1690,

At 1620, 1515 cm ^-1 .

(20) 7- (2-Allyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (5-aminomethyl-1,3,4-liadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid (syn isomer), m.p.

161-164 ° C (with decomposition).

IR (Nujol): 3350, 3220, 1770, 1670, 1620, 1525 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO + D ₂₀ O): 3.6 (2H, bs), 4.35 and 4.58 (2H, ABq, J = 15Hz), 4.2-4.8 ( 4H, m), 5.0-5.5 (2H, rn), 5.05 (1H, d, J = 5Hz), 5.75 (1H, d, J = 5Hz), 5.7-6 , 4 (1H, m).

(21) 7- [2-Allyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (2- (N-tert-butoxycarbonylamino) ethyl} -1H -tetrazol-5-yl] -thionethyl-3-cephem-4-carboxylic acid (color isomer), powder.

(22) 7 - [(2-Amyloxy] amino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [1- (2-aminoethyl) -1H-terazol-5-yl] - thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p.

165-169 ° C (with decomposition).

IR (Nujol): 3350, 3200, 1768, 1670, 1610, 1522 ^cm-1 wavenumber.

(23) 7- (2-Hydroxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl- 3-cephem-4-carboxylic acid (syn isomer), m.p. 165-170 ° C (with decomposition).

IR spectrum (nujol): 3350, 3250, 1780, 1680, 1620, IS30 cm ^-1 .

(24) 7- (2-Hydroxyimino-2- {5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1,3,4-thiadiazol-2-yl) -thiomethyl-3 -acephem-4-carboxylic acid (color isomer), m.p. 170-175 ° C (with decomposition).

IR (Nujol): 3480, 3350, 1770, 1690, 1620, 1530, ^cm-1 wavenumber.

(25) 7- {2-Hydroxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1,3,4-thiadiazol-2-yl) -thiomethyl-3 -cephem-4-carboxylic acid (anti-isomer), m.p. 155-160 ° C (bonding).

IR spectrum (nujol): 3350, 3250, 1780, 1680, 1620, 1520 cm ^-1 ,

Example 37

22-25. The following compounds were prepared as described in Examples 1 to 4:

(1) 7- {2-Allitoxynmino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (5-aminomethyl-1,3,4-thiadiazol-2-yl) ) -thiomethyl 3-cephem-4-carboxylic acid (color isomer), m.p. 161-164 ° C (with decomposition).

IR (Nujol): 3350, 3220, 1770, 1670 1620, 1525 cm @ ^-1 (2) 7- [2-Allyloxyimino-3- (1- (2-aminoethyl) -1H-tetrazol-5-yl] - thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 165-169 ° C (with decomposition).

IR (Nujol): 3350, 3200, 1768, 1670, 1610, 1522 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO + D ₂ O, δ): 3.41 (2H, bs), 3.60 (2H, bs), 4.3-5.0 (4H, m), δ 05 (1H, d, J = 4.5Hz),

5.73 (1H, 'd, J = 4.5Hz), 4.9-5.6 (2H, m), 5.7-6.4 (1H, m).

41

-411

183,006

Example 38

0.95 g of 742-trityloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1,3,4-thiadiazol-2-yl) -methyl-3-cephemcarboxylic acid (color isomer), 0.6 ml of concentrated hydrochloric acid and 10 ml of methanol were stirred at room temperature for 7 hours. Methanol was then distilled off from the reaction mixture and the pH of the residue was adjusted to 5 by addition of ethyl acetate and aqueous sodium bicarbonate solution. Ethyl acetate was added to the separated aqueous phase and the pH of the mixture was adjusted to 2 with 10% hydrochloric acid;

The separated ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to a total volume of 10 ml. The precipitate was collected by filtration, washed with ethyl acetate and diethyl ether and, after drying, 0.3 g of 7- [2-hydroxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- ( 1,3,4-thiadiazol-2-yl) -thiomethyl-1,3-cephem-4-carboxylic acid (color isomer) is obtained, m.p. 170-175 ° C (with decomposition).

IR (Nujol): 3480, 3350, 1770, 1690, '1620, 1530 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.61 and 3.73 (2H, ABq, J = 18Hz), 4.30 and 4.57 (2H, ABq, J = 13Hz), 5.13 ( 1H, d,

J = 4Hz), 5.83 (1H, dd, J = 4 and 8Hz),

8.03 (2H, s), 9.40 (1H, d, J-8Hz),

9.57 (1H, s), 11.93 (1H, s).

Example 39

Following the procedure of Example 38, the following compounds were prepared:

(1) 7- [2-Hydroxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem- 4-carboxylic acid (color isomer), m.p. 165-170 ° C (with decomposition). 35

IR (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.70 (2H, bs),

3.97 (3H, s), 4.33 (2H, broad s),

5.13 (1H, d, J = 4Hz), 5.83 (1H, dd, 40 J = 4 and 8Hz), 8.03 (2H, s), 9.43 (1H, d, J = 8Hz) , 11.93 (1H, s).

(2) 7- [2-Hydroxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1,3,4-thiadiazol-2-11) -thiomethyl-3 -cephem-4-carboxylic acid (anti-isomer), m.p. 155-160 ° C (dec. 45).

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, δ): 3.70 (2H broad s),

4.35 and 4.53 (2H, ABq, J = 13Hz),

5.13 (1H, d, J = 4Hz), 5.73 (1H dd,

J = 4 and 8Hz), 8.03 (2H, s), 8.92 (1H, 50d, J = 8Hz), 9.53 (1H, s).

IR (Nujol): 3350, 3250, 1780, 1680, 1620, 1520 cm ^-1 .

Example 40 ⁵⁵

A mixture of phosphorus pentachloride (1.89 g) and methylene chloride (20 ml) was stirred at room temperature for 15 minutes. 2.2 g of 2- (1-tert-butoxycarbonyl-ethoxyimino) -2- (5-aminol, 2,4-thiadiazol-3-yl) -acetic acid are then added at -15 ° C. and the mixture was stirred at -10 to -15 ° C for 30 minutes. To the resulting solution was added a solution of 1.4 g of 7-amino-3-cephem-4-carboxylic acid and 8.4 g of trimethylsilylacetamide in 20 ml of methylene chloride at -20 ° C and the mixture was stirred for 65 minutes - After stirring at 10 to -15 ° C and then for 30 minutes at 0 to 5 ° C, methylene chloride is distilled off from the reaction mixture, and ethyl acetate and a little water are added to the residue. The resulting solution was poured into aqueous sodium bicarbonate solution and the aqueous phase was separated.

Ethyl acetate was added to the aqueous phase, the mixture was acidified with 6N hydrochloric acid and extracted twice with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, treated with activated carbon and evaporated. The residue was triturated with diisopropyl ether and the precipitate was collected by filtration as a pale yellow powder, 2.5 g of 7- (2- (1-tert-butoxycarbonyl-ethoxyimino) 2- (5-amino-1,2,4-thiadiazole). 3-yl) -acetamido] -3-cephem-4-carboxylic acid (syn-isomer) is obtained, m.p. 250 ° C.

IR (Nujol): 3400, 3250, 3150, 1770, 1720, 1680, 1610, 1520, 1290, 1240, 1150, 980, 740 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 1.50 (12H, bs);

3.63 (2H, m), 4.73 (1H, q, J = 7Hz),

5.17 (1H, d, J = 5Hz), 5.92 (111, dd,

J = 5c 81 (2z), 6.53 (1H, m), 8.17 (2H, m), 9.4 and 9.6 (1H, d, J = 8llz).

Example 41

1-3, 5, 7-12, 32-34. Example 40 and Examples 40 and 40 were prepared as follows:

(1) 7- [2- (4-Chloro-phenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3 (1-allyl-1H-tetrazole-5- yl) thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 120-125 ° C (with decomposition).

IR (Nujol): 3290, 3180, 1770, 1680, 1615, 1580, 1520, 1480 cm ^-1 .

NMR _(DMSO-d6, δ): 3.73 (2H br s), 4.40 (2H, br s), 5.17 (1H, d,

J = 5Hz), 4.87-5.20 (2H, m), 5.20-

5.60 (2H, m), 5.90 (1H, dd, J = 5 and 8Hz), 5.60-6.30 (LH, m), 7.32 (2H, d, J = 9Hz) , 7.48 (2H, d, J = 9Hz), 8.32 (2H, broad s), 9.90 (1H, d, J = 8Hz).

(2) 7- {2- (4-Chloro-phenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-methyl-1H-tetrazole) 5-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 130-135 ° C (with decomposition).

IR (Nujol): 3400, 3300, 3280, 1770, 1670,1615,1580,1520,1480 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 3.72 (2H, br s), 3.92 (3H, s), 4.32 (2H, br s);

5.18 (1H, d, J = 5Hz), 5.87 (1H, dd, J = 5 and 8Hz), 7.25 (2H, d, J = 9Hz),

7.42 _V 2H, d, J = 9Hz), 8.25 (2H, broad s), 9.85 (1H, d, J = 8Hz).

(3) 7- [2- (4-Chloro-phenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -cephalosporanic acid (color isomer), m.p. 125 ° C (with decomposition).

IR (Nujol): 3400, 3300, 3190, 1770, 1720, 1650, 1620, 1580, 1520, 1480 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 2.02 (3H, s), 3.58

-421

183.0-6 (211bs), 4.75 and 4.98 (2H, ABq, j = -13Hz), 5.22 (1H, d, J = 5Hz),

5.87 (1H, dd, J = 5 and 8Hz), 7.27 (2H, d, J = 91Hz), 7.42 (211, d, J = 9Hz),

8.28 (2H, bs), 9.85 (111, d, 5.1 KHz) (4) 7 - [2- (4-chlorophenoxyimino) -2- (5-amino-1,2,4-thiadiazole-3] -yl) -ac (amido} -3- (2-carboxyethyl) -1H-tetrazol-5-yl] thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 135-

140 ° C (with decomposition) 10

IR (Nujol): 3400, 3270, 3190, 1770, 1680, 1620, 1585.1520, 1480 ^cm-1 hulláms / ámnál.

Nuclear Magnetic Resonance Spectrum (DMSO-d6, δ): 2.70 3.10 (2H, m),

3.70 (2H, bs), 4.10 4.60 (4H, 15m), 5.20 (1H, d, J = 511). 5.87 (1H, dd, J = 5 and 8tlz), 7.28 (211, d, J = 9Hz), 7.45 (211, d, J = 9Hz),

8.30 (211 bs), 9.85 (1H, d, J = 8Hz) 20 (') 7-t2- (chlorophenoxy) -mino -2- (5-amino-1,2,4- tiadiaibl-3-yl) acetamido] -3- {2-karboxinietil-3-oxo-2,3-dihydro-l, 2,4-triazolo [4,3-b] pyridazin-6-yl] 4iometil-3-cephem-4katbonsav (color isomer), m.p. 140-145 ° C (with decomposition) 25

IR (Nujol): 3400, 3300, 3190, 065, 1700, 1620, 1580, 1540, 1520, 1480 ^cm-1 hullámszáinnál.

Nuclear Magnetic Resonance Spectrum (DMSO-d6, δ): 3.80 (2H, bs),

4.28 (2Η, broad s), 4.73 (2H, s), 5.27 (1H, d, J = 5Hz), 5.90 (1H, dd, J-5 and Hz), 7.12 (1H , d, J = 10Hz),

7.32 (2H, d, J = 9Hz), 7.47 (2H, d, J = 9Hz), 7.72 (1H, d, J = 10Hz),

8.30 (2H, bs), 9.92 (1H, d, 35) = 81¼).

(6) 7- [2- (4-Chloro-phenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-yletrazole 1,5-b] pyridazine 6-yl) thionethyl-3-cephem-4-cationic acid (color isomer), m.p. 140145 ° C (with decomposition). 40

IR spectrum (δ): 3350, 3240, 1780, 1685, 1625, 1530, 1490 cm ^-1 ,

Nuclear Magnetic Resonance Spectrum (DMSO-d6, δ): 3.70 (2H, bs),

4.22 5S 4.62 (211, ABq, J = 13Hz), 45

5.22 (111, d, J = 5Hz), 5.93 (1H, dd,) = 5 and 8Hz), 7.27 (211, d, J = 9Hz), 7.42 (2H, d, J = 9Hz) ), 7.73 (1H, d,) = 911 /), 8.28 (2H, bs), 8.59 (III, <1, J = 9Hz), 9.87 (1H, d, 50J). = 8Hz), (7) 7- {2- (δ-tert-butyl-cinylphenyl-benzyloxyimino) -2- (5-amyl-1,2,4-thiadlazob341) -9C6-amido] -3- (1,3 , 4-Thiadiazole-241) -Tlomethyl-3-cephem 4 = cfflonic acid (color isomer), m.p. 105-110 ° C (with decomposition). 55

IR spectrum (m.p.): 3400, 3300, 3180, 1780, 1720, 1680, 1620, 1520 cm @ ^{-1 of} judgmentulate.

Nuclear Magnetic Resonance Spectrum (DMSO-t6, H 1.40 (911, s), 3,503.83 (211, 1H), 4.37 and 4.60 (211, ABq, 60) = 1311), 5.10 and 5.18 (1H, d, j = S) tz), 5.63 (s), 5.67-6.0 (111, Hi), 7.47 (5U, s), 8.20 (211); S), 9.62 (1/211, s), 9.64 (1/211, 1,) 9.47-77 (111.8). 65 (8) 7- [2- (o-tert-Butoxycarbonyl-benzylimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetarnido] -3-cefcm-4-carbonic acid (color isomer), m.p. 90-95 ° C (with decomposition),

IR spectrum (nujol): 3400, 3380, 3230, 1780, 1730, 1685, 1635, 1530 cm @ -1).

Nuclear Magnetic Resonance Spectrum (DMSO-d6 ₎ δ: 1.38 (9H, s), 3.60 (2H, broad s), 5.0-5.20 (1H, nt),

5.63 (1H, s), 5.72 6.03 (111m), 6.37-6.67 (1H, m), 7.47 (511, s),

8.18 (2H, bs), 9.43-9.70 (1H, m).

(9) 7-N- (6-tert-butoxycarbonyl-benzyloxymethyl) -2; (5-amino-1,2,4-thiadiazol-3-yl) -acetamide-3- (tert-butoxy) -carbonylamino) -ethyl} -1H-methyl-3-cephem-4-carboxylic acid (color isomer), novel;

105-110 ° C (with decomposition).

IR spectrum (nujol): 336, 3220, 1783, 159, 1625, 1525 cm @ ^-1 .

NMR spectrum (DMSO d _6, δ): 1.38 (18) 1, s), 3,173,87 (4H, m), 4.17 to 4.65 (pyrimidin4 M.), from 5.0 to 5, 28 (1H, m), 5.12 (1H, m), 5.58-6.0 (1H, m), 7.47 (SiI, s).

8.17 (2H, bs), 9.45-9.75 (1H, m).

(10) 7-] 2- (2-Propynyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (2-carboxyethyl) -1H- tehazol5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 125-130 ° C (with decomposition).

IR spectrum (nujol): 3400, 3260, 3190, 2580, 1765, 1710, 1670, 1620, ISCtif?

NMR _(DMSO-d6, δ): 2.92 (2M, t, j ^ 6ÍÍ / L, 3.47 (IH, t, J = 2Hz), _3? O7 12H, br s), 4 , 17-4.60 (411, new), 4.77 (2H, d, J = 2Hz), 5.08 (III, d,) = 311), 5.77 (1H, dd, J = 5) and 8JU). g, δ (2H, bs), 9.57 (1H, d,) = (11) 7- [2- (2-Propynyloxyimino) -2- (S-amine) -4,2,4-9% diazole- 3-yl) -acetamido] -cephalosporanic acid (color-tasteHiof)

IR spectrum (nujol): 3400, 3270, 3180, 770, 1720, 1655, 1520 cm @ -1.

NMR _(DMSO-d6, δ): 1.98 (31], _s) 2 45 (IH, t, J = 211z), 3.48 QU, _no sharp s), 4.72 (211, d, ) = 2Hz), 4.67 and 4.92 (2H, ABq,) = 13112), 5.08 (HI, d, J = 51), 5.77 (HI, dd,) = 5 and 8Hz), 8.07 (2H, bs), 9.55 (111, d, J = 8Hz).

(12) 7-β-tert-Butoxycarbotyl-ethoxyimideipq-2.) G. _the acetamide Amino-1,2,4-tiadia2ol-3-yl)] -3-cephem-4-carboxylic acid (syn isomer), mp .: 165-170 ° C (dec);

IR (nujol): 3350, 3250, 3180, 1790 1720, 1660, 1630, 1620, 1320 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (I) MS-d ₆ , δ): 1.40 (9H, g), 3.57 (211, bp), 4.60 (21). ; θ7 (111, d, J = 4Hz), 5.83 (111, dd,) = 4 and 8Hz), 6.47 (1H, broad g), 8J (2H, s), 9.50 (111 , d, J = 81k).

(13) 7- [2- (1,1-Dloxo-thiophen-3-yl) -oxynintino-2- (§-asbino-1,2,4-thiadiazole-341) theta.mido] -3- ( 1,3,4-thiadiazol-2'-yl) -thiomethyl-3-cefgm-4-carboxylic acid (color isomer), qb .; 170-175 ° C (with decomposition).

, 43

-43183 006

IR (Nujol): 3300, 3200, 1770, 1670, 1620, 1520 ^cm-1 wavenumber.

NMR d _é IDMS, δ): 2.30-2.50 (2H, m), 3.0 3.57 (411, m), 3.70 (2H, br s), 4.33 and 4.57 (2H, ABq, J = 13Hz), 5.0-5.15 (1H, m), 5.17 (1H, d, J = 4Hz), 5.83 (1H, dd, J = 4 and 8Hz),

8.23 (2H, s), 9.60 (1H, s), 9.67 (111, d, J = 8Hz) (14) 7- [2-Allyloxyimino-2- (5-amino-1,2,4) -thiadiazol-3-yl) -acetainido] -3- (N-carboxymethyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p.

140-145 ° C (with decomposition).

1R spectrum (nujol); 3300, 3200, 1770, 1720, 1670, 1620, 1520 cm ^-1 .

NMR spectrum (t> _MSO-d6, δ): 3.63 (2H, br s);

4.23 and 4.43 (2H, ABq, J = 14Hz), 4.60-4.73 (211, m), 5.10 (III, d, J = 4Hz), 5.30 (2H, s), 5.07-5.50 (2H, m), 5.67-6.20 (2H, ni), 8.15 (2H, s), 9.63 (1H, d, J = 8Hz).

(15) 7- [2- (2-Propynyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-carboxymethyl-1H-tetrazol-5-yl) - acetamido) -3- (1-carboxymethyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p.

135-140 ° C (with decomposition).

IR (Nujol): 3250, 3150, 1770, 1720, 1670, 1620, 1520 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 3.47 (IH, t, J = 2Hz),

3.63 (2H, broad s), 4.22 and 4.43 (2H, ABq, J = 14Hz), 5.07 (1H, d, J = 4Hz), 5.28 (2H, s), 9 , 63 (1H, d, J = -8Hz).

(16) 7- [2-Allyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (2-carboxyethyl) -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p.

140-145 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1720, 1670, 1620, 1520 ^cm-1 hullámNMR spectrum _(DMSO-d6, δ): 2.87 (2H, t, J = 6Hz);

3.63 (2H, broad s), 4.37 (2H, t, J = 6Hz), 4.20 and 4.47 (2H, ABq, J = 14Hz), 4.57-4.67 (2H, m), 5.07 1H, d, J = 411z), 5.10-5.43 (2H, m), 5.67-6.13 (2H, m), 8.10 (2H, s), 9.58 (1H, d, J = 8Hz).

(17) 7- [2- (tert-Buloxycarbonylmethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-f- (2-carboxyethyl) - 1H-Tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 150-155 ° C (dec.).

IR (Nujol): 3300, 3200, 1770, 1720, 1700, 1620, 1520 ^cm-1 wavenumber.

NMR (DMSO-d _6, δ). 1.50 (9H, s), 3.00 (2H, t, J = 6Hz), 3.73 (2H, broad s),

4.43 (2H, broad s), 4.50 (2H, t, J = 6Hz), 4.67 (2H, s), 5.17 (1H, d, J = 4Hz), 5.87 (1H , dd, J = 4 and 8Hz), 8.18 (2H, s), 9.53 (1H, d, J = 8Hz).

(18) 7- [2- (tert-Butoxycarbonyl-methoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- {3- (4- metil4.4

-piperazinyl) -propyl] -1H-tetrazol-5-yl] -thiomethyl-3-cimethylcarboxylic acid (color isomer), m.p. 220-225 ° C (with decomposition).

IR spectrum (nujol). J300, 1700, 1680, 1605, 1520 cm @ ¹ .

NMR _(DMSO-d6, δ): 1.40 (911, s), 1,962,10 (2H, m), 2.38 -2.50 (4H, m), 2.60 (311, s ), 2.95 3.10 (611, m), 3.52 and 3.65 (2H, ABq, J = 16Hz), 4.20-4.40 (4H, m), 4.60 (2H, s), 5.06 (1H, d, J = 4Hz), 5.70 (1H, dd, J = 4 and 8Hz), 8.12 (2H, s), 9.44 (1H, d, J = 8 Hz).

(19) 7- (2- (1-tert-butoxycarbonyl-2-methylpropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -ephephalosporanic acid 130-140 ° C (with decomposition).

IR (Nujol): 3400, 3300, 3200, 1780, 1720-1680, 1620, 1520, 1460, 1370, 1230, 1150, 1030, 730 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 1.03 (6H d, J = 7 Hz.),

1.43 (9H, s), 2.03 (3H, s), 1.9-2.2 (1H, m), 3.6 (2H, m), 4.26 and 4.34 (1H, d, J = 6Hz), 4.68 and 5.05 (2H, ABq, J = 13Hz), 5.19 (1H, d, J = 5Hz),

5.87 (1H, dd, J = 5 and 8Hz), 8.10 (2H, bs), 9.48 (1H, d, J = 8Hz).

(20) 7- [2- (1-tert-butoxycarbonyl-propexite minino) -2 (5-amino-1,2,4-thiadiazol-3-yl) -acetamido} -3- (N , 3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 101-105 ° C (with decomposition).

IR (Nujol): 3300, 3150, 1770, 1720, 1620, 1520, 1450, 1370, 1250, 1150, 1010, 900, 840, 720 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 0.93 (3H, t, J = 7Hz),

1.42 (9H, s), 1.8 (2H, m), 3.7 (2H, m),

4.6 (3H, m), 5.18 (1H, d, J = 5Hz),

5.87 (1H, dd, J = 5 and 8 Hz), 8.20 (2H, broad s), 9.5 (1H, m), 9.58 (1H, s).

(21) 7- (2- (1-tert-butoxycarbonylpropoxyimino) -2- (5-amino-1,2,4-thiazolazol-3-yl) acetamido] cephalosporanic acid (color isomer), 95-105 ° C (with decomposition),

IR (Nujol): 3400, 3300, 3200, 1780, 1720, 1620, 1530, 1230, 1150, 1010, 890, 840, 740 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 0.95 (3H, t, J = 7ttz)

1.39 (9H, s), 1.8 (2H, m), 2.02 (3H, s), 3.5 (2H, m), 4.47 (1H, m), 4.67 and 5 , 03 (2H, ABq, J = 13Hz), 5.14 (1H, d, J = 5Hz), 5.83 (1H, dd, J = 5 and 8Hz), 8.07 (2H, broad s), 9.37 and.

9.43 (1H, d, J = 8Hz).

(22) 7- (2- (1-tert-butoxycarbonyl-ethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido) -3- (1,3,4-thiadiazole) 2-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 120-128 ° C (with decomposition).

IR (Nujol): 3280, 3180, 1770, 1720 1680, 1620, 1520 _L 1240, 1150 1000, 740, 720 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (DMSO-d6, δ): 1.4 (12H, m), 3.76

-441

183,006 (2Η, m), 4.30 and 4.67 (2H, ABq, J = 13Hz), 4.70 (111, q, J = 7Hz), 5.22 (1H, d, J = 5Hz) , 5.88 (1H, dd, J = 5 and 8Hz), 8.20 (211, broad s), 9.47 (1H, m), 9.60 (1H, s).

(23) 7- (2- (1,1-tert-Butoxycarbonyl-ethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -ephephalosporan [beta] (color isomer) 138-145 ° C (with decomposition).

IR (Nujol): 3280, 3180, 1780, 1720, 1680, 1620, 1520, 1230, 1150, 840 ^cm-1 wavenumber.

NMR _IDMS-d6, δ): 1.47 (12H, m), 2.07 (3H, s), 3.58 (2H, m), 4.5-5.1 (3H, m) , 5.19 (1H, d, J = 5Hz), 5.87 (1H, dd, J = 5 and 8Hz), 8.10 (2H, broad s), 9.40 and 9.50 (1H, d, J = 8 Hz).

(24) 7- [2- (1-Methyl-1-tert-butoxycarbonyl-ethoxyimino) 2- (5-amno-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1, 3,4-Thiadiazol-2-yl) -methyl-3-cephem-4-carboxylic acid (color isomer), m.p. 115-120 ° C (with decomposition).

IR (Nujol): 3280, 3170, 1780, 1720, 1680, 1520, 1140, 990, 750 cm @ ^-1 .

NMR _(DMSO-d6, fi): 1.40 (9H, s), 1.46 (6H, s), 3.7 (2H, m), 4.26 and 4.63 (2H, ABq , J = 13Hz), 5.18 (1H, d, J = 5Hz), 5.83 (1H, dd, J = 5 and 8Hz),

8.13 (2H, bs), 9.40 (1H, d, J = 8Hz), 9.53 (1H, s).

(25) 7- (2- (1-tert-Butoxycarbonyl-1-cyclopentyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamide) -3- (1,3 M.p. 140-143 ° C (with decomposition), 4-thiadiazole-2-yl) -thomac-3-cephem-4-carboxylic acid (color isomer).

IR (Nujol): 3300, 3180, 1770, 17201670, 1620, 1520, 1245, 1150, 1060, 995, 840 ^cm-1 wavenumber.

NMR _(DMS0-d6, 5): 1.40 (9H, s), 1.8 (4H, m), 2.1 (4H, m> 3,7 (2H, tn), 4, 27 and 4.68 (2H, ABq, J = 13Hz), 5.18 (1H, d, J = 5 and 8Hz), 8.1 (2H, broad s), 9.39 (1H, d, J = 8Hz), 9.53 (1H, s).

(26) 7- (2- (1-Methyl-tert-butoxyl-1-yl) -propyl-ethoxyimino> 2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido) -ephephalosporanic acid ( 135-140 ° C (with decomposition), m.p.

IR spectrum (nujol): 3400, 3300, 3180, 1780, 1720, 1690, 1620, 1540, 1300, 1220, 1140, 1030, 990, 840, 740 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (DMSO-d6, δ): 1.57 (9H, s), 1.62 (6H, s), 2.03 (3H, s), 3.57 (2H, m),

4.69 and 5.06 (2H, ABq, J = 13Hz),

5.19 (1H, d, δ = 5Ηζ), 5.89 (1H, dd, J = 5 and 8Hz), 8.21 (2H, broad s), 9.32 (1H, d, J1 = 8Hz) ).

(27) 7- (2- (1-tert-butoxylcarbonyl-1-clopenyl) oxyloxy) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -cephalosporanic acid (color) 98-102 ° C (with decomposition).

IR (Nujol): 3350, 3230, 1790, 1730, 1630, 1530, 1340, 1160, 1070, 1040, 1000 cm @ ^-1 .

Nuclear Magnetic Resonance Spectrum (DMSO-d6, δ): 1.47 (911, s), 1.80 (4H, m), 2.10 (4M, in), 2.13 (311, s),

3.60 (2H, m), 4.73 and 5.1 (211, ABq, J = 14Hz), 5.22 (1H, d, J5zil.

5.88 (1H, dd, J = 5 and 8 Hz), 8.15 (2H, m), 9.43 (1H, d, J = 8).

(28) 7- (2- (1-methyl-1-tert-butoxycarbonyl-e-toximino) 2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- ( 1- (2- (N-tert-butoxycarbonylamino) ethyl) -1H-tetrazol-5-yl] thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 96-100 ° C (with decomposition).

IR (Nujol): 3300, 3150, 1780, 1680, 1570, 1240, 1160, 990 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 1:45 (18H s.), 1.52 (6H, s), 3.33 (2H, m.), 3.67 (2H, m),

4.30 (4H, m), 5.10 (1H, d. J = 5Hz). 5.85 (1H, dd, J = 5 and 8Hz). 6.92 (1H, m), 8.13 (2H, m), 9.40 (1H, d, d, J = 8Hz).

(29) 7- {2- (1-Methyl-1-tert-butoxycarbonyl-ethoxyl-lithium) · 2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamyclo) -3-cephem -4 "carboxylic acid (color isomer), m.p. 215 ° C.

IR (Nujol): 3400, 3300, 3150, 1780, 1710, 169Ό, 1620, 1520, 1240, 1140, 980 ^cm-1 wavenumber.

NMR _(DMSO-d6, fi): 1.40 (9H, $), 1.47 (6H, s), 3.60 (2H, m), 5.1? (1H, d, J = 5Hz, 5.92 (1H, dd, JSfe 8Hz),

6.50 (1H, m), 8.22 (2H, m), 9.50 (1H, d, WHz).

(30) 7- [2- (1-tert-Butoxycarbonyl-ethoxymimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -azethanamlo (-3- (1-allyl-1 H- Tetazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid (syn isomer), m.p.

IR spectrum (nujol); 3300, 3150, 1780, 1720, 1680, 1620, 1520, 1240, 1150, 1090, 1000 cm @ ^-1 .

NMR (DMSO-d _e, fi): 1.40 (12H, bs), 3.67 (2H, m), 4.2 and 4.50 (2H, ABq, JM3Hz), 4.67 (IH, q, J = 6Hz),

4.93 (2H, m), 5.07 (1H, d, J = 5Hz), 5.13-5.37 (2H, m), 5.83 (1H, dd, J = 5 and 8Hz), 5.83-6.22 (1H, m), 8.10 (2H, bs), 9.40 and 9.52 (1H, d, J = 8Hz), (31) 7- (2- (1-phenylethoxymethyl) ) -2- (5-amino-1,2,4-thiadiazole, ol-3-yl) acetamido-3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4- Carboxylic acid (syn isomer), m.p. 175 ° C.

IR (Nujol): 3400, 3250, 3150, 1750, 1650, 1610, 1520, 1400, 1240, 1160.1060, 1000, 700 ^cm-1 wavenumber.

NMR _(DMSO-d6, fi): 1.57 (3H, d, J = 8Hz),

3.73 (2H, m), 4.32 and 4.72 (2H, ABq, J = 131 Iz), 5.22 (1H, d, J = 5Hz), 5.3-5.5 (III, m). ), 5.93 (2H, dd, J = 5 and 8Hz), 7.36 (5H, m), 8.13 (2H, m), 9.57 (1H, s), 9.72 (1H, d, J = 8Hz).

(32) 7- (2- (3,4-Dichloro-phenoxyl-amino) -2- (5-amino-1,2,4-thiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color isomer m.p. 210 ° C.

IR (Nujol): 3450, 3300, 3200, 1760, 1660, I560, 1290, 1210, 1000, 900, 940, 730 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (DMSO-d6, δ): 3.63 (2H, m), 5.17

-45183 006 (JH, d, J = 5Hz), 5.91 (1H, dd. J = S and 8Hz), 641 (1H, m), 7.13-7.73 (311m). 8.28 (2H, bs), 9.87 (1H, d, J = 8Hz).

(33) 7- [2- (p-Tolyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -1-acetamido] -3- (1,3,4-thiadiazole); 2-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 150 ° C. The product is formed in a mixture of o-allyl isomer.

IR (Nujol): 3350, 3250, 1780, 1680, 1630, 1530, 1510, 1230. 1050, 910, 820 ^cm-1 wavenumber.

NMR spectrum (DMSO d δ _f.): 2.23 (1 / 5H, s), 2.27 (9 / 5H, s), 3.71 (2H, m) and 4.61 .4,21 ( 211, ABq, J = 13Hz). 5.23 (1H, d, J = 5Hz), 5.90 (111, m), 7.16 (4H, m),

8.23 (2H, in), 9.56 (1H, s), 9.86 (1H, d, J = 8Hz).

(34) 742- (3-Trifluoromethyl-phenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-allyl-1H-tetrazol-5-yl) -methyl- 3-cephem-4-carboxylic acid (color isomer), m.p. 155 ° C.

IR (Nujol): 3300, 3200, 1770, 1680, 1620, 1520, 1320, 1160, 1120, 1060, 980, 930, 700 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 3.56 and 3.82 (2H, AB quartet, J = 18 Hz), 4.20 and 4.60 (2H, ABq, J = 14Hz), 4.95 ( 2H, m), 5.18 (1H, d, J = 5Hz), 5.12-5.24 (211, m), 5.92 (1H, dd, J = 5 and 8Hz), 5,726.12 ( 1H, m), 7.50 (4H, m), 8.26 (2H, m), 9.84 (1H, d, J = 8Hz).

(35) 7- (2- (3-Trifluoromethyl-phenoxyimino) -2- (5-amino-2,4-thiadiazol-3-yl) -acetamido] -3- (1-methyl-1H-tetrazol-5-yl) - thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 170 ° C.

IR (Nujol): 3300, 3200, 1770, 1680, 1620, 1520, 1320, 1160, 1120, 1060, 930, 790, 700 ^cm-1 wave, at number ·

NMR _(DMSO-d6, δ): 3.77 (2H, m), 3.97 (3H, s), 4.37 (2H, m), 5.27 (IH, d, J = 5 Hz ), 5.95 (1H, dd, J = 5 and 8Hz),

7.60 (4H, m), 8.33 (2H, m), 9.97 (1H, d, J = 8Hz).

(36) 7- {2- (4-Fluorophenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-methyl-1H-tetrazole-5- yl) thiomethane] -3-cephem-4-carboxylic acid (syn isomer), decomposition point 170 C. ^S

IR (Nujol): 3450, 3350, 3200, 1780, 1710, 1680, 1610, 1510, 1590, 1240, 1200, 1170, 1090, 990, 910, 840 cm ^-1 .

NMR _(DMSO-d6, δ): 3.73 (2H, m), 3.93 (3H, s), 4.33 (2H, m), 5.23 (IH, d, J = 5 Hz ), 5.90 (111, dd, J = 5 and 8Hz), 7.17-7.28 (4H, m), 8.37 (2H, m), 9.87 (1H, d, J = 811z). ).

(37) 7- [2- (2,4-Dichloro-phenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color isomer), m.p. 240 ° C.

IR (Nujol): 3250, 1770, 1660, 1620, 1540, 1520, 1280, 1230, 1100, 1050, 970, 920, 810, 750 cm @ -1.

NMR _(DMSO-d6, δ): 3:56 (. 2H m), 5.11 (IH, d, J = 5Hz), 5.91 (., 111, dd, J «S and 8Hz), 6:47 (111, m), 7.47 -7.63 (3H. in), 8.21 (2H, m), 9.81 (1H, d,

J = 8Hz).

(38) 7- {2- (2,4-Dichloro-phenoxy-amino) -2- (5-anino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1,3,4-thiadiazol-2-yl) ) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 165 ° C.

IR (nujol): 3300, 3200, 1770, 1080. 10 1620, 1520, 1250, 1230, 1IQO '

1060, 960, 910, 810 cin at wave number ¹ .

NMR _(DMS0-d6, δ): 3.71 (2H, m). 4.23 and 4.67 (2H, ABq, J = 14Hz), 5.25 (1H.

d, J = 5Hz). 5.93 (111, dd, J = 5 and

8Hz), 7.50-7.67 (311 m), 8.25 (2H, m), 9.57 (1H s). 9.88 (1H, d, J = 8Hz).

(39) 7- [2- (2-Cyclopenten-1-yloxyimino) -2- (5-amino-1,2,4,4-thiadiazol-3-yl) -acetanido] -3-diethyl-3-cfem-4- Carboxylic acid (color isomer), m.p. 165-218 ° C (with decomposition). IR (nujol) 3350, 3250, 3140, 3050.

1750, 1705, 1665, 1625, 1550, 1535 ^cm-1 wavenumber.

. NMR (DMSO-d ₆ + D ₂ O, δ): 1.6 2.6 (4H, m), 2.00 (3H, s), 3.0-3.9 (2H, m), 5.05 (1H, d, J = 4.5Hz), 5.2 -5.5 (1H, m), 5.70 (1H, d, J = 4.5Hz).

5.7-6.3 (2 H, m).

(40) 7- (2-Cyclopentyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-methyl-3-cephem-4-carboxylic acid (colorless) m.p. 170-212 ° C (with decomposition).

IR (Nujol): 3350, 3120, 3050, 1750, 1705, 1668, 1625.1556, 1534 ^cm-1 wavenumber. .

Nuclear Magnetic Resonance Spectrum (DMSO-d ₆ + D ₂ O, δ): 1.3-2.2 (8H,

m), 2.03 (3H, s), 3.0-3.9 (2H, m), 4.77 (1H, broad s), 5.10 (1H, d, J = 4.5Hz), 5.73 (1H, d, J = 4.5Hz).

(41) 7- [2- (2-Cyclohexen-1-yloxyimino) -2- (5-amino) ·

1.2.4-Thiadiazol-3-yl> acetamido] -3-methyl-3-cephem-4-carboxylic acid (color isomer), m.p. 180-205 ° C (with decomposition).

IR (Nujol): 3340, 3250, 3120, 3050, ₄₅ 1750, 1705, 1665, 1625, 1535 cm "l hulláinszámnál.

NMR (DMSO-D _e + D ₂ O, δ): 1.3-2.4 (6H, m), 2.03 (3H, s), 3.1-3.7 (2H, m) .

4.70 (1H, bs), 5.10 (til, d, ₅₀ J = 4.511z), 5.73 (1H, d, J = 4.5Hz),

5.7- 6.0 (2) 1, m).

(42) 7- [2- (2-Cyclopenten-1-yloxyimino) -2- (5-enylno-1,2,4-thiadiazol-3-yl) -acetamido] -2-methyl-3-cephetn-4-carboxylic acid (colorless) 142-148 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1775, 1650, 1630, 1525 ^cm-1 wavenumber.

NMR _(DMSO-d6 + Djo, δ): 1.41 (3H, d,

1-7.51Iz), 1.9-2.6 (4H, m), 3.5 4.1 (1H, m), 5.16 (111, 0.1 J-4.5Hz),

5.2-5.5 (1H, m), 5.6-6.4 (3H, tn ¹⁾

6.62 (1H, d, J = 6Hz).

(43) 7- (2- {3- (N-tert-Butoxycarbonyl-amino) -propoxymethyl} -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamide ] -3- (1,3,4-thiadiazazl-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn65 isomer).

46I

183,006

IR (Nujol): 32ÖO, 3160, 1773, 1685, 1620 ^cm-1 wavenumber.

NMR (DMSO-d "+ D ₂ 0, δ): 1.41 (911, s);

1.6-2.1 (211, m), 2.8-3.3 (2H, m), 3.75 (2H, broad s), 4.0-4.5 (2H, m),

4.35 and 4.65 (2H, ABq, J = 1411z),

5.20 (1H, d, J = 5Hz), 5.83 (1H, d, J = 5Hz), 9.58 (1H, s), (44) 7-12- {3- (N-tert- butoxycarbonyl-amino) -propoxiimmo} -2- (5-amino-l, 2,4-thiadiazol-3-yl) acetamido] -3- [l- (2-hidrpxietil) -lH-tetrazol-5-yl ] thiomethyl-3-cephem carboxylic acid (color isomer).

IR (Nujol): 3200, 3160, 1775, 1720, 1700, 1675, 1620 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (DMSO-d ₆ + D ₂ O, δ): 1.37 (9H, s),

1.5-1.9 (2H, m), 2.6-3.2 (2H, m),

3.4-3.9 (4H, m), 3.9-4.4 (6H, m),

5.10 (1H, d, J = 5Hz), 5.80 (1H, d, J = 5Hz).

(45) 7- [2- {3- (N-tert-butoxycarbonyl-amino) -propoxyimino} -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamide] 3- (5-Methyl-1,3,4-thiadiazol-2-yl) -thiomethyl-3-cetem-4-carboxylic acid (syn isomer).

IR (Nujol): 3300, 3150, 1775, 1710, 1700, 1670, 1650, 1620 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (DMSO-d 6 + D ₂ O, δ): 1.40 (9H, s),

1.6-2.1 (2H, m), 2.71 (3H, s),

2.9-3.3 (2H, m), 3.71 (2H, broad s), 4.0-4.8 (4H, m), 5.18 (1H, d, J = 4.5Hz) , 5.88 (1H, d, J = 4.5Hz).

(46) 7- {2- {3- (N-tert-Butoxy-carbonyl-amino) -propoxymethyl} -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamide ] 3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 81-119 ° C.

IR (Nujol): 33 "), 3180, 1773, 1715, 1700, 1670, 1620 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (DMSO-d ₆ + D ₂ O, δ): 1.35 (9H, s),

1.5-2.0 (2H, m), 2.7-3.2 (2H, m),

3.68 (2H, bs), 3.9-4.5 (4H, m),

3.92 (3H, s), 5.12 (1H, d, J = 4.5Hz),

5.83 (1H, d, J = 4.5Hz).

(47) 7- [2- {4- (N-tert-butoxycarbonylaminomethyl) benzyloxyl} -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamide] -3- methyl 3-cephem-4-carboxylic acid (syn isomer).

IR (nujol): 3300, 3170, 1760, 1680 cm ^-1 .

NMR (DMSO-d _e, 5): 1.65 (9H, s), 2.0 (3H, s), 3.4 (2H, m), 4.14 (2H, d, J = 6Hz ), 5.1 (1H, d, J = 4.5Hz), 5.2 (2H, s), 5.75 (1H, dd, J = 4.5 and 8Hz).

(48) 7- [2-cyclopentyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-hydroxycephem-4-carboxylic acid (color isomer), 169-173 ° C (with decomposition).

IR (Nujol) 3440, 3250, 1750, 1660,

1520,1400,1240,1060,990,720 cm ^-1 .

NMR _(DMSO-d6, δ): 1.7 (8H, m), 2.77 (IH, m), 3.0-3.5 (IH, m), 3.7-4.1 (1H, s), 4.43 (1H, d, J = 6Hz), 4.73 (1H, m), 5.16 (1H, d, J = 5Hz), 5.47 (1H, dd, J) = 5 and 8Hz), 8.02 (2H, broad s), 9.33 (1H, d, J = 8Hz).

(49) 7- [2 - {] - (cyclohexyloxycarbonyl) ethoxylamino} -2 (5-amino-1,2,4-thiadiazol-3-yl) acelamido] -3-cerem-4-carboxylic acid ( color isomer), m.p. 160-163 ° C (with decomposition).

IR (Nujol): 3420, 3300, 3180, 1775, 1720, 1685, 1610, 1520, 1290, 1230, 1040, 980, 740 cm -1.

NMR _(DMSO-d6, δ): 1.50 (311, d, J = 6Hz), 1.0-2.1 (10H, m), 3.62 (2H, m).

4.80 (1H, q, J = 6llz), 4.6-5.0 (1H m), 5.15 (1H, d, J = 5Mz), 5.90 (111, dd, J = 5 and 8Hz), 6.50 (1H, m),

8.13 (2H, bs), 9.39 (1 / 2H, d, J = 8Hz), 9.53 (1 / 2H, d, J = 8Hz) (50) 7- [2- (1-tert- butoxycarbonyl-1-cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color isomer), m.p. 165-169 ° C. (while staring).

IR (Nujol) 3400, 3300, 3200, 1770.

1710, 1680, 1610, 1520, 1290 1240, 1150, 1000, 970, 740 cm at ¹ wave.

NMR _(DMSO-d6, δ): 1.42 (9H, s), 1.77 (4H, m), 2.05 (4H, m), 3.60 (2H, m);

5.13 (1H, d, J = 5Hz), 5.87 (1H, dd, J = 5 and 8Hz), 6.47 (1H, m), 8.13 (2H, m), 9.33 (1H, d, J - 81lz) (51) 7- [2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadlazol-3-yl) -acetamido] -3- (1- {2- ( N, N-dimethylamino) ethyl} 1H-terazol-5-yl] thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 170-173 ° C (with decomposition).

IR (Nujol): 3400, 3280, 3150, 1760, 1665, 1610, 1520 cm ^-1 . '(52) 7- [2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiazol-3-yl) -acetamido] -3- [1- {3- (N, N- dimethylamino) propyl) -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 170-175 ° C (with decomposition).

IR (Nujol) 3400, 3280, 3160, 1760.

1665, 1610, 1520 cm ^-1 wave number.

(53) 7- [2- (2-Propynyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [1- {3- (N-tert- butoxycarbonylamino) -propyl} -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 85-90 ° C (with decomposition)

IR spectrum (nujol): 3400, 3290, 3200, 1770 1680, 1620, 1520 cm ^-1 .

(54) 7- (2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [1- {3- (N-tert-butoxycarbonylamino) -propyl} -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 185-190 ° C (with decomposition)

IR (Nujol): 3300, 3200, 1770, 1680 1620, 1520 cm ^{-1 at} (55) 7-12- (2,2,2-trifluoroethoxyimino) -2-p-amino-1,2,4-thiadiazole 3-yl-acetamido] -3- (1-carboxymethyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer) m.p. 130-132 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1720, 1670, 1620, 1520 cm ^-1 .

(56) 7- [2- (1-Carboxy-2-methyl-propoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- {3- ( N-tert-butoxycarbonylamino) -propyl} -1H-tetrazol-5-yl] -thio47

-471

183,006 methyl 3-cephem-4-carboxylic acid (color isomer), m.p.

192-195 ° C (with decomposition).

IR (Nujol): 3400-3200, 1780, 1680, 1520, 1450, 1360, _ 1240, 1160, 1620, 1020, 730 ^cm-1 hulláinszámnál.

(57) 7-1,2 '(1-Carboxypropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [1- {3- (N-tert-butoxycarbonyl) -amino) -propyl} -1H-tetrazol-5-yl] -thioethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 185-192 ° C (dec.

IR (Nujol): 3300, 3200, 1770, 1680, 1620, 1520, 1450, 1360, 1250, 1160, 1000, 730-710 cm @ -1.

(58) 7- [2- {3- (N-tert-butoxycarbonylamino) propoxyimino} -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamide] -3- [1 {3- (N-tert-Butoxycarbonylamino) -propyl) -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer).

IR (Nujol): 3300, 3150, 1775, 1715, 1675, 1650, 1615 ^cm-1 wavenumber (59) 7- (2- (1 - karboxietoxiimino) -2- (5-amino-2,4 -thiadiazol-3-yl) -acetamido] -3- [1- {3- (N-tert-butoxycarbonylamino) -propyl} -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4- arm: bonic acid (color isomer), m.p. 110-115 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1680, 1600, 1520, 1250, 1000, 720 ^cm-1 wavenumber.

(60) 7- (2- (1-Carboxy-1-cyclopentyloxy-oxy) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- {3- (N-tert-butoxycarbonylamino) -propyl} -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 200-205 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1680, 1520, 1250, 1160, 1000 cm @ ^-1 .

(61) 7- (2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1- (3-morpholinopropyl) -1H-tetrazole-5 -yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 190-194 ° C (with decomposition),

IR (Nujol): 3300, 3200, 1770, 1680, 1610, 1530, 1240, 1180, 1090, 1060, 880, 760 ^cm-1 wavenumber.

(62) 7- (2- (1-Carboxy-1-methylethoxyimino) -2- (5-amyl, 2,4-thiadiazol-3-yl) -acetamido] -3- (1- {3- (N- tert-butoxycarbonylamino) -propyl} -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer).

IR (Nujol) 3300, 3150, 1770, 1680,

1520,1240,1160,990 ^cm-1 wavenumber.

(63) 7- [2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl-3-yl) -acetamido] -3- (4-methyl-5-oxo-6-) hydroxy-4,5-dihydro-1,2,4-triazin-3-yl) thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 210-214 ° C (with decomposition).

IR (Nujol): 3250, 3180, 1760,

1720-1660, 1590, 1520, 1240, 1090, 1050, 720 ^cm-1 wavenumber.

(64) 7- (2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1- {4- (N-tert-butoxycarbonylamino)) butyl} -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

IR (Nujol): 3300, 3200, 1770, 1680, 48

1620, 1520, 1240, 1160, 1090, 1060, 890 ^cm-1 wavenumber.

(65) 7- [2-Carboxy-phenoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (3-piperidinopropyl) -155-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 223-228 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1670, 1610, 1520 ^cm-1 wavenumber ynal Dissolve.

ig (66) 7- [2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-carboxymethyl-1H-tetrazol-5-yl) -thiomethyl-3 -cephem-4-carboxylic acid (color isomer), m.p. 170-175 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1765, 1720, ₁₅ 1660, 1620, 1520 ^cm-1 wavenumber. .

(67) 7- (2-Carboxymethoxyimino-2- (5-amino-1,2,4-liadiazol-3-yl) -acetamido] -3- (1- (6- (N-tert-butoxycarbonylamino)) - hexyl} -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), light yellow powder.

νυ8) 7- (2- (1-Carboxyethoxyimino) -2- (5-amino-1,2,4-thiazol-3-yl) acetamido] -3- (5- (N-tert-butoxycarbonylamino) ) -methyl-1,3,4-thiadiazol-2-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 210-215 ° C (with decomposition).

IR (Nujol): 3300, 1770, 1680, 1620, 1520, 1240, 1140 ^cm-1 wavenumber.

(69) 7- [2- (2-Propynyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (3-aminopropyl) -1H-tetrazole 5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 165-170 ° C (with decomposition).

IR (Nujol): 3450, 3300, 3210, 1770, 1670, 1620, 1525 ^cm-1 wavenumber.

(70) 7- (2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (3-aminopropyl) -1H-tetrazol-5-yl] ] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 195-200 ° C (with decomposition).

IR (Nujol): 3150, 1760, 1660, 1640,

1520 cm 'at wave number ¹ .

(71) 7- [2- (1-Carboxy-2-methyl-propoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamide] -3- [1- (3-aminopropyl) 1H-Tetrazol-5-yl] -thiomethyl-3-cephem-4-carbonsa (color isomer), m.p. 183-189 ° C (with decomposition).

IR (Nujol): 3400-3100, 3150, 1770, 1670, 1620, 1520, 1380, 1280, 1230, 1180, 1100, 1020, 900, 730 ^cm-1 wavenumber.

(72) 7- [2- (1-Carboxypropoxyimino) -2- (5-amino-1,2,450-thiadiazol-3-yl) -acetamido] -3-11- (3-aminopropyl) -1H-tetrazole-5 -yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 183-188 ° C (with decomposition).

IR (nujol) 3400-3150, 1770, 1670,

1620, 1530, 1380, 1280, 1230,

1180, 1100, 1050.1010, 730 ^cm-1 wavenumber.

(73) 7- [2- (1-Carboxyethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-11- (3-aminopropyl) -1H- tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p.

185-188 ° C (with decomposition).

IR (Nujol): 3300, 3150, 1760, 1660, 1620, 1520, 1230, 1000, 720 ^cm-1 wavenumber.

(74) 7- [2-Carboxymethoxyimino-2- (5-amino-1,2,4-thia55-diazol-3-yl) -acetamido] -3- [1- (4-aminobutyl) -1H-tetrazole- 481

183,006

5-yl] -thioethyl 3-celem-4 carboxylic acid (color isomer), m.p. 191-194 ° C (with decomposition).

IR (nujol): 3300, 3150, 1760, 1670, 1620, 1520, 1230, 1170, 1050, 890, 740, 720 cm @ -1.

(75) 7- (2- (1-Carboxy-1-yl-ethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1- (3-aminopropyl) - 1H * -tetrazol-5-yl] -liomethyl-3-cephene-4-carboxylic acid (color isomer), m.p. 200-203 ° C (with decomposition).

Spcktrinn IR (Nujol): 3300, 3150, 1760, 1660, 1620, 1520, 1160.990 ^cm-1 wavenumber.

(76) 7- [2- (1-Carboxy-1-cyclopentyloxy-amino) -2- (5-anino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1- (3-aminopropyl) 15 H-terazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (syn isomer), m.p. 202-205 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1760, 1660, 1620, 1520, 1180, 1060, 1000,

730 cm at wave number ¹ . 20 (77) 7- (2- (1-Carboxyethoxyimino) -2- (5-amino-1,2,4-thiadtazol-3-yl) -acetamido] -3- (5-amino-ethyl-1,3,4) -thiadiazol-2-yl) -thiomethyl-3-cephem-4-cialic acid (color isomer), m.p. 207-210 ° C (with decomposition).

IR (Nujol): 3300, 3150, 1760, 1660, 25 1620, 1520, 1230, 1170, 1090, 1060, 1040, 990 ^cm-1 wavenumber.

(78) 7- [2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1- (6-aminohexyl) -1H-tetrazole-5-one. -yl-thiomethyl 3-cephem-4-carboxylic acid (color isomer), m.p.

185-188 ° C (with decomposition).

IR (Nujol) 3300, 3200, 1760, 1670,

1620, 1520, 1240, 1180, 1060 cm ^-1 . 35 (79) 7- [2- (3-Aminopropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid (syn isomer), m.p.

165-183 ° C (with decomposition).

IR (nujol): 3150, 1765, 1660, 1630, 401570, 1520 cm ^-1 .

(80) 7- {2- (3-Aminopropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1- (2-hydroxyethyl) -1H-tetrazole-5- N-thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 170-185 ° C (with decomposition).

IR (Nujol): 3140, 1760, 1660, 1610, 1580, 1520 cm ^-1 .

(81) 7- [2- (3-Aminopropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (5-methyl-1,3,4-thiadiazole-2- il) thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p.

192-195 ° C (with decomposition).

IR (nujol): 3250, 3140, 1760, 1640, 1620, 1585, 1525 cm ^-1 .

(82) 7- [2- (3-Aminopropoxyimino) -2- (5-amino-1,2,4-55-thiadiazol-3-yl) -acetamido] -3- (1-methyl-1H-tetrazole-5- il-thio 'methyl-3-cephem-4-carboxylic acid (color isomer), m.p.

180-184 ° C (with decomposition).

IR (Nujol): 3160, 1760, 1660,

At 1590 cm ^-1 .

(83) 7- [2- (4-Aminomethyl-benzyloxyimino) -2 (5-amino-2,4-thiadiazol-3-yl) -acetamido] -3-methyl-3-cephem-4-carboxylic acid (color isomer), m.p. 230-240 ° C (with decomposition).

IR (Nujol): 1750 ^cm-1 wavenumber.

(84) 7- (2 (3 - aminopropoxyimino) -2- _(5-amino-2) ⁶⁵ 4-thiadiazol-3-yl) acetamido] -3- (l- (3-yl) acetamido] - 3- (1- (3-aminopropyl) -1H-tetrazol-5-yl) -liomethyl-3-cephem-4-carboxylic acid (color isomer).

IR (Nujol): 3300, 3150, 1760, 1660, 1607, 1595, 1520 ^cm-1 wavenumber (85) 7- (2- (O-karboxibenziloxiimino) -2- (5-thiadiazol-3 amino1.2.4- -yl) -acet [nido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p.

150-155 ° C (with decomposition).

IR (Nujol) 3400, 3290, 3160, 2500.

1770, 1720, 1615, 1520 cm @ ¹ .

(86) 7- (2 ^(a, -karboxibenziloxiimino) -2- (5-amino1.2.4- thiadiazol-3-yl) acetyl acetamido] -3-cephem-4-carboxylic acid (syn isomer), mp .: 170 -175 ° C (with decomposition).

IR (Nujol): 3400, 3280, 3160, 2600, 1770, 1720, 1670, 1625, 1520 ^cm-1 wavenumber.

(87) 7- [2- (α-Carboxybenzyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-1- (2-aminoethyl) -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer) m.p. 190-195 ° C (with decomposition).

IR (Nujol): 3400, 3300, 3150, 1765 1670, 1610, 1520 ^cm-1 wavenumber.

(88) 7- (2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadlazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color isomer), m.p. -185 ° C (with decomposition).

IR (Nujol): 3350, 3250, 1770, 1720 1680, 1630, 1530 ^cm-1 wavenumber.

(89) 7- [2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- {3- (4-methyl-1-piperazinyl) propyl} -1H-tetrazol-5-yl] thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 185-190 ° C (with decomposition).

IR (Nujol): 3300, 1760, 1670, 1600 1520 ^cm-1 wavenumber.

(90) 7- [2- (1-Carboxy-2-methyl-propoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -cephalosporanic acid (color isomer).

IR (Nujol): 3400-3150, 1770, 17301670, 1720, 1620, 1460, 1370, 1230, 1030, 730 ^cm-1 at a wave number.

(91) 7- (2- (1-Carboxypropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl 3-cephem-4-carboxylic acid (color isomer), m.p. 153-158 ° C (with decomposition).

IR (Nujol): 3300, 3180, 1770, 17201670, 1620, 1520, 1220, 1060, 1000, 900, 730 ^cm-1 wavenumber.

(92) 7- (2- (1-Carboxypropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -cephalosporanic acid (color isomer), m.p. 115-120 ° C. (during decomposition).

IR (Nujol): 3400, 3300, 3200, 1770, 1720-1670, 1620, 1520, 1230, 1030-1010, 890, 740 to 720 ^cm-1 wavenumber.

(93) 7- (2- (1-Carboxyethoxyimino) -2 (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1,3,4-yl thiazole); 2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer), m.p. 165-168 ° C (with decomposition).

IR (Nujol) 3400-3200, 1770, 1710, 49

-491

1S3 006

1670, 1620, 1520, 1230, 1170, 1000, 900, 720 cm @ -1.

(94) 7- (2- (1-Carboxy-1-methylethyloxy) amino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) ) thioethyl 3-cephem-4-carboxylic acid (color isomer), m.p.

164-167 ° C (with decomposition).

IR (Nujol): 3300, 3200, 2800-2300, 1770, 1720-1660, 1620, 1520,

1160, 1060, 990, 800 cnf *.

(95) 7- (2- (1-Carboxy-1-cyclopentyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetanido] -3- (1,3,4) -thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 165-169 ° C (with decomposition).

IR (Nujol): 3300, 3180, 1770, 1720 1660, 1620, 1520, 1240, 1180, 1060, 1000, 720 ^cm-1 wavenumber.

(96) 7- (2- (1-Carboxy-1-methylethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-eephem-4-carboxylic acid (color isomer), mp 215-220 ° C (with decomposition).

IR (Nujol): 3400, 3250, 3200, 1770, 1670, 1520, 1290, 1240, 1160, 1000, 980, 740 ^cm-1 wave number, (97) 7- (2- (t-k * iboxietoxiimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (colorless) m.p. 180 ° C.

IR (Nujol): 3300, 3150, 1770, 1680, 1610, 1520, 1260, 1100, 1040, 1000 cm ^-1 .

(98) 7- [2- (1-Carboxyethoxyimino) -2- (5-amino-1,2,4-thiazol-3-yl) acetamido] -3-cephem-4-carboxylic acid (color isomer), m.p. -235 ° C (with decomposition).

IR (Nujol): 3400, 3250, 3150, 1760, 1720, 1660, 1610, 1550, 1290, 1240, 1170.970, 740 ^cm-1 wavenumber.

(99) 7- [2- (1-Carboxy-1-cyclopentyloxyimino) -2454-tmino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color isomer), m.p. 212-217 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1670, 1620, 1520, 1280, 1240, 1180, 1000, 970, 730 cm- ¹ .

(100) 7- [2- (1-Carboxyethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -cephalosporanic acid (color isomer).

IR (Nujol): 3300, 3200, 1770, 1710, 1670, 1520, 1230, 1040 ^cm-1 wavenumber.

(101) 7- [2- (1-Carboxy-1-methylethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] - [1- (2-aminoethyl) -1H-tetrazole-5- yl] -thiomethyl-3-cepherm-4-carboxylic acid (syn isomer), m.p. 195-200 ° C (with decomposition).

IR (Nujol): 3150, 1760, 1670, 1620, 1520, 1170, 990 ^cm-1 wavenumber.

(102) 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-1- {3- (4-methyl-1-piperazinyl) ) propyl} -1H-tetrazole-5-yl-thiomethyl-3-cephem-4-carboxylic acid. (color isomer), m.p. 175-180 ° C (with decomposition).

IR (Nujol): 3300, 1770, 1650, 1610, 1520 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 1.70-1.80 (811, m),

1.80-2.10 (211, m), 2.30-2.50 (4H, m). 2.60 (3H, s), 2.8-3.3 (611, m),

3.60 (2H, bs), 4.30 4.50 (4H, mL, 4.67-4.83 (1H, m), 5.10 (1H, d, J = 4Hz), δ, 77 (1) 1, dd, J = 4 and 8Hz), 8.17 (2H, N-, 9.50 (111, d, J = 8Hz).

(103) 7- (2-Cyclopentyloximino-2- (5-amino-1,2,4-thia-10-diazol-3-yl) -acetamido] -3-carbamoyloxymethyl-3-carboxylic acid (color isomer), m.p. 175-150 ° C (with decomposition).

IR (Nujol) 3400. 3300, 3180, 1770,

1710, 1670, 1620, 1520 cnf ¹ 15.

NMR _(DMSO-d6, δ): 1.40 to 2.0 (811, m),

3.53 (2H, broad s) -, 4.67 and 4.85 (2H, ABq, J = 13 I lz), 4.67-5.07 (1H, m), 5.15 (1H, d, J = 5Hz) ), Δ 5.78 (1H, dd, J = 5 and 8Hz), 6.55 (2H, broad s), 8.08 (2H, broad s),

9.45 (1H, d, J = 8Hz).

(104) 7- (242-Cyclopenten-1-yloxyimino) -2- (5-amino-6,2,4-thiadiazol-3-yl) -acetamide? -3-carbamoyloxymethyl 3-cephem-4-carboxylic acid («dt -teaenetl, 16-5-170 ^e C (with decomposition).

IR spectrum (mtjot): WJ, VHC,

167®, 1615, 1520 cm ^-1

Mimózámnál.

Spektatm NMR _(DMSO-d6, δ): 1.97 to 2.47 (4H, m);

3.50 (2H, bs), 4.65 and 4.85 (2H, ABq, J = 1311 /), 5.12 (1H, d, J = 5Hz), 5.17-5.50 (1H , m), 5.67-6.27 (3H, m), 6.55 (2H, broad _s ), 8.10 (2H, broad s), 9.47 (1H, d,

J = 8Hz).

(105) 7- {2-cyclopentyloxyimino-2- (5-amino-1,2,4-thiazolidin-3-yl) acetamido] -2-methyl-3-eephem-4-carboxylic acid (syn isomer).

<0 IR (Nujol): 3420, 3400, 3270, 3180, 2430, 1790, 1775, 1690, 1675, 1640, 1615, 1600, 1495 ^cm-1 wavenumber.

NMR _(DMSO-d6, 5): 1.43 (3H, d, J = 7Hz), <5 1.5-2.1 (8H, m), 3.73 (IH, q, J = = 7Hz), 4.5-4.9 (1H, m), 5.07 (1H, d, J = 5Hz), 5.84 (1H, dd, J = 5 and 9Hz), 6.50 (1H , d, J = 6Hz), 8.02 (2H, bs), 9.38 (1H d, J = 9Hz).

(106) 7- (2- (2-oxo-3-tetrahydrofuryloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl)) - acetamido] -3- (1,3,4-thiadiazole) m.p. 165-170 ° C (with decomposition). -i) -thiomethyl-3-cephem-4-carboxylic acid (color isomer).

IR (nujol): 3300, 3200, 1770, 1680,

1620, 1525 cm ”at ¹ wave.

Nuclear Magnetic Resonance Spectrum (DM'Od ₆ , δ): 2.27-2.70 (2H m),

3.70 (2H, broad s), 4.17-4.73 (4H, m), 5.15 (1H, d, J = 4Hz), 5.18 (1H, t, J = 7Hz, δ, 83 (1H, dd, J = 4 and βθ8Hz), 8.13 (2H, bs), 9.50 (1H, s), 9.60 (1H, d, J = 8Hz).

(107) 7- (2- (2-Oxo-3-tetrahydrofuryloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color) 175-180 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1775, 1670,

-501

183,006

1620, 1530 cm at wave number ¹ .

NMR _(DMSO-d6, δ): 2,35-2.67 (2H, m);

3.57 (2H, bs), 4.17-4.50 (2H, m), 07 (HI, d, J = 4Hz), 5.15 (111, t, J = 8Hz), 5.82 ( 1H, dd, J = 4 and 8Hz), 6.43 (111, t, J = 5Hz), 8.17 (2H, broad s), 9.60 (1H, d, J = 8Hz).

(108) 7- (2- (1-Cyclohexyloxycarbonylethoxyimino) -2 (5-methylthio-1,2,4-thiadiazol-3-yl) -acetamido) -3- [1- {3 (e.g. (M 1 -hydroxymethyl) -propyl) -1H-tetrazol-5-yl) titanium glycol-3-cephem-4-carfenic acid (color isomer), m.p.

145-150 ° C (with decomposition).

IR spectrum (nujol). 3400-3250, 1780, 1680, 1620, 1520, 1240, 1220, 1160, 1100, 1000, 740, 720 ^cm-1 wavenumber.

NMR spectrum (DMSO d δ _sixth): 1.0-2.3 (15H, ra),

1.40 (9H, s), 3.0 (2H, tn), 3.7 (211, m), 4.3 (4H, m), 4.5-5.0 (1H, m), 4 , 77 (1H, q, J = 711 /), 5.13 (1H, d, J = 5Hz), 5.86 (1H, m), 6.83 (1H, m), 8.12 (2H, broad s), 937 (1 / 2H, d, J = 8Hz), 9.51 (1/211, d, J = 8Hz).

(109) 7- (2- (1-benzyloxycarbonylethoxyimino) -2- (5-amino-1,2,4-thiadiazyl-3-yl) acetamido) -3-cephem-4-carboxylic acid (color isomer), mp: 177-180 ° C (during rollover),

IR (Nujol): 3400, 3300, 3200, 1770, 1730, 1680, 1610, 1520, 1240, 1160, 1040, 980.740 ^cm-1 wavenumber

NMR _<DMSO-d6, o): 1.47 (3H, d, J = 7Hz),

3.57 (211, m), 4.88 (HL q, 1 = 711 /),

5.10 (1H, d, J = 5Hz), 5.18 (2H, s),

5.87 (1H, dd, J = 5 and 8Hz), 6.45 (1H, m), 7.31 (5H, broad s), 8.10 (2H, broad s), 9.40 and 9, 55 (1H, d, J = 8Hz).

(110) 7 - (2- (1b, 2 -Exo-2-carboxyl-ethoxyimino) -2- (5-amiflo-1,2,4-thiazol-3-yl) -acetamido] -3- [1- (3- (N-tert-butoxy-cafbonriarnino) 1-propyl) -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (syn isomer), m.p. 113-117 ° C (with decomposition).

Speklnnn IR (Nujol): 3300, 3200, 1780, 1680, 1620, 1520, 1250, 1160, 1100, 1040, 1000, 740, 700 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 1.43 (9H, s), 133 (3H, d, J = 6Hz), 2.0 (2H, ra), 3.03 (2H, ra), 3.70 (2K, m), 4.10-4.67 (4H, m), 4.88 (1H, q, J = 6Hz), 5.10 (1H, d, 3-5Hz), 5, 17 (2H, s), 5.80 (1H, dd, J = 5 and 8Hz), 6.53 (1H, m),

7.30 (5H, s), 8.10 (2H, broad s), 9.40 and 9.55 (1H, d, J = 8Hz).

(111) 7- (2- (1-Butoxycarbonyl-ethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido) -3-cephem-4-carboxylic acid (color isomer) 147-151 ° C (with decomposition).

IR (Nujol): 3400, 3300, 3200, 1770, 1720, 1680, 1610, 1520, 1280, 1235, 1155, 1045, 980, 740 ^cm-1 wavenumber.

NMR (DMSO-d _6> δ): 0.87 (3H, t, J = 6Hz), 1.46 (3H, d, J = 7 Hz), 0.8-1.8 (4H, m) , 3.6 (211, m), 4.08 (2H, t, J = 6Hz),

4.74 (1H, q, J = 7Hz), 5.08 (1H, d, J = 5Hz), 5.83 (111, dd, J-5 and 8Hz), 6.4 (111, m), 8.07 (2H, s / sharp s), 9.39 and 9.44 (111, d, KCl / I (112) 7- [2- (1-butoxycarbonyl-ethoxyimino) -2- (Samino- 1,2,4-Thiadiazol-3-yl) -acetamido] -3-tert- {(N-tert-butoxycarbonylamino) propyl} -1H-indazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), op; 149 - 155 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1790, 1700, 1620, 1520, 1250, 1160, 1100, 1040, 1W, 740, 720 cm ^-1 .

NMR (DMSO-d δ _sixth): 0.26 (3H, t, J = 7Hz),

1.40 (9H, s), 1.0-1.7 (4H, m), 1.43 (3H, d, J = 7Hz), 1.7-2.3 (2H, m), 3, 0 (2H, m), 3.7 (2H, m), 4) - 4.5 (6H, m), 4.77 (1H, q, J = 7Hz), 5.15 (1H, d, J = 6Hz), 5.8 (1H, m), 8.13 (211, broad s), 9.5 (111, m).

(113) 7-) 2- (2-D-Phenylglycyl} aminoethoxyimino) -2- (5ainino-1,2,4-tradiazol-3-yl) acetamido] -2-methyl-3-cephem-4-carboxylic acid (color) 204-222 ° C (with decomposition).

IR (Nujol): 3260, 3150, 1760, 1665, 1616, 1512, 1400, 1045 ^cm-1 wavenumber.

(114) 7-) 2- (3-D-Phenylglycylaminopropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -2-methyl-3-cephhenyl-4-carboxylic acid (color isomer 203-231 ° C (with decomposition).

IR (nujol): 3280, 1170, 1760, 1660, 1600, 1520, 1400 cm @ -1. .

Nuclear Magnetic Resonance Spectrum (D ₂ ObDCl, δ): 1.47 (3H, d, J = 7.5Hz), 1.7-2.3 (2H, m), 3.40 (2H, t, J 7Hz), 3.88 (1H, q, J = 7.5Hz),

4.33 (2H, t, J = 61 H), 5.18 (1H, d, J = 4.5), 5.20 (1H, s), 5.95 (1H, d, J = 4.5 Hz) ), 6.90 (1H, d, J = 6.0Hz),

7.57 (5H, s).

(115) 7- (2- (1-Cyclohexyloxycarbonylethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (3-aminopropyl) -1H-tetrazole-5- III-J-thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 175-178 ° C (with decomposition).

IR spectrum (nujol): 3400-3200, 1765, 1680, 1610, 1520-12020, 1100, 1000, 890, 790 cm ^-1 .

NMR _(DMSO-d6, δ): 0.9-2.0 (13H, m);

2.2 (2H, m), 2.9 (2Η, m), 3.6 (2H, m), 4.0-5.1 (5H, m), 4.76 (1H, q, J = 7Hz), 5.03 (111, d, J = 5Hz), 5.77 (1H, m), 8.17 (211, broad s), 9.45 (1H, m).

(116) 7- [2- (1-Benzyloxycarbonylethoxyimino) -2- (5 amino-1,2,4-thiadiazol-3-yl) -acetanimido] -3- [1- (3-aminopropyl) -1H-te Trazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 162-166 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1760, 1680, 1620, 1520, 1100, 1040, 1000, 740 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (DMSO-d6, δ): 1.47 (311, d, J = CdI2),

1.23 (211, m), 2.90 (2H, m). 3.60 (211, m), 4.43 (411, m), 4.90 (111, q, J = 6Hz), 5.07 (1H, d, J = 511 /), 5.20. 51

-51183 006 (2Η, s), 5.77 (1H, m), 7.43 (5H, s),

8.23 (2 H, m), 9.57 (1 H, m).

(117) 7- [2- (1-Butoxycarbonylethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (1-aminopropyl) -1H-tetrazol-5-yl] - thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 158-163 ° C (with decomposition).

IR (Nujol): 3400-3200, 1770, 1680, 1610, 1530, 1300, 1290, 1050, 1040, 1000, 960, 900, 790, 740,

720 cm at wave number ¹ . 10 (118) 7- [2- (3-Aminopio-poxy-imino) -2- (5-amino-2,4-thiadiazol-3-yl) -acetamido] -2-methyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester, hydrochloride ( 91 DEG -156 DEG C. (with decomposition).

IR (Nujol): 3150, 1780, 1745, 1670, 151625, 1525 cm ^-1 .

(119) 7- (2- (3-Aminopropoxy-amino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3- cephem-4-carboxylic acid pivaloyloxy methyl ester hydrochloride (color isomer), m.p. 110-125 ° C (dec. 20).

IR (Nujol): 1780, 1745, 1670, 1625, 1525 ^cm-1 wavenumber.

(120) 7- [2- (3-Anrinopropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (5-methyl-1,3,4-thiadiazole -2-yl) -thiomethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester hydrochloride (color isomer), m.p. 88-153 ° C (with decomposition).

IR (Nujol): 2150, 1780, 1745, 1650,

1625, 1525 cm '. 30

Nuclear Magnetic Resonance Spectrum (DMSO-d, + D ₂ O, δ): 1.16 (9H, s),

1.6-2.2 (2H, m), 2.6-3.1 (2H, m),

2.68 (3Η, s), 3.76 (2H, broad s),

4.20 and 4.53 (2H, ABq, J = 18Hz),

4.24 (2Η, broad s), 5.18 (1H, d, 35 J = 4.5Hz), 5.6-6.0 (3H, m).

(121) 7- [2- (3-Amino-propoxyimino) -2- (5-anno-1,2,4-thiadiazol-3-yl) -acetamido} -3- {1- (2-hydroxy-ethyl) -1H-tetrazole-5-fl]. -thiomethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester hydrochloride (color isomer), m.p. 150-175 ° C 40 (with decomposition).

IR spectroscopy (Nujol): 3150, 1780, 1740, 1670, 1630, 1520 ^cm-1 wavenumber.

(122) 7- [2- (3-Aminopropoxy-amino) -2- (5-amino-2,4-thiadiazol-3-yl) -acetamido] -3- (1,3,4-thiadiazol-2-yl) -45 pivaloyloxymethyl ester of thiomethyl-3-cephem-carboxylic acid hydrochloride (color isomer), m.p. 96-155 ° C (with decomposition).

IR (Nujol) 3300, 3150, 1775, 1730,

1670, 1625, 1530 cm ^{-1 at} A-50.

(123) 7- [2- (4-Amino-dimethyl-benzyloxy-methoxy) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-methyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester hydrochloride (syn-isomer), m.p. 160-168 ° C (with decomposition).

IR (Nujol): 1780, 1745, 1670, 1628 ^cm-1 wavenumber.

(124) 7- [2- (Allyloxylmino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (2-aminoethyl) -1H-tetrazole- 5-yl] thiomethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester form (color isomer), m.p. 95-105 ° C (with decomposition).

IR (Nujol): 1790, 1735, 1452, 1370, 1118, 990 cm ^-1 .

NMR (DMSO-d _é + D ₂ 0, δ) 1.2 (9H, s);

3.2-3.35 (2H, m), 3.7 (2H, broad s),

4.2-4.6 (2H, m), 4.7 (2H, broad s), 4.8-5.2 (1H, m), 5.25 (1H, d, J = 4.5Hz), δ , 45 (2H, m), 5.7-6.25 (2H, m), 5.8 (1H, d T = 4.5Hz).

(125) 7- (2-Cyclopentyloxyimino-2-amino-1,2,4-thiadiazol-3-yl) -acetamido] -2-methyl-3-cephem-4-carboxylic acid 1-acetoxyethyl ester (color isomer).

IR (Nujol): 3400, 3310, 3150, 1780, 1770, 1750, 1675 cm ^-1 .

(126) 7- (2-cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -2-methyl-3-cephem-4-carboxylic acid 1-isobutyryloxyethyl ester (color isomer), amorphous powder.

IR (Nujol) 3400, 3300, 3170, 1780,

1745, 1675, 1620, 1525 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (DMSO-d6 ₎ δ): 1.08 (6H, d, J = 7Hz),

1.2-2.2 (14H, m), 2.2-2.9 (1H, m), 3.88 (1H, q, J = 7Hz), 4.6-5.0 (1H, m), 5.12 (1H, d, J = 4.5Hz), 5.90 (1H, dd, J = 4.5 and 8Hz), 6.63 (1H, d, J = 7Hz), 8.06 (2H , broad s), 9.43 (1H, d, J = 8Hz).

(127) 7- (2- (2-Cyclopenten-1-yloxyimino) -2- (5-amino-2,4-thiadiazol-3-yl) -acetamido] -2-methyl-3-cephem-4-carboxylic acid -acetoxypropyl ester (color isomer), m.p. 11 - 28 ° C (with decomposition).

IR (Nujol): 3400, 3280, 3150, 1780, 1750, 1730, 1620 cm ^"1 wavenumber.

(128) 1- {2-Azidoethoxycarbonyloxy) ethyl-7- [2- (2-cyclopenten-1-yloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamide] -2 methyl 3-cephem-4-carboxylate (color isomer), m.p. 85-100 ° C (with decomposition),

IR (Nujol): 3310, 2200, 1760-1785, 1680 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (DMSO-d ₆ + D ₂ O, δ): 1.48 (3H, d, J = 6Hz), 1.5 (3H, d, J = 4.5Hz). 2.0-2.5 (4H, m), 3.5-4.1 (1H, m), 3.63 (2H, t, J = 4Hz), 4.30 (2H, t, J = 4Hz) ), 5.16 (1H, d, J = 4.5Hz),

5.2-5.45 (1H, m), 5.7-6.2 (2H, m), 6.0-6.2 (1H, m), 6.6-6.8 (1H, m), 6.7 (1H, d, J = 6Hz).

(129) 7- [2- (2-Cyclopenten-1-yloxyimino) -2- (S-amino-1,2,4-thiadiazol-3-yl) -acetamido] -2-methyl-3-cephem-4-carboxylic acid-1 -ethoxycarbonyloxyethyl ester (color isomer).

IR (Nujol): 3420-3300, 3150, 1780, 1760, 1675, 1620 cm ^-1 .

(130) 7- [2- {3- (N-tert-Butoxycarbonylamino) -propoxyimino} -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamide] 2-methyl-3- cephem-4-carboxylic acid pivalol) ximethyl ester (color 55 isomer), powder, m.p. 66-75 ° C (with decomposition).

IR (nujol): 3300, 1780, 1745, 1680, 162C = cm ^-1 .

(131) Pivaloyloxymethyl-7- [2- {3- (N-tert-butoxycarbonylamino) -propoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamide] -3- ( 1-Methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), powder.

IR (Nujol): 3300, 1780, 1745, 1680, 1620 ^cm-1 wavenumber.

(132) Pivaloyloxymethyl-7- [2- {3- (N-tert-butoxycarbonyl-65-amino] -propoxyimino} -2- (5-amino-1,2,4-thiadiazol-3-yl) -52183 006-acetamide] - 3- (5-methyl-1,3,4-thiadiazzo) -2-yl) thiomethyl-3-cephem-4-carboxylic acid (color isomer).

IR (Nujol): 3300, 3J5O, 1783, 1745, 1675, 1615 ^cm-1 wavenumber.

NMR (DMSO-d ₆ + D> 0, 5): 1.15 (9H, s), 5 1.37 (9H s.), 1.5-2.0 (2H, m), 2, 65 (3H, s), 2.8-3.2 (2H, m), 3.5-3.8 (211, m), 3.9-4.3 (2H, m),

4.16 and 4.53 (211, ABq, J = 13IIz),

5.17 (1H, d, J = 4.5Hz), 5.6-6.0 (3H, m).

(133) Pivaloloxymethyl-7- {2- [3- (N-tert-butoxycarbonylamino) propoximino-2- (5-amino-1,2,4-thiadiazol-3-yl] acetamido] -3- 1- (2-hydroxyethyl) -1H-tetrazol-5-yl] -thiomethyl-3-cephenr-4-carboxylic acid (color isomer), powder, m.p. 88-101 ° C (with decomposition) .

IR (Nujol): 3300, 1780, 1750, 1675, 1620 ^cm-1 wavenumber.

(134) Pivaloyloxymethyl-7-12- {3- (N-tert-butoxycarbonylamino) -phthoxyphimino} -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3 - (1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylate (color isomer), powder, m.p. 71-84 ° C (with decomposition).

IR Spectrum (Nitroi): 3300, 1780, 1745, 1680,

1615 cm ^{-1 at the} epithelium. 25 (135) P (valoyl-ηxymethyl-7- [2- (2-cyclobexen-1-yloxyl) -2- (5-methyl-1,2,4-thiadiazol-3-yl) -acetamido] -cephalosporanate 93-101 ° C (with decomposition).

IR spectroscopy (Nujol): 3400, 3300, 3180, 1780.30 1740, 1675, 1615, 1525 ^cm-1 huHámszámnál.

(136) 7- (2- (2-Cyclopenten-1-yloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -2-methyl-3-cephem-4-carboxylic acid phthalide -3-yl ester (color isomer), m.p. 131-144 ° C 35 (with decomposition).

IR (Nujol): 3420, 3210, 3150, 1780, 1740, 1675, 1620, 1525 cm ^- 'wavenumber.

(137) 7- [2- (2-Cyclopenten-1-yloxyimino) -2- (5-amino-

1.2.4-Thiadiazol-3-yl) -acetamido} -2-methyl-3-cephem-4-carboxylic acid pivaloltexymester (color isomer), m.p.

124 ° C (with decomposition).

IR (Nujol) 3400, 3300, 3270, 1775,

1740, 1670, 1620, 1520 cm ^{-1 at} 45.

(138) 7- [2- (2-cyclopenten-1 -tloxiimino) -2- _(5-amino-> 2,4-tradíazöl-3-yl) acetamido] -2-methyl-3-cephem-4-carboxylic acid -1-benzoyloxyethyl ester (color isomer), m.p. 132137 ° C (with decomposition). 50 λ spectrum (nujol): 3400, 3300, 3160, 1780, 1738, 1680, 1620 cm @ -1 ^. wave number.

Nuclear Magnetic Resonance Spectrum (DMSO-d ₆ + D ₂ O, δ): 1.43 (3H, d,

J = 7Hz), 1.62 (3H, d, J = 5Hz), 55 1.7-2.4 (4H, m), 3.84 (1H, q, J = 7Hz), 5.0-5 , 4 (1H, m), 5.13 (1H, d, J = 4.5Hz), 5.6-6.3 (3H, m),

6.70 (1H, d, J = 6Hz), 7.16 (1H, q,

J = 5Hz), 7.3-8.2 (5H, m). 60 (139) 7- [2- {4- (N-tert-butoxycarbonylamino) -methyl-benzyloxyimino} -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-methyl- 3-Cephem-4-carboxylic acid pivalol oxymethyl ester (color isomer), powder.

IR (Nujol): 3300, 1780, 1750, 1680 ^cm-1 wavenumber.

(140) 7- {2-Allyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- {2- (N-tert-bulloxycarbonylamino) ethyl) -1H -tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (color isomer), powder.

IR (Nujol): 3300, 1780, 1750, 1680 ^cm-1 wavenumber.

(141) 7-] 2- {2- (N- / N-tert-butoxycarbonyl) -D-phenylglycylamino / ethoxyimino) -2- (5-amino-1,2,4-thiazo] -3-yl acetamido] -2-methyl-3-cephem-4-carboxylic acid (color isomer), m.p. 77-91 ° C (with decomposition).

IR (Nujol): 3300, 3160, 1775, 1680, 1660, 1630, 1525 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 1.37 (9H, s), 1.40 (3H, d, J = 8Hz). 3.1-4.2 (5H, m), 5.08 (1H, d, J = 4.5Hz), 5.10 (1H, d, J = 8Hz), 5.90 (1H, dd, J) = 4.5 and 9Hz), 6.53 (1H, d, J = 7.5Hz). 7.32 (5H, s), 8.13 (2H, broad s), 9.48 (1H, d, J = 9Hz).

(142) 7- {2- {3- (N- [2- (1-Amino-1-cyclohexyl) -acetyl} -amino} -propoxyimino} -2- (5-amino-1,2,4-thiothiazole) 3-yl) acetamido] -2-methyl-3-cephem-4-carboxylic acid (color isomer), m.p. 198-224 ° C (with decomposition).

IR (Nujol): 3250, 3150, 1760, 1640 1580, 1520 cm ^{-1 at} (143) 7- [2- {3- (N- / N-tert-butoxycarbonyl) -D-phenyl] glycylamino] -. propoxyimino} -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -2-methyl-3-cephem-4-carboxylic acid (color isomer).

IR (Nujol): 3300, 3200, 1775, 1700, 1650, 1525 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (DMSO-d ₆ + D ₂ O, δ): 1.3-1.6 (12H, m), 1.6-2.0 (2H, m), 2.8-3.4 ( 2H, m), 3.82 (1H, q, J = 7.5Hz), 3.9-4.3 (2H, m), 5.05 (1H, d, J = 4.5Hz), δ, 83 (1H, d, J = 4.5Hz), 6.48 (1H, d, J = 6Hz).

Example 42

5.7 g 7- [2- (1-tert-butoxycarbonylethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -cephalosporanic acid (color isomer), 3.9 g l - a mixture of (3- (N-tert-butoxycarbonylamino) propyl] -1H-tetrazol-5-thiol and 2.5 g of sodium bicarbonate in 150 ml of a pH 6.8 phosphate buffer solution, After stirring for 6 hours at 70 DEG C., the reaction mixture was cooled with ice and washed several times with ethyl acetate, ethyl acetate was added to the aqueous phase, the mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The residue was triturated with diethyl ether and the precipitate was collected by filtration as a brown powder (3.5 g) 7- [2- (1-carboxyethoxyimino) -2- (5-amino-1,2) , 4-Thiadiazol-3-yl) -acetamido] -3- [1- (3- (N-tert-butoxycarbonylamino) -propyl) -1H-tetrazole-5-11] thiomethyl-3-cephem-4 carboxylic acid (color isomer) m.p. 110-115 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1680, 1600, 1520, 1250, 1000, 720 cm ^-1 .

-53183 006

NMR are (DMSO-d _e + Djo, 5): 1.4 (12H, m), 2.02 (2H, m). 2.98 (2H, t, J = 6Hz),

3.70 (2 H, m). 4.1 4.5 (4H, m),

4.70 (1H, q, J = W. 5.13 1H, d, J-5H / 1.5. 5.85 (1H, d, U5Hz)

Example 43

Using the methods described in Examples 14, 17 and 42, the following animals were prepared:

(J) 7- (244-Chloro-eftaximino) -2- (5-amino-1,2,4-thiadiazol-3-d) acetarthyl} dot-3- (1-aBil-1H-tetrazol-5-yl) thiomethyl -3-ephene-4-carboxylic acid (color isomer), m.p. 120-125 ° C (with decomposition).

NMR (nujol): 3290, 3180, 1770, 1680, 1615, 1580, 1520, 1480 cm '.

(2) 7- [2- (4-Chloro-oxyimino) -2- (5-amine-1,2,4-thia-Ba (4-3-e) -acetate] anitdo-3- (1-niethyl) -1H-tetrazole -5-yl) thio-3-cis-3-cephem-4-carboxylate (syn isomer), m.p. 130135 ° C (with decomposition).

IR Spectrum (Fluoft. 3400, 3300, 3280, 1770 1670, 1615, 1580, 1520, 1480 cm @ ^{-1 of} sulfamate).

(3) 7- {2- (4-Chloro (enoxymethyl) -2- {5-aminoethyl}, 2,4-thiadiazol-3-yl) -acetamyl}} '3- {1- (2-oxybethylethyl) -1H -tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid (syn isomer), m.p. 135-140 ° C (with decomposition).

IR (Nujol): 3400, 3270, 3190, 1770, 1680, 1620, 1585.1520, 1480 ^cm-1 htrllámszámnái.

(4) 7- {2- (4-SpheroTTO-trans-tin) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamide} -3- {2-carboxymethyl-3-oxo-2,3-dihydro 1,2,4-thiazolo [4,3-b] tridazin-6-yl] thi [methyl] -3-cephem-4-carboxylic acid (color isomer), m.p. 140-145 ° C (dec.).

IR spectrum (nujol): 3400, 3300, 3190, 1765, 1700, 1020, 1580, 1540, 1520, 1480 cm @ -1, (5) 7-t2- (4-chlorophenoxymethyl) -2- ( 5-Amino-1,2,4-thiadiazide <d-3-yl) -acid »MoI-3- (Tetrazolo [1,5-b] pyridazin-6-yl) tert-butyl] -biphthalic acid (« m.p. 140145 ° C (with decomposition).

IR (Nujol): 3350, 3240, 1780, 1685 1625, 1530, 1490 em ¹ wavenumber.

(6) 7-η 2 - (tert -butoxyl-2-yl) amino) -2- (5'-trio-1,1'-thiazol-2-yl) -acetamidol-5-thiazol-2-yl-thiadiazol-2-yl) -Tomethyl1-3 -cephem-4-carboxylic acid (color isomer), mp J 05-110 ° C (with decomposition).

IR (Nujol): 3400, 3300, 3180, 1780, 1720, 1680, 1620, 1520 ^cm-1 huUámszámflál.

(7) 7- (2- (trans -Toxoxycarbonylbenzyloxymethyl) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [1- (2- (N-tert-butoxycarbonylamino) ) -ethyl) -1H-tert-azole-Sil] thiomethyl-3-cephetn-4-catonic acid (color isomer), m.p. 105-110 ° C (with decomposition).

IR (Nujol): 3360, 3220, 1785, 1690, 1625, 1525 ^cm-1 wavenumber.

(8) 7- [2- (2-Propynyloxylamino) -2- (5-amino-1,2,4-thiadtazol-3-yl) -acetamido] -3- (2-quinoxyethyl) -1H- tetrazol-5-yl-thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 125-130 ° C (with decomposition).

IR (Nujol) 3400, 3260, 3190, 2580.

1765, 1710, 1670, 1620, 1520 cm ^-1 .

(U> 7- (2- (thiolan-1,1-dioxide-3-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido) -3- (1, 3,4-Thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer), m.p.

IR (Nujol): 3300, 3200, 1770, 1670 1620, 1520 ^cm-1 hullámszáronál (10) 7-f2-alliloxiimino-2- (5-amino-l, 2,4-thiadiazole, 3 .... yl) -acetamido] -3- (1-carboxymethyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p.

140-145 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1720 1670, 1620, 1520 ^cm-1 wavenumber.

(11) 7- (2- (2-Propyryloxyimino) -2- (5-amino-1,2,4-thiazol-3-yl) -acetamido] -3- (1-carboxymethyl-11'-tetrazol-5-yl) ) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p.

135-140 ° C (with decomposition):

IR (Nujol): 3250, 3150, 1770, 1720 1670, 1620, 1520 ^cm-1 wavenumber.

(12) 7- (2-aHyloxyimino-2- (5-amino-1,2,4-azadiazol-3-yl) -acetamido] -3- [1- (2-carboxyethyl) -1H-tetrazol-5-yl]. thiomethyl-3-cephem-4-carboxylic acid (syn isomer), m.p.

140-145 ° C (with decomposition),

IR (Nujol): 3300, 3200, 1770, 1720 1670, 1620, 1520 ^cm-1 wavenumber.

(13) 7- (2- (tert-Butoxycarbonylmethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [142-carboxyethyl) -1H-tetrazole-5- yl] thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 150-155 ° C (with decomposition).

IR (Nujol): 3300. 3200, 1770, 1720 1700, 1620, 1520 ^cm-1 wavenumber.

(14) 7- (2- (tert-Butoxycarbonylmethoxymethyl) -2- (5-amyloxy-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1- (3- (4-methyl) -ptperazinyl) propyl) -1H-tetrazol-5-yl] -tioraetil 3-cephem-4-carboxylic acid (syn isomer), mp .: 220 to 225 ^Q C (dec).

IR (Nujol): 3300, 1700, 1680, 1605, 1520 010 ^-1 .

(15) 7- {2- (1-tert-Butoxycarbonyl-propoxymethyl) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1,3,4-thiadiazol-2-yl) ) -Tamethyl-3-cephem-4-carboxylic acid (color isomer), m.p.

101105 ^ 0 (dec.).

IR (Nujol): 3300, 3150, 1770, 1720, 1620, 1520, 1450, 1370, 1250, 1150, 1010, 900, 840, 720 cm @ -1.

(16) 7- (2- (1-tert-Butoxycarbonylethoxymethyl) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamidoph -3- (1,3,4-thiadiazol-2-yl) > thiomethyl-3-cephen-4-carboxylic acid (color isomer), m.p. 120-128 ° C (with decomposition).

IR (Nujol): 3280, 3180, 1770, 1720, 1680, 1620, 1520, 1240, 1150, 1000, 740, 720 ^cm-1 wavenumber.

(17) 7- (2- (1-Methyl-1-tert-butoxycarbonylethoxymino) -2 (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3 (1,3,4-thiadiazole) 2-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 115-120 ° C (with decomposition).

IR (Nujol): 3280, 3170, 1780, 1720,

-54183 006

1680. 3520, 1140, 990, 750 cm 'hultah.

(18) 7-J2 (l-tert-one butoxakarbonil -ciklopentiloxiitniíiw> 2- _{(5-amino-4-one} 2 íjadáazol-3-yl) -acefrmido] -3- (1,3,4-IJA ) dazazol-2-yl) -tk> m? - {3-cephern-4-cric acid (syn isomer). 140 DEG-343 DEG C. (with decomposition).

(wíjojjk 3300, 3180, 1770, 17203670, 3620, 1520, 1245, 1150, 3060, 995, 840 ^cm-1 hullámszamnál ..

(19) 7-12- (1 -roelal-3-tert-butoxybenzylethoxyimino) 2- (5-amino-3,2,4-pyridazin-3-yl) -3-acetamido] -3-yl- {2- (N-tert-butoxylcafbonslarow) o) -ethyl} -I-tetrazol-5-yl] -thiomethyl-3-one-ee-n-4-yl] -WI-acid (color isomer), m.p.

96- 1Ö0 ⁰ C (under bori®).

IR spectrum (nujol). 3300, 3150, 1780, 1680, 1570, 1240, 1160, 990 cm @ -1.

(20) 7- [2- (1-tert-By-3-oxy] -carbonylethoxyimino) -2- (5-amino-1,2,4-thiaza) -3-f) -acetamido] -3- (1-allyl-1H-tetrazole-5-one) m.p. 96-100 ° C (with decomposition). -Tomethyl-N-cephenyl-carboxylic acid (color isomer).

IR (Nujol): 3300, 3150, 1780, 1720, 1680, 3620, 1520, 1240, 1150, 1090, 1000 ^cm-1 hulláinszámnál.

(21) 7- (2- (1-Phenyl-phenoxy) -2- {5-amino-1,2,4-thiadiazole <4-3-yl) -acetamidol-3- (1,3,4-thiadiazol-2-yl). ) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), decomposes at 175 ° C.

IR (Nujol): 3400, 3250, 3150, 1750, 1650, 1610, 1520, 1400, 1240, 1160.1060, 1000.700 ^cm-1 wavenumber.

(22) 7- (2 - (- totyloxymethyl) -2 "(5 amino-1,2,4-thiazol-3-8M (N, N-H-13,4-thiophene) -Methyl-2> thio-Beta-3-pefcni4- carbomic acid (color isomer), m.p. 150 ° C, mixed with the otoloyl isomer.

IR (nujol): 3350, 3250, 1780, 1680, 1630, 3530, 1510, 1230, 1050, 910.820 cm ^-1 huliámszámnál.

(23) 7- (2- (3-Trifluoromethyl-phenoxy) -amino) -2- (5-amino-2,4-thiadiazole-3-d) -acetamoyl-3- (1-allyl-1H-tetrazol-5-yl) -thiometh-3-cephen-4-one. cyanobenzoic acid (color isomer), m.p. 155 ° C,

IR (Nujol): 3300, 3200, 1770, 1680, 1620, 1520, 1320, 1160, 1120, 1060, 980, 930, 700 ^cm-1 hutíámszámnál.

(24) 7- (2 - {- (trifluoromethyl-phenoxy) -amino) -2-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-methyl-1H-tetrazol-5-yl) -methyl- 1H-tetr3Zol-5-yl) -thiomide-3-ce-fem-4-carboxylic acid (color isomer), m.p. 170 ° C.

IR (Nujol): 3300, 3200, 1770, 1680, 1620, 3520, 1320, 1160, 1120, 1060, 930, 790, 700 ^cm-1 huHámszámnál.

(25) 7- {2- (4-Fluorophenoxy) -mino> 2- (5-amino-}, 2,4-thiadiazol-3-yl) -acetamido] -3- (1-methyl-1H-tetrazol-5-yl) ) -tiometH-3-cephem-4-carboxylic acid (syn isomer), 170 ^° F. bornláspontja

IR (Nujol): 3450, 3350, 3200, 1780, 1710, 1680, 1610, 1510, 1590, 1240, 1200, 1170, 1090, 990, 910, 840 cm ^-1 .

(26) 7- (2- (2,4-Dichlorophenoxy) amino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamoyl] -3- (1,3,4-thiazol-3-yl). -2-yl) -thiomethyl-3-cefcm-4-carboxylic acid (color isomer), m.p. 165 ° C.

IR (Nujol): 3300, 3290, 1770, 1680, 1620, 1520, 1250, 1230, 1100, 1060, 960, 910, 810 cm &lt; -1 &gt;

(27) 7- [2- (3- (N-tert-Butoxycarbonylamino) -propoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido-3 (1,3), 4-Thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (sleigh isomer).

IR (Nujol): 3200, 3160, 1773, 3685, 1620 ^cm-1 wavenumber.

(28) 7- (2- (3- (N-tert-Butoxycarbonylamino) -propoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-fl (2) -hydroxyethyl) -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer).

IR (Nujol): 3200, 3160, 1775, 1720.

1700, 1675, 1620 cm- ¹ (29) 7- (2- (3- (N-tert-butylcarbonylamino) -pyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3) -yl) -acetamido] -3- (5-methyl-1,3,4-thiadiazol-2-yl) -methyl-3-cephem-4-carboxylic acid (color isomer).

IR (Nujol): 3300, 3150, 1775, 1710, 1700, 1670, 1650, 1620 cm @ -1.

(30) 7- (2- (3- (N-tert-Butoxycarbonylamino) -propoxyimino) -2- (5-amino-1,2,4-thiadiazin-3-yl) -acetapnido-3- (1-methyl- 1H-Tetrazol-5-yl ') -thiomethyl-3-cephera-4-carboxylic acid (color isomer), m.p. 81-119 ° C (with decomposition).

IR spectrum (nujol): 3300, 3180, 1773, 1735, 1700, 1670, 1620 cm @ -1 ^. wave number.

(31) 7- (2-Carboxymethoxyimino-2- (5-affine-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1- (2- (N, N-dinethylamine) ethyl) - 1H-Tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 170-173 ° C (dec.).

IR spectrum (nujol): 3400, 3280, 3150, 1760, 1665, 1610, 1520 cm &^lt; -1 &gt;

NMR (DMSO-d ₆ + D, O): 8 2.53 (OH, s).

3.07-3.37 (2H, m), 3.50-3.77 (2H, m), 4.10-4.37 (2H, m), 4.43-4.83 (4H, m) ), 5.10 (1H, d, J = 5Hz).

5.80 (1H, d, J = 511).

(32) 7- (2-Carboxymethoxymino-2- (5-anthio-1,2,4-thiadiazol-3-yl) -acetamido-3-yl - {3- (N, N-dimethylamino) propyl} -1H-tetrazole-541I-thionyl-3-cephem-4-carboxylic acid (color isomer), m.p. 170-175 ° C (with decomposition).

IR (nujol): 3400, 3280, 3160, 1760, 1665, 1610, 1520 an ' ¹ .

NMR _(DMSO-d6, 8): 2.10-2.43 (2H, m);

2.70 (6H, s), 2.92-3.28 (2H, m), 3.45-3.80 (2H, m), 4.17-4.80 (6H, m), δ, Δ (1H, δ, J = 5Hz), 5.84 (1H, dd, J = 5 and 8Hz), 8.15 (2H, bs), 10.1 (1H, d, J = 8Hz).

(33) 7- {2- (2-Propynyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- {3- (N-tert- butoxycarbonylamino) -propyl) -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 85-90 ° C (with decomposition)

IR (nujol): 3400, 3290, 3200, 1770, 1680, 1620, 1520 cm ^-1 .

-55183 006

NMR _(DMSO-d6, δ): 1.40 (9H, s), 1,772.17 (2H, m), 2.78 to 3.23 (2H, m);

3.50 (1H, t, J = 2Hz), 3.73 (2H, broad s), 4.07-4.53 (4H, m), 4.82 (2H, d, J = 2Hz), δ , 15 (1H, d, J = 5Hz), 5.85 (1H, dd, J = 5 and 8Hz),

8.17 (2H, bs), 9.65 (1H, d, J = 8Hz).

(34) 7- [2-Carboxyimide: Ethoxyimino-2- (5-amino-1,2,4-thiadiazole-3-H) -acetamido] -3- [1- {3- (N-tert-butoxycarbonylamino) pr. opil} -1H-tetrazaz-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 185-190 ° C (with decomposition).

IR spectra (nujol): 3300, 3200, 1770, 1680, 1620, 1520 cm ^-1 .

NMR _(DMSO-d6, δ): 1.33 (9H, s), 1,672,12 (2H, m), 2.77 to 3.07 (2H, m);

3.63 (2H, broad s), 4.07-4.43 (4H, m), 4.60 (2H, s), 5.05 (1H, d, J = 4Hz), 5.77 (1H , dd, J = 4 and 8Hz), 8.08 (2H, s), 9.47 (1H, d, J = 8Hz).

(35) 7- (2- (2,2,2-trifluoroethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido} -3- (1-carboxymethyl-1-tetrazole-5) -yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 130-132 ° C (with decomposition).

IR (nujol): 3300, 3200, 1770, 1720, 1670, 1620, 1520 cm ^-1 .

NMR _(DMSO-d6, δ): 3.73 (2H, br s);

4.30 and 4.53 (2H, ABq, J = 14Hz), 4.73 and 4.97 (2H, ABq, J = 8Hz),

5.10 (1H, d, J = 4Hz), 5.35 (2Η, s),

5.87 (1H, dd, J = 4 and 8Hz), 8.23 (2H, s), 9.80 (1H, d, J = 8Hz).

(36) 7- (2- (1-Carboxy-2-methyl-propoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-11- {3- (N-tert-butoxyl) carbonylamino) -propyl) -1H-tetrazol-5-yl] -thiomethyl-13-cephem-4-carboflic acid (color isomer), m.p. 192-195 ° C (with decomposition).

IR (mqol): 3400-3200, 1780, 1680, 1520, 1450, 1360, 1240, 1160, 1020, 730 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (DMSO d ₆ , δ): 0.98 (6H, d, J = 7Hz), 1 J 8 (9H, s), 1.8-2.2 (3H, m), 24-3.2 (2H, m), 3.7 (2H, m), 4, - 4.7 (5H, m), 5.12 (1H, d, J = 5Hz), 5.7-6.9 (1H , m), 8.03 (2H, broad s), 9.42 (1H, d, J = 8Hz).

(37) 7- (2- (1-Carboxypropoxy-amino) -2- (5-amino-1,2,4- _; thiadlazol-3-yl) -acetamodol-3-11- (3- (N-tert-butoxycarbonylamino) ) -propyl) -1H-tetrazol-5-yl} -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 185-192 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1680, 1620, 1520, 1450, 1360, 1250, 1160, 1000, 730-710 cm ^-1 .

NMR _(DMSO-d6, δ): 1.08 (3H, t, J = 7Hz),

1.35 (9H, s), 1.6-2.1 (4H, m),

2.6-3.1 (2H, m), 3.7 (2H, m), 4.1-4.6 (5H, m), 5.10 (1H, d, J = 6Hz), δ, 81 (1H, dd, J = 5 and 8Hz),

6.8 (1H, m), 8.10 (2H, bs), 9.45 and 9.47 (1H, d, J = 8Hz).

(38) 7- [2- {3- (N-tert-butoxylcarbomlamino) -propoxy-nitro] -2- {5-amino-1,2,4-thiadtazol-3-yl) -acetamido] -3- [1556 { 3- (N-tert-Butoxycarbonylamino) -propyl} -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer).

IR (Nujol): 3300, 3150, 1775, 1715, 1675, 1650, 1615 ^cm-1 wavenumber.

NMR (DMSO-D _e + D ₂ O, §): 1.37 (18H, $),

1.5-2.1 (4H, mX 2.7-3.3 (4H, m).

3.5-3.9 (2 H, m). 3.9-4.3 (8 H, m). 5.13 (lH, d, 1-4.511 /), 5.83 (IH d, J = 4,5t), (39) 7- [2- (l-karboxietoxilmino> 2- (5-amltKbl _l 2, 4-tert-Diazol-3-n) -acetamidoyl-3- [1- {3- (N-tert-butoxybenzylcarbonyl) -1'-amino-propyl} -1H-tetrazol-5-yl-1-thiomethyl-3 -cephem-4-carboxylic acid (color isomer), m.p. 110-115 ° C (with decomposition)

IR (Nujol) 3300, 3200, 1770, 1680.

1600, 1520, 1250, 1000, 720 cm @ ¹ .

Nuclear Magnetic Resonance Spectrum (DMSO-d ₆ + D ₂ O, δ): 1.4 (12H, m).

2.02 (2H, m), 2.98 (2H, t, J = 6Hz),

3.70 (2H, m), 4.1-4.5 (4H, m),

4.70 (1H, q, J = 7Hz), 5.13 (1H, d. J = 5HzX 5.85 (1H, d, J = 5Hz).

(40) 7- {2- (1-Carboxy-1-cyclopentyloxy) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1- {3- ( N-tert-butoxycarbonylanone-n-propyl} -1H-tetraazol-5-yl] thiomethyl-3-clement-4-carboxylic acid (color isomer), m.p. 200-205 ° C (decomposition "", IR spectrum ( Nujol): 3300, 3200, 1770, 1680, 1520, 1250, 1160, 1000 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (DMSO d6, δ): 1.38 (9H, s), 1.68 (4H, m), 20 (6H, m), 2.96 (2H, m),

3.70 (2H, mX 4.26 (4H, m>, 5.12 (1H, d, J = 5Hz), 5.82 (1H, dd, J = 5 and 8Hz), 6.86 (1H, m) , 8.14 (2H, m), 9.40 (1H, d, J = 8Hz).

(41) 7- [2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1- (3-morpho-cyclopropyl) -1H-terrazole; 5-H] -thiomethyl-3H-ephem-4-carboxylic acid (color isomer), m.p. 190-194 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 16®), 1610, 1530, 1240, 1180, 1090, 1060, 880, 760 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (DMSO-d6, δ): 2.17 (2H, m), 2.62 (6H, m), 3.67 (6H, m), 4.37 (4H m), 4.67 (2Η, broad s), 5.15 (1H, d, J = 5Hz), 5.83 (1H, ad, J = 5 and 8Hz), 8.17 (2H, m), 9.73 (1H, d, J = 8Hz).

(42) 7- (2- (1-Carboxy-1-methylethoxy) -minoX2- (5-amino-1,2,4-thiadixzol-3-yl) -acetamido] -3- [1- {3- {N-tert-butoxycarbonylamino) - propyl} -1H-tetrazol-5-yl-thiomethyl-3-cephem-4-carboxylic acid (color isomer).

IR (Nujol) 3300, 3150, 1770, 1680,

1520,1240,1160,990 cm at wave number ¹ .

NMR _(DMSO-d6, δ): 1.45 (15H, br, »)> 2.0 (2H, m), 3.0 (2H, m), 3.77 (2H, m), 4 , 10-4.40 (4H, m), 5.20 (1H, d, J = 5Hz), 5.87 (1H, dd, J = 5 and 8Hz), 6.87 (1H, m), δ , 20 (2H, bs), 9.47 (1H, d, J = 8Hz).

(43) 7- [2-Carboxymethoxlimino-2- (5-amino-1,2,4-tla-diazol-3-yl) -acetamido] -3- (4-methyl-5-oxo-6-hydroxy) <4 5-oz ·

-561

183,006 hydro-1,2,4-triazin-3-yl) thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 210-214 ° C (with decomposition).

IR (Nujol): 3250, 3180, 1760, 1720 1660, 1590, 1520, 1240, 1090, 1050, 720 ^cm-1 wavenumber. 5

NMR (DMSO-d ₆ + I) Ο _2. δ): 3.30 (311, s).

3.65 (2H, m), 4.10 (2H, m), 4.65 (2H, broad s). 5.11 (1H, d, J = 5Hz),

5.82 (1H, dd, J = 5 and 8Hz).

(44) 7- [2-Carboxymethoxyimino-2- (5-amino-1,2,4-thia-diazol-3-yl) -acetamido] -3-] 1- {4- (N-tert-butoxycarbonylamino) butyl} -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer).

IR (nujol) 3300, 3200, 1770, 1680,

1620, 1520, 1240, 1160, 1090, 15 1060, 890 cm ^- 'wavenumber.

NMR _(DMSO-d6, δ): 1.0- 2.0 (4H, m);

1.33 (9H, s), 2.90 (2H, m), 3.66 (2H, m), 4.0-4.5 (4H, m), 4.62 (2H, broad s), δ, Δ (1H, d, J = 5Hz), δ 5.80 (1H dd, J = 5 and 8Hz), 6.75 (1H, m), 8.13 (2H, bs), 9.55 (1H , d, J = 8Hz).

(45) 7- {2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadrazol-3-yl) -acetamido] -3- [1- (3-piperidinopropyl) -1H-tetrazole-5 -yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 223-228 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1670, 1610, 1520 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 1,30-1-, 83 (OH, m), 30 2.1-2.3 (2H, m), 2.8-3.3 (6H, m), 3.60 (2H, bs), 4.0 = 4.50 (4H, m), 4.60 (2H, s), 5.06 (1H; d, J = 4Hz), δ, 80 (1H, dd, J = 4 and 8Hz), 8.15 (2H, s), 10.1 (1H, d, 35 J = 8Hz).

(46) 7- (2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-arboxymethyl-1H-tetrazol-5-one). trroma-3-cephem-4-carboxylic acid (color isomer), m.p.

170-175 ⁰ C (dec). ⁴ θ

IR (Nujol): 3300, 3200, 1765, 1720, '1660, 1620, 1520 ^cm-1 hulllm number.

NMR _(DMSO-d6, δ): 3.67 (2H, br s);

4.27 and 4.47 (2H, AB quartet; JMSHz), ⁴⁵ 4.67 (2H, s), 5.13 (IH, d, J = 4Hz),

5.33 (2H, s), 5.87 (1H, dd, Jfc = 4 'and 8Hz), 8.20 (2H, s), 9.60 (4H,' d) J = 8Hz).

(47) 7- [2-Carboxymethoxyimino-2- (5-amino-1,2,4-thia-diazol-3-yl) -acetamido} -3- [1- {6- (N-tert-butoxycarbonate) amino) hexyl} -1H-tetrazol-5-yl] -thiomethyl-3-cephem-44d8r-: acid (color isomer), pale yellow powder.

(48) 7- [2- (1-Carboxyethoxyimino) -2- (5-amino-1 H) -2,4-thiadiazol-3-yl) -acetamido] -3- [5- (N-tert-butoxybenzyl) methyl] -1,5 amino) -methyl-1,3,4-thiadiazol-2-yl] -thiomethyl-3-cephem-4-clicic acid (color isomer), m.p. 210-215 ° C (dec.) . '

IR (Nujol): 3300, 1770, 1680, 1620/1520, 1240, 1140 ^cm-1 wavenumber. 6 °

SpektnJm NMR _(DMSO-d6, δ): 1.43 (12H, bs);

3.70 (2H, m), 4.27-4.87 (5H, m), 5.20 (1H, d, J = 5 and 8Hz), 7.70 (1H, m),

8.17 (211, broad s), 9.50 (111, d, J = 8Hz).

(49) 7- [2- (2-Propynyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (3-aminopropyl) -1H-tetrazole-5- yl] thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 165-170 ° C (with decomposition).

IR (Nujol): 3450, 3300, 3210, 1770, 1670, 1620, 1525 ^cm-1 wavenumber.

(50) 7- [2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamidol-3- [1- (3-aminopropyl) -1H-tetrazol-5-yl] ) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 195-200 ° C (with decomposition).

IR (Nujol): 3150, 1760, 1660, 1640. 1520 ^cm-1 wavenumber.

(51) 7- [2- (1-Carboxy-2-methyl-propoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamide) -3- (1- (3-aminopropyl) 1H-Tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 183-189 ° C (with decomposition).

IR (Nujol) 3400-3100, 3150, 1770, 1670, 1620, 1520, 1380, 1280, 1230, 1180, 1100, 1020, 900,

730 cm at wave number ¹ .

(52) 7- [2- (1-Carboxypropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-] 1- (3-aminopropyl) -1H-tetrazol-5 -yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 183-188 ° C (with decomposition).

IR (Nujol): 3400-3150, 1770, 1670, 1620, 1530, 1380, 1280, 1230, 1180, 1100, 1050, 1010, 730 ^cm-1 wavenumber.

(53) 7- [2- (1-Carboxyethoxyimino) -2- (5-amino-1,2,4-thiazol-3-yl) acetamido] -3- {1- (3-aminopropyl) -1H-tetrazole -5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 185-188 ° C (with decomposition).

IR (Nujol): 3300, 3150, 1760, 1660, 1620, 1520, 1230, 1000, 720 ^cm-1 wavenumber.

(54) · 7- (2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazolyl) -acetamido] -3- [1- (4-aminobutyl) -1H-trazol] yl] thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 191-194 ° C (with decomposition).

IRísppkkíum (Nujol): 3300, 3150, 1760, 1670, 1620, 1520, 1230, 1170, 1050, 890, 740, 720 ^cm-1 wavenumber.

(55) 7- (2- (1-Carboxy-1-methylethoxy-1R) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-11- (3-aminopropyl) - 1H-Tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 200-203 ° C (with decomposition).

IR (Nujol): 3300, 3150, 1760, 1660, 1620, 1520, 1160, 990 ^cm-1 wavenumber.

(56)! 7- (2- (1-Carboxy-1-cyclopentyloxyimino) -2- (5-amino-1,2,4-thiazol-3-yl) -acetamido] -3- {1- (3-aminopropyl) 1H-Tetrazot-5-yl] -thiomelyl-3-cephem-4-carboxylic acid (color isomer), m.p. 202-205 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1760, 1660, 1620, 1520, 1180, 1060, 1000, 730 ^cm-1 wavenumber.

(57) 7- {2- (1-Carboxyethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (5-aminomethyl-1,3,4- thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 207-210 ° C (with decomposition).

-571

183,006

IR (Nujol): 3300. 3150, 1760, 1660, 1620, 1520, 1230, 1170, 1090, 1060, 1040, 990 ^cm-1 wavenumber.

(58) 7- [2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1-ylamino-hexyl) -1H-tetrazol-5-yl] - thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 185-88 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1760, 1670, 1620, 1520, 1240, 1180, 1060 ^cm-1 haítámszámnál.

(59) 7- {2- (3-aminopropoxyimino) -2- (5-amino-1,2,4-thiazol-3-yl) acetamido] -3- (1,3,4-thiadiazol-2-one) yl) -thiomethyl-3-ctfem-4-k3fbanoic acid (color isomer), m.p.

165-183 ° C (with decomposition).

. IR (Nujol): 3150, 1765, 1660, 1630, 1570, 1520 ^cm-1 wavenumber.

(60) 7- [2- (3-aminopTOpexhmino) -2- (5-amino-1,2,4-thioladiazol-3-yl}) - acetamido] -3- [1- (2-hydroxyethyl) -1H- tetrazo; -5-ylthiomethyl} -3-cephem-4-carboxylic acid (color isomer), m.p. 170-185 ° C (with decomposition).

IR (Nujol): 3140, 1760, 1660, 1610, 1580, 1520 ^cm-1 wavenumber.

(61) 7- [2- (3-Amino-topo-pyrimino) -2 '(5-amino-1,2,4-thiadiazol-3-yl) -acetamido} -3- (5-methyl-1,3,4-thiadiazole -2-yl) thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 192-195 ° C (with decomposition).

IR (Nujol): 3250, 3140, 1760, 1640, 1620, 1585, 1525 ^cm-1 wave number (62) 7- [2- (3-prop © xiimino) -2- (5-amino-2, 4-Thiadiazol-3-yl) -acetamidol-3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p.

180-84 ° C (with decomposition). .

IR spectrum (nmol): 3160, 1760, 1660, 1590 epi- ¹ .

(63) 7- [2- (3-Aminopropoxymethyl) -2- (5-amino-), 2,4-thiadiazo-yl] -acetamoyl-3- (1- {3-armnopropyl) -1'-tetrahydro-5-yl. 1-methylmethyl) -3-cepheir-4-carboxylic acid (color isomer).

IR (Nujol): 3300, 3150, 1760, 1660, 1607, 1595, 1520 ^cm-1 hullámszántnál.

(64) 7- {2- (? -Carboxybenzyloxyimino) -2- (5-amino-1,2,4-thiadiazole: ol-3-a) -acetamidol-3- (1,3,4-thiadiazyl-B-2? m.p. 150-155 ° C (with decomposition), methyl 3-cephem-4-carboxylic acid (color isomer).

IR (Nujol): 3400, 3290, 3160, 2500, 1770, 1720, 1615, 1520 ^cm-1 wavenumber.

(65) 7- {2- (α-Carboxybenzyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -hydro] -3- [1- (2-amino) ethyl] -1H-triazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 190-195 ° C (dec.).

IR (Nujol): 3400, 3300, 3150, 1765, 1670, 1610, 1520 ^cm-1 wavenumber.

(66) 7- (2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (3- (4-methyl-1-ptperazinyl)) propyl} - 1 H -tetrazol-5-yl] -thiomethyl-3-cfem-4-carboxylic acid (color isomer), m.p. 185-190 ° C (with decomposition).

IR (nujol): 3300, 760, 1670, 1600, 1520 cm ^-1 .

(67) 7- (2- (1-Carboxypropoxyimino) -2- (S-amino-1,7,4-thiadiazo) -3-yl) -acetamido] -3- (h3,4-thiadiazol-2-yl) 58 thiomethyl- 3-Cephem-4-carboxylic acid (color isomer), m.p.

153-158 ° C (with decomposition).

IR spectrum (nujol); 3300, 3180, 1770, 1720- 1670, 1620, 1520, 1220, 1060, 1000, 900, 730 ^cm-1 wavenumber.

(68) 7- [2- (1-Carboxyethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1,3,4-thiadiazole-2-3) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p.

165-168 ° C (with decomposition).

IR (Nujol): 3400-3200, 1770, 1710, 1670, 1620, 1520, 1230, 1170, 1000, 900, 720 ^cm-1 wavenumber.

(69) 7- {2- (1-Carboxy-1-methylethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido} -3- (1,3,4-thiadiazol-2) -fl) thiomethyl-3-cephem-4-carboxylic acid (color isoform), m.p.

164-167 ° C (with decomposition).

IR (Nujol): 3300, 3200, 2800-2300.

1770, 1720-1660, 1620, 1520, 1160, 1060, 990, 800 ^cm-1 wavenumber (70) 7- (2- (1-carboxy-1 -ciklopentaoxiimino) -2- (5-amino-2 , 4-Thiadiazol-3-yl) -acetamido] -3- (1,3,4-thiadiazol-2-yl) -thiomethyl-3-eephem-4-carboxylic acid (color isomer), m.p.

165-169 ° C (during rollover)

IR spectra (nujol): 3300, 3180, 1770, 1720-1660, 1620, 1520, 1240, 1180, 1060, 1000, 720 cm ^-1 huBam number, __________.

(71) 7- (2- (1-Carboxyethoxymethyl) -2- (5-anino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-allyl-1H-tetrazole-5) -yl) -thiomethyl-3-cephem-4-carbonyl (a isomer), m.p. 180 ° C.

IR (Nujol): 3300, 3150, 1770, 1680, 1610, 1520, 1260, 1100, 1040, 1000 cm ^- 'wavenumber.

(72) 7- (2- (1-Carboxy-1-methylethoxymethyl) -245-amteo-1,2,4-thiadiazol-3-yl) -acetamoyl-3- (142-aminoethyl) -1H-tetrazol-5-yl J -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 195-200 ° C (with decomposition).

IR (Nujol): 3150, 1760, 1670, 1620, 1520, the 1170.90 ^»1 wavenumber.

(73) 7- (2-Cyclopentyloxyimino-2- (5-anti-bo-1,2,4-thiadiazol-3-n) -acetamido} -3- (1- (3- (4-methyl-1-piperazin)) Propyl) -1H-tetrazol-5-yl) -thiolethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 175-180 ° C (with decomposition).

IR (Nujol): 3300, 1770, 1650, 1610, 1520 cm ^"1 wavenumber.

(74) 7- (2,4-Oxo-3-tetrahydrofuryloxy-amino) -2- (5-amino-1,2,4-iiadisol-3-yl) -acetamido} -3- (1,3,4-thiadia-2d-2-yl) ) -thiomethoxy-3-cephem-4-carboxylic acid (color isomer) m.p.

165-170 ° C (with decomposition).

IR (nujol): 3300, 3200, 1770, 1680, 1620, 1525 cm ^-1 .

(75) 7- (2- (1-Cyclohexyloxyphenyl) ethoxy] -2- (5-amino-1,2,4-thiadlazol-3-yl) -acetamido] -3-yl- (3- (N-tert-butoxycarbonylamino) -pyropyl -1H-tetrazole-541] thiomethyl-3-cephem-4-carboxylic acid (syn isomer), m.p.

145-150 ° C (with decomposition).

IR (Nujol): 3400-3250, 1780, 1680, 1620, 1520, 1240, © 122, 1160, 1100, 1000, 740, 720 ^cm-1 wavenumber.

-58j (76) 7- [2- (1-Benzyloxycarbonylethoxyimino) -2- (5-fluoro-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (3- (N -tert-butoxycarbonylamino) -propyl} -1H-tetrazol-5-yl-thiomethyl-3-cephemA-carboxylic acid (color isomer), m.p. 113-117 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1780, 1680, 1620, 1520, 1250, 1160. 1100, 1040, 1000, 740, 700 cm ^-1 .

(77) 7- [2- (1-Butoxycarbonylethoxyimino) -2- (5-amino-10,2,4-thiadiazol-3-yl) -acetamido] -3- [1- {3- (N-tert-butyl) -butoxycarbomlamino) -propyl} -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 149-155 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1780, 1700, 15 1620, 1520, 1250, 1160, 1100, 5040, 1000, 740, 720 ^cm-1 wavenumber.

(78) 7- [2- (1-Cyclohexyloxycarbonyl-ethoxyimino) -2 (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (3-amino-propyl) -1 H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 175-178 ° C (with decomposition).

5R (Nujol): 3400-3200, 1765, 1680, 1610, 1520, 1220, 1100, 1000, 890, 790 ^cm-1 hullámszámnáí. 25 (79) 7- [2- (1-Benzyloxycarbonyl-ethoxyimino) -2- (5-afnino-J, 2,4-thiadiazol-3-yl) -acetamido] -3- [1- (3-aminopropyl) 1H-Tetrazol-3-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 162-166 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1760, 1680, 301620, 1520, 1100, 1040, 1000,

740 cm ^"1 hullámszámná ¹ (80) 7- ί 2- (1-ethoxyimino toxikarbonil butyl) -2- (5 -aminol-, 2,4-thiadiazol-3-yl) acetamido] -3- [1 - ( 3-aminopropyl) -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 158-163 ° C (with decomposition).

IR (Nujol): 3400-3200, 1770, 1680, 1610, 1530, 1300, 1290, 1050, 1040, 1000, 960, 900, 790, 740,

720 cm ''. 40 (81) 7- [2- (3-Aminopropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-methyl-1H-tetrazole-5- il) thiomethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester hydrochloride (color isomer), m.p. 110-125 ° C (with decomposition).

IR (Nujol): 1780, 1745, 1670, 1625, 1525 45 cm ^<-1 wavenumber.

(82) 7- [2- (3-Aminopropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (5-methyl-1,3,4-thiadiazole); 2-yl) thiomethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester hydrochloride (color isomer), m.p. 88-153 ° C (dec. 5θ).

IR (Nujol): 2150, 1780, 1745, 1650, 1625, 1525 cm ^"1 wavenumber.

(83) 7- [2- (3-Aminopropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (2-hydroxyethyl) -1H-tetra- 55 zol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester hydrochloride (color isomer), m.p. 150-175 ° C (with decomposition).

IR (Nujol): 3150, 1780, 1740, 1670,

1630, 1520 ^cm-1 wavenumber, θθ (84) 7- [2- (3-aminopropoxyimino) -2- (5-amino-l, 2,4-thiadiazol-3-yl) acetamido] -3- (i, 3, 4-Thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester hydrochloride (color isomer), m.p. 96-155 ° C (with decomposition).

IR (Nujol): 3300, 3) at 50, 1775, 1730, 1670, 1625, 1530 cin ¹ .

(85) 7- [2-Allyloxyimino-2- (5-atnino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (2-aminoethyl) -1H-tetrazol-5-yl] -thiomethyl-3-cephemA-carboxylic acid pivaloyloxymethyl ester formate (color isomer), m.p. 95-105 ° C (dec.).

IR spectrum (nujol): 1790, 1735, 1452, 1370, 1118, 990 cm ^-1 .

(86) 7- [2- (3- (N-tert-Butoxycarbonylamino) -propoxyimino} -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-methyl) -1H-Tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (color isomer), powder.

IR (Nujol): 3300, 1780, 1745, 1680, 1620 ^cm-1 wavenumber.

(87) 7- [2- {3- (N-tert-butoxycarbonylamino) -propoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3 (5-methyl) -1,3,4-Thiadiazol-2-yl] -thiomethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (color isomer).

IR (Nujol): 3300, 3150, 1783, 1745, 1675, 1615 ^cm-1 hullámszámnáí.

(88) 7- [2- {3- (N-tert-butoxycarbonylamino) -propoxyimino} -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamide] -3- [1 ( 2-hydroxyethyl) -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (color isomer), m.p.

88-101 ° C (with decomposition).

IR (Nujol): 3300, 1780, 1750, 1675. 1620 ^cm-1 wavenumber.

(89) 7- [2- {3- (N-tert-butoxycarbonylamino) -propoxyimino} -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3 ( 1,3,4-Thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (color isomer), powder, m.p. 71-84 ° C (with decomposition).

IR (Nujol): 3300, 1780, 1745, 1680, 1615 ^cm-1 wavenumber.

(90) 7- [2-Allyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- {2- (N-tert-butoxycarbonylamino) ethyl} -1 H-te Trazol-5-yl] -thiomethyl-3-cephemA-carboxylic acid pivaloyloxymethyl ester (color isomer), powder.

IR (Nujol): 3300, 1780, 1750, 1680 ^cm-1 wavenumber.

(91) 7- [2- (4-chlorophenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 150-155 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1670, 1620, 1520 ^cm-1 wavenumber.

(92) 7- [2- (4-Fluorophenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1,3,4-thiadiazole-2- ii) thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 140-145 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1680, 1620, 1520 ^cm-1 wavenumber.

(93) 7- [2-Phenoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-carboxymethyl-1H-tetrazol-5-yl) -thiomethyl- 3-cephemA carboxylic acid (color isomer), m.p.

175-180 ° C (with decomposition).

IR spectrum (nujol): 3400, 3200, 1770, 1700, 1660, 1620, 1580, 1510 cm ^-1 .

(94) 7- [2-Phenoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-allyl-1H-tetrazole-5 3cefemA-carboxylic acid (color isomer), m.p. 145-150 ° C (with decomposition).

-59183 006

IR (Nujol): 3450, 3350, 3180, 1780, 1710, 1680, 1610.1590, 1510 ^cm-1 wavenumber.

(95) 7-t2-Phenoxyimino-2- (5-amino-1,2,4-thiadiazole-3'-acetamido-N-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid ( 155-158 ° C (with decomposition).

IR (Nujol): 3400, 3300, 1770, 1720, 1680, 1620, 1590, 1520 cm ^-1 .

(96) 7- [2- (2-methoxy-5-nitrophenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-cobic acid (color isomer), m.p.

160-169 ° C (with decomposition).

IR (Nujol): 3380, 3220, 3100, 1780, 1690, 1620, 1600, 1520, 1340, 1280, 1085, 1065, 820, 750 ^cm-1 wavenumber.

(97) 7- [2- (4-Fluorophenoxymethyl) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamidol-3- (tetrazolyl, 5-b) pyridazin-6-yl. ) thiothetyl-3-cefm4-carboxylic acid (color isomer), m.p.

125-130 ° C (with decomposition).

IR Spectrum (Nujol): 3350, 3190, 1770, 1670, 1615, 1520, 1495 cm ^-1 .

(98) 7- [2- (4-klörfenöxiimino) -2- (5-amino-l, 2,4-thia _'L thiadiazol-3-yl) acetamido] -3- (5-hydroxymethyl-1, 3,4-Thiadiazol-2-yl) -thiophenyl-3-oephem-4-oxy) -cisic acid (color isomer), m.p. 135-140 ° C (with decomposition).

IR (nujol): 3450, 3280, 3180, 1760, 1720, 1660, 1620, 1580, 1520, 1480 cm ^-1 .

I (99) 7- [2- (4-Chloro-phenoxyimino) -2- (5-amino-1,2,4-thia-5'-thiomethyl-3-ethyl) -4-carboxylic acid (Color Isomer), m.p. 135-140 ° C (with decomposition).

IR (Nujol): 3400, 3250, 3170, 1765, 1700, 1680, 1650, 1615, 1580, 1510, 1480 cm ^-1 .

(100) 7- [2- (4-chlorophenoxyimino) -2- (5-amino-1,2,4-thiadiazot-3-yl) -acetamido] -3- {1- (2-hydroxyethyl) -1H- tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 120-125 ° C (with decomposition).

IR (Nujol): 3400, 3300, 3180, 1765, 1670, 1615, 1580,1520,1480 ^cm-1 wavenumber.

(101) 7- [2- (3,4-Dichlorophenoxyimino) -2- (5-amino-1,2,4-thiazol-3-yl) -acetamethyl-3- (1,3,4-thiadiazol-2) -yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 160 ° C.

IR (Nujol): 3300, 3200, 1770, 1680, 1620, 1520, 1250, 1205, 1060 ^cm-1 wavenumber.

(102) 7- [2- (3'-Transmethyl-phenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1,3,4-thiadiazol-2-yl) -thiomethyl-3 cephem-4-carboxylic acid (color isomer), m.p. 164 ° C.

IR (Nujol): 3300, 3180, 1765, 1670, 1610, 1520, 1320, 1165, 1120, 1060, 930, 790, 700 ^cm-1 wavenumber · i (103) 7- [2- (3-etoxikarbonilfenoximuno) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (color isomer), mp 162 ° C.

IR (Nujol): 3350-3150, 1770, 172060

1660, 162Ó, 1520, 1290, 1270, 1100, 1060, 900, 760 ^cm-1 wavenumber.

(104) 7- [2- (4-Fluorophenoxyimino) 2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1- (2-hydroxyethyl) -1H-tetrazole -yl] -thiomethyl-3-cephem-4-carbonyl (m.p. 145-150 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1670, 1610, 1520 ^cm-1 wavenumber.

(105) 7- (2- (4-Fluorophenoxyimino) -2- (5-amino-1,2,4-thiadlazol-3-yl) -acetamido] -3 (1-carboxymethyl-1H-tetrazol-5-yl). thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 150-155 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1720, 1670, 1620, 1520, 1500 ^cm-1 wave number (106) 7-L2- (4-fluorfenoxilnrino) -2- (5-amino-2, 4-Thiadiazol-3-yl) -acetamido] -3- [2-carboxymethyl-3-oxo-2,3-dihydro-1,2,4-triazolo (4,3-b} pyridazin-6-yl] -thiomethyl-3-cephem- 4-carboxylic acid (color isomer), m.p. 165-170 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1710, 1620, 1540, 1520, 1500 cm @ ^-1 .

(107) 7- {2- (4-Fluorophenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (2-cathoxyethyl) -1H-tetrazole-5 -yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer),

140-145 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1700, 1620, 1520, 1500 ^cm-1 wavenumber.

(1-8) 7- {2- (4-Fluoro-phenoxyimino) -2- (5-amino-1- (2,4-thiadazol-3-yl) -acetamido] -3- (1-allyl-1H-tetrazol-5) -thi) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 145-150 ° C (with decomposition).

IR (Nujol): 3450, 3350, 3150, 1780, 1705, 1670, 1610, 1510 ^cm-1 wavenumber.

(109) 7-1,2-Phenoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (2-aminoethyl) -1H-tetrazole-5 -yl] thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 18 DEG-185 DEG C. (with decomposition).

IR (Nujol): 3300, 3250, 1760, 167cm, 1620, 1590, 1520 ^cm-1 huiíémszámnál.

(110) 7-] 2- (t-Butoxycarbonyl-methoxymethyl) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (tetrazo [1,5- b] pyridazin-6-yl) ) -thiomethyl-3 cephem-4-carboxylic acid (color isomer), m.p. 125-130 ° C (with decomposition).

IR (Nujol): 3400, 3300, 3180, 1770, 1720, 1680, 1620, 1525 ^cm-1 wavenumber.

(111) 7- [2- (3 - (- N-tert-Butoxycarbonylamino) propoxynino} -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] 3-f {-2 (N-tert-butoxycarbonylamino) ethyl} -1H-tetrazol-5-yl] thiomethyl-3-cephem-4-catoxylic acid (color isomer), m.p. 107-112 ° C (with decomposition).

IR spectrum (nujol):

(? 12) 7- [2- (2,2,2-Trifluoroethoxyimino? -2- (5-amino, 2,4-thiadiazol-3-yl) -acetamido] -3- (1-allyl-1H) -tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 125-130 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1680, 1620, 1520 cm ^-1 .

(113) 7- [2- (2,2,2-Trifluoroethoxyimino) -2- (5-amino-601)

183,006

1.2.4-Thiadiazol-3-yl) -acetate 3-dimethyl-1 H -tetrazol-5-yl) -thiomephil-3-cephem-4-carboxylic acid (syn isomer), m.p. 145-150 ° C (with decomposition).

IR (Nujol): 3300, 3200. 1770, 1680, 1620, 1525 ^cm-1 wavenumber.

(114) 7- [2 '- {2- (tert-butyl-3-bromonibinino) -ethoxyimino) -2- (5-amino-1,2,4-tetrahydro-diazol-3-yl) -acetamido} -3-tert-butyl-2-one. - (N-tert-butoxycarboylethylaminol-ethyl-1 H -tetrazol-5'-yl) -thiomethyl-3-ephem-4-carboxylic acid (color isomer).

181-18: 6 ° C (with decomposition).

IR (Nujol): 3320. 1780, 1680. 1620.

1520. 1165 cm at wave number ¹ .

(115) 7-1,2-Tritloximino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (5-methyl-1,3,4-thiadiazol-2-yl) -thiomethyl · 3-cefcm4-carboxylic acid (color isomer), m.p. 146-161 ° C (with decomposition).

IR spectrum (nujol): 3420, 1780, 1680, 1615, 1525 cm @ -1.

(116) 7- [2- (2- (N-tert-Butoxycarbonylamino) -ethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-oxadimethyl-1H) -tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 105 ° C (with decomposition).

IR (nujol): 3305, 3) 60. 1770, 1670,

1520, 1245 ^cm-1 wave number, (117) 7- [2- (tert-butoxycarbonylmethoxyimino) -2- (5-anin-l, 2,4-iiadiazQl-3-yl) acetamido] -3- (l, 3,4-Thiazolidazol-2-yl) thiomethyl-3-eephem-4-carboxylic acid (syn isomer), m.p. 140-145 ° C (with decomposition).

IR (Nujol): 3300, 3175, 1770, 1720, 1680, 1620, 1520 cm ^-1 .

(1183 7- [2- (tert -B-Toxicarbonyl-methoxyimino) -2- (5-amino-1,2,4-tradiazole-3-3) -acetamido] -3- (1-allyl-1H-tetrazole-5-) yl) -thiomethyl-3-cephem-4-caffonic acid (color isomer), m.p. 130-135 ° C (with decomposition).

IR (nujol) 3400, 3280, 3180, 1770, 1720; 1680, 1620, 1520 cm @ ¹ .

(119) 7- [2- (tert-Butoxycarbonylmethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1- {2- (N-tert-butoxycarbonylamino)) -ethyl} -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 110-115 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1775, 1680, 1620, 1520 cm ^-1 .

(120) 7- [2- (tert-Butoxycarbonylmethoxyimino) -2- (5-amino-1,2,4-thiadiazzo) -3-yl] acetamido] 3- (1-phenyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 135-140 ° C (with decomposition).

Spektnim IR (Nujol): 3400, 3300, 3200, 1775, 1720, 1685, 1620, 1525.1500 ^cm-1 wavenumber.

(121) 7- [2- (3-Amino-propoxy-amino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (2-amino-ethyl) -1H-tetrazol-5-yl] - thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 184-196 ° C (with decomposition).

IR (Nujol) 3400-3100, 1760, 1660,

1610, 1520, 1170, 1060.1010 ^cm-1 wavenumber.

, (122) 7- [2- (2-Aminoethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-carboxymethyl-1 H -tetrazol-5-one). ii) thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 190-198 ° C (with decomposition).

IR (Nujol): 3250, 3160, 1760, 1650,

1615. 1522, at 1020 cm-1, (123) 7-l-2-k: η 4 -oxynoyloxymethyl-2- (5-ylmethyl-1,2,4-thiadiazole-3-11) -acetamtdo] -3- (1.3 M.p. 170-175 ° C (with decomposition), 4-tL: tdi: i-ol-2-H) -tlo5 mole-3-c-methyl-4-carboxyl:?

IR (Nujol): 3250, 3150, 1770, 1710, 1680, 1610, 1520 cm @ -1.

(124) 7 - [2-Carboxybutyrimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -nectamido] -3- (1-alpha-1H-1H-tetrazol-5-yl) M.p. 145-150 ° C (with decomposition) · tlomethyl-3-cfem-4-carboxylic acid (m.p.

IR (Nujol) 3400, 3300, 3200, 1765.

It IS 1720, 1680, 1620, 1520 ^cm-1 wavenumber.

(126) 7- [2-Carboxymethoxymethyl-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (telzolo] 1,5-h} pyrid azithyl-6-yl) -thienethyl-3- ccfcni-4-carboxylic acid (syn isomer), mp .: 170 -175 ^P C (dec);

IR (Nujol): 3400, 3300, 3180, 1760, 1660, 1625. 1S65, 1520 cm @ -1.

(127) 7-] 2-Carboxymethoxy-Hmino-2- (5-amino-1,2,425-thiadiazol-3-yl) -acetamido] -3- (1- (2-aminoethyl) -111-tetrazol-5-yl m.p. 185-190 ° C (with decomposition). -Tomelrel-3-cis-cm-4-carronic acid (color isomer).

Spoktrum IR (Nujol): 3250, 1755, 1660, 1590, 15 20 ^cm-1 liullámszámnál.

(128) 7- [2- (2,2,2-Trifluoroctoxynthino) -2- (5-amino-1,2,4,4-thiadiazoth-34L) -acetainido] -3- (1- (2-aminoethyl) -1H-tetrazole M.p. 185-190 ° C (with decomposition). -5-yl) -tomethyl-3-cefcyl-4-carboxylic acid (color isomer).

IR (Nujol): 3300, 3170, 1760. 1670,

1615, 1500 cin ¹ , (129) 7-] 2-Carboxymethoxylino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetatnido] -3- (1-phenyl-1 H- tetrazol-5-yl) -tk-methyl-3-cefcm-4-carboxylic acid (color isomer), m.p. 155-16 ° C (with decomposition).

⁴⁰ IR (nujol): 3400, 3300, 3180, 1765, 1720, 1680, 1615, 1520, 1495 cm- ^s .

(130) 7-1,2-Hydroxyimino-2- (S-amino-1,2,4-tladla-2-ol-3-yl) -acetamido] -3- (5-phenyl-3,4-thiazol-2-yl) -thiomethyl M.p. 153-162 ° C (with decomposition). -3,5-cephem-4-carboxylic acid (syn isomer).

IR (nujol): 3260, 3160, 1763, 1665, 1608, 1520 cm ^-1 .

(131) 7- [2-Hydroxyimino-2- (5-amino-1,2,4-thiadiazol-5-yl) -acetamido] -3- (5-methyl-1,3,4-thiadiazol-2-one). il) -thiomethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (color isomer), m.p. 132-135 ° C (with decomposition).

IR (Nujol): 3270, 3160, 1775, 1745, 1675, 1610, 1520, 1115 ^cm-1 wavenumber.

Example 44

3.4 g 7- [2- (1-Carboxylethoxyimino) -2- (5-amino-1,2,4-thia60-diazol-3-yl) -acetamido] -3- [1- {3- (N- A solution of tert -butoxycarbonylamino) -propyl} -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer) in formic acid (34 ml) was stirred at room temperature for 2 hours. The reaction mixture was then worked up in the usual manner 1.1 pt

-61183 006

7-12-Carboxylate Toxic-2 - (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-11 - (3-amyropropyl) -1H-letrazole Yield: -5-yl N-thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 185-188 ° C (with decomposition).

IR (Nujol): 3300, 3150, J760, Í660, 1620, 1520, 1230, 1000, 720 ^cm-1 wavenumber.

Spectrum in (DMSO-d ₆ + D 0, _δ?): 1.48 (3H, d, J -7 'z.), 2.3 (2H mj 2.9 (211, m),..

3.6 (2H, m), 4.1-5.0 (4H, m). 4.70 (1H, q, J = 7Hz). 5.10 (1H, d, J = 5Hz), 5.85 (1H, m).

Example 45

2.7 £ 7 - (2- {3- (N-tert-butoxycarbonylamino) -propoxymethyl) -2-amyro-1,2,4-thiadiazol-3-yl) -acetamido] -3 (1,3 Pivalodoxymethyl ester of 4-thiadiazol-2-yl) -LiTiethyl-3-cephem-4'-carboxylic acid (color isomer), 24 drops of anteol and

A solution of 26.6 ml of 0.6 π hydrochloric acid in 18 ml of doxane is stirred for 30 minutes at room temperature. The insoluble material was separated by decantation and then dissolved in water. The general instructor was washed twice with ethyl acetate and then lyophilized with 1.8 g of 7- (2/3-aminopropoxy-methyl) -2,5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3 p-1,3-thiadiazol-2-yl) -tinetto-3-cephem-4-carboxylic acid pivalorloxymethyl ester hydrochloride (color isomer), m.p. 90-155 ° C (dec.).

IR spectrum (nujol): 3300, 3) 50, 1775, 1730, 16TO, 1625, 1530 cm @ 1: 'A Λ. ··.'. ' «You.

Nuclear Magnetic Resonance Spectrum (M @ 1M + O10, δ). 1.20 (9H, s),

1.9-2.5 (2H, m), 2.9-3.5 (2H, mj,

3.78 (2H, bs), 4.27 and 4.63 (21), ABq, J-14Hz), 4.2-43 (2H, m), 525 (1H, d, J = 2.51 ), 5.6-6.1 (3H, m), 9.42 (1H, s).

Example 46

The following compounds were prepared by the procedure of Examples 22-25, 44 and 45:

(1) 7- [1,2-Propynyloxyimino] -2,5-amino-1,2,4-thiadiazol-3-yl} -acetarro [d] -3- [1,3-aminopropyl] -1H-tetrazole-5H] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 165-17 ° C (with decomposition).

IR (Nujol): 3450, 3300, 3210, 177, 1670, 1620, 1525 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (DMSO-d6, δ): 1.90-2.37 (2H, m), 2.67-3.03 (2H, m), 3.47 (1H, t, J = 2Hz) , 3.37-3.53 (2H, m), 3.934.60 (4H, m), 4.75 (2H, d, J = Hz), 5.0 (1H, d, J = 5Hz), δ , 68 (1H, dd, J-5 and 8Hz), 8.12 (2H, bs), 9.50 (1H, d, J = 8Hz).

(2) 7 - [(2 ') - Ethoxy] imino-2' - (5'-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [(3-aminopropyl) -1H-tetrazole-5'-thiomethyl] -3-cephero-4-carboxylic acid (color isomer), m.p. 195-200 ° C (with decomposition).

IR (Nujol): 3150, 1760, 1660, 1640, 1520 ^cm-1 wavenumber.

Spektruln NMR _(DMSO-d6, δ): 2.0 to 2.30 (2H, m), 2.73 to 3.0 (2H, m), 3.60 (2H, br s), 420 4.50 (4H, m), 4.60 (2H, s), 5.08 (111, d, J-411z), 5.83 (111, dd,

J = 4 and 811z), 8.23 (2H, s). 10.20 (1H.d, J = 8Hz).

(3) 7- (2- (1-Carboxy-2-methyl-propoxy) -amino) -2- (5-amino-12,4-thiadiazol-3-yl) -acetamido] -3-11 (3-aminopropyl) -1H-tetrazole -5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 183-189 ° C (with decomposition).

IR spectrum (nujol): 3400-3100, 3150, 1770, 1670, 1620, 1520, 1380, 1280, 1230, 1180, 1100, 1020, 900,

730 cm at wave number ¹ .

NMR (DMSO-d ₆ + D ₂ O, δ): 0.98 (6H, d, J = Hz), 2.2 (3H, m), 3.6 (2H, m);

3.9 (2H, m), 4.3 (5H, m), 5.06 (1H, d, J = 5Hz), 5.70 (1/21), d, J = 5Hz), 5.82 (1 / 2H, d, J = 5I) z).

(4) 7- (2- (1-Carboxypropoxyimino) -2,5-amino-1,2,4-thiadiazol-3-yl) -acetaldido] -3- {1- (3-aminopropyl) -1H-tetrazole- 5-N-thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 183-188 ° C (with decomposition).

IR (Nujol) 3400-3150, 1770, 1670, 1620, 1530, 1380, 1280, 1230,

1180, 1100, 1050, 1010, 730 ^cm-1 wavenumber.

NMR (l> _MSO-d6, δ): 0.98 (3H, t, J = 7Hz),

1.7-2.3 (4H, m), 2.7-3.1 (2H, m),

3.4-3.7 (2H, m), 4.2-4.8 (5H, m), 5.07 (1H, d, J = 5Hz), 5.6-6.9 (1H, ro) ), 8.13 (2H, bs), 10.08 (1H, m).

(5) 7- (2-Carboxymethoxy-imino-2/5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1/4-aminobutyl] -1H-tetrazol-5-yl. ] -thiomethyl-3-cephem-4-carbonic acid (color isomer), m.p.

191-194 ° C (with decomposition).

IR (Nujol): 3300, 3150, 1760, 1670, 1620, 1520, 1230, 1170, 1050, 890, 740, 720 ^cm-1 wavenumber.

NMR spectroscopy (DMSO-d ₆ + D Ο _3, δ): 1.2-2.1 (4H, m), 2.80 (2H, t, J = 6Hz), 3.6 (2H, m) , 4.3 (4H, tn), 4.60 (2H, broad s),

5.10 (1H, d, J = 5Hz), 5.82 (1H, d, _____ J = 5Hz).

(6) 7- (2- (1-Carboxy-1-methylethoxyimino) -2- (5-amino-1,2-N-thiazol-4-yl) -ethylenedioxy-3- {1- (3-aminopropyl) -1-tetraazo [5] mp 200-203 ° C (with decomposition).

IR spectrum (nujol); 3300, 3150, 1760, 1660,

1620,1520,1160,990 cm ' ¹ wave number.

NMR _(DMSO-d6, δ): 1.50 (6H, s), 2.20 (2H> m), 2.90 (2H, m), 3.60 (2H, m), 430 ( 411, m), 5.10 (1H, d, J = 5Hz), 533 (1H, m), 8.20 (2H, broad 5),

9.87 (111, d, J = 8Hz).

(7) 7- (2/1-Carboxy-1-cyclopentyloxyimino) -2- (5-amino-1,2,4'-thiadiazol-3-yl) -α-ctamldo] -3- (1 (3- amnopropyl) 1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 202-205 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1760, 1660, 1620, 1520, 1180, 1060, 1000, 730 cm @ -1.

NMR (DMSO-d _6, δ). 1.70 (4H, m), 2.10 (6H, tn), 2.90 (2H, m), 3.11 and 3.60 (2H, ABq, J-18 liz), 4.40 (4H, m), 5.08 (1H, d,) (5Hz), 5.8 (1H, dd,

-62183 006

J = 5 and 81fe). 8.23 (2H, m), 9.78 (8) 7- [2- (γ-catboxK) η-crimino) -2 (5-amino-1,2,4-iadiazole-5-yl] -acetamachlor-1-yl] -aminoloylcyl-1,3,4-liadiazol-2-yl) -thiometh-3-cephffirre-4-carboxylic acid (color isomer), m.p.

207-210 ° C (during Ix).

IR spectrum (nujol). 3300, 3150, 1760, 1660, J62O, 1520, 1230, 1170, 1090, 1060, 1040, 990 ^cm-1 wavenumber. 10

Nuclear Magnetic Resonance Spectrum (DMSO-tle 4 D ₂ O, δ): 1.43 (3H, d.

J = 5Hz), 3.60 (2H, m), 4.0 4.93 (5H m), 5.05 and 5.15 (1H, d,

J = 5Hz), 5.70 (1H, m), 8.1 (2H, broad) .9.5 (1H, d, J = 8Hz) 15 (9) 7- [2-Carloxymethoxyimino-2- (5) -anino-1,2,4-thiadiazol-3-yl) -acetaphtho [beta] -11- [6-aminohexyl] -1H-telazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer ), op .:

185-188 ° C (dec.).

IR (Nujol): 3300, 3200, 1760, 1670, 20 1620, 1520, 1240, 1180, 1060 cnt ^-i wavenumber.

NMR (DMiüU _ft-d, δ): 1.10 to 1.57 (611 in), 1.57 1.97 (211, m), 2.70 (211, m), 3 # 3 ( 2H, ni), 4.27 (4H, ni), 4.57 25 (211, wind s), 5.03 (111, d, J = 5Hz), 5.72 (? 1, dd, J = 5 and g (lz), 8.13 (2H, ni), 9.80 (HI, d, J = 8Hz).

(10) 7- [2- (3-Aminopropoxyimino) -2- (5-amino-1,2,4-thiadazol-3-yl) acetamido] -3- (1H, 4-thiadiazol-2-yl) thio 30 methyl-3-cephem-4-carbonaphthoic acid (color isomer), m.p.

165-183 ° C (with decomposition).

Nuclear Magnetic Resonance Spectrum (DMSO-d 4 D ₂ O, δ): 1.6-2.3 (2H, m), 2.6-3.2 (211, m), 3.2-3.7 (211, m), 3.9 4.7 (411, m), 4.97 (111, d, 35 J = 4.5Hz), 5.68 (111, d, J4.5, 11z).

9.50 (111, s).

(11) 7- [2- (3-Aminopropoxymethyl) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido} -3 '{1 H (2 H -methroethyl) -1 H -tetrazol-5-yl. ] thiomethyl-3-cephem-4-carboxylic acid (syn-isomer of) m.p .: ^40170-185 ° C (dec).

IR (Nujol): 3140, 1760, 1660, 1610,

1580, 1520 cm ^{- at the} wave number.

Nuclear Magnetic Resonance Spectrum (DMSOd ₆ 4D ₂ O, δ): 1.6-2.4 (2H,

m), 2.7-3.4 (2H, m), 3.3-3.9 (4H, ^45m ), 3.9-4.7 (6H, m), 4.97 (1H, d) , J = 4.5Mz), 5.67 (111, d, J = 5Hz).

(12) 7- [2- (3-Aminopropoxy-amino) -2- (S-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (5-methyl-1,2,4- thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp .: ⁵⁰

192-195 ° C (with decomposition).

IR (nujol): 3250, 3140, 1760, 1640, 1620, 1585, 1525 cm ^-1 .

NMR (D ₂ 04 1X1, δ): 2.0 to 3.4 (2H, m), ⁵⁵ 3.00 (311, s), 3.22 (211, t, J = 7Hz),

3.74 and 3.92 (211, ABq, J = 18Hz),

4.36 and 4.53 (211, ABq, J = 14Hz), 4.54 (211, t, J = 71lz), 5.28 (111, d,

J = 4.5Hz), 5.82 (1H, d, J = 4.5Hz). 6 ° (13) 7- (2- (3-Aminopropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido (-3- (1-tetpethyl-yl) tetrazol-5-yl) thiomethyl-3-cephem-4 kaibonic acid (color isomer), m.p.

180-184 ° C (with decomposition).

IR (Nujol): 3160, 1760, 1660, 1590 ^cm-1 hiilfámszámnál.

NMR (D ₂ 04-DCI, δ): 1.9 2.4 (2H, m), 3.20 (3H, t, J = 8Hz), 3.80 (2H 'brs), 4:02 ( 3H, s), 4.22 (211, broad s), 4.52 (211, t, J = 6Hz),

5.25 (1H, d, J = 5Hz), 5.85 (1H, d, J = 5Hz).

(14) 7- (2- (4-Aminomethyl-benzyloxyimino) -2- (5-amino-2,4-thiadiazol-3-yl) -acetamido] -3-methyl-3-cephem-4-carboxylic acid formate (color isomer), m.p. 230-240 ° C (with decomposition).

IR spectrum (nujol): 1750 cm @ ^-1 .

Nuclear Magnetic Resonance Spectrum (DMSO-d ₆ + D ₂ O, δ): 1.86 (3H, s),

3.25 (2H, m), 3.97 (2H, s), 4.94 (111, d, J = 4.5Hz), 5.6 (2H, s),

5.6 (1H, d, J = 4.511z), 7.35 (4H, m), 8.20 (111, s).

(15) 7- {2- (3-Aminopropoxy-amino) -2- (5-amino-1,2,4-thiazol-3-yl) -acetamido] -3- [3-aminopropoxy] -1H-tetrazol-5-yl] thiomethyl-3-cephem-4-carboxyl band (color isomer).

IR (Nujol): 3300, 3150, 1760, 1660, 1607, 1595, 1520 cm ^- 'wavenumber.

Nuclear Magnetic Resonance Spectrum (DMSO-d 4 -D ₂ O, δ): 2.0-17 (411, m), 3.0-3.5 (4H, m), 3.4-4.0, 2H, m ), 4.0-4.9 (6H, m), 3.20 (1H, d, J = 4.5Hz), 5.81 (1H, d,) Μ, 5Ηζ).

(16) 7- (2- (2-D-Phenyl) ((trans) methyl-1,245'-amino-1,2,4-thiadiazol-3-yl) -acid; 2-methyl-3-cephem-4-carboxylic acid (syn isomer), m.p. 204-222 (decomposition).

IR (Nujol): 3260, 3150, 1760, 1665.

1615, 15) 2, 1400, 1045 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (DMSO-d ₆ 4 -D ₂ O, δ): 1.43 (311, d, J = 7Hz), 3.13-4.45 (5H, ni), 4.98 (1H, s) ), 5.02 (1H, d, J = 4.5Hz), 5.85 (1H, d, J = 4.5Hz), 6.27 (1H, d, J = 6Hz), 7.43 (5H , s).

(17) 7- [2- (3-D-Phenylglycylamino-propoxylamino) -2- (5-amino-1,2,4-thiadiazo-3-yl) -acetamido] 2-methyl-3-cephem-4-carboxylic acid (color) m.p. 203-231 ° C (with decomposition).

IR (Nujol): 3280, 1170, 1760, 1660, 1600, 1520, 1400 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (D ₂₀ O + PCl, δ): 1.47 (3H, d, J = 7.5Hz), 1.7-2.3 (2H, m), 3.40 (2H, t, J = 7Hz), 3.88 (111, q, J = 7.5Hz), 4.33 (2H, t, J = 6Hz), 5.18 (1H, d, J = 4.5Hz), δ, 20 (1H, s), 5.95 (III, d, J = 4.5Hz), 6.90 (1H, d, J = 6Hz), 7.57 (511, s).

(18) 7- (2- (1-Cyclohexyloxycarbonyl-ethoxyimino) -2 (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (3-aminopropyl) - 1H-tetrazol-5-yl] thiomethyl-3-cephem-4 carboxylic acid (color isomer), m.p. 175-178 ° C (with decomposition).

IR (Nujol) 3400-3200, 1765, 1680, 1610, 1520, 1220, 1100, 1000, 890, 790 cm @ -1.

NMR _(DMSO-d6, δ): 0.9-2.0 (13H, m);

2.2 (211, ni), 2.9 (211, m), 3.6 (2H, m), 4.0 5.1 (5H, m), 4.76 (111, q, J = 711z) ), 5.03 (111, d, J = 511z), 5.77

-63183 006 (HI, ml, 8.17 (211, broad s), 9.45 (111, m).

(19) 7- [2- (l-benzyloxycarbonyl-imino) -2- ^{(5-amino-1,2,} thiadiazol-3-yl) acetamido] -3- [l- (3-aminopropyl) lH- Thiazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 162-166 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1760, 1680, 1620, 1520, 1100, 1040. 1000, 740 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 1.47 (3H, d, J = 6Hz);

2.23 (2H, m), 2.90 (2H, m), 3.60 (2H, m), 4.43 (411, m), 4.90 (1H, q, J = 6Hz), δ , 07 (1H, d, J = 5Hz),

5.20 (2H, s), 5.77 (1H, m), 7.43 (5H, s), 8.23 (2H, m), 9.57 (1H, m).

(20) 7- [2- (1-Butoxycarbonyl-ethoxy] imino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetaroid] -3- [1- (3-aminopropyl) -1H-tetrazol-5-yl] ] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 158-163 ° C (with decomposition).

IR (Nujol): 3400-3200, 1770, 1680, 1610, 1530, 1300, 1290, 1050, 1040, 1000, 960, 900, 790, 740, 720 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 0.85 (3H, t, J = 6Hz), 1.1-1.8 (4H, m), 1.43 (3H, d, J = 6Hz) , 1.9-2.4 (2H, m), 2.7-3.1 (2H, m), 3.5 (2H, m), 3.9-4.4 (2H, m), 4 , 10 (2H, t, J = 6Hz), 4.3-4.6 (2H, m), 4.78 (1H, q, J = 7Hz), 5.02 (1H, d, J = 5Hz) , 5.7 (1H, m),

8.2 (2Η, broad s), 10.1 (1H, m).

(21) 7- [2- (2- (3-Amino-propoxy-imino) -2- {5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -2-methyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester hydrochloride ( 91 DEG -156 DEG C. (with decomposition).

IR spectroscopy (Nujol): 3150, 1780, 1745, 1670, 1625, 1525 ^cm-1 wavenumber.

NMR (DMSO-d _h + _D2 O, 6): 1.13 (9H, s);

1.43 (3H, d, J = 7Hz), 1.7-2.3 (2H, m), 2.5-3.2 (2H, m), 3.5-4.5 (3H, m) ), 5.10 (1H, d, J = 5Hz),

5.6-6.1 (3H, m), 6.63 (1H, d, J = 7Hz).

(22) 7- [2- (3-Aminopropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-methyl-1H-tetrazol-5-one) il) thiomethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester hydrochloride (color isomer), m.p. 110-125 ° C (with decomposition).

IR (Nujol): 1780, 1745, 1670, 1625, 1525 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (DMSO-d ₆ + D ₂ O, δ): 1.13 (9H, s),

1.7-2.3 (2H, m), 2.6-3.2 (2H, m), 3.75 (2H, broad s), 3.90 (3H, s), 4.0-4.7 (4H, m), 5.12 (1H, d, J = 4.5Hz), 5.6-6.1 (3H, m).

(23) 7- [2- (3-aminopropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (5-methyl-1,3,4-thiadtazole); 2-yl] thiomethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester hydrochloride (color isomer), m.p. 88-153 ° C (with decomposition).

IR (Nujol): 2150, 1780, 1745, 1650, 1625, 1525 ^cm-1 wavenumber.

NMR (DMSO-d ₆ + ₂ Ρ Ο, δ): 1.16 (9H, s);

1.6-2.2 (2H, m), 2.6-3.1 (2H, m),

2.68 (3H, s), 3.76 (2H, broad s), '

4.20 and 4.53 (2H, ABq, J = 18Hz),

4.24 (2H, bs), 5.18 (1H, d, J = 4.5Hz), 5.6-6.0 (3H, m).

(24) 7- [2- (3-Aminopropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (2-hydroxyethyl) -1H-tetrazole -5yl] -thiomethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester hydrochloride (syn isomer), m.p. 150-175 ° C (with decomposition).

IR (Nujol): 3150, 1780, 1740, 1670.

1630, 1520 cm @ ¹ .

NMR (DMSO-d ₆ + D ₂ 0, δ): 1.20 (9H, s)

1.7-2.3 (211, m), 2.6-3.2 (2H, m).

3.5-4.0 (4H, m); 4.0-4.6 (6H, m)

5.17 (1H, d, J = 5Hz), 5.6-6.1 (3H, m).

(25) 7- [2- (4-Aminomethyl-benzyloxyimino) -2- (5-amino-2,4-thiadiazol-3-yl) -acetamido] -3-methyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester hydrochloride (syn isomer), mp .: 160-168 ⁰ C (dec).

IR (Nujol): 1780, 1745, 1670, 1628 ^cm-1 wavenumber.

(26) 7- {2-Allyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- {1- (2-aminoethyl) -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester formate (color isomer), m.p. 95-105 ° C (with decomposition).

IR (Nujol): 1790, 1735, 1452, 1370, 1118, 990 ^cm-1 wavenumber. • NMR (DMSO-de + D ₂ b, δ): 1.2 (9H, s);

3.2 - 3.35 (2H, m), 3.7 (2H, broad s).

4.2-4.6 (2H, m), 4.1-4.6 (2H, m),

4.7 (2H, bs), 4.8-5.2 (1H, m),

5.25 (1H, d, J = 4.5Hz), 5.45 (2H, m), 5.7-6.25 (2H, m), 5.8 (1H, d, J = 4.5Hz).

Example 47

2.35 g of 7- [2- (1-tert-butoxycarbonyl-ethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (colorless) isomer), a mixture of trifluoroacetic acid (16 mL) and anisole (3 mL) was treated at room temperature for 40 minutes. The reaction mixture was evaporated and the residue was triturated with diisopropyl ether and washed with diisopropyl ether (2.3 g) as a white powdered 7- [2- (1-carboxyethoxyimino)

2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color isomer) is obtained.

The powder was filtered through a solution of 0.44 g of sodium bicarbonate in 50 µl of water and the precipitate was filtered off and washed with water to give a light brown powder / 1.1 g of the same product, m.p. 230-235 ° C (dec. while).

IR (Nujol): 3400, 3250, 3150, 1760, 1720, 1660, 1610, 1550, 1290, 1240, 1170, 970, 740 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (DM 9 Q-d ₆ , δ): 1.46 (3H, d, J = 8Hz),

3.46 (2H, m), 4.72 (1H, q, J = 7Hz),

5.15 (1H, d, J = 5Hz), 5.58 (1H, dd, J = 5 and 8Hz), 6.50 (Here, m),

8.20 (2H, m), 9.40 and 9.57 (1H, d, J = 8Hz).

Example 48

3.0 g of 7- [2- (α-tert-butoxycarbonyl-benzyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetate] -3- [1- {2- (N-tert-butyl) -64183 006 bu Toxycarbonylamino) -ethyl) -! H-tetrazol-5-yl] -thiomethyl-3-cephene-4-carboxylic acid (color isomer). A mixture of 3θ ml of trifluoroacetic acid and 6 ml of anisole was stirred for 1 hour at room temperature. The reaction mixture was then treated as described above with 1.16 g of 7- (2- (carboxybenzyloxy-5-yino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (2-Aminoethyl) -111 -1-tetrazol-5-yl] -methyl-3-cephem-4-carboxylic acid (color isomer), m.p. 190-195 ° C (with decomposition).

IR (Nujol): 3400, 3300, 3J.5O, 1765, 10 1670, 1610, 1520 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 3.10 to 3.77 (4H, in), 4.13 to 4.37 (2H, m), 4.40 to 4.77 (2H, m) , 5.0-5.23 (111, m), 5.57 (1 / 2H, 15s), 5.65 (1 / 2H, s), 5.53-5.93 (1H, m), 7.27 -7.80 (5H ni), 8.28 (2H, broad s).

Example 49

By the methods described in Examples 27, 47 and 48, the following compounds were prepared:

(1) 7- [2- (α-Carboxy-benzyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1,3,4-thiadiazol-2-yl) - thioethyl 25

3-cephem-4-carboxylic acid (color isomer), m.p. 150-155 ° C (with decomposition).

IR spectrum (nujol): 3400, 3290, 3160, 2500, 1770, 1720, 1615, 1520 cm ^-1 . 30

NMR (DMSO-d _é, δ): 3.12 to 3.88 (2H, m), 4.08 to 4.68 (2H, m), 5.04 (1 / 2H, d, J = 5Hz), 5.10 (1 / 2H, d, J = 51 Iz),

5.62 (1H, s), 5.64-5.88 (1H, m), 7.12-7.68 (511, m), 8.14 (2H, broad s), 9.52 ( 1 / 2H, s), 9.54 (1 / 2H, s), 9.36-9.72 (111, m).

(2) 7- [2 - (N-carboxybenzyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido-3-cephem-4 carboxylic acid (color isomer), m.p. 170 -175 ° C (with decomposition). 40

IR (Nujol): 3400, 3280, 3160, 2600, 1770, 1720, 1670, 1625, 1525 cm ^-1 .

NMR (DMSO-d _e, δ): 3.24 to 3.68 (2H, m);

5.02 (1 / 2H, d, J = 5Hz), 5.08 (1 / 2H, 45d, J = 5Hz), 5.64 (1H, s), 5.68-5.96 (1H, m), 6.28-6.60 (1H, in), 7.167.64 (5H, m), 8.16 (2H, bs), 9.54 (1 / 2H, d, J = 8Hz), 9.62 (1 / 2H, d, J = 8Hz). 50 (3) 7- [2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color isomer), m.p. 180-185 ° C (with decomposition).

IR (Nujol): 3350, 3250, 1770, 1720,

1680, 1630, 1530 cm ^{1 at} wave number 55.

NMR _(DMSO-d6, δ): 3.53 (2H, d, J = 3 Hz);

4.63 (2H, s), 5.07 (111, d, J = 4Hz), 5.85 (1H, dd, J = 4 and 8Hz), 6.45 (1H, t, J = 31tz), δ, 13 (2H, s), 9.50 60 (1H, d, J = 8Hz).

(4) 7- (2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadlazol-3-yl) -acetamido] -3- [1- {3- (4-methyl-1-piperazine) -yl) propUj (-ni-tetrazol-5-yl] -tiometi1-3-cephem-4-carboxylic acid (syn isomer), mp .: 185-190 ° C (dec). ⁶⁵

IR (Nujol): 3300, 1760, 1670, 1600, 1520 cm @ ^-1 .

NMR _(DMSO-d6, o): 1.80-2.10 (211, m), 2.30-2.50 (411, m), 2.60 (311, s);

2.8-3.3 (611, in), 3.60 (211, broad s), 4.20-4.50 (411, in), 4.60 (2H, s), 5.10 (1H , d, J = 4Hz). 5.83 (111, dd, J = 4 and 8Hz), 8.15 (211, s), 10.17 (1Π, d, J = 8Hz).

(5) 7- (2- (1-Cathoxy-2-methylpropoxynino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -ephephalosporanic acid (color isomer).

IR (Nujol): 3400-3150, 1770, 17301670, 1720, 1620, 1460, 1370, 1230, 1030, 730 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 0.97 (6H, d, J = 7Hz), 2.03 (3H, s), 1.9-2.3 (IH, m), 4.27 and 4.35 (1H, d, J = 6Hz), 4.65 and 5.02 (211, ABq, J = 13Hz), 5.15 (1H, d, J = 5), 5.7-6, 0 (1H, ni), 8.03 (2H, bs), 9.42 (JH, d, J = 8Hz).

(6) 7- (2- (1-Carboxypropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido (-3- (1,3,4-thiadiazol-3-yl)) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 153-158 ° C (with decomposition).

IR (Nujol): 3300, 3180, 1770, 17201670, 1620, 1520 _L 1220, 1060, 1000, 900, 730 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 0.97 (3H, t, J = 7Hz),

1.83 (2H, m), 3.56 and 3.80 (2H, ABq, J = 18Hz), 4.25 and 4.55 (2H, ABq, J = 14Hz), 4.52 (1H, t, J = 7Hz),

5.14 (1H, d, J = 5Hz), 5.82 (1H, dd, J = 5 and 8Hz), 8.1 (2H, bs), 9.46 (1H, d, J = 8Hz), 9 , 52 (1H, s).

(7) 7- [2- (1-Carboxypropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -cephalosporanic acid (color isomer), m.p. 115-120 ° C. during decomposition).

IR (Nujol) 3400, 3300, 3200, 1770, 1720-1670, 1620, 1520, 1230,

1030-1010, 890, 740 to 720 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 1.07 (3H, t, J = 6Hz), 1.8 (2H, m), 2.00 (311, s), 3.5 (2H, m ), 4.63 and 5.02 (2H, ABq, J = 14Hz), 4.5 (1H, m), 5.14 (2H, d, J = 5Hz),

5.84 (1H, dd, J = 5 and 9Hz), 8.11 (2H, broad), 9.5 (1H, m).

(8) 7- (2- (1-Carboxyethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 165-168 ° C (with decomposition).

IR (Nujol): 3400-3200, 1770, 1710, 1670, 1620, 1520, 1230, 1170, 1000, 900, 720 ^cin-1 hullániszámnál.

NMR _(DMSO-fi, δ): 1.43 (3H, d, J = 7Hz),

3.7 (211, m), 4.23 and 4.60 (211, ABq, J = 14Hz), 4.68 (111, q, J = 7Hz),

5.15 (111, d, J = 5), 5.83 (111, dd, J = 5 and 811z), 8.1 (211, broad s), 9.3-9.6 (111, m), 9 , 50 (111, s).

(9) 7- (2- (1-Carboxy-1-methylethoxyimino) -2- (5'amino)

-65183 006

1.2.4-Thiadiazol-3-yl) -acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. C (during decomposition).

IR (Nujol): 3300, 3200, 2800-2300,

1770, 1720-1660, 1620, 1520, 5

1160, 1060, 990, 800 cm @ ¹ .

NMR _(DMSO-d6, δ): 1.47 (6H, s), 3.53 and

3.87 (2H, ABq. J = 20), 4.24 and

4.63 (211, ABq, J = 14Hz), 5.17 (1H, 10 (i, J = 51W, 5.83 (1H, dd, J = 5 and 8Hz)), 8.2 (2H, broad s ), 9.44 (1H, d, J = 8Hz), 9.50 (111, s).

(10) 7- (2- (1-Carboxyl-1-cyclopentyloxy) -mino) -2 '(5-amino-1,2,4'-thiadiazol-3-yl) -acetamido] -3- (1,3,4-thiadiazole- Mp 165-169 ° C (with decomposition).

IR (Nujol): 3300, 3180, 1770, 17201660, 1620, 1520, 1240, 1180, 1060, 1000, 720 ^cm-1 wave 20 number.

Nuclear Magnetic Resonance Spectrum (DMSO-d6, δ): 1.8 (4H, m), 2.1 (411, m), 3.7 (211, m) _; 4.30 and 4.68 (211, ABq, J = 13Hz), 5.20 (1H, d,

J = 5Hz), 5.87 (1H, dd, J = 5 and 8Hz), 25

8.3 (2H, bs), 9.48 (1H, d, J = SH2), 9.60 (1H, s).

(11) 7- [2- (1-Carboxy-1-methylethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid isomer isomer, m.p. 215-220 ° C (with decomposition). 30

HŰspéktrum (Nujol): 3400, 3250, 3200, 1770, 1670, 1520, 1290, 1240, 1160, 1000, 980, 740 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 1.57 (6H, s), 3.70 35 (2H, m), 5.22 (IH, d, J = 5Hz), 5.97 (IH, dd, J = 5 and 8 Hz), 6.58 (1H, m),

8.25 (2H, bs), 9.52 (1H, d, J = 8Hz), (12) 7- [2- (1-Carboxyethoxyimino) -2- (5-amino-1,2,4- ⁴ -thiadiazol-3-yl) -acetamido} -3- (1-allyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p.

180 ° C.

IR (Nujol) 3300, 3150, 1770, 1680,

1610, 1520, 1260, 1100, 1040, 1000 ^{45 cm-1} wavenumber.

NMR _(DMSO-d6, 5): 1.46 (3H, d, J = 8Hz),

3.50 and 3.74 (2H, ABq, J = 18Hz),

4.2 and 4.46 (2H, ABq, J = 1411z),

4.72 (IH, q, J = 8Hz), 4.98 (2H, m), ⁵⁰ 5.12 (111, d, J = 51Iz), 5.2 to 5.36 (2H, m), 5 , 76-6.1 (3H, m), 8.12 (2H, m),

9.48 Ancient 9.56 (1H, d, J = 8Hz).

(13) 7- (2- (1-Carboxyl-1-cyclopentyloxyimino) -2- (5-amino-1,2,4-gallazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid. Mp 212-217 ° C (with decomposition).

IR (Nujol) 3300, 3200, 1770, 1670, 1620, 1520, 1280, 1240, 1180,

1000, 970, 730 cm ^-1 . ⁶⁰

NMR (DMSO-d _e, δ): 1.70 (4H, m), 2.30 (411, ffl), 3.60 (2H, m), 5.10 (IH, d, J = 5Hz ), 5.87 (111, dd, J = 5 and 8Hz), 6.47 (1H, m), 8.20 (2H, m), 9.00 (1H, d, J = 8Hz). ⁶⁵ (14) 7- [2- (1-Carboxyethoxyimino) -2- (5-amino-1,2,4-liadiazol-3-yl) -acetamido] -ephaphosporanoic acid (color isomer).

IR (Nujol): 3300, 3200, 1770, 1710, 1670, 1520, 1230, 1040 ^cm-1 'wavenumber.

NMR _(DMSO-d6, δ): 1.47 (3H, d, J = 8Hz), 2.03 (3H, s), 3.58 (2H, m), 4,135,00 (IH, m ), 4.68 and 5.03 (2H, ABq, J = 8Hz), 5.26 (1H, d, J = 5 and 8Hz), 8.15 (2H, bs), 9.42 and 9.55 (1H, d, J = 8Hz).

(15) 7- (2- (1-Carboxy-1-methylethoxyimino) -2- (5-amino, 2,4-thiadiazol-3-yl) -acetamido-3- [1- (2-aminoethyl) -1H-tetrazole -5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 195-200 ° C (with decomposition).

IR (Nujol): 3150, 1760, 1670, 1620, 1520, 1170, 990 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (DMSO-d ₆ + D ₂ O, δ): 1.50 (6H, s), 3.27 (2H, m), 3.60 (2H, m), 4.17 (2H, m) ), 4.57 (2H, m), 5.10 (111, d, J = 5Hz), 5.80 (1H, d, J = 5Hz).

Example 50

At room temperature, while stirring at room temperature, 66 mg of plvaloyl chloride was added with 115 mg of 7- (2-cyclopentyloxyl) -no-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido-3-hydroxy-cepham-4-carboxylic acid (color isomer). To a solution of tetrahydrofuran (5 mL) was added sodium acetate (82 mg) after 5 minutes, stirred at room temperature for 10 minutes, evaporated and added ethyl acetate and diluted with aqueous sodium bicarbonate. Ethyl acetate was added to the aqueous phase, and the pH of the mixture was adjusted to between 1 and 2 by the addition of hydrochloric acid, and the extract was washed with water and washed with water and brine, dried over magnesium sulfate and evaporated. triturated with diethyl ether 70 mg of white powder of 7- [2-cyclopentyloxy-imino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem- 4-carboxylic acid (color isomer), m.p. 175 ° C.

IR (Nujol): 3520, 3420, 3320, 3220, 3160, 1770, 1685, 1655, 1635, 1625, 1570, 1505 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (DMSO-d6, δ): 1.33-2.07 (8H, m), 3.43-3.77 (2H, m), 4.60-4.93 (1H, m) , 5.15 (1H, d, J = 5Hz), 5.90 (1H, dd, J = 5 and 8Hz), 6.43-6.67 (1H, m), 8.23 (2H, broad s) ), 9.63 (1H, d,

J = 8Hz).

*

Example 51

By the method described in Example 50, the following compounds were prepared:

(1) 7- [2- (α-tert-Butoxycarbonyl-benzyloxy-amino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color isomer) 90-95 ° C (dec.),

IR (Nujol): 3400, 3380, 3230, 1780, 1730, 1685, 1635, 1530 ^cm-1 wavenumber.

(2) 7- [2-tert-butoxycarbonylmethoxyimino-2- (5-amyl)

-66Λ

183,006 no-1,2,4-thiothiazol-3-yl) acetamido] -3-cephem-4-carboxylic acid (color isomer), m.p. 165-170 ° C (with decomposition).

IR (Nujol): 3350, 3250, 3180, 1790, 1720, 1660, 1630.1620, 1520 ^cm-1 wavenumber. 5 (3) 7- [2- (1-Methyl-1-tert-butoxycarbonyl-ethoxyimino) 2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color isomer), m.p. 215 ° C.

IR (Nujol) 3400, 3300, 3150, 1780,

1710, 1690, 1620, 1520, 1240, 10 1140, 980 ^cm-1 wavenumber.

(4) 7- [2- (1-tert-Butoxycarbonyl-ethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color) (isomer), m.p. 250 ° C.

IR (Nujol): 3400, 3250, 3150, 1770, 15 1720, 1680, 1610, 1520, 1290, 1240, 1150, 980 to 740 ^cm-1 wavenumber.

(5) 7- (2- (3,4-Dichlorophenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cephem-4-carboxylic acid (color iso- mer), m.p. 210 ° C.

IR (Nujol): 3450, 3300, 3200, 1760, 1660, 1560, 1290, 1210, 1000, .970, 940, 730 ^cm-1 wavenumber.

(6) 7- {2- (2,4-Dichloro-phenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color isomer m.p. 240 ° C.

IR (Nujol): 3250, 1770, 1660, 1620, 1540, 1520, 1280, 1230, 1100, 1050, 970, 920, 810, 750 ^cm-1 wavenumber 30.

(7) 7-N- {1- (Cyclohexyloxycarbonyl) ethoxyimino} -2 (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cephem-4-carboxylic acid (colorless) m.p. 160-163 ° C (with decomposition).

IR (Nujol): 3420, 3300, 3180, 1775, 35 1720, 1685, 1610, 1520, 1290, 1230, 1040, 980, 740 ^cm-1 wavenumber.

(8) 7- [2- (1-tert-Butoxycarbonyl-1-cyclopentyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-40

4-carboxylic acid (color isomer), m.p. 165-169 ° C (with decomposition).

IR (Nujol): 3400, 3300, 3200, 1770, 1710, 1680, 1610, 1520, 1290, 1240, 1150, 1000, 970, 740 ^cm-1 wavenumber 45.

(9) 7- [2- (α-carboxybenzyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cephem-4-carboxylic acid (color isomer), m.p. 170-175 ° C (with decomposition).

IR (Nujol): 3400, 3280, 3160, 2600, 501770, 1720, 1670, 1625, 1520 cm @ -1.

(10) 7- [2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamidol-3-cephem-4-carboxylic acid (color isomer), m.p. 185 ° C (with decomposition). ⁵⁵

IR (Nujol): 3350, 3250, 1770, 1720 1680, 1630, 1530 cm ^"1 wavenumber.

(11) 7- {2- (1-Carboxy-1-methylethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid ® (color) m.p. 215-220 ° C (with decomposition).

IR (Nujol): 3400, 3250, 3200, 1770, 1670, 1520, 1290, 1240, 1160, 1000, 980, 740 ^cm-1 wavenumber. ® (5) 7- (2- (1-Carboxyethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cepherno-4-carboxylic acid (color isomer 230-235 ° C (with decomposition).

IR (Nujol): 3400, 3250, 3150, 1760, 1720, 1660, 1610, 1550, 1290, 1240, 1170, 970, 740 ^cm-1 wavenumber.

(13) 7- (2- (1-Carboxy-1-cyclopentyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color) m.p. 212-217 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1670, 1620, 1520, 1280, 1240, 1180, 1000, 970, 730 ^cm-1 wavenumber.

(14) 7- [2- (2-Oxo-3-tetrahydrofuryloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cephem-4-carboxylic acid (color) 175-180 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1775, 1670, 1620, 1530 ^cm-1 wavenumber.

(15) 7- (2- (1-Benzyloxycarbonyl-ethoxyimino) -2T-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color isomer), m.p. 177-180 ° C (with decomposition).

IR (Nujol): 3400, 3300, 3200, 1770, 1730, 1680, 1610, 1520, 1240, 1160, 1040, 980, 740 ^cm-1 wavenumber.

(16) 7- (2- (1-Butoxycarbonyl-ethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color isomer), m.p. 147-151 ° C (with decomposition).

IR (Nujol): 3400, 3300, 3200, 1770, 1720, 1680, 1610, 1520, 1280, 1235, 1155, 1045, 980, 740 ^cm-1 wavenumber.

(17) 7- (2-Phenoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cephem-4-carboxylate: 4-nitrobenzyl ester (colorless). 140-145 ° C (with decomposition).

IR (Nujol): 3300, 1775, 1720, 1680, 1625, 1600, 1590, 1520 ^cm-1 wavenumber.

(18) 7- [2-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] (4-fluorophenoxyimino) -3-cephem-4-carboxylic acid 4-nitrobenzyl ester (colorless) 135-140 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1720, 1680, 1625, 1605,1500,1495 ^cm-1 wavenumber.

(19) 7- [2- (4-Chloro-phenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid 4-nitrobenzyl ester (color) 155-160 ° C (with decomposition).

IR (Nujol): 3300, 3180, 1770, 1720, 1680, 1625, 1600, 1580, 1520, 1480 ^cm-1 wavenumber.

(20) 7- [2- (3-Trifluoromethyl-phenoxyimino) -2- (5-amino-2,4-thiadiazol-3-yl) -acetamido) -3-cephem-4-carboxylic acid 4-nitrobenzyl ester (color isomer), 136-140 ° C (dec.)

while watching). IR (Nujol): 3370, 3200, 1780, 1730, 1690, 1680, 1630, 1610, 1520, 1450 1325, 1280, 1160, 1125, 975, 8 50, 740 cm ^-1 húllámszám- at.

(21) 7- [2- (3-Trifluoromethyl-phenoxyimino) -2- (5-amino, 2,4-yiadiazol-3-yl) -acetamidol-3-cfem-4-carboxylic acid (color isomer), decomposition point : 193 ° C.

IR (Nujol) 3450, 3320, 3200, 1770, 67

-67183 006

1710, 1665, 1630, 1560, 1515, 1325, 1170, 1110, 940 cm ^-1 .

(22) 7-1,2-Phenoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cephem-4-carboxylic acid (color isomer), m.p. 168-170 ° C (with decomposition).

IR (Nujol) 3400, 3200, 1780, 1660, 1620, 1600, 1590, 1540 cm ^-1 .

(23) 7- [2- (4-chlorophenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cephem-4-carboxylic acid (color isomer), 145-150 ° C (with decomposition).

IR (Nujol): 3400, 3260, 3180, 1775, 1675, 1625, 1600,1520,1480 ^cm-1 wavenumber.

(24) 7- [2- (4-Fluorophenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cephem-4-carboxylic acid (color isomer), m.p. -135 ° C (with decomposition).

IR (Nujol): 3400, 3270, 3180, 1765, 1675, 1605, 1500 cm ^-1 .

(25) 7- [2-Allyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid 4-nitrobenzyl ester (color isomer), m.p. 125-130 ° C (with decomposition).

• IR (Nujol): 3300, 1770, 1720, 1680, 1630, 1610, 1520 ^cm-1 wavenumber.

(26) 7- [2-Allyloxy] oximino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cephem-4-carboxylic acid (color isomer), m.p. -165 ° C (with decomposition).

(27) 7- [2- (2-Cyano-dopenten-1-yl) -oxymimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetarnido] -3-cephem-4-carboxylic acid (color isomer 180-185 ° C (with decomposition).

TR spectrum (nujol): 3500, 3430, 3300, 3200, 1770, 1690, 1660, 1640, 1620, 1580, 1510 cm ^-1 .

(28) 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color isomer), m.p. -175 ° C.

IR (Nujol): 3520, 3420, 3320, 3220, 3160, 1770, 1685, 1655, 1635, 1625, 1570, 1505 cm ^-1 .

(29) 7- [2- (2-Cyclohexen-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cephem-4-carboxylic acid (color isomer) 175-180 ° C (with decomposition).

IR (nujol): 3300, 3200, 1770, 1670, 1630, 1520 cm ^-1 .

(30). 7- [2-Cycloheptyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color isomer), white powder, m.p. 175 ° C (with decomposition).

IR (Nujol): 3400, 3300, 3200, 1770, 1670, 1620, 1520, 1280, 1240, 1160, 1000, 980, 730 ^cm-1 wavenumber.

Example 52

Following the procedure described in Example 30, the following compounds were prepared:

(1) 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -2-methyl-3-cephem-4-carboxylic acid lacethoxyethyl ester (color isomer) ).

IR (Nujol): 3400, 3310, 3150, 1780, 1750, 1675 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 1.2-1.6 (6H, m);

1.5-2.1 (8H, m), 2.07 (3H, s),

3.6-4.1 (1H, m), 4.6-5.0 (1H, m), 5.17 (1H, d, J = 4.5Hz), 5.95 (1H, dd, J = 4 , 5 and 8Hz), 6.67 (1H, d, J = 6Hz), 6.90 (1H, q, J = SH2), 8.12 (2H, bs), 9.45 (1H, d, J = 8Hz).

(2) 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -2-methyl-3-cephem-4-carboxylic acid 1-isobutyryloxyethyl ester (color isomer), amorphous powder.

IR (Nujol): 3400, 3300, 3170, 1780, 1745, 1675, 1620, 1525 ^cm-1 wavenumber.

NMR _(DMSO-d6, he): 1.08 (6H, d, J = 7Hz),

1.2-2.2 (14H, m), 2.2-2.9 (1H, m),

3.88 (1H, q, J = 7Hz), 4.6-5.0 (1H, m), 5.12 (1H, d, J = 4.5Hz), 5.90 (1H, dd, J 4.5 and 8Hz), 6.63 (1H, d, J = 7Hz), 8.06 (2H, broad s), 9.43 (1H, d, J = 8Hz).

(3) 7- [2- (2-Cyclopenten-1-yloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -2-methyl-3-cephene-1-carboxylic acid 1-acetoxy -propyl ester (color isomer), m.p. 110-128 ° C (with decomposition).

IR spectrum (nujol): 3400, 3280, 3150, 1780, 1750, 1730, 1620 cm @ ^-1 .

Nuclear Magnetic Resonance Spectrum (DMSO-d ₆ + D ₂ O, δ): 0.92 (3H, t, J = 7.5Hz), 1.42 (3H, d, J = 7Hz),

1.8-2.5 (4H, m), 1.5-2.3 (2H, m), 2.05 (3H, s), 3.6-4.1 (1H, m), δ, 10 (1H, d, J = 4.5Hz), 5.1-5.5 (1H, m),

5.7-6.3 (3H, m), 6.4-6.9 (2H, m).

(4) 7- [2- (2-Cyclopenten-1-yloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -2-methyl-3-cephem-4-carboxylic acid 1 - (2-Azidoethoxycarbonyloxy) ethyl ester (color isomer), m.p. 85-100 ° C (with decomposition).

IR (nujol): 3310, 2200, 1760-1785, 1680 cm @ -1.

NMR (DMSO-d ₆ + D ₂ O, δ): 1.48 (3H, d, J = 6Hz), 1.5 (3H, d, J = 4.5Hz), 2.0 to 2, Δ (4H, m), 3.5-4.1 (1H, m),

3.63 (2H, t, J = 4Hz), 4.30 (2H, t, J = 4Hz). 5.16 (1H, d, J = 4.5Hz),

5.2-5.45 (1H, m), 5.7-6.2 (2H, m),

6-6.2 (1H, m.) 6.6-6.8 (1H, m),

6.7 (1H, d, J = 6Hz).

(5) 7- {2- (2-Cyclopenten-1-yloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -2-methyl-3-cephem-4-carboxylic acid ethoxycarbonyloxyethyl ester (color isomer).

IR (Nujol): 3420, 3300, 3150, 1780, 1760, 1675, 1620 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (DMSO d ₆ + D ₂ O, δ): 1.23 (3H, t, J = 8?), 1.42 (3H, d, J = 7Hz), 1.88 (3H, d, J = 5Hz), 1.8-2.5 (4H, m), 3.6-4.1 (1H, m), 4.18 (2H, q, J = 8Hz), 5.18 ( 1H, d, J = 5Hz),

5.2-5.6 (1H, m), 5.9-6.3 (211, m), 5.95 (1H, d, J = 5Hz), 6.8 (111, d J = 7HzV 6 83 OH .q. J = 5Hz).

(6) 7-12- {3- (N-tert-butoxycarbonylamino) -propoxymethyl} -2- (5-amino-1,2,4-thiadlazol-3-yl) -acetamido] -2-68183 006 methyl-3 pcealoyloxymethyl ester of cephem-4-carboxylic acid (styrene isomer), powder, m.p. 66-75 ° C (with decomposition).

SpekIrum IR (Nujol): 3300, 1780, 1745, 1680, 1620 ^cm-1 wavenumber.

• (7) 7- (2- {3- (N-tert-Biotoxycarbonylamino) -propoxyimino} -2- (5-amino-1,2.4-1,13 (liazol-3-yl) -acetamide) -3- ( 1-Methyl-1H- (etrazol-5-yl) -lionic (yl-3-cefcm-4-carboxylic acid pivaloyloxymethyl ester (color isomer), powder.

* IR spectrum (nujol). 3300, 1780, 1745, 1680,

1620 cm 'at wave number ¹ .

(8) 7- {2- {3- (N-tert-Butoxycarbonylamino) -propoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (5-methyl- 1,3,4-Thiadiazol-2-yl) thiomethyl-3 cephem-4-carboxylic acid pivaloyloxymethyl ester (color isomer).

IR (Nujol): 3300, 3150, 1783, 1745, 1675. 1615 ^cm-1 wavenumber.

NMR (DMSO-d ₆ + D ₂ 0, 5): 1.15 (911, s), 1.37 (9H, s), 1.5-2.0 (2H, m), 2.65 (3H, s), 2.8 - 3.2 (2H, m), 3.5 - 3.8 (2H, m), 3.9 - 4.3 (2H, m), 4.16 and 4 , 53 (2H, ABq. J = 13), 5.17 (1H, d, J = 4.5Hz), 5.6-6.0 (3H, m).

(9) 7- [2- {3- (N-tert-butoxycarbonylamino) -propoxyimino} -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetanudo] -3- [1 ( 2-hydroxyethyl) -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid pivaloyloxyethyl ester (color isomer), powder, m.p. 88-101 ° C (with decomposition).

IR (Nujol): 3300, 1780, 1750, 1675, <1620 ^cm-1 wavenumber.

(10) 7- [2- {3- (N-tert-Butoxycarbonylamino) -propoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamide] -3 (1,3,4) -thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (color isomer), powder, m.p. 71-84 ° C (with decomposition).

IR (Nujol): 3300, 1780, 1745, 1680, 1615 ^cm-1 wavenumber.

(11) pivaloyloxymethyl ester of 7- {2- (2-cyclohexen-1-yloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -cephalosporanic acid, m.p. 93 -101 ° C (with decomposition).

IR (Nujol): 3400, 3300, 3180, 1780, 1740, 1675, 1615, 1525 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (DMSO-d ₆ + D ₂ O, δ): 1.13 (9H, s), 1.4-2.2 (6H, m), 2.02 (3H, s), 3.58 (2H, s), 4.50-4.93 (1H, m), 4.68 and 4.90 (2H, ABq, J = 13.5Hz), 5.18 (1H, d, J = 4, 5Hz), 5.6-6.2 (5H, m).

(12) 7- [2- (2-Cyclopenten-1-yloxyimino) -2- (5-amino-2,4-diadiazol-3-yl) -acetamido] -2-methyl-3-cephem-4- phthalide 3-carboxylic acid ester (color isomer), m.p. 131-144 ° C (with decomposition).

IR (Nujol): 3420, 3210, 3150, 1780, 1740, 1675, 1620, 1525 ^cm-1 wavenumber.

1 H NMR (DMSO-d 6 + D ₂ O, δ): 1.45 (3H, d,

J = 7Hz), 1.9-2.5 (4H, m), 5.13 (1H, d, J = 4.5Hz), 5.2-5.5 (1H, m),> 5.7 -6.3 (311, m), 6.75 (1 / 2H, d,

J = 6Hz), 6.77 (1 / 2H, d, J = 6Hz), 7.62 (1 / 2H, s), 7.65 (1 / 2H, s), 7.83 (411, broad s) ).

(13) 7- (2- (2-cyclopentenyl-1-oxyimino) -2- (5-amino-2,4-thiadiazol-3-yl) -acetanido] -2-methyl-3-cephem-4-carboxylic acid; pivaloyloxymethyl ester (color isomer), m.p.

111-124 ° C (with decomposition).

IR (Nujol) 3400, 3300, 3270. 1775.

1740, 1670, 1620, 1520 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (DMSO-d ₆ + D ₂₀ O, δ): 1.17 (911, s).

1.45 (3H, d, J = 7Hz), 1.9-2.4 (411, m), 3.7-4.0 (1H, m), 5.1-5.6 (1H, m ), 5.13 (1H, d, J = 4.5Hz), 5.7 6.3 (5H, m), 6.65 (III, d, J = 7Hz).

(14) 7- [2- (2-Cyclopenten-1-yloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -2-methyl-3-cephem-4-carboxylic acid 1 benzoyloxyethyl ester (color isomer), m.p.

132-137 ° C (with decomposition).

IR (Nujol): 3400, 3300, 3160, 1780, 1738, 1680, 1620 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (DMSO-d ₆ + D ₂ O, δ): 1.43 (3H, d, J = 7Hz), 1.62 (3H, d, J = 5Hz),

1.7-2.4 (4H, m), 3.84 (1H, q, J = 7Hz), 5.0-5.4 (1H, m), 5.13 (111, d, J = 4 , 5Hz), 5.6-6.3 (3H, m), 6.70 (1H, d, J = 6Hz), 7.16 (1H, q, J = 5Hz), 7.3-8.2 (5H, m).

(15) 7- [2- {4- (N-tert-Butoxycarbonylamino) -methyl-benzyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamide] -3-methyl-3 pivaloyloxymethyl ester of acephem-4-carboxylic acid (color isomer), powder.

IR (Nujol): 3300, 1780, 1750, 1680 ^cm-1 wavenumber.

(16) 7- [2-Allyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- {2- (N-tert-butoxycarbonylamino) ethyl} -1H -tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), powder.

IR (Nujol): 3300, 1780, 1750, 1680 ^cm-1 wavenumber.

Example 53

A solution of 127.2 mg of 2- (1-amino-1-cyclohexyl) -acetyl chloride hydrochloride in 2 ml of methylene chloride was treated with 132 mg in 5 minutes.

7- [2- (3-Amino-propoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -2-methyl-3-cephene-4-carboxylic acid (color isomer) and 0.6 ml of bis (trimethylsilyl) acetic acid in 6 ml of methylene chloride are added dropwise with stirring and cooling at -30 ° C, and the mixture is stirred for an additional 30 minutes at -30 ° C to -35 ° C. Stirring is continued after the addition of a saturated aqueous solution of sodium hydrogen chloride, and the reaction mixture is worked up in the usual manner with 85 mg of 7- [2- {3- (N- (2-t-aminolecyclohexyl) -acetyl) -amino. ) -propoxyimino} -2- (5-amine-1,2,4-thiadiazol-3-yl) -acetamido] -2-methyl-3-cephene-4-carboxylic acid (color isomer), m.p. 198-224 ° C. during decomposition).

IR (Nujol): 3250, 3150, 1760, 1640, 1580, 1520 cm ^"1 wavenumber.

Nuclear Magnetic Resonance Spectrum (D ₂ O + DCl, δ): 1.0 - 2.2 (15H, m).

2.65 (2H, s), 3.1-3.6 (2K, m). 3.6-4.1 (1H, m), 4.1-4.6 (2U, m), 5.0-5.3 (1H, m), 5.95 (jf, d, J = 4 , 5Hz), 6.82 (111, d, J = 61U) 54. example

The following compounds were prepared as described in Example 53:

-691

183 006 (1) 7- (2- (2 - ({N - (N-tert-butoxycarbonyl) -D-phenylglycylamino) -ethoxyimino} -2- (5-amino-1,2,4-thiadiazole-3) -yl) acetamido] -2-methyl 3-cephem-4-carboxylic acid (color isomer), m.p. 77-91 ° C (with decomposition).

IR (Nujol): 3300, 3160, 1775, 1680, 1660, 1630, 1525 ^cm-1 wavenumber.

NMR (DMSO-d δ _sixth): 1.37 (. S 9H), 1.40 (311, d, I = 8 Hz), 3.1 4.2 (5H, m). 5.08 (1H, d, J = 4.5Hz), 5.10 (1H, d, J = 8Hz). 5.90 (1H, dd, J = 4.5 and 9Hz), 6.53 (1H, d, J = 7.5Hz), 7.32 (5H, s), 8.13 (211, broad s) , 9.48 (1H, d, J = 9Hz).

(2) 7- [2- {3 - {{N- (N-tert-butoxycarbonyl) -D-phenylglycylamino}} -propoxyimino} -2- (5-atnino-1,2,4-thiadiazol-3-one). yl) acetamido] -2-methyl-3-cephem-4-carboxylic acid (color isomer).

Spcktrum IR (Nujol): 3300, 3200, 1775, 1700, 1650, 1525 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (DMSO-d ₆ + D ₂ O, δ): 1.3-1.6 (12H, m), 1.6-2.0 (2H, m), 2.8-3.4 ( 2H, m), 3.82 (1H, q, J = 7.5Hz), 3.9-4.3 (2H, m), 5.05 (1H, d, J = 4.5Hz), δ, 83 (1H, d, J = 4.5Hz), 6.48 (1H, d, J = 6Hz).

Production Example 23

20.00 g of potassium iodate are added at room temperature

To a stirred solution of 7.7 g of iodine in 70 ml of concentrated hydrochloric acid was stirred for 1.5 hours at 35-40 ° C. Acetic anhydride (30 ml) was then added at a temperature below 10 ° C for 0.5 h, followed by addition of 1,2-dichlorobenzene (44.69 g), also at a temperature below 10 ° C and for 0.5 h. The mixture was stirred at the same temperature for 1 hour and then at room temperature for a further 19 hours. The reaction mixture was poured into ice-water (500 mL) and washed with diethyl ether. To the aqueous phase was added a solution of sodium chloride (8.9 g) in water (50 ml), the precipitate was collected by filtration, washed with ice water to give 58 g of 3,4,3 ', 4'-tetrachlorodiphenyliodonium chloride, m.p. -186 ° C (with decomposition).

IR (Nujol): 1555, 1450, 1250, 1210, 1170, 1125, 1030 ^cm-1 wavenumber.

Production Example 24

By the methods of Preparation Example 23, the following compounds were prepared:

(1) 3,3'-Di (trifluoromethyl) diphenyl iodonium chloride. IR (Nujol): 3600-3200, 1600, 1420;

1320, 1310, 1190, 1170, 1120, 1095, 1085, 1055, 800, 700, 685 cm ^{&lt; 1} &gt; (2) 3,3'-dicarboxydiphenyl iodonium bromide. IR (Nujol) 3400, 1700, 1290, 1250,

1210, 1170, 1050, 750 cm ^-1 wave number.

(3) 3,3'-di (ethoxycarbonyl) diphenyl iodonium bromide, m.p. 154-157 ° C.

Spcktrum IR (Nujol): 1730, 1295, 1280, 1255, 1110, 1020, 750 ^cm-1 wavenumber.

Production Example 25

According to the preparation examples 1- (1) and 1- (2). The following compounds are prepared:

(1) N- (3-phthalimidopropoxy) phthalimide, m.p. 168-170 ° C.

IR (Nujol): 1790, 1770, 1730, 1710, 1390, 1060, 725, 705 ^cm-1 wavenumber.

(2) N- (1-cyclohexyloxycarbonylethoxy) phthalimide, m.p. 50-54 ° C.

NMR spectrum (Nujol): (DMSO-d _6, δ). 1.51 (3H, d, J = 7Hz), 0.9-2.1 (10H, m), 4.7 (1H, m), 4.82 (1H, q, J = 7Hz), 7, 87 (4H, s).

(3) N- (α-tert-butoxycarbonylbenzyloxy) phthalimide.

(4) N- (1-tert-butoxycarbonyl-2-methylpropoxy) phthalimide, m.p. 84-87 ° C.

IR (Nujol): 1790, 1730, 1360, 1160, 1140, 1000, 880, 780, 700 ^cm-1 wavenumber.

(5) Ν - (1- tert -butoxycarbonylpropoxy) phthalimide, m.p. 49-52 ° C.

NMR (DMSO-d _é, δ): 1.02 (3H, t, J = 7Hz),

1.40 (9H, s), 1.9 (2H, m), 4.55 (1H, t, J = 6Hz), 7.82 (4H, s).

(6) N- (1-tert-butoxycarbonylethoxy) phthalimide, m.p. 80-82 ° C.

NMR _(DMSO-d6, δ): 1.42 (9H, s), 1.48 (3H, d, J = 7Hz), 4.72 (IH, q,

J = 7Hz), 7.86 (4H, s).

(7) N- (1-tert-butoxycarbonyl-1-methylethoxy) phthalimide, m.p. 96-100 ° C.

NMR _(DMSO-d6, δ): 1.42 (9H, s), 1.48 (6H, s), 7.87 (4H, s).

(8) N- (1-butoxycarbonylethoxy) phthalimide, m.p. 48-53 ° C.

IR (Nujol): 1755, 1720, 1210, 1140, 1110, 1080,875,695 cm ^-1 .

(9) N- (1-benzyloxycarbonyl-ethoxy) -phthalimide, m.p.

IR (Nujol): 1790, 1740, 1450, 1210, 1190, 1110, 1080, 980, 880, 735, 700 ^cm-1 wavenumber.

(10) N- (2-oxo-3-tetrahydrofuryloxy) phthalimide, m.p. 140-142 ° C.

IR (Nujol): 1785, 1760, 1720, 1605, 1215, Π85, 870, 695 ^cm-1 wavenumber.

Production Example 26

By the method of Preparation Example 2, the following compounds were prepared:

(1) 3-Aminopropoxy-2'-dihydrochloride. Nuclear Magnetic Resonance Spectrum (D ₂ O, δ): 2.20 (211, m), 3.27 (2H,).

t, J = 7Hz), 4.33 (2H, t, J = 6Hz). ⁽ (2) 1-phenylethoxyamine).

(3) 1-tert-Butoxycarbonyl-2-methylpropoxyamine.

(4) α-tert-butoxycarbonylbenzyloxyamine.

(5) 1-Butoxycarbomyl-ethoxyamine.

Production Example 27

By the method of Preparation Example 17, the following compounds were prepared:

-701

183 006 (1) 2- (tert-Butoxycarbonylmethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer), m.p.

155 ° C (with decomposition).

IR (nujol): 3420, 3230, 3100, 1725, 1610, 1530 cm ^-1 .

NMR _(DMSO-d6, δ): 1.45 (9H, s), 4.70 (2H, s), 8.12 (2H, br s).

(2) 2- (1-Cyclohexyloxycarbonylethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer), m.p. 175180 ° C (with decomposition) .

IR (nujol): 3380, 3260, 3170, 1720, 1610, 1520, 1220, 990, 710 cm ^-1 .

(3) 2- (tkdan-1,1-dioxide-3-yloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer), m.p. 200205 ° C (dec.) while).

IR (Nujol): 3300, 1720, 1620, 1530 ^cm-1 hullámszánmál.

(4) 2- (α-tert-butoxycarbonyl-benzimidoyl) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer), m.p. 155-160 ° C. during decomposition).

IR (Nujol): 3440, 3350, 3250, 1750, 1730, 1640, 1535 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 1.37 (9H, s), 5.67 (IH, s), 7.45 (5H, s), 8.25 (2H, br s).

(5) 2- (1-tert-Butoxycarbonyl-2-methylpropoxyimino) 2- (5-amino-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer), m.p. 158-162 ° C. C (during decomposition).

IR (Nujol): 3600, 3400, 1740, 1720, 1630 ^cm-1 hullámszánmál.

NMR _(DMSO-d6, δ): 0.95 (6H, d, J = 7Hz),

1.8-2.4 (1H, m), 4.33 (1H, d, J = 6Hz), 8.13 (211, wind s).

(6) 2- (1-tert-Butoxycarbonyl-propoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer), m.p. 152-155 ° C (dec.) while).

NMR _(DMSO-d6, δ): 0.94 (3H, t, J = 7Hz), 1.42 (9H, s), 1.80 (2H, m), 4.51 (IH, t , J = 6Hz), 8.16 (2H, bs).

(7) 2- (1-tert-Butoxycarbonyl-ethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer), m.p. 155156 ° C (with decomposition).

IR (Nujol): 3400, 3300, 3200, 1720, 1710, 1620, 1520 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 1.2-1.7 (12H, m), 4.72 (IH, q, J = 7 Hz), 8.2 (2H, br s).

(8) 2- (1-tert-Butoxycarbonyl-1-methylethoxyimino) -2 (5-amino-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer), m.p. 180-181 ° C. C (during decomposition).

IR (Nujol): 3400, 3300, 3200, 1745, 1715, 1630, 1530 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 1.38 (9H, s), 1.43 (6H, s), 8.15 (2H, br s).

(9) 2- (1-Butoxycarbonyl-ethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer), m.p. 120123 DEG C. (with decomposition).

IR (Nujol): 3400, 3300, 3200, 1725, 1615, 1510, 1410, 1210, 1170, 1135, 1100, 1040, 990, 870, 720 ^cm-1 wavenumber.

NMR (DMSO-d _é, δ): 0.85 (3H, t, J = 6Hz);

1.43 (3H, d, J = 7Hz), 1.0-1.7 (4H, m), 4.12 (2H, t, J = 6Hz), 4.85 (1H, q, J = 7Hz), 8.04 (2H, bs).

(10) 2- (1-Benzyloxycarbonyl-ethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer), m.p. 129-133 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1720, 1620, 1530 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 1.45 (3H, d, J = 6Hz), 4.97 (IH, q, J = 6Hz), 5.18 (2H, s).

7.31 (5H, s), 8.17 (2H, broad).

Production Example 28

The following compounds were prepared as described in Preparation Example 15:

(1) 2- (1,1-Doxothiothiolan-3-yloxyimino) -2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (color isomer), m.p. 214 ° C (dec.) while).

IR (Nujol): 32Ö0, 1720, 1680, 1600, 1530 ^cm-1 wavenumber.

NMR (DMSO-d _s, δ): 2.30-2.50 (2H, m), 2.90 to 3.83 (4H, m), 5.10-5.50 (1H, m) , 8.92 (1H, s).

(2) 2- (1-Phenylethoxyimino) -2- (5-formamido-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer), m.p. 174-175 ° C (with decomposition) .

IR spectrum (nujol): 3100, 1720, 1690, 1550 cm ^-1 .

NMR _(DMSO-d6, δ): 1.58 (3H, d, J = 6Hz);

5.44 (1H, q, J = 6Hz), 7.32 (5H, m),

8.78 (1H, m), 13.34 (1H, broad s).

Production Example 29

Prepared as described in Production Example 15

To an aqueous solution containing 2- (3-aminopropoxyimino) -2- (5-formamido-1,2,4-thiadiazol-3-yl) acetate acetate (color isomer), 20 g triethylamine and 27 g 2-tert-butoxycarbonyloxyimino A solution of -2-phenylacetonitrile in dioxane (270 mL) was added and the mixture was stirred at room temperature for 2 hours. After the dioxane was evaporated, the aqueous solution was adjusted to pH 6 with 10% hydrochloric acid and washed with ethyl acetate. Ethyl acetate was added to the aqueous phase and the pH of the mixture was adjusted to 3 with 10% hydrochloric acid. The organic layer was washed with brine, dried over magnesium sulfate and evaporated to dryness. The residue was triturated with diisopropyl ether to give 14.2 g of 2- [3- (N-tert-butoxycarbonylamino) -propoxyimino] -2- (5-formamido- 1,2,4-thiadiazol-3-yl) acetic acid (color isomer), m.p. 115-117 ° C (with decomposition) is obtained.

IR (Nujol): 3320, 3150, 1740, 1680, 1560-1530, 1400, 1230, 1140, 1040, 1030, 890 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 1.47 (9H, s), 1.97 (2H, m), 3.10 (2H, t, J = 7Hz), 4,3Q (211, t , J = 7Hz), 8.80 (111, s).

Production Example 30

The following compounds were prepared as described in Preparation Examples 13 and 29:

(1) 2- (2- (N-tert-butoxycarbonylamine, = ethoxyimino)) ···

-711

183,006

2- (5-formamido-1,2,4-thiadiazzo) -3-yl) -acetic acid (color isomer), m.p. 139-145 ° C (with decomposition).

IR (Nujol): 3400, 3J5O, 1748, 1700, 1690, 1540 cm ^"1 wavenumber.

Nuclear Magnetic Resonance Spectrum (DMSO-d ₆ + D ₂ O, δ): 1.45 (9H, s), δ

3.40 (2H, t, J = 6Hz), 4.32 (2H, t, J = 6Hz), 8.07 (1H, s).

(2) 2- [4- (N-tert-Butoxycarbonylaminomethyl) -benzyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer). _ 10

IR (Nujol): 3300, 3150, 1700 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 1.65 (9H, s), 4.12 (2H, d, J = 5.5Hz), 5.19 (2H, s);

7.21 (4H, s). ₁₅

Production Example 31

The following compounds were prepared as described in Preparation Example 4: 20 (1) 2- [2- (N-tert-Butoxycarbonylamino) -ethoxyimino] 1- (5-amino-1,2,4-thiadiazol-3-yl). ) acetic acid (color isomer), m.p. 172-177 ° C (with decomposition).

IR (Nujol) 3300, 3140, 1738, 1680,

1628, 1595, 1550, 1527, 1285, 25 1245, 1165, 1120 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (DMSO-d ₆ + D ₂ O, δ): 1.42 (9H, s), 3.35 (2H, t, J = 6Hz), 4.22 (2H, t, J = 6Hz) . 30 (2) 2- (3- (N-tert-Butoxycarbonylamino) -propoxyimino] -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer).

IR (Nujol): 3300, 3150, 2600-2400, 1720-1660, 1620, 1530, 1250, 1160, 1030, 720 cm @ -1.

NMR _(DMSO-d6, δ): 1.33 (9H, s), 1.82 · (2H, m), 3.03 (2H, m), 4.17 (2H, t,?

J = 6Hz), 6.73 (1H, broad s), 8.13 (2H, broad s). 40 (3) 2- (4-chlorophenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), m.p. 150-155 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1710, 1640,

1580, 1530 cm ^-1 . 45

NMR _(DMSO-d6, δ): 7.37 (2H, d, J = 9Hz),

7.67 (2H, d, J = 9Hz), 8.50 (2H, broad s).

(4) 2- (4-Fluorophenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer), m.p. ^- . 140-145 ° C (dec. 50).

IR (Nujol): 3450, 3300, 3200, 1730, 1630, 1530, 1500 cm ^{-1 wave:} figure.

NMR _(DMSO-d6, δ): 7.17 (2H, s), 7.27 55 (2H, s), 8.27 (2H, s).

(5) 2- [1-tert-Butoxycarbonyl-1-cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer), m.p. 174-175 ° C. C (during decomposition).

IR spectrum (nujol); 3400, 3300, 3200, 1745, 170 1715, 1630, 1530 cm at wave number ¹

NMR _(DMSO-d6, δ): 1.37 (9H, s), 1.65 (4H, m), 1.97 (4H, m), 8.17 (2H, br s). 65 (6) 2- (1-Phenylethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer), m.p. 103-107 ° C (with decomposition).

IR (Nujol): 3250, 3150, 1710, 1610, 1520 cm ^-1 .

NMR _(DMSO-d6, 5Y 1.57 (3H, d, J = 6Hz), 5.42 (1H, q, J = 6Hz), 7.40 (5H, m);

8.20 (2 H, m).

Production Example 32

7.2 g of 2-hydroxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (color isomer) in methanolic sodium hydroxide solution (83.7 ml of methanol and 83.7 ml of aqueous sodium hydroxide) (prepared from a hydroxide solution), 11.4 g of 4,4'-difluorodiphenyl iodonium chloride are added and the mixture is stirred at room temperature for 1 hour. The resulting oily substance was separated by decantation and the solution was concentrated under reduced pressure, the methanol was evaporated. The aqueous solution was acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated to dryness. Trituration of the residue with 4 * 2 - [beta] - [beta] -piperidine gave 6.0 g of 2- (4-fluorophenoxyimino) -2- (5-formamidol, 2,4-thiadiazol-3-yl) -acetic acid (color isomer). m.p. 130-135 ° C (with decomposition).

IR (Nujol): 3100, 3050, 1730, 1690, 1530, 1500 cm ^"1 huöámszámnál.

Nuclear Magnetic Resonance Spectrum (DMSO-d6, _δ ), 7J (2U s), 7.27, (2H, s), 8.83 (1H, s), 13.43 (1H, s)

Production Example 33

As described in Preparation Example 32, the following compounds were prepared: _t (1) 2- (4-Chlorophenoxyimino) -2- (5-formamido-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer), m.p. 155-160 ° C (with decomposition) ).

IR (Nujol): J180, 1725, 1690, 1580, 1530 cm ^-1 .

NMR _(DMSO-d6, δ): 7.30 (2H, d, J = 9Hz), 7.57 (2H, d, J = 9Hz), 9.0 (1H, s).

(2) 2- (2-Methoxy-5-nitrophenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetic acid (syn isomer), m.p. 125-128 ° C (dec.) while).

IR (Nujol): 3400, 3280, 1740, 1720, 1690, 1630, 1590, 1510, 1340, 1275, 970, 720 cm ^-1 .

NMR _(DMSO-d6, δ): 3.93 (3H, s), 7.27 (1H, d, J = 8Hz), 8.01 (1H, d, J = 8Hz), 8.07 (1H, s), 8.30 (2H, broad s).

Production Example 34

The following compound was prepared as described in Preparation Example 21.

2 <1-tert-butoxycarbonyl-1-cyclopentyl-oxyimino) -2- (5-formamido-1,2,4-thiadiazol-3-yl) -acetic acid (syn isomer), m.p. 140-141 ° C. during decomposition).

IR (Nujol): 3550, 1730, 1670, 1550, 1540, 1280, 1255, 1150, 980, 720 cm ^-1 .

NMR _(DMSO-d6, δ): 1.48 (9H, s), 1.83 (4H, m), 2.03 (4H, m), 8.87 (1H, s);

13.6 (1H, safe).

-721

183,006

Production Example 35. In the same manner as in Preparation Example 32, starting from 2-hydroxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer), the latter of which was prepared in Preparation Example 4. Prepared as described above, the following compounds were prepared:

(1) 2- (o- and p-Tolyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer).

NMR _(DMSO-d6, δ): 2.20 (IH, s), 2.27 (2H, s), 6.97 7.43 (4H, m), 8.33 ¹⁰ (2H, br s).

(2) 2- (3,4-Dichlorophenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (color isomer), m.p. 177-178 ° C.

IR (Nujol): 3300, 1710, 1625, 1585, 1530, 1300, 1210, 1120.980 cm ^{-1 at 15} .

NMR _(DMSO-d6, δ): 6.83 to 7.73 (3H, m), 8.38 (2H, br s).

(3) 2- (3-Trifluoromethyl-phenoxyimino) -2- (5-amino-1,2,4-n-thiadiazol-3-yl) -acetic acid (color isomer), m.p. 167-168 ° C. (during decomposition).

IR (nujol): 3250, 1645, 1620, 1590, 1450, 1320, 1170, 1140, 1010, 995, 845, 730 cm @ ^-1 . -c

NMR _(DMSO-d6, δ): 7.63 (4H, m), 8.44 (2H, br s).

(4) 2- (3-Ethoxycarbonyl-phenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer), m.p. 161-164 ° C (with decomposition) .

IR (Nujol): 3400, 3300, 3180, 1755, 1720, 1690, 1630, 1590, 1545, 1410, 1290, 1275, 970, 900, 755 cm @ -1.

NMR _(DMSO-d6, o): 1.36 (3H, t, J = 7Hz), ₃₅

4.40 (12H, q, J = 7Hz), 7.4-8.0 (3H, m), 8.5 (2H, broad s).

(5) 2- (3-Carboxy-phenoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer), m.p. 186-188 ° C (with decomposition). 40

IR (Nujol) 3420, 3150, 1735, 1690, 1620, 1580, 1265, 1200, 1000,980,

760 cm at wave number ¹ .

NMR _(DMSO-d6, δ): 7.3-8.0 (4H, m);

8.30 (2H, bs), 45 (6) 2-Phenoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (color isomer), m.p. 145-147 ° C (with decomposition).

IR (Nujol): 3350, 3170, 2500, 1730, 1710, 1645, 1630.1595, 1535 ^cm-1 wavenumber. 50

Production Example 36

64.8 g of a mixture of S-methyl- (5-formamido-1,2,4-thiadiazol-3-yl) -thiol 55-glyoxylate and 1-carboxy-3-hydroxypropoxyamine, the latter being 65.0 g N- (2-oxo-3-tetrahydrofuryloxy) phthalimide, 50 ml of concentrated hydrochloric acid and 200 ml of water were refluxed for 1 hour, treated as described in Preparation Example 17.

33.2 g of 2- (1-carboxy-3-hydroxypropoxyimino) -2- (5-amino, 2,4-thiadiazol-3-yl) -acetic acid (color isomer) are obtained, m.p. 188 ° C (with decomposition).

IR (Nujol) 3400, 3250, 3100, 1710,

1620, 1540 cm @ ¹ . 65

NMR _(DMSO-d6, δ): 1.73-2.10 (2H, m), 3.50 (211, t, J = 6Hz), 4.73 (111, t, J = 6Hz). , 8.13 (2Ή, s).

Production Example 37

33.0 g of 2- (1-carboxy-3-hydroxypropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (color isomer) prepared in 2.8 L of methanol To this solution was added 120 g of anhydrous magnesium sulfate and 60 g of acetic anhydride. The mixture was stirred at room temperature for 30 minutes, filtered and the filtrate was evaporated to dryness. The residue was triturated with acetone (200 mL) and ethyl acetate (1 L) was added. The mixture was stirred at room temperature for 1 hour and the precipitate was collected by filtration and washed with ethyl acetate. The precipitate was dissolved in water (200 mL) and ethyl acetate (500 mL), acetone (200 mL) and 6N hydrochloric acid (40 mL) were added.

The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated with diethyl ether, filtered and washed with diisopropyl ether to give 26.5 g of 2- (2-oxo-3-tetrahydrofuryloxyimino) -2- (5-amino-1,2,4-thiadiazole-3-). il) -e gives acetic acid (color isomer), m.p. 185-187 ° C (with decomposition).

IR (Nujol): 3400, 3300, 3200, 1775, 1730, 1640, 1605, 1535 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 2.27 to 2.70 (2H, m), 4.17 to 4.50 (2H, m), 5.27 (IH, t, J = 8Hz) , 8.22 (2H, s).

Preparation Example 38 (1) Following the procedure of Preparation Example 22- (1), the following compound was prepared:

Methyl-N- (6-acetamidohexil) dithiocarbamate. NMR _(DMSO-d6, δ): 1.33 (8H, br s);

1.80 (3H, s), 2.50 (3H, s), 3.07 (2H, m), 3.53 (2H, m), 7.77 (1H, m),

9.80 (1H, m).

(2) The following compounds were prepared as described in Production Example 22- (2):

(a) 1- (4-acetamidobutyl) -1H-tetrazole-5-thiol.

IR (Nujol): 3300, 1620, 1560, 1520 cm ^-1 .

NMR _(DMSO-d6, δ): 1.23 to 1.93 (4H, m), 1.77 (3H, s), 3.10 (2H, m), 4.23 (2H, m ), 7.80 (1H, broad s).

(b) 1- (6-acetamidohexyl) -1H-tetrazole-5-thiol, oil.

(3) The following compounds were prepared as described in Preparation Example 22- (3):

(a) 1- (4-Aminobutyl) -1H-tetrazole-5-thiol hydrochloride, white powder.

(b) 1- (6-aminohexyl) -1H-tetrazole-5-thiol hydrochloride, a red oil.

(4) The following compounds were prepared as described in Preparation Example 22- (4):

(a) 1- [4- (N-tert-butoxycarbonylamino) -butyl] -1H-tetrazol-5-thiol, m.p. 107-108.5 ° C.

IR (Nujol): 3200, 1640, 1520 ^cm-1 wavenumber.

NMR (DMS0-d _s, δ): 1.37 (911, s), 2.1 1,38- (4H, m), 2.97 (2H, m), 4.23 (2H, m ), 6.73 (1H, broad s).

-73183 006 (b) 1- [6- (N-tert-butoxycarbonylamino) hexyl] -1H-tetrazol-5-thiol, oil.

NMR (DMSO-d δ _sixth): 1.40 (15H, m), 1.77 (211, m), 2.93 (.211, m), 4.20 (2H, m), 6 , 70 (1H, broad s).

Preparation Example 39 (1) To a solution of 402 g of N- (3-bromopropyl) phthalimide in 2.5 L of acetone was added 225 g of 1-methylpiperazine and 415 g of potassium carbonate. The resulting mixture was refluxed for 3.5 hours. The reaction mixture was cooled, filtered, and the filtrate was washed with 500 mL of acetone. The filtrate and washings were combined and concentrated under reduced pressure. The remaining starting material was removed by azeotropic distillation using benzene as solvent to give 502 g of N- [3- (4-methyl-1-piperazinyl) propyl] phthalimide as an oil.

IR (film): 1770, 1700 ^cm-1 wavenumber.

(2) To a solution of 502 g of N- (3- (4-methyl-1-piperazinyl) propyl] phthalimide in 3.0 L of ethanol was added 187.6 g of 100% hydrazine hydrate. After refluxing for 5 hours, the reaction mixture is cooled and filtered, the filtrate is washed with 1 L of ethanol, the filtrate and washings are combined and concentrated under reduced pressure to give 146.6 g of 3- (4-methyl-1-piperazinyl) as a distillate under reduced pressure. of propylamine having a boiling point of 127-128 ° C / 34 mm Hg.

(3) To a solution of potassium hydroxide (57.3 g) in methanol (250 ml) was added 3- (4-methyl-1-piperazinyl) propylamine (146 g), followed by stirring and ice-cooling for 40 minutes.

Add 70.6 g of carbon disulfide. The resulting mixture was stirred for 3.5 hours under ice-cooling, and then the reaction mixture was concentrated under reduced pressure. The residual oil was dissolved in 400 mL of water and washed twice with diethyl ether. The washed aqueous phase was cooled with ice and 132.1 g of methyl iodide was added with stirring. The resulting mixture was stirred for 2 hours under ice-cooling and then extracted with ethyl acetate (3 x 400 mL) and chloroform (2 x 400 mL). The extracts were combined, dried over magnesium sulfate and evaporated under reduced pressure to give 139.3 g of methyl N- [3- (4-methyl-1-piperazinyl) propyl] dithiocarbamate.

The product thus obtained is used directly in the next step without further purification.

(4) To a solution of 139.3 g of methyl N- [3- (4-methyl-1-piperazinyl) propyl] dithiocarbamate from Preparation 39- (3) in 420 ml of water and 280 ml of ethanol

47.6 g of sodium azide are added. The resulting mixture was heated under reflux for 3 hours. The reaction mixture was then concentrated under reduced pressure, and the concentrate was washed successively with ethyl acetate and diethyl ether and then concentrated. Ethanol was added to the residue and the mixture was filtered. The filtrate was concentrated under reduced pressure and 6N hydrochloric acid was added to the resulting oil. The mixture was concentrated under reduced pressure and the residue was recrystallized from isopropyl alcohol (containing a little water) to give 48.1 g of 1- [3- (4-methyl-1-piperazinyl) propyl] -1H-pyrazole-5-thiol dihydrochloride. mp 239-243 ° C.

Nuclear Magnetic Resonance Spectrum (D ₂ O, δ): 2.3-2.8 (2H, m), 3.07 ¹ (311, s), 3.3 3.7 (2H, m), 3.75 ( 8H, s), 4.42 (2H, t, J = 6Hz).

Example 55

By the methods described in Examples 30, 40, 42, 44, 45, 47 and 48, the following compounds were prepared:

(1) 7- [2- (2-Oxo-3-tetrahydro-furyloxyimino) -2- (510 amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1 - {3- (N-tert-butoxycarbonylamino) -propyl} -1H-tetrazol-5-yl] -thioethyl-3-cephem-4-carboxylic acid (stn-isomer), m.p. 130-135 ° C (with decomposition).

IR (Nujol) 3300, 3200, 1780, 1680,

1620, 1525 ^cm-1 wavenumber.

(2) 7- [2- (2-Oxo-3-tetrahydro-furyloxyimino) -2- (5-amino-1,2,4-diazol-3-yl) -acetamido] -3- (1- (3-aminopropyl) -1H-tetrazol-5-yl] thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 210-215 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1670, 1620, 1525 ^cm-1 wavenumber.

(3) 7- (2- (1-Methyl-1-carboxyethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -cephalosporanic acid (color isomer). 210-220 ° C (with decomposition).

IR (Nujol): 3400, 3300, 3200, 1770, 1720, 1700-1670, 1620, 1520, 1230, 1150, 1060, 1020, 995, 975, 920, 740, 720 cm ^"1 wavenumber.

(4) 7- (2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -2-methyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (color isomer) ), amorphous powder.

IR (nujol): 3450, 3360, 3200, 1790, 1750, 1680, 1625, 1530 cm @ -1.

(5) 7- [2- (1-Methyl-1-tert-butoxycarbonyl-ethoxyimino) -2 '- (5-amino-1,2,4-thiadiazol-3-yl) -acetamide] -3-11- ( 3-aminopropyl) -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 198-203 ° C (with decomposition).

IR (Nujol): 3450-3300, 3200, 1770, 1680, 1600-1615, 1525, 1140, 990, 970, 750, 720 cm ^"1 wavenumber.

(6) 7- (2- (1-Carboxyethoxy) amino) -2- (5-amino-1,2,4-thia45 diazol-3-yl) acetamide] -3- {S- {2- (N-tert-butyl) butoxycarbonylamino) ethyl} -1,3,4-thiadiazol-2-yl] thiomethyl] -3-cephem-4-carboxylic acid (color isomer), m.p. 202-204 ° C (with decomposition).

IR spectrum (nujoO: 3350, 3200, 1780, 1680, 1620, 1520, 1250, 1170, 1100,

1050, 1000 cm at wave number ¹ .

(7) 7- [2- (1-Carboxyethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (5- (2-amino) ethyl) -1 _> 3,4-Thiadiazol-2-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 200-204 ° C (with decomposition).

IR (Nujol) 3350, 3200, 1770, 1680,

1620, 1520, 1240, 1180, 1100, 1060, 1040, 1000 cm @ ¹ .

f8) In-1 H -is-2-Cyclopenyvyl-t-yloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido} -3-cephem-3- m.p. 155-160 ° C (with decomposition). ylmethyl] -4'-carbamoylpyridinium-4-carboxylate (syn isomer).

IR (Nujol): 3300, 3150, 1770, 1675, 1610, 1560, 1520 ^cm-1 wave ·

6®.

-741

183 006 (9)? - (7- {2- (1-Methyl-1-carboxyethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido} -3-cephem-3- m.p. 180-185 ° C (with decomposition). ylmethyl] -4'-carbamoylpyridinium-4-carboxylate (color isomer).

IR (nujol): 3300, 1770, 1680, 1620, 5 1560, 1520 cm @ -1.

Example 56

F -3, 5, 7-12, 32-34. and Examples 40 and 40 were prepared as follows:

7- t -Carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1- (2-carboxyethyl) -1H-tetrazol-5-yl (thiomethyl-3- cephem-4-carboxylic acid (color isomer), m.p.

215-220 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1720, 1680, 1620, 1520 cm ^-1 .

NMR _(DMSO-d6, δ): 2.93 (2H, t, J = 6Hz);

3.67 (211, broad s), 4.33 (2H, broad s), 4.43 (2H, t, J = 6Hz), 4.67 (2H, s), 5.10 (1H, d, J = 4Hz), 5.83 (1H, dd, J = 4 and 8Hz), 8.13 (2H, s),

9.50 (1H, d, J = 8Hz).

J Example 7

14-17. and Example 42, the following compound was prepared:

7- [2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamidol-3- [1- (2-carboxyethyl) -1H-tetrazol-5-yl] - thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 215-220 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1720,

1680, 1620, 1520 cm- ^{1 at} 35 numbers.

NMR _(DMSO-d6, δ): 2.93 (2H, t, J = 6Hz);

3.67 (2H, broad s), 4.33 (2H, broad s), 4.43 (2H, t, J = 6Hz), 4.67 (211, s),

5.10 (1H, d, J = 4Hz), 5.83 (1H, dd, 40 J = 4 and 8Hz), 8.13 (2H, s), 9.50 (111, d, J = 8Hz) .

Example 58

Following the procedure described in Examples 27, 47 and 48, the following compound was prepared:

7- (2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido) -3- [1- (2-carboxyethyl) -1H-tetrazol-5-yl] -thiomethyl -3-cephem-4-carboxylic acid (color isomer), m.p. 215-220 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1720, 1680, 1620, 1520 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 2.93 (2H, t, J = 6Hz), _5S

3.67 (2H, broad s), 4.33 (2H, broad s), 4.43 (2H, t, J = 6Hz), 4.67 (2H, s), 5.10 (1H, d, J = 4Hz), 5.83 (1H, dd, J = 4 and 8lz), 8.13 (2H, s),

9.50 (1H, d, J = 8Hz). θθ

Example 59

To a cooled solution of 1.25 g of phosphorus pentachloride in 30 ml of methylene chloride was added 1.5 g of 2- (2-cyclopenten-1-yloxylimino) -2- (5-amino-1,2,4-thiadiazol-3-one). il) Acetic acid (color isomer) was added at -15 ° C and the mixture was stirred at -13 to -10 ° C for 30 minutes. However, a mixture of 1.82 g of N- (7-amino-3-cefcm-3-ylmethylpyridinium-4-carboxylate dihydrochloride and 10 g of trimethylsilylacetamide in 50 ml of methylene chloride was stirred for 10 minutes at room temperature and The cooled solution was added to the above activated mixture and the mixture was stirred for 15 minutes at 10 C. The reaction mixture was added to a solution of 3.6 g of sodium bicarbonate in 100 ml of water and stirred for 15 minutes at room temperature. The phase was separated, adjusted to pH 2 with 10% hydrochloric acid and washed with ethyl acetate, and the aqueous solution was subjected to column chromatography on a nonionic adsorption resin (Diaion HP-20, Mitsubishi Chemical Industries) using 100 ml of resin. The column is washed first with water and then eluted with 40% aqueous methanol. The eluate containing the desired product is collected, the methanol is evaporated under reduced pressure and lyophilized. 1.5 g of N- [7- {2- (2-cyclopenten-1-yloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido} -3- as a white powder. m.p. 190-195 DEG C. (decomposition), m.p. 190-195 DEG C. (dec.).

IR (Nujol): 3350, 3200, 1780, 1660, 1620, 1530 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (D ₂ O + NaHCO ₃ , δ): 1.9-2.5 (411, in), 3.23, 3.60 (2H, ABq, J = 16Hz), 5.2-6, 1 (7H, m), 7.9-9.1 (5H, m).

Example 60

The following compounds were prepared as described in Examples 1-3, 5, 7-12, 32-34, 40 and 59:

(1) N- (7- (2- (tert-Butoxycarbonylmethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido} -3-cephem-4-methyl-pyridinium-4) Carboxylate (color isomer), m.p. 150-155 ° C (with decomposition).

^IR (Nujol): 3300, 3200, 1770, 1680, 1620, 1530 ^cm-1 wavenumber.

(2) N-17- {2-Carboxymethoxy-methyl-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido} -3-cephem-3-yl (pyridinium-4-carboxylate (color isomer) 150-155 ° C (with decomposition).

IR (Nujol): 3350, 3200, 1780, 1680, 1530 cm ^-1 .

(3) N- [7- {2-cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido} -3-cephem-3-ylmethyl] -pyridinium 4-carboxylate (syn isomer) 180 DEG -185 DEG C. (with decomposition).

IR (nujol): 3300, 3200, 1780, 1670, 1620, 1530 cm ^-1 .

(4) N- [7- {2- (1-Carboxyethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido} -3-cephem-3-ylmethyl] -4'-carbamoylpyridinium; 4-carboxylate (color isomer), m.p. 170-175 ° C (with decomposition).

IR (Nujol): 3300, 3160, 1770, 1680, 1610, 1560, 1520 ^cm-1 wave number, (5) N- [7- {2- (l-tert-butoxycarbonyl-imino) -2- (5-amino- 1,2,4-thiadiazol-3-yl) -acetamido} -3-cephem-3-ylmethyl] pyridinium 4-carboxylate (color isomer), m.p. 160-165 ° C (with decomposition).

IR (Nujol): 3290, 3160, 1770, 1725, 75

-75183 006

1670, 1620, 1525 cm @ ¹ .

Nuclear Magnetic Resonance Spectrum (CD ₃ OD + D 6 O, δ): 1.2-1.6 (1211, m), 3.20 and 3.67 (211, ABq, J -18Hz),

4.40 4.90 (1H, ni). 5.20 (111, d, J = 5Hz), 5.33-5.80 (2H, ni), 5.92 (111, d, J = 5Hz), 7.9 9.4 (511, m) .

(6) N- [7- {2- (1-Carboxyethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido} -3-cephem-3-ylmethyl] -pyridinyl] -4- carboxylate (color isomer), m.p. 175-180 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1775, 1670, 1620, 1520 ^cm-1 wavenumber.

(7) N-17- {2- (1-Benzyloxycarbonyl-ethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido} -3-cephem-3-methyl-pyridinium -4-carboxylate (color isomer), m.p. 178-182 ° C (with decomposition).

IR (nujol): 3250, 3150, 1770, 1670, 1620, 1520 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (DMSO-d ₆ + D ₂ O, δ): 1.45 (3H, d, J = 7Hz), 3.10 and 3.60 (211, ABq, J = 16Hz), 4.87 ( 1H, q, J = 7Hz),

5.20 (2H, s), 4.97 5.10 (211, m),

5.25 (1H, d, J = 5Hz), 5.83 (1H, d, J = 5Hz), 7.43 (511s), 8.27 (2H, m), 8.63 (1Η, m) , 9.38 (2 H, m).

(8) 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (5-methyl-1,3,4-thiadiazol-2) -yl) -thiomethyl-3-eephem-4-carboxylic acid (color isomer), m.p.

150-155 ° C (with decomposition).

IR (Nujol): 3300, 3190, 1770, 1670, 1620, 1520 ^cm-1 wavenumber.

(9) 7- [2- (2-Cyclopenten-1'-yloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (5-methyl-1,3,4) -thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid (syn isomer), m.p. 150-155 ° C (with decomposition).

IR (Nujol): 3350, 3220, 1775, 1680, 1620, 1525 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 1.90 to 2.50 (4H, m);

2.70 (311, s), 3.68 (2H, broad s),

4.25 and 4.53 (2H, ABq, J = 13Hz),

5.15 (1H, d, J = 5Hz), 5.23-5.53 (1H, m), 5.70-6.30 (3H, m), 8.15 (2H, broad s), 9 , 52 (1H, d, J = 8Hz).

(10) 7- (2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1H-tetrazol-5-yl) -thiomethyl-3-cephem-4 Carboxylic acid (color isomer), m.p. 150-155 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1670, 1620, 1530 cm '.

(11) N- [7- {2-Ethoxycarbonyl-methoxy-imino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido} -3-cephem-3-methyl] -pyridinium-4-carboxylate (color isomer), m.p. 184-188 ° C (with decomposition).

spektruni IR (Nujol): 3400-3100, 1770, 1670, 1610, 1520 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 1.17 (311, t, J = 7Hz), 3.05 and 3.53 (2H, AB quartet, J = 18 Hz), 4.13 (211, q, J = 7Hz), 4.70 (2H, s), 5.08 (III, d, J = 5Hz), 5.17 and 5.70 (2H, ABq, J = 1311z), 5.72 (1H, dd, J = 5 and 8 Hz), 8.16 (4H, m), 8.62 (111, m), 9.50 (3H, m).

(12) 7- (2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (2-hydroxyethyl) -1H-tetrazole

5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p.

145-150 ° C (with decomposition).

IR (Nujol): 3350, 3220, 1775, 1670, 1620, 1525 ^cm-1 wavenumber.

(13) ^7- [2- (2-Cyclopenten-1-yloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (2-hydroxyethyl) -1H-tetrazole- S-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 135-140 ° C (with decomposition).

IR spectrum (nujol). 3350, 3250, 1750, 1675, 1620, 1525 ^cm-1 wavenumber.

(14) 7- [2- (2-Cyclopenten-1-yloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1H-tetrazol-5-yl) -thiomethyl -3-cephem-4-carboxylic acid (color isomer), m.p.

150-155 ° C (with decomposition).

IR (Nujol): 3350, 3200, 1780, 1680, 1620, 1520 ^cm-1 wavenumber.

Example 61

14 -17. The following compounds were prepared according to the procedures described in Examples 1 and 2 and 42:

(1) N- [7- {2- (2-Cyclopenten-1-yloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido} -3-cephem-3-ylmethyl Pyridinium 4-carboxylate (color isomer), m.p. 190-195 ° C (with decomposition).

IR (Nujol): 3350, 3200, 1780, 1660, 1620, 1530 ^cm-1 wavenumber.

, (2) N- [7- {2- (tert-Butoxycarbonylmethoxyimino) -2 (5-amino-1,2,4-thiadiazol-3-yl) -acetamido} -3-cephem-3-ylmethyl] pyridine-4-carboxylate (color isomer), m.p.

150-155 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1680, 1620, 1530 ^cm-1 wavenumber.

(3) N-17- {2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido} -3-cephem-3-ylmethyl] -pyridine-4-carboxylate (color isomer) 150-155 ° C (with decomposition).

IR (Nujol): 3350, 3200, 1780, 1680, 1530 ^cm-1 huHámszámnál.

(4) N- [7- {2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-3-ylmethyl} -j) iridinium 4-carboxylate (color) isomer), m.p .: 180-185 ^e C (dec).

IR (Nujol): 3300, 3200, 1780, 1670, 1620, 1530 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 1.4-2.0 (8H, m), 3.17, 3.53 (2H, AB quartet, J = 18 Hz), 4.60 to 4.83 ( 1H, m), 5.10 (1H, d, J = 4Hz), 5.30 and 5.83 (2H, ABq, J = 1411z), 5.87 (1H, dd, J = 4 and 8Hz), 8.17 (2H, s), 9.50 (1H, d, J = 8Hz), 8.0-9.7 (5H, m).

(5) N- [7- {2- (1-Carboxyethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido} -3-cephem-3-methylmethyl} -4'- m.p. 170-175 ° C (with decomposition), carbamoylpyridinium-4-carboxylates (color isomer).

IR (Nujol): 3300, 3160, 1770, 1680, 1610, 1560, 1520 ^cm-1 wavenumber.

NMR (DMSO-d _é, δ): 1.38 (3H, d, J = 7Hz),

3.10-3.60 (2H, m), 4.40-4.83 (1H, m), 5.10 (1H, d, J = 5Hz), 5.28-6.00 (3H, m) ), 8.22 (2H, bs), 8.48 (211, d, J = 611z), 9.48 (2H, d, J = 6Hz), 9.32-9.65 (1H, m) .

-761

183 006 (6) Ν- [7- {2- (1-tert-Butoxycarbonyl-carbonyl-oxyimino) -2 (5-amino-1,2,4-indiazol-3-yl) -acetanndo} -3-ephenyl- 3-methylmethyl-pyridine-4-carboxylate (color isomer), m.p.

160-165 ° C (with decomposition).

IR (Nujol): 3290, 3160, 1770, 1725, 5 1670, 1620, 1525 ^cm-1 wavenumber.

(7) N-17- {2- (1-Carboxyethoxy-amino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido} -3-cephein-3-ylethynyl] -pyridinium 4-carboxylate (color) m.p. 175-180 ° C (dec. 10).

IR (Nujol): 3300, 3200, 1775, 1670, 1620, 1520 cm @ -1.

(8) N- [7- {2- (1-Benzyloxycarbonyl-ethoxyimino) -2 (5-amino-1,2,4-thiadiazzo) -3-yl) -acetamido} -3-cephetn-3-yl- 15 methylpyridinium 4-carboxylate (syn isomer), m.p.

178-182 ° C (with decomposition).

IR (Nujol): 3250, 3150, 1770, 1670, 1620, 1520 ^cm-1 wavenumber.

(9) 7- [2-Cyclopentyloximino-2- (5-amino-1,2,4-thia-diazol-3-yl) -acetamido] -3- (5-methyl-1,3,4-thiadiazole -2-yl) thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p.

150-155 ° C (with decomposition).

IR (Nujol): 3300, 3190, 1770, 1670,

1620, 1520 cm @ ¹ . 25

NMR _(DMSO-d6, δ): 1.27 to 2.07 (811, m);

2.67 (3H, s), 3.68 (2H, broad s), 4.23 and 4.53 (2H, ABq, J = 13Hz), 4.60-4.93 (1H, m), δ , 13 (1H d, J = 5Hz), 5.80 (1H, dd, J = 5 and 8Hz), 30

8.10 (211, broad s), 9.47 (1H, d, J = 8Hz).

(10) 7- [2- (2-Cyclopenten-1-yloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamide] -3- (5-methyl-1,3,4- thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), m.p. 35-150-155 ° C (with decomposition).

IR (Nujol): 3350, 3220, 1775, 1680, 1620, 1525 ^cm-1 wavenumber.

(11) 7-] 2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1H-tetrazol-5-yl) -thiomethyl-3-40 cephem-4-carboxylic acid (color isomer), m.p. 150-155 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1770, 1670, 1620, 1530 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 1.5-2.0 (8H, m), 45 3.62 and 3.72 (2H, AB quartet, J = 17 Hz);

4.20 and 4.42 (2H, ABq, J = 14Hz), 4.65-4.84 (1H, m), 5.15 (1H, d, J = 4Hz), 5.80 (1H, dd) , J = 4 and 8Hz), 8.10 (2H, s), 9.50 (1H, d, J = 8Hz).

(12) N-17- {2-Ethoxycarbonylmethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido} -3-cephem-3-ylmethyl-pyridinium-4-carboxylate (color isomer 184-188 ° C (with decomposition).

IR (Nujol): 3400-3100, 1770, 1670, 1610, 1520 ^cm-1 wavenumber.

(13) 7- [2-Cyclopentyloxy] amino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- [1- (2-hydroxyethyl) -1H-tetrazol-5-one. yl] thiomethyl-3-cefcm-4-carboxylic acid (color isomer), m.p. 145-150 ° C (with decomposition).

IR (Nujol): 3350, 3220, 1775, 1670, 1620, 1525 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 1.22 to 2.15 (8H, m), 3.47 to 4.00 (4H, m), 4.10 to 4.57 (4H,

m), 4.57 4.90 (111, m). 5.12 (111, d, J = 5Hz), 5.80 (III, dd, J = 5 and 8Hz),

8.10 (211, broad s), 9.47 (1H, d J = 8lfz).

(14) 7-] 2- (2-cyclopvi) vi-1-yloxynino, -2-tazine,

1.2.4-Thiadiazol-3-yl) -acetamido] -3- [1- (2-hydroxyl) -1H-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid (color isomer), 135-140 ° C (with decomposition).

IR (Nujol): 3350, 3250, 1775, 1675, 1620, 1525 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 1.90 2.47 (411 in), 3.53 to 3.90 (4H, m), 4.13 4.53 (411, m), 5 , 10 (1H, d, J = 5Hz), 5.20-5.50 (111, ni), 5.63-6.23 (3H, m), 8.12 (211, broad s), 9, 43 (1H, d, J = 8Hz).

(15) 7- [2- (2-Cyclopenten-1-yloxyquinoino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1H-tetrazol-5-yl) -thiomethyl -3-cephem-4-carboxylic acid (color isomer), m.p.

150-155 ° C (with decomposition).

IR (Nujol): 3350, 3200, 1780, 1680, 1620, 1520 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 1.8-2.5 (411, m);

3.67 (2H, bs), 4.20 and 4.43 (211, ABq, J = 15Hz), 5.13 (1H, d, J = 4Hz), 5.3-5.5 (1H, m), 5.80 (1H, dd, J = 4 and 8Hz), 5.8-6.4 (211, in), 8.13 (2H, s), 9.53 (111, d, J = 8 Hz).

Example 62

1.8 g of N- [7- (2-tert-butoxycarbonylmethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido) -3-cephem-3-ylmethyl To a solution of pyridine-4-carboxylate (color isomer) in 18 ml of formic acid was added 0.5 ml of concentrated hydrochloric acid and the mixture was stirred at room temperature for 1 hour. (The solvent is then evaporated under reduced pressure and the residue is triturated with acetone, filtered, washed with acetone and diisopropyl ether to give a powder.) The powder is dissolved in 5 ml of water and subjected to column chromatography on a nonionic absorption resin (Diaion HP -20 Mitsubishi Chemical Industries), 50 ml. The column was washed first with 500 mL water and then eluted with 40% aqueous methanol. The eluates containing the target product were combined, the methanol was evaporated under reduced pressure and, after lyophilization, 800 mg of white powdery Kb (7- {2-carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazate) m.p. 150-155 ° C (with decomposition) is obtained (-I) -acetamido} -3-cephem-3-ylmethyl] -pyridinium-4-carboxylate (color isomer).

IR (Nujol): 3350, 3200, 1780, 1680, 1530 ^cm-1 wavenumber.

Nuclear Magnetic Resonance Spectrum (D ₂ O + NaHCO ₃ , δ): 3.27 and 3.63 (2H, ABq, J = 18Hz), 4.70 (2H, s), 5.30 (1H, d, J = 4Hz), 5.40 and 5.60 (2H, ABq, J = 14Hz), 5.93 (1H, d, J = 4Hz), 8.0-9.1 (5H, m).

Example 63 _t

The following compounds were prepared as described in Examples 27, 47, 48 and 62:

(1) N-17- {2- (1-Carboxyethoxy-amino) -2- (5-amino-1,2,4-t; adiazol-3-yl) -acetamido) -3-cephem-3-ylmethyl] -4 ' -carbamoylpyridium 4-carboxylate (color isomer), m.p.

170-175 ° C (with decomposition).

-771

183,006

IR spectra (nujol): 3300. 3160, 1770, 1680, 1610, 1560, 1520 cm ^-1 .

(2) N- [7- {2- (1-Carloxycarboxylamino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acclamido} -3-cis-cm-3-n-methylcarbonyl-4-carboxylate ( m.p. 175-180 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1775, 1670, 1620, 1520 cm ^"1 wavenumber.

Nuclear Magnetic Resonance Spectrum (D ₂ (H ₂ Na ₂ CO 3, δ): 1.50 (3H, d, J = 7Hz), 3.25 δ 3.67 (2H ABq. J = 18Hz), 4.40 4.90 (1H, m), δ 32 (111d, 1-511 /), 5.42 and 5.60 (2H, ABq, J = 15Hz), 5.83 6.00 (111, m),

7.9 9.1 (5H, in).

Production Example 40

Prepared in the same manner as in Preparation Example 17, 2-Methoxycarbonyl-ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetic acid (color isomer), m.p. C (during decomposition).

IR spectrum (nujol): 3380, 3280, 3180, 1750, 1710, 1610, 1510, 1260, 1230 cm ^-1 .

NMR (DMSO-d _é, δ): 3.73 (3H, s), 4.87 (2H, s), 8.2 (2H, br s).

Example 64

To a cooled solution of 1.46 g of phosphorus pentachloride in 30 ml of methylene chloride is 2.11 g of 2- (1-methyl-1-ethoxycarbonyl-ethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl). acetic acid (color isomer) was added at -18 ° C and the mixture was stirred at -14 to -11 ° C for 30 minutes. To the reaction mixture was added dry n-hexane (90 mL) at a temperature below -10 ° C, and the mixture was stirred for several minutes and then the solvent was removed by decantation. The residue was triturated with n-hexane and the powdered activated acid was separated by filtration. At the same time, a mixture of 2 g of N- [7-amino-3-cephem-3-ylmethyl] pyridine-4-carboxylate dihydrochloride and 10 g of trimethylsilylacetamide in methylene chloride was stirred for 10 minutes at room temperature and then cooled to -18 ° C. The above powder was added to the cold solution and the mixture was stirred for 30 minutes at -13 to -10 ° C and then for 30 minutes at -5 to 0 ° C. The reaction mixture was then

It was poured into a solution of sodium bicarbonate (3.6 g) in water (100 ml) and stirred at room temperature for 15 minutes, then adjusted to pH 1 with 6N hydrochloric acid. The aqueous phase was separated, washed with ethyl acetate and subjected to column chromatography using a nonionic adsorption resin (Diaion HP-20 (100 mL). The column was first treated with water, 5% aqueous ethanol, then 10% aqueous The fractions containing the target product were collected, the ethanol was evaporated under reduced pressure and, after lyophilization, 1.30 g of N- [7- {2- (1-methyl-1-ethoxycarbonyl) ethoxyimino) -2- (5-amino-1,2,4-thiaziazol-3-yl) -acctaini (lo} -3-cfem-3-ylethyl) -pyridinium 4-carboxylic acid (color isomer) is obtained as a white powder, and mp 164-168 ° U (with decomposition).

IR (Nujol): 3350-3150, 1770, 1720, 1670, 1620, 1520 ^cm-1 wavenumber.

NMR _(DMSO-d6, δ): 1.15 (3H, t, J = 7Hz), 1.45 (611, s), 3.03 and 3.55 (2H, AB quartet, J = 18 Hz) , 4.10 (2H, q, J = 7Hz), 5.11 (1H, d, J = 5Hz), 5.20 cs 5.67 (2H, ABq, J = 13Hz), 5.75 (1H, 2d, J = 5 and 8 Hz), 8.20 (4H, m), 8.57 (111, m), 9.47 (3H, m).

Example 65

The following compounds were prepared as described in Examples t-3, 5, 7-12, 32-34, 40, 59 and 64:

(1) 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -2-methyl-3-cephem-4-carboxylic acid acetoxymethyl ester (color) 183-185 ° C (with decomposition).

IR (Nujol): 3350, 3250, 1790, 1760, 1740, 1715, 1675,1610,1535 ^cm-1 wavenumber.

NMR _(DMSO-fi, δ): 1.43 (3H, d, J = 7Hz).

1.4-2.0 (8H, m), 2.08 (3H, s),

3.6-4.1 (1H, m), 4.6 -4.9 (1H, m), 5.17 (1H, d, J = 5Hz), 5.8-6.0 (3H, m), 6.73 (1H, d, J = 6Hz).

8.16 (2 H, s).

(2) N- (7- {2- (2-Cyclohexen-1-yloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido} -3-cephem-3-ylmethyl). pyridine-4-carboxylate (color isomer), m.p. 150-155 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1775, 1660,

1610, 1520 cm ^-1 . NMR _(DMSO-d6, δ): 1.5-2.0 (6H, m);

3.13, 3.57 (2H, ABq, J = 17Hz),

4.6 - 4.7 (1H, m), 5.07 (1H, d, J = 4Hz), 5.27, 5.60 (2H, ABq, J = 14Hz), 5.80 (1H, 2d, J) = 4 and 8Hz), 5.77-6.0 (2H, m), 8.17 (2H, s), 8.0-8.4 (2H, m), 8.43-8.80 (1H , m), 9.4-9.5 (2H, m), 9.55 (1H, d, J = 8Hz).

(3) N- [7- {2-carboxymethoxy-2- (5-amino-l, 2,4-thiadiazol-3-yl) acetamido} -3-cephem-3-ylmethyl] ^-4, carbamoyl pyridine-4-carboxylate (color isomer), m.p. 175-180 ° C (with decomposition).

IR (Nujol): 3350, 3200, 1775, 1680, 1615, 1565, 1525 ^cm-1 wavenumber.

(4) N- [7- {2-Methoxycarbonyl-ethoxy-amino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido} -3-cephem-3-ylmethyl] -pyridinium-4 Carboxylate (color isomer), m.p. 165-170 ° C (with decomposition).

IR (Nujol): 3300-3150, 1760, 1670, 1620, 1520 cm ^-1 .

(5) N- [7- (2-methyl-1-carboxyethoxy-amino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido) -3-cephem-3 -ylmethyl] -pyridinium-4-carboxylate (color isomer), white powder, m.p. 176-180 ° C (dec.).

IR (Nujol): 3400-3150, 1770, 1670, 1620, 1520 ^cm-1 wavenumber.

(6) N- {7- {2- (1-Methyl-1-tert-butoxycarbonyl-ethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamide} - 3-cephem-3-ylmethyl] -pyridinium-4-carboxylate (color isomer), m.p. 176-180 ° C (with decomposition).

IR (nujol): 3300, 3200, 1780, 1730, 1680, 1620, 1520 cm ^-1 .

-781

183,006

NMR (DMSO-d ₆ -D ₂ O, δ): 1.40 (15H, bs), 3.08, 3.42 (2H, AB quartet, J = 18 Hz), 5.13 (IH, d , J = 5Hz),

5.40 (2H, m), 5.80 (1H, d, J = 5Hz),

8.17 (2H, m), 8.65 (1H, m), 9.37 (2H, m).

Example 66

14-17. and Examples 42 and 42 were prepared as follows:

(1) N- [7- {2- (2-Cyclohexen-1-yloxyimino) -2- (5-amino, 2,4-thiadiazol-3-yl) -acetamido} -3-cephem-3-ylmethyl] pyridine-4-carboxylate (color isomer), m.p. 150-155 ° C (with decomposition).

IR (Nujol): 3300, 3200, 1775, 1660, 1610, 1520 ^cm-1 wavenumber.

(2) N- [7- {2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido} -3-eephem-3-ylmethyl] -4'- carbatnoylpyridinium 4-carboxylate (color isomer), m.p.

175-180 ° C (with decomposition).

IR (Nujol): 3350, 3200, 1775, 1680/1615, 1565, 1525 ^cm-1 wavenumber.

NMR (DMSO-d ₆ - D ₂ O, δ): 3.23, 3.55 (2H, AB quartet, J = 18 Hz), 4.67 (2H, .s);

5.10 (1H, d, J = 5Hz), 5.35, 5.72 (2H, ABq, J = 15Hz), 5.80 (1H, d, J = 5Hz), 8.43 (2H, d) , J = 6Hz), 9.38 (2H, d, J = 6Hz).

(3) N- [7- (2-Methoxycarbonylmethoxyimino-2- (5-amothio-1,2- 4-thiadiazol-3-yl) -acetamido} -3-cephem-3-ylmethyl) -pyridinium-4- carboxylate (color isomer), m.p. 165-170 ° C (with decomposition).

IR spectrum (nujol). 3300-3150, 1760, 1670, 1620, 1520 cm ^-1 .

(4) N- [7- {2- (1-Methyl-1-carboxy-ethoxy] -amino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido} -3-cephem-3- m.p. 176-180 ° C (with decomposition), methylmethyl] -pyridinium 4-carboxylate (color isomer), m.p.

IR (Nujol): 3400-3150, 1770, 1670, 1620, 1520 cm ^-1 .

(5) N- [7- (2- (1-Methyl-1-ethoxycarbonyl-ethoxyimino) -2 (5-amino-1,2,4-thiadiazol-3-yl) -acetamido} -3-cephem) 3-imyl tylpyridinium N-carboxylate (color isomer), white powder, m.p. 164-168 ° C (with decomposition).

IR (Nujol): 3350-3150, 1770, 1720, 1670, 1620, 1520 ^cm-1 wavenumber.

(6) N- [7- (2- (1-methyl-1-tert-butoxycarbonyl-ethoxymethyl) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido} -3-cephem -3-ylmethyl] -pyridine 4-carboxylate (color isomer), m.p. 176-180 ° C (with decomposition).

IR (nujol): 3300, 3200, 1780, 1730, 1680, 1620, 1520 cm ^-1 .

Example 67 To a cooled mixture of trifluoroacetic acid (mL) and anisole (4.4 mL) was added N- [7 - ₍ {2- (1-methyl-1-tert-butoxycarbonyl-ethoxyimino) -2- (5-amino-1)). , 2,4-Thiadiazol-3-yl) -acetamido} -3-cephem-3-ylmethyl-pyridinium-4-carboxylate was added and the mixture was treated at room temperature for 40 minutes. The mixture was evaporated to remove trifluoroacetic acid and the triturate the residue with isopropyl ether to give a yellowish powder.

The powder was dissolved in aqueous sodium bicarbonate solution, adjusted to pH 1 with 6N hydrochloric acid and washed with ethyl acetate. The aqueous solution was subjected to column chromatography using a nonionic adsorption resin (Diaion HP-20, 140 mL). The column was first washed with water and eluted with 5% and 10% aqueous isopropyl alcohol, respectively. The fractions containing the target product were combined, evaporated to remove isopropyl alcohol and, after lyophilization, 2.20 g of N- [7- {2- (1-methylcarboxyethoxyimino) -2- (5-amino-1,2,4-thiadiazole) -3-yl) acetamido) -3-cephem-3-ylmethyl] -pyridinium-4-carboxylate (color isomer) is obtained as a white powder and m.p. 176-180 ° C (with decomposition).

IR (Nujol): 3400-3150, 1770, 1670, 1620, 1520 ^cm-1 wavenumber.

NMR (DMSO-d ₆ + D ₂ O, δ): 1.48 (6H, s), 3.10, 3.62 (2H, AB quartet, J = 18 Hz), 5.12 (IH, d, J = 5Hz), 5.45 (2H, m),

5.78 (1H, d, J = 5Hz), 8.13 (2H, m), 8.58 (1H, m), 9.38 (211, m).

Example 68

The following compound was prepared as described in Examples 27, 47, 48, 62 and 67:

(1) N- [7- {2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido-3-cephem-3-ylmethyl] -4'-carbaryloyl-pyridinium-4- carboxylate (color isomer), m.p. 175-180 ° C (with decomposition).

IR (Nujol): 3350. 3200. 1775, 1680, 1615, 1565, 1525 ^cm-1 wavenumber.

Example 69

3.7 g of 2-tert-butoxycarbonylmethoxyimino-2- (5-amino) '

1,2,4-Thiadiazol-3-yl] -acetic acid (color isomer) was added to a stirred solution of 2.5 g of phosphorus pentachloride in 40 ml of methylene chloride at -15 ° C.

The mixture was stirred at -5 to -15 ° C for 1 hour. Thereafter, 120 ml of diisopropyl ether are added to the reaction mixture at -10 ° C and the mixture is stirred for 5 hours at 15-20 ° C. The precipitate was collected by filtration and washed with dry diisopropyl ether.

To a stirred suspension of 2.0 g of 7-amino-3-ethyl-3-cephem-4-carboxylic acid in 40 ml of tetrahydrofuran was added 8.6 g of trimethylsilylacetamide and the mixture was heated at 35-40 ° C for 20 hours. agitated. The above precipitate was then added to the solution at -10 ° C and the mixture was stirred at -10 ° C to -5 ° C for 40 minutes. To the resulting solution was added a mixture of ethyl acetate and water and the separated organic layer was poured into water and the pH of the mixture was adjusted to 7.5 with saturated aqueous sodium carbonate solution. The separated aqueous layer was acidified to pH 2.0 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated.

1.71 g of 7- [2-tert-butoxycarbonyl-methoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-methyl-3-cephem-4- Carboxylic acid (color isomer) is obtained.

IR (Nujol): 3290, 3180, 1760 (broad), 1730, 1680, 1620 cm ^-1 .

NMR (DMSO-d _é delta): 1.43 (9H, s), 2.02 (3H, s), 3.45 (2H, q, J = 9Hz), 4.62

-79183006 (2Η, s), 5.08 (1H, d, J = 5Hz), 5.73 (1H, dd, J = 5Hz), 8.0Hz). 8.09 (2H, br s), 9.41 (1H, d, J = 8Hz).

Example 70

Following the procedure of Example 69, the following compounds were prepared:

(1) 4-Nitrobenzyl-7- (2-tert-butoxycarbonylmethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-chloro-3-cephem-4 carboxylate (color isomer).

IR (Nujol): 1780, 1725, 1675, 1605 cm ^1st

NMR _(DMSO-d6, delta): 1.42 (9H, s), 3.86 (2H, q, J = 18 Hz), 4.61 (2H, s);

5.29 (1H, d, J = 5Hz), 5.44 (2H, s), 5.92 (1H, dd, J = 5Hz, 8Hz), 7.67 (2H, d, J = 8Hz), 8.24 (2H, d, J = 8Hz), 9.58 (1H, d, J = 8Hz).

(2) 7- [2-tert-Butoxycarbonylmethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-chloro-3-cephem-4-carboxylic acid (color) isomer).

IR (Nujol): 1770, 1710, 1670, 1610 cm @ -1.

(3) 7- [2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-chloro-3-cephem-4-carboxylic acid (isomer).

IR (Nujol): 3390, 3280, 1770, 1720, 1670, 1620 ^cm-first

(4) 7- [2-Carboxy-tetroxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-methyl-3-cephem-4-carboxylic acid (color isomer ).

IR (nujol): 3390, 3280, 1763, 1720, 1665 cm ^-1 .

(5) 7- [2-tert-Butoxycarbonylmethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -2-methyl-3-cephem-4-carboxylic acid ( syn isomer).

IR (Nujol): 3230, 1770, 1710, 1680, 1620 ^cm-first

NMR _(DMSO-d6, delta): 1.28 -1.61 (12H, m), 3.67 (IH, m), 4.63 (2H, s);

5.10 (1H, d, J = 5Hz), 5.91 (1H, dd, J = 5Hz, 8Hz), 6.55 (1H, d, J = 6Hz), 8.9 (2H, broad s), 9 , 46 (1H, d, J = 8Hz).

(6) 7- (2-Carboxy-methoxy-imino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamidol-2-methyl-3-cephem-4-carboxylic acid isomer).

IR (nujol): 3380, 3250, 1770, 1720, 1675, 1630 cm ^-1 .

Example 71 Trifluoroacetic acid (1.5 g) 7- [2-tert-butoxycarbonylmethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-methyl A suspension of 3-cephem-4-carboxylic acid (color isomer) in methylene chloride and 1.5 ml anisole was stirred at room temperature and the mixture was stirred at the same temperature for 1.5 hours. To the resulting solution was added diisopropyl ether (50 mL) and the mixture was stirred. The precipitate was collected by filtration and washed with diisopropyl ether. The precipitate was added to a mixture of ethyl acetate and water and the pH of the mixture was adjusted to 7.5 with saturated aqueous sodium carbonate solution. The separated aqueous phase was acidified to pH 2.2 by addition of 10% hydrochloric acid solution while cooling with ice. 80

The precipitate was collected by filtration, washed with ice water and dried over phosphorus pentoxide (0.82 g) 7- [2-carboxymethoxyimino-2- (5-anino-1,2,4-thiadiazol-3-yl) -acetamido] -3- methyl 3-cephem-4-carboxylic acid (color isomer) ka-, red

IR spectrum (nujol): 3390, 3280, 1763, 1720,

1665 cm

NMR _(DMSO-d6, delta): 2.01 (311, s);

3.43 (2H, q. J = 18Hz). 4.63 12H. s);

5.06 (111, d, J = 4Hz). 5.73 (1H, dd,

J = 4Hz, 8Hz), 8.9 (211, broad s).

9.39 (1H, d, J = 8Hz).

Example 72

In the same manner as in the previous example, the following compounds were prepared:

(1) 7- [2-Carboxy-nethoxy-imino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-chloro-3-cephem-4-carboxylic acid (color isomer) .

IR (nujol) 3390, 3280, 1770, 1720,

1670, 1620. ^1st

NMR _(DMSO-d6, delta): 3.80 (2H, q,

J = 18Hz), 4.64 (211, s), 5.26 (1H, d, J = 5Hz), 5.83 (1H, dd, J = 5Hz).

8 Hz). 8.10 (2H, bs), 9.58 (1H, d, J = 8Hz).

(2) 7- [2-Carboxy-methoxy-imino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -2-methyl-3-cephem-4-carboxylic acid »( syn isomer).

IR spectrum (nujol); 3380, 3250, 1770, 1720,

1675.1630 cm ^1st

NMR _(DMSO-d6, delta): 1.46 (3H, d,

J = 7Hz), 3.82 (1H, m), 4.67 (2H, s),

5.11 (1H, d, J = 5Hz), 5.93 (1H, dd,

J = 5Hz), 8Hz), 6.55 (1H, d, J = 6Hz),

8.23 (2H, bs), 9.47 (1H, d,

J = 8Hz).

Claims (8)

PATENT CLAIMS A process for the preparation of 7- [2-substituted or unsubstituted oxyimino-2- (amino-1,2,4-thiadiazolyl) acetamido] -3-cephem and -cepham-4-carboxylic acid derivatives of formula I and their pharmaceutically acceptable derivatives. salts thereof, which formula R ^{1 is} amino or C 1-4 alkanoylamino; R ^{2 is} hydrogen, phenyl; With 1 to 3 halogens, Phenyl substituted with C 1-6 -alkoxy, C 1-6 -alkyl, nitro, halo-C 1-6 -alkyl and C 1-6 -alkoxycarbonyl; phenyl (C1-C6) alkyl; triphenyl (C 1 -C 6) alkyl; C 1-6 alkylthio (C 1-6) arylalkyl; halogen (C 6) alkyl; phenoxy (C1-C6) alkyl; cyano (C1-C6) alkyl; C 1-6 -alkoxycarbonyl-C 1-6 -alkyl, phenyl (C 1-6) -alkoxycarbonyl-C 1-6 -alkyl or cyclo (C 3-8) -alkoxycarbonyl (C 1-6) -alkyl ; di- (C 1-6) alkylcarbamoyl (C 1-6) alkyl; C1-C6 alkoxy (C1-C6) alkoxy (C1-C6) alkoxy; C 1-6 alkylsulfonylC 1-6 alkyl; C 1 -C 6 alkoxycarbo-801 183,006 nylamylthio (C1-C6) alkyl; amino (C 1 -C 6) -alkyl; carboxy (C 1 -C 6) -alkyl; phenyl (C 1 -C 6) -alkyl substituted with (C 1 -C 6) -alkoxycarbonyl; phenyl (C 1 -C 6) substituted with carboxy; phenyl (C1-C6) alkyl substituted with (C1-C6) alkyl (C1-C6) -alkyl; phenyl (C1-C6) substituted with amino (C1-C6) -alkyl; alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, carboxy or C1-C6 alkoxycarbonyl-substituted C3-C8 cycloalkyl, cyclo (C3-C6) alkenyl, 2-oxo substituted thiolanyl or oxo substituted tetrahydrofuryl; R ^{3 is} hydrogen or C 1-6 alkyl; R ^{4 is} hydrogen, carbamoyloxy (C 1-6) alkyl, or (C 1-6) alkanoyloxy) (C 1-6) alkyl; pyridinium (C 1 -C 6) alkyl optionally substituted with carbamoyl; thiadiazolylthio (C1-C6) alkyl; thiadiazolylthio optionally substituted with C 1-6 alkyl, hydroxy (C 1-6) alkyl, C 1-6 alkoxycarbonylamino (C 1-6) alkyl, or amino (C 1-6) alkyl - (C 1 -C 6) alkylopolyol; C 1-6 alkyl, hydroxy (C 1-6) alkyl, amino (C 1-6) alkyl, C 1-6 -alkoxycarbonyl-amino-C 1-6 -alkyl or C 1-6 -alkanoylamino-C 1-6 -alkyl, di-C 1-6 -alkylamino- (C 1-6) alkyl, C 2 -C 6 alkenyl, carboxy (C 1 -C 6) alkyl, C 1 -C 6 alkoxycarbonyl (C 1 -C 6) -alkyl, phenyl, morpholino-C 1 -C 6 alkyl, piperidino) 1 Tetrazolylthio (C 1 -C 6) alkyl substituted with C 6 -C 6 alkyl or C 1 -C 6 alkyl piperazinyl (C 1 -C 6) alkyl; tetrazolopyridazinylthio (C 1 -C 6) alkyl; dihydro-triazinopyridazinylthio (C1-C6) -alkyl substituted with oxo and carboxy (C1-C6) alkyl; C 1-6 alkyl, hydroxy, or halogen; ^R5 is carboxy or nitro-substituted phenyl (C 1-6) -alkoxycarbonyl, C1-6 alkanoiloxl- (Cl-C6) -alkoxycarbonyl, C1-6 alkoxikaibonlloxi- (l - C6) alkoxycarbonyl, azidocsoportlal substituted C 1 -C 6 -alkoxycarbonyloxy (C 1 -C 6) -alkoxycarbonyl, benzoyloxy (C 1 -C 6) -alkoxycarbonyl and phthalidyloxycarbonyl, and the bold black line represents a chemical bond or a double bond, provided that R ⁵ is -COO when R ^{4 is} pyridinium (C 1-6) alkyl optionally substituted with carbamoyl, wherein a) Formula II! cut a compound or a reactive amino derivative thereof, wherein R ³ , R ⁴ and R ⁵ , and the bold black line above are represented by a general kdjilotd compound 111, its reactive carboxylsaline / edge; or a salt thereof, wherein R * and R ³ are leni nuii. given or b) Formula Ib! wherein R ¹ , R ³ , R ³ and R ⁴ and ii are bold black lines of formula Ia as defined above. or a salt thereof wherein R ¹ , R ² , R ³ , R ⁴ and the bold black line are as defined in h.nl and R ^Ia represents védett'karhoxicsoport, preferably nitro substituted phenyl ·) of 1- 6 carbon atoms) · alkoxycarbonyl, C1-6 alkanoyloxy · (1- C6) -alkoxilkarbonil- I to 6 carbon atoms, alkoxycarbonyloxy · (l- C 6 -C 6 alkoxycarbonyl, azido-substituted C 1 -C 6 alkoxycarbonyloxy (C 1 -C 6) alkoxycarbonyl, benzoyloxy (C 1 -C 6) alkoxycarbonyl or phthalidyloxycarbonyl, carboxyl, c) for the preparation of compounds of formula ld wherein R ¹ , R ³ , R ³ , R ⁵ and the bold black line are as defined above; R ^{4f is} a pyridinium group optionally substituted with a carbamoyl group, or a group -S-R '' ¹ where R ^{4e is} thiadiazolyl; C 1-6 alkyl, hydroxy)! C 6 -alkyl, protected amino-C 1-6 -alkyl, preferably C 1-6 -alkoxycarbonylamino-C 1-6 -alkoxy or amino-C 1-6 -alkyl > port-substituted thiadiazolyl; bet rtizolll * group; C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, amino- (C 1-6) -alkyl, protected amino-C 1-6 -alkyl-alkylsulfonyl, preferably C 1-6 -alkoxycarbonyl. C 1-6 -alkyl or C 1-6 -C 6 -alkylamino, C 1-6 -alkyl, C 1-6 -alkyloylamino) C 1-6 -alkyl, C 2-6 -alkyl, carboxy- - (C 6 -C 6) -alkyl, protected carboxy (C 1 -C 6) -alkyl, preferably (C 1 -C 6) -alkoxy-carbonyl (C 1 -C 6) -alkyl, preferably (C 1 -C 6) -alkoxycarbonyl (C 1 -C 6); tetrazolyl substituted with omos) alkyl, phenyl, morphoH10O, C 1-6 alkyl, piperidino, C 1-6 alkyl, and C 1-6 alkyl substituted with piperazinyl (C 1-6) alkyl; a tetrazolopyridazinyl group, a dihydrophthiazolopyridazyl group substituted with oxo and cathoxy (C 1-6 alkyl), or a dihydrotriazinyl group substituted with oxo, hydroxy and C 1-6 alkyl; C 1-6 alkylene; or a salt of these compounds, a compound of formula Ic, wherein R ¹ , R ² , R ³ , R 'are represented by a bold black line as defined above, R ^{4a is} a radical which may be substituted by a group R ^4f , R ^4f is as defined above or a salt thereof with a compound of formula R ⁴¹ ', wherein ^R4b is pyridine optionally substituted with carbamoyl, or hl -81183 006 with a compound of formula R ^4e -SH, or a reactive derivative thereof, wherein R ^4d is as defined above, or d) for the preparation of compounds of the formula If, wherein R ¹ , R ² , R ', R ⁵ and the bold black line are as defined above; ^R4d fl substituted 6-amino-alkyl groups szénatoniosj tiadiazoljltio- (I C6) alkyl or amino (l- C6) -alkyl substituted tclrazoliltio- (l - 6) -alkyl, and the salts of these compounds for the preparation of a general down wherein R ¹ , R ² , R ³ , R ⁵ and the thick black line are as defined above and R ^{4c is} protected with amino (C 16) alkyl, preferably C 1-6 alkoxycarbonylamino (C 1-6). thiadiazolylthio (C 1 -C 6) alkyl substituted with -alkyl or protected amino (C 1 -C 6) alkyl. preferably a tetrazolylthio (C1-C6) alkyl group substituted with (C1-C6) alkoxycarbonylamino (C1-C6 (om) alkyl) or (C1-C6) alkanoylamino (C1-C6) alkyl, or a salt thereof, the amino protecting group being cleaved , obsession e) for the preparation of compounds Ij, or a salt thereof, wherein R ^1, R ^3, R ^4, R ^s and the thick black line are as defined above and R ^Ig amino- (l -6) -alkyl, amino (C1-6) -alkyl substituted phenyl (Ci-6-alkyl sz.énatomosj, a compound of formula II wherein R ^1, R ^3, R ⁴ , R ⁵ and the thick black line as defined above and ^{R2f is a} protected amino (C1-C6) alkyl group, preferably an acylamino (C1-C6) alkyl group, or a protected amino (C1-C6) alkyl group, preferably a (C1-C6) alkoxycarbonylamino (1-) alkyl group; A (C 1 -C 6) -alkyl-substituted phenyl (C 1 -C 6) -alkyl or a salt thereof is deprotected, or f) for the preparation of compounds of formula 11 or salts thereof, wherein R, R ³ , R ⁴ , R ⁵ and the bold black line are as defined above; and R ^{2e is} C 3 -C 8 cycloalkyl substituted with carboxy (C 1 -C 6) alkyl, carboxy-substituted phenyl (C 6 -C 6) alkyl or carboxy substituted with a compound of formula Ik or a salt thereof, wherein R ¹ , R ³ , R ⁴ , R ⁵ and the bold black line are defined above, and R ^{2d is} protected carboxy (C 1-6) alkyl, preferably C 1-6 alkoxycarbonyl (C 1-6) alkyl, phenyl (C 1-6) alkoxycarbonyl, C 1-6 alkyl, or 3-8 C 1-6 -alkyl substituted with a protected carboxy group, preferably C 1-6 -alkoxycarbonyl, or substituted with a protected carboxy group, preferably C 1-6 -alkoxycarbonyl; , cleaving the carboxyl protecting group, or g) for the preparation of compounds of formula In or salts thereof wherein R ¹ , R ² , R ³ , R ⁴ and the bold black line are as defined above, and - COOR ⁸ is preferably nitro-substituted phenyl (C 1 -C 6) alkoxycarbonyl. C 1-6 alkanoyloxy (C 1-6) alkoxycarbonyl, C 1-6 alkoxycarbonyloxy (C 1-6) alkoxycarbonyl, C 1-6 alkoxycarbonyloxy (C 1-6) alkoxycarbonyloxy, benzoyloxy (Cl-C6) -alkoxycarbonyl, benzoyloxy (Cl-C6) -alkoxycarbonyl or ftalidiloxi group, a lm compound or a salt thereof, wherein R ^1, R ^2, R ^3, R ⁴ and the thick black formula line ^{5 is} esterified with an R ⁸ esterifying agent as defined above, or h) for the preparation of compounds of formula Ih or salts thereof, wherein R, R ³ , R, R ⁵ and the thick black line are as defined above for a compound of formula Ig or a salt thereof, wherein R *, R ³ , R ⁴ , R ⁵ and the thick black line as above and R ^{2a is a} hydroxy protecting group, preferably triphenyl (C1-C6) alkyl, this hydroxy protecting group is cleaved, or i) Ip Compounds of formula or a salt thereof, wherein R ^1, R ^{2 and} R are as defined above, with a described compound or a salt thereof, wherein ^{R1, R2} and ^R5 are as defined above, is dehydrated, obsession j) for the preparation of compounds of the general formula (I) or their salts, wherein R ', R ³ , R ⁴ , R ⁵ and the bold black line are as defined above; ^{R2b is a} protected amino (C1-C6) alkyl group, preferably an acylamino (C1-C6) alkyl group, a compound of formula Iq or a salt thereof, wherein R ¹ , R ³ , R ⁴ , R ^s and the bold black line are as defined above and R ^{2c is} imino (C 1 -C 6) alkyl protected with an amino protecting group. A process for the preparation of a color isomer of a compound of formula I wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and the bold black line are as defined in claim 1, characterized in that: starting from properly substituted materials. 3. A process for the preparation of a color isomer of a compound of formula I wherein R ¹ , R ² , R ³ , R ⁴ and R ^{5 are} as defined in claim 1 and the thick black line represents a double bond, characterized in that it is based on appropriately substituted materials. The process of claim 3, wherein the compound of formula 1 is wherein R ¹ , R ² , R ³ , R ⁴ and R ^{5 are} as defined in claim 1 and the bold black line represents a double bond and lib ' is prepared in the form of the B isomer, characterized in that it is based on appropriately substituted materials. 5. A process according to claim 1 for the preparation of compounds of formula I - where ^R2 carboxy (Cl-C6) alkyl, C 3-8 cycloalkyl or C 3-8 cycloalkenyl, R ^{3 is} hydrogen, -82183 006 R ^{4 is} hydrogen, thiadiazolylthio-C 1-6 -alkyl, C 1-6 -alkyl or amino-C 1-6 -alkyl substituted tetrazolylthio (C 1-6) -alkyl, tetrazolo-pyridazinylthio (I) Pyridinium (C 1 -C 6) alkyl substituted with -C 6 -alkyl or carbamoyl, and ^R5 is carboxy, with the proviso that R ^and -COO group, where R ⁴ substituted carbamoyl pyridinium (l -C 6) alkyl, and R ¹ as defined in claim 1, the black line represents a double bond and - wherein the preparation of substituted phenylpyrazole type herbicides. Method of implementing the method of claim 5: 7- [2- (c) Clopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color isomer), 7- (2- (2-Cyclopenten-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (colorless) isomer) 7- [2- (2-Cyclohexen-1-yl) -oxylamino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color isomer ) 7- [2- (1-Carboxyethoxy-amino) -2 - (-5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3-cephem-4-carboxylic acid (color isomer), 7- [2- (2-ciklopentiloxiímifio-2- (5-amino-l, 2,4-t adiazol-3-yl) acetamido-3- (l, 3,4-thiadiazol-2-yl)! - thiomethyl-3-cephem-4-carboxylic acid (color isomer), 7-L2- (2-cyclopenten-l-yl) -oxiimtno-2- (5-amino-l, 2,4-thiadiazol-3-yl) acetamido] -3- (l, 3,4-thiadiazol-2- (i) thiomethyl-3-cephem-4-carboxylic acid (color isomer), 7- [2- (2-Cyclohexen-1-yl) oxyimino-2- (5-amino-1,2,4-thiadazol-3-yl) acetamido] -3- (1,3,4-thiadiazol-2) -yl) -thiomethyl-3-cephem-4-carboxylic acid (color isomer), 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem- 4-carboxylic acid (color isomer), 7- [2- (2-Cyclopenten-1-yl) oxyimino-2- (5-amino-1,2,45 thiadiazol-3-yl) acetamido] -3- (1-methyl-1H-telrazole) -5-yl) thiomethyl-3-cephem-4-carboxylic acid (color isomer), 7- (2- (2-Cyclohexen-1-yl) oxyimino-2- (5-amino-1,2,4-thiadazol-3-yl) acetamido] -3- (1-methyl-1 H -tetrazol-5-one) -yl) thiomethyl-3-cephem-4-carboxylic acid (color isomer), 7- [2- (1-Carboxyethoxyimino) -2- (5-amino-1,2,4-thiadiazole) 3-yl) -acetamido] -3- [1- (3-aminopropyl) -1H-tetrazol-5-yl] thiomethyl-3-cephem-4-carboxylic acid (color isomer), 7 '- (2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (tetrazolo [1,5-b] pyridazin-6-yl) -thi -3-cephem-4-carboxylic acid (color isomer), 7- [2- (2-Cyclopenten-1-yl) -oximino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (tetrazolo [1,5-b) ] pyridazin-6-yl) thiomethyl 3-cephem-4-carboxylic acid (color isomer), 7- (2- (2-Cyclohexen-1-yl) -oxyquinoxo-2- (5-amino-1,2,420-thiadiazol-3-yl) -acetamido] -3- (tertrazolo [1,5-b] pyridazin-6-yl) thiomethyl-3-cephem-4-carboxylic acid (color isomer) and N- [7- {2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido} -3-cephem-3-methylmethyl-4'-carbanylpyridinium-4- carboxylate (color isomer) 25 characterized by starting from appropriately substituted materials, 7. A process for the preparation of a pharmaceutical composition. characterized in that a compound of the general formula 1 according to claim ¹ , wherein R *, R ¹ , R ³ , R ⁴ , R ⁵ and the bold black line are as defined in claim 1 - or a pharmaceutically acceptable salt thereof. may be used in admixture with inert additives in the usual dosage forms, preferably tablets, pills, suppositories, capsules, dragees, injection solutions, emulsions 35 or slurry.