NEW CEPHEM COMPOUNDS, PROCESSES FOR THEIR PREPARATION, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND THEIR STARTING COMPOUNDS

Abstract: Cephem compounds of the formula wherein R¹ is amino or a protected amino group; R² is lower aliphatic hydrocarbon group which may be substituted with suitable substituent(s), or cyclo (lower)alkenyl; and a group of the formula: is a heterocyclic cation group containing more than one nitrogen atom which may be substituted with suitable substituent(s); and pharmaceutically acceptable salts thereof, and pro­ cess for their preparation, and also a pharmaceutical composition comprising, as an effective ingrediant, the above compound in association with a pharmaceutically acceptable, substantially non-toxic carrier or excipient. The invention also relates to the starting conpounds and their preparation.

Description: NEW CEPHEM COMPOUNDS, PROCESSES FOR THEIR PREPARATION ; PHARMACEOTICAL COMPOSITIONS CONTAINING THEN AND THEIR STARTING COMPOUNDS The present invention relates to new cephem com- pounds and phramaceutically acceptable salts thereof. More particularly, it relates to new cephem compounds and pharmaceutically acceptable salts thereof, which have antimicrobial activities and to processes for preparation thereof, to pharmaceutical composition comprising the same, and to a method of using tile same therspeutically in the treatment of infectious diseases in human being and animals. Accordingly, it is one object of the present invention to provIde new cephem compounds and pharmaceutically acceptable salts thereof, which are active against a number of pathogenic microorganisms. Another object ote the present invention is to provide processes for the preparation of new cephem compounds and pharmaceutically acceptable salts thereof. A further object of the present invention is to provide pharmaceutical composition comprising, as active ingredients, said new cephem compounds and pharmaceutically acceptable salts thereof. Still further object of the present invention is to provide a method for the treatment of infectious diseases caused by pathogenic bacteria in human being and animals. The object new cephem compounds are novel and can be represented by the following general formula (I). EMI2.1 wherein R1 is amino or a protected amino group; R2 is lower aliphatic hydrocarbon group which may be substituted with suitable substituent (s),or cyclo(lower)alkenyl ; and a group of the formula: EMI2.2 is a heterocyclic cation group containing more than one nitrogen atom, which may be substituted with suitable substituent(s). According to the present invention, the new cephem compounds (I) can be prepared by some processes which are illustrated in the following scheme. Process 1 EMI2.3 or a salt thereof EMI3.1 or a salt thereof Process 2 EMI3.2 Elimination of carboxy-protective group EMI3.3 or a salt thereof wherein , R2 and a group of the formula: are each as defined above: EMI3.4 R3 is a rnun which can be substituted with a group of the for a compound of the formula: EMI3.5 heterocyclic compound containing more than one nitrogen atom, which may be substituted with suitable substituent(s); R4 is a protected carboxy group; and X is an acid residue. Among the starting compounds of the present invention, the compound (IV) is novel and can be prepared by the following methods. EMI4.1 or its reactive derivative at the carboxy group or a salt thereof or its reactive derivative at the amino group or a salt thereof EMI4.2 or a salt thereof EMI4.3 or a salt thereof EMI4.4 wherein RÚ. R2. R4. X. a compound of the formula: formula: EMI5.1 and a group of the are each as defined above. Regarding the object compound (I) and the starting compounds CII), (IV), (V), (VII), (VIII) and (IX), it is to be understood that said object and starting compounds include syn isomer, anti isomer and a mixture thereof. For example, with regard to the object compounds (I), syn isomer means one geometrical isomer having the partial structure represented by the following formula: EMI5.2 Cwherein R1 and R2 are each as defined above) and anti isomer means the other geometrical isomer having the partial structure represented by the following formula: EMI5.3 Cwherein R1 and R2 are each as defined above). Regarding the starting compounds (II), (IV), (V) (VII), (VIII) and CIX) as mentioned above, the syn isomer and the anti isomer can also be referred to the same geometrical isomers as illustrated for the compound (I), Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salt and include a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'dibenzylethylenediamine salt, etc.), an organic acid salt (e.g. acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), an inorganic acid salt (e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.), or a salt with an amino acid (e.g. arginine, aspartic acid, glutamic acid, etc.), and the like. In the above and subsequent descriptions of the present specification,suitable examples and illustrations of the various definitions which the present invention include within the scope thereof are explained in details as follows. The term "lower" is intended to mean 1 to 6 carbon atoms, unless otherwise indicated. Suitable "protected amino" for R1 may include an acylamino or an amino group substituted by a conventional protecting group such as ar(lower)alkyl which may have at least one suitable substituentCs)Ce.g. benzyl, trityl, etc.) or the like. Suitable acyl. moiety in the terms "acylamino" and "acyloxy" may include carbamoyl, aliphatic acyl group and acyl group containing an aromatic or heterocyclic ring, And, suitable examples of the said acyl may be lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.); lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, l-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiarybutoxy- carbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.); lower alkanesulfonyl Ce.g. mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc,); arenesulfonyl (e.g. benzenesulfonyl, tosyl, etc.); aroyl (e.g. benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, indancarbonyl, etc.); ar(lower)alkanoyl (e.g. phenylacetyl, phenylpropionyl, etc,); ar(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxyzarbonyl, etc.), and the like. The acyl moiety as stated above may have at least one suitable substituent(s) such as acyl (e.g. lower alkanoyl), halogen (chlorine, bromine, fluorine and iodine) or the like. Suitable lower aliphatic hydrocarbon group may include lower alkyl5 lower alkenyl, lower alkynyl and the like. Suitable "lower alkyl" is one having 1 to 6 carbon atom(s) and may include methyl1 ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, tert- pentyl, hexyl and the like, and preferably one having 1 to 4 carbon atomCs). Suitable "lower alkenyl" is one having 2 to 6 carbon atoms and may include vinyl, allyl5 isopropenyl, l-propenyl, 2-butenyl, 3-pentenyl and the like, and preferably one having 2 to 4 carbon atoms. Suitable "lower alkynyl" is one having 2 to 6 carbon atoms and may include ethynyl, 2-propynyl, 2-butynyl, 3-pentynyl, 3-hexynyl and the like, and preferably one having 2 to 4 carbon atoms. The lower aliphatic hydrocarbon group as mentioned above may be substituted with 1 to 3 suitable substituent(s) such as carboxy5 protected carboxy as mentioned below, halogen (e.g. chlorine, bromine, etc.), lower alkylthio (e.g. methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio, etc.) or the like. Suitable "cyclo(lower)alkenyl" may include one having 3 to 6 carbon atoms, for example, cyclopentenyl, cyclohexenyl or the like, preferably one having 5 to 6 carbon atoms. Suitable R3 may include an acid residue such as acyloxy, halogen Ce.g. chlorine, bromine, iodine or fluorine), azido or the like, wherein acyl moiety in the term "acyloxy" can be referred to the ones as exemplified above. Suitable heterocyclic cation group containing more than one nitrogen atom means saturated or unsaturated, monocyclic or polycyclic heterocyclic cation group containing more than one nitrogen atom. Preferable heterocyclic cation group containing more than one nitrogen atom-may be unsaturated 5 to 6-membered heteromonocyclic cation group containing more than one nitrogen atom, for example, imidazolio, pyrazolio, triazolio Ce.g. 1,2,3-triazolio, 1,3,4triazolio or 1,2,4-triazolio), tetrazolio, pyridazinio, pyrimidinio, pyrazinio, triazinio (e.g. 1,2,3triazinio, 1,2,4-triazinio or 1,3,5-triazinio), tetrazinio, etc.; unsaturated condensed heterocyclic cation group containing more than one nitrogen atom, for example, indazolio, benzimidazolio, cinnolinio, phthalazinio, quinazolinio, quinoxalinio, 1,5-naphthyridinio, purinio, pteridinio, etc or the like: wherein said heterocyclic cation group containing more than one nitrogen atom may be substituted with 1 to 3 suitable substituentCs) such as hydroxy; lower alkyl (e2g. methyl, ethyl5 propyl5 isopropyl, butyl, isobutyl, pentyl, hexyl, etc.);amino; halogen (e.g. chlorine1 bromine, iodine or fluorine); lower alkoxy (e.g. methoxy, ethoxy, propoxy, etc.); lower alkylthio (e.g. methylthio , ethylthio, propylthio, -iso-propylthio, etc-.); carboxy; rotected carboxy ; lower alkenyl as mentioned above ; hydroxylower)alkyl(e.g., hydroxymethyl,hydroxyethyl, etc.) ; or the like Suitable "protected carboxy" may include "esterified carboxy" and suitable ester moiety in the term esterified carboxy" may be the ones such as lower alkyl ester Ce.g. methyl ester, ethyl ester, propyl ester, isopropyl ester1 butyl ester, isobutyl ester, t-butyl ester1 pentyl ester, t-pentyl ester, hexyl ester, l-cyclopropylethyl ester, etc.); lower alkenyl ester Ce.g. vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g. ethynyl ester, propynyl ester, etc.); mono(or di or tri)-halo(lower)alkyl ester (e.g. 2iodoethyl ester, 2,2,2-trichloroethyl ester, etc.); lower alkanoyloxy(lower)alkyl ester (e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester1 hexanoyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl esters etc.); lower alkanesulfonyl(lower)alkyl ester Ce.g. mesylmethyl ester, 2-mesylethyl ester etc.); ar(lower)alkyl ester, for example, phenyl(lower)alkyl ester which may be substituted with one or more suitable substituent(s)(e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester' diphenylmethyl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5 ditertiarybutylbenzyl ester, etc.); aryl ester which may have one or more suitable substi tuent(s)(e.g. phenyl ester, tolyl ester, tertiarybutylphenyl ester, xylyl ester, mesityl ester1 cumenyl ester, etc.), and the like. Heterocyclic compound containing more than one nitrogen atom means corresponding heterocyclic compound to a heterocyclic cation group containing more than one nitrogen atom as mentioned above. Suitable acid residue for X can be referred to the ones as stated above. Preferred embodiments of the object compounds (I) are as follows. Preferred embodiment of R1is amino; R2 is lower alkyl, carboxy(lower)alkyl, lower alkylthio(lower)alkyl, lower alkenyl, lower alkynyl or cyclo(lower)alkenyl ; and a group of the formula: -NQ3 is triazolio, imidazolio, pyrimidinio, pyrazolio, pyridazinio or pyrazinio, each of which may be substituted with one lower alkyl, amino, lower alkenyl, halogen, hydroxy or hydroxy(lower)alkyl. The processes for preparing the object compounds of the present invention are explained in details in the following. Process 1 : The object compound (I) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (III). Suitable salt of the compound CII) can be referred to the ones exemplified for the compound (I). The present reaction may be carried out in a solvent such as water,. phosphate buffer, acetone, chloroform, acetonitrile, nitrobenzene, methylene chloride, ethylene chloride, formamide, dimethylformamide, methanol, ethanol, ether, tetrahydrofuran, dimethylsulfoxide, or any other organic solvent which does not adversely affect the reaction, preferably in ones having strong polarities, Among the solvents, hydrophilic solvents may be used in a mixture with water. The reaction is preferably carried out in around neutral medium. When the compound (II) is used in a free form, the reaction is preferably conducted in the presence of a base, for example, inorganic base such as alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate, organic base such as trialkylamine, and the like. The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature, under warming or under heating. The present reaction is preferably carried out in the presence of alkali metal halide (e.g. sodium iodide, potassium iodide, etc.), alkali metal thiocyanate (e.g. sodium thiocyanate; potassium thiocyanate, etc.) etc. Process 2 The compound (I) or a salt thereof can be prepared by subjecting the compound CIV) to elimination reaction of carboxy-protective group. In the present elimination reaction, all conventional methods used in the elimination reaction of the carboxy protective group, for example, hydrolysis, reduction, elimination using Lewis acid, etc. are applicable, When the carboxy protective group is an ester, it can be eliminated by hydrolysis or elimination using Lewis acid. The hydrolysis is preferably carried out in the presence of a base or an acid. Suitable base may include an inorganic base and an organic base. Suitable acid may include an organic acid (e.g. formic acid, acetic acid, propionic acid, etc.) and an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, etc.). The present hydrolysis is usually carried out in an organic solvent, water or a mixed solvent thereof. The reaction temperature is not critical, and it may suitably be selected in accordance with the kind of the carboxy protective group and the elimination method. The elimination using Lewis acid is carried out by reacting the compound (IV) with Lewis acid such as boron trihalide (e.g. boron trichloride, boron trifluoride, etc.), titanium tetrahalide (e.g. titanium tetrachloride, titanium tetrabromide, etc.), tin tetrahalide (e.g. tin tetrachloride, tin tetrabromide etc.), aluminum halide (e.g. aluminum chloride, aluminum bromide, etc.), trihaloacetic acid (e.g. trichloroacetic acid, trifluoroacetic acid, etc.) or the like. This elimination reaction is preferably carried out in the presence of cation trapping agents (e.g. anisole, phenol, etc.) and is usually carried out in a solvent such as nitroalkane (e.g. nitromethane, nitroethane, etc.), alkylene halide (e.g. methylene chloride, ethylene chloride, etc.), diethyl ether, carbon disulfide or any other solvent which does not adversely affect the reaction. These solvents may be used as a mixture thereof. The reaction temperature is not critical, and the reaction is usually carried out under cooling, at ambient temperature or under warming. The reductive elimination can be applied preferably for elimination of the protective group such as halo(lower)alkyl (e.g. 2-iodoethyl, 2,2,2trichloroethyl, etc.) ester, ar(lower)alkyl (e.g. benzyl, nitrobenzyl, etc.) ester or the like, The reduction method applicable for the elimination reaction may include, for example, reduction by using a combination of a metal (e.g. zinc, zinc amalgam, etc.) or a salt of chromium compound (e.g. chromous chloride, chroiuous acetate1 etc.) and an organic or inorganic acid (e.g. acetic acid, propionic acid, hydrochloric acid, etc.); and conventional catalytic reduction in the presence of a conventional metallic catalyst (e.g. palladium on carbon, Raney nickel, etc.). This reduction is usually carried out in a solvent such as water, alcohol (e.g. methanol, ethanol, etc.), tetrahydrofuran or any other solvent which does not adversely affect the reaction. These solvents may be used as a mixture thereof. The reaction temperature is not critical, and the reaction is-usually carried out under cooling, at ambient temperature or under warming. The Preparations of the starting compound (IV) are explained in detail in the following. Preparation 1 The compound (IXt can be prepared by reacting the compound (VIII) or a salt thereof with the compound of the formula: N The reaction' can be carried out according to a similar manner to that of Process 1. Preparation 2 The compound CIV) can be prepared by reducing the compound CIX). The present reduction can be carried out in the presence of conventional reducing agent which can reduce t group in cephalosporin compound to -S- group, for example, phosphorus halide such as phosphorus trihalide (e.g. phosphorus trichloride, etc.). The object compounds (I) of the present invention exhibit high antimicrobial activity and inhibit the growth of a number of microorganisms including pathogenic Gram-positive and Gram-negative bacteria, For therapeutic administration, the cephalosporin compounds according to the present invention are used in the form of pharmaceutical preparation which contain said compounds in admixture with a pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external administration, The pharmaceutical preparations may be in solid form such as capsule, tablet, dragee, ointment or suppository, or in liquid form such as solution, suspension, or emulsion. If desired, there may be included in the above preparations auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives. Smile the dosage of the compounds may vary from and also depend upon the age and condition of the patient, an average single dose of about 50 mg., 100 mg., 250 mg., and 500 mg. of the compounds according to the present invention has proved to be effective for treating of infectious diseases caused by a number of pathogenic bacteria. In general amounts, daily dose between 1 mg/body and about 1000 mg/body or even more may be administered. Now in order to show the utility of the object compounds (I), test data on anti-microbial activity of representative compounds of the present invention are shown below. Test method One loopful of an overnight culture of each test strain in Trypticase-soy broth 8 viable cells per ml,) was streaked on heart infusion agar (HI-agar) containing graded concentrations of antibiotics, and the minimal inhibitory concentration (MIC) was expressed in terms of vg/ml after incubation at 370C for 20 hours. Test compounds (l) 7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol- 3-yl)acetamido]-3-(2-methyl-l-pyrazoliomethyl) 3-cephem-4-carboxylate (syn isomer), (2) 7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol 3-yl)acetamido]-3-(l-pyridaziniomethyl)- cephem 4-carboxylate (syn isomer). (3) 7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol- 3-yl)acetamido]-3-(1-pyridaziniomethyl)-3 cephem-4-carboxylate (syn isomer). Test Results EMI15.1 <tb> <SEP> Test <SEP> M <SEP> I <SEP> C <SEP> (Mg/ml) <tb> Bacteria <SEP> Test <SEP> Compound <tb> <SEP> (1) <SEP> (2) <SEP> (3) <tb> Pr.vulgaris <tb> IAg-1025 <SEP> 0.78 <SEP> 0.39 <SEP> 6.25 <tb> Pr.mirabilis <tb> 140 <SEP> 0.39 <SEP> 0.39 <SEP> 0,39 <tb> The following Preparations and Examples are given for the purpose of illustrating the present invention. Preparation 1 To a cold solution of phosphorus pentachloride (16.6 g) in methylene chloride (150 ml) was added 2-ethOxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) (17.3 g) at -180C and the mixture was stirred for 15 minutes at -13 to -10 C. On the other hand, a mixture of 7-amino-3 acetoacetoxymethyl-3-cephem-4-carboxylic acid (25.1 g) and trimethylsilylacetamide (80 g) in methylene chloride (400 ml) was warmed to make a clear solution and (to be continued to the next) page cooled to -l00C. The cold solution was added to the above activated mixture and the mixture was stirred for 1 hour at -100C. The reaction mixture was poured into an aqueous solution (450 ml) of sodium bicarbonate (42 g) and stirred for 1 hour at room temperature. The aqueous layer was separated out, adjusted to pH 2 with 6N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated with diethyl ether to give a powder of 7-[2-ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3- acetoacetoxymethyl-3-cephem-4-carboxylic acid (syn isomer) (24.5 g), mp. 101 to 1060C (dec.). IR (Nujol) : 3400, 3300, 3170, 1770, 1710, 1660, 1620, 1525, 1145, 1035 cm 1 EMI17.1 To a mixture of l-methyl-1,2,3-triazole (2.5 ml), sodium iodide (18.0 g) and water (3.0 ml) was added sodium 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)- acetamido]cephalosporanate (syn isomer) (5.34 g) at 80 C under stirring, which was continued for one hour at the same temp,erature. The mixture was cooled to room temperature, diluted with water (25 ml) and adjusted to pH 2.8 with 1N hydrochloric acid. An insoluble material was filtered off and the filtrate was washed with ethyl acetate, evaporated to remove ethyl acetate and subjected to column chromatography on a non ionic adsorption resin Diaion HP-20 (trademark : prepared by Mitsubishi Chmeical Industries ( (160 ml). After the column was washed with water, the elution was carried out with 20% aqueous methanol. The eluants containing an object compound were collected, evaporated to remove methanol under reduced pressure and lyophilized to give 7-[2-ethoxyimino-2-(5-amino1,2,4-thiadiazol-3-yl)acetamido-3-[3-methyl-1-(1,2,3triazolio)methyl)-3-cephem-4-carboxylate (Syn isomer) (1.0 g), mp. 141 to 1450C (dec.). IR (Nujol) : 3400-3100, 1770, 1660, 1610, 1530, 1035 cm-Ú NMR (DMSO-d6, 6) : 1.23 (3H, t, J-7Hz), 3.15 and 3.55 (2H, ABq, Jcl8Hz), 4.13 (2H, q, Jg7Hz), 4.30 (3H, s), 5.00 ClH, d, J=5Hz), 5.30 and 5.59 (2H, ABq, J-14Hz), 5.67 (lH, 2d, J-5 and 8Hz), 8.16 (2H, bs), 8.82 (1H, s), 9.06 C1H, s), 9.42 (1H,d, J-BHz) Example 2 To a mixture of sodium iodide (12.25 g), 5methylpyrimidine (1.867 g), water C2.5 ml) and acetonitrile (7.5 ml) was added 7-12-ethoxyimino-2-(5- amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylic acid (syn isomer)(5.0 g) at 600C under stirring, which was continued for one hour at the same temperature. The reaction mixture was cooled to ambient temperature, diluted with a mixture of water (150 ml) and ethyl acetate (100 ml) and then adjusted to pH 2 with IN hydrochloric acid. The aqueous layer was separated out, washed with ethyl acetate, evaporated to remove ethyl acetate and subjected to column chromatography on a non ionic adsorption resin Diaion HP-20 C150 ml). After the column was washed with water, the elution was carried out with 30% aqueous methanol. The eluants containing an object compound were collected, concentrated to 40 ml under reduced pressure, passed through acidic alumina (10 g) and lyophilized to give 7-[2- ethoxyimino-2-[5-amino-1,2,4-thiaciazol-3-yl)actamido] 3-(5-methyl-1-pyrimidiniomethyl)-3-cephem-4-carboxylate (syn isomer)(1.45 g), mp. 135 to 1400C (dec.). IR (Nujol) : 3250, 3150, 1770, 1660, 1610, 1520 cm NMR (D2O, 6) : 1.32 (3H, t,. J=7Hz], 2.58 C3H, s), 3.28 and 3.72 C2H, ABq, J=18Hz), 4.33 (2H, q, J-7Hz), 5.30 (1H, d, J=5Hz), 5.37 and 5.60 (2H, ABq, J-14Hz), 5.90 (1H, d, J=5Hz), 9.25 (2H, s), 9.60 (1H, s) Example 3 The following compounds were obtained according to similar manners to those of Examples 1 and 2. (1) 7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl) acetamido)-3-(2-methyl-l-pyrazoliomethyl)-3 cephem-4-carboxylate (syn isomer), mp. 148 to 158 C (dec.). IR (Nujol) : 3400-3100, 1770, 1665, 1610, 1530 cm NMR (D2o, d) : 1.34 (3H, t, J=7Hz), 3.19, 3.57 (2H, ABq, J=l8Hz), 4.11 C3H, s), 4.37 C2H, q, J=7Hz), 5.27 (1H, d, J=5Hz), 5.23 and 5.57 (2H,ABq, J=15Hz), 5.88 (1H, d, J=5Hz), 6.78 (1H, t, J=3Hz), 8.21 (2H, d, J-3Hz) (2) 7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol 3-yl)acetamido]-3-(l-pyridaziniomethyl)-3-cephem 4-carboxylate Csyn isomer), mp. 155 to 1600C Cdec.). IR (Nujol) : 3400-3100, 1770, 1660, 1610, 1530, 1350, 1040 cm NMR (D2O,# ) : 1.23 C3H, t,Je7Hz), 3.03-3.92 C2H, m), 4.20 C2H, q, J=7Hz), 5.10 (1H, d, J=5Hz), 5.4-5.9 CZH, m), 5.77 C1H, d, J=5Hz), 7.67 (1H, m), 8.42 (1H, m), 9.20 C1H, m), 9.52 C1H, m) (3) 7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3 yl)acetamido]-3-(1-pyraziniomethyl)-3-cephem 4-carboxylate (syn isomer), mp. 165 to 1700C (dec.). IR (Nujol) : 3250, 3150, 1770, 1660, 1610, 1520 cm 1 NMR (D2O, 6) : 1.30 C3H, t, J=7Hz), 3.27 and 3.72 (2H, ABq,J=18Hz), 4.33 (2H,q, J=7Hz), 5.30 C1H, d, J=5Hz). 5.47 and 5.75 C2H, ABq, J=14Hz), 5.90 C1H, d, J=5Hz), 9.13 C2H, bs), 9.45 C2H, bs) (4) 7-[2-Methoxyimino-2-[5-amino-1,2,4-thiadiazol 3-yl)acetamido]-3-(l-pyridazoniomethyl]-3 cephem-4-cerboxylate (syn isomer), mp. 165 to 1700C (dec.). IR CNujol) : 3400-3100, 1770, 1660-1580, 1530, 1040 cm1 NMR (D2O, #) : 3,47 and 3,83 (ZH, ABq, J=18Hz), 4.05 (3H, s), 5.25 (1H, d, J=SHz), 5,72 C2H, broad s), 5.87 (1H, d, J=5Hz), 8.5-8.7 (2H, m), 9.4-9.6 (1H,m), 9.7-9.9 (1H,m) (5) 7-[2-Methoxyimino-2-[5-amino-1,2,4-thiadiazol-3 yl)acetamido]-3-(2-methyl-l-pyrazoliomethyl)-3 cephem-4-carboxylate (syn isomer), mp. 100 to 1100C (dec.). IR (Nujol) : 3400-3100, 1770, 1660, 1610, 1530, 1285, 1035 cm1 NMR [D2O, # ) : 3.15 and 3.87 C2H, ABq, J=18Hz), 4.05 C3H, s), 4.08 C3H, s), 5.21 (1H, d, J=5Hz), 5.22 and 5.49 (2H, ABq, J=14Hz), 5,83 (1H,d, J=5Hz), 6.7-6.8(1H, m), 8.1-8.3 (2H,m) (6) 7-[2-Pthoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl] acetamido]-3-(2-ethyl-1-pyrazoliomethyl)-3-cephem 4-carboxylate (syn isomer), mp. 150 to 1550C (dec.). IR (Nujol) : 3300, 3100, 1770, 1670, 1610, 1525 cm NMR (D2O,#) : 1.32 (3H, t, J=7Hz), 1,53 (3H,t, J=7Hz), 3.13 and 3.54 C2H. ABq, J=18Hz), 4.33 C4H, q, J=7Hz), 5.25 (1H, d, J=5Hz), 5.4 (2H, m), 5.85 (1H, d, J=5Hz), 6.7-6.9 (1H, m), 8.2-8.3 (2H, m) (7) [2-Allyloxymino-2-(5-amino-1,2,4-thiadiazol-3 yl)acetamido]-3-(2-methyl-l-pyrazoliomethyl)-3 cephem-4-carboxylate (syn isomer), mp. 165 to 175 C (dec,). IR (Nujol) : 3200, 3100, 1770, 1670, 1610, 1520 cm 1 NMR [D2O, 6) : 3.20 and 3.60 (2H, ABq, J=18Hz), 4.13 [3H,s], 4,60-4.93 [2H,m],5.30 [1H,d, J=5Hz], 5.16-5.63 C4H, m), 5.8-6.4 (2H, m), 6.80 (1H,t, J=3Hz), 8.20 (2H,d, J=3Hz) (8) 7-[2-(2-Propynyloxyimino)-2-(5-amino-1,2,4 thiadiazol-3-yl)acetamido]-3-(1-pyridaziniomethyl) 3-cephem-4-carboxylate (syn isomer), mp. 160 to 165 C (dec.). IR (Nujol) : 3250, 3200, 3100, 1770, 1660, 1620, 1520 cm-Ú NMR (D2O, 6) : 3.03 (1H, t, J=2Hz), 3,48 and 3.83 (2H, ABq, J=18Hz),4.93 (2H, d, J=2Hz), 5.27 C1H, d, J=5Hz), 5.73 (2H, broad s), 5.88 (1H, d, J=5Hz), 8.60 [2H, m), 9.47 (1H, m), 9.83 C1H, m) (9) 7-[2-(2-Propynyloxyimino)-2-(5-amino1,2,4 thiadiazol-3-yl)acetamido]-3-(2-methyl-l pyrazoliomethyl]-3-Cephem-4-carboxylate [syn isomer), mp. 160 to 700C (dec.). -1 IR (Nujoul] : 3250-3 90, 1760, 1670, 1610, 1520 cm NMR CD2O, 6) : 3.05 (1H, t, J=2Hz), 3.20 and 3.58 [2H, ABq, J=18Hz], 4.13 C3H, s), 4.97 C2H, d, J=2Hz), 5.30 (1H, d, J=5Hz), 5.27 and 5,57 C2H, ABq, J=14Hz), 5.92 (1H, d, J=5Hz), 6.80 (1H, t, J=3Hz), 8,23 C2H, broad s) (10) 7-[2-Methylthiomethoxyimino-2-(5-amino-1,2,4 thiadiazol-3-yl)acetamido]-3-(2-methyl-l pyrazoliomethyl)-3-cephem-4-carboxylate [syn isomer), mp. 145 to 1500C (dec,). IR (Nujol) : 3280, 3100, 1770, 1665, 1605, 1525 cm 1 NMR (D2O+CD3OD, 6) : 2.23 (3H, s), 3.25 and 3.47 C2H, ABq, J=18Hz), 4.10 C3H, s), 5.25 (1H, d, J=5Hz), 5.35 C2H, s), 5.28 and 5,48 C2H, ABq, J=14Hz), 5.87 (1H, d, J=5Hz), 6.77 C1H, m), 8,20 (11) 7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4 thiadiazol-3-yl)acetamido]-3-(2-methyl-l pyrzoliomthyl)-3-cephem-4-carboxylate (syn isomer), mp. 165 to 1700C (dec.). IR (Nujol) : 3400, 3290, 3160, 3110, 1770, 1670, 1615, 1525 cm 1 NMR (D2O+NaHCO3, #) : 3.27 and 3,47 (2H, ABq, J=18Hz), 4.10 (3H, s), 4.70 C2H, s), 5.27 (1H, d, J=5Hz), 5,32 and 6,45 [2H,ABq, J=14Hz), 5,92 (1H, d, J=SHz), 6.78 C1H, m), 8.22 (2H, m) (12) 7-[2-(2-Cyclopenten-l-yloxyimino)-2-(5-amino-l,2,4- thiadiazol-3-yl)acetamido]-3-(2-methyl-l pyrazoliomethyl)-3-cephem-4-carboxylate (syn isomer), mp 155 to 1600C (dec.). IR (Nujol) : 3250, 3100, 1770, 1660, 1605, 1525 cm 1 NMR (D2O+CD3OD, #) : 1.83-2.63 (4H, m), 3.20 and 3.43 (2H, ABq, J=18Hz), 4.12 C3H, s), 5.17 (1H, d, J=5Hz), 5.13-5.67 (3H, m), 5.80 (1H, d, J=5Hz), 5.73-6.33 C2H, m), 6.77 (1H, m), 8.20 (2H, m) (13) 7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl) acetamido]-3-(2-allyl-l-pyrazoliomethyl)-3-cephem 4-carboxylate Csyn isomer), mp. 130 to 1400C (dec.). IR (Nujol) : 3400-3100, 1770, 1660, 1610, 1530 cm 1 NMR (D2O, 6) : 1.32 C3H, t, Jz7Hz), 3.13 and 3,46 C2H, ABq, J=l8Hz), 4.31 (2H, q, J=7Hz), 5.0-5.3 (4H, m), 5,20 (1H, d, J=5Hz), 5.29 and 5,39 C2H, ABq, J=14Hz), 5,82 (1H, d, J=5Hz), 5,8-6.2 C1H, m), 6.8 (1H, m), 8.2 C2H, m) (14) 7-[2-Ethoxyimino-2-[5-amino-1,2,4-thiadiazol-3-yl) acetamido]-3-(3-chloro-lpyridaziniomethyl)-3 cephem-4-carboxylate (syn isomer), mp. 145 to 1500C (dec.). IR (Nujol) : 3300-3100, 1775, 1670, 1610, 1530 cm 1 (15) 7- [2 -Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)- acetamido]-3-[3-methyl-1-(1,3,4-triazoliomethyl0]-3 cephem-4-carboxylate (syn isomer), mp. 153 to 157 C (dec.). IR (Nujol) : 3400-3100, 1770, 1660, 1610, 1530 cm NMR (DMSO-d6, 6) : 1.22 C3H, t, J=7Hz), 3.3-3.7 (2H, m), 4.05 (3H, s), 4.13 [ZH, #, J=7Hz), 4.7-5.3 (2H, m), 4.98 (1H, d, J=5Hz, 5,63 (1H, 2d, J=5 and 8Hz), 8.10 (2H, broad s), 9.30 (1H, s), 9.33 (1H, d, J=8Hz), 10.25 (1H, s) (16) 7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl) acetamido]-3-[4-methyl-l-(1,2,4-triazoliomethyl)] 3-cephem-4-carboxylate (syn isomer), mp, 159 to 1640C (dec.). IR (Nujol) : 3400-3100, 1770, 1660, 1605, 1530 cm 1 NMR (DMSO-d6, 6) : 1.23 C3H, t, J=7Hz), 3.1-3.8 (2H, m), 3.91 (3Hj s), 4.12 (2H, q, J=7Hz), 4.98 (1H, d, J=5Hz), 5.0-5.5 (2H, m), 5.63 (1H, 2d, J=5 and 8Hz), 8,13 (2H, broad s), 9.03 C1H, s), 9. (1H, d, J=8Hz), 10.25 (1H, 917) 7-[2-Ethoxyimno-2-[-amino-1,2,4-thiadiazol-3-yl) acetamido]-3-(3-hydroxy-l-pyridaziniomethyl)-3 cephem-4-carboxylate (syn isomer), mp. 159 to 163 C (dec.). IR (Nujol) : 3400-3100, 1775, 1670, 1610, 1520 cm 1 NMR (DMSO-d6, 6) : 1.27 C3H, t, J=7Hz), 3.56 (2H, broad s), 4.16 C2H, q, J=7Hz), 4,9-5.6 (3H, m), 5.83 (1H, 2d, J=5 and 8Hz), 6.91 (1H, d, J=9Hz), 7.6 C1H, m), 8.09 (2H, broad s), 8.44 C1H, d, J=4Hz), 9.54 (1H, d, J=8Hz) (18) 7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3- yl)acetamido]-3-(3-methyl-l-imidazoliomethyl)-3-3 cephem-4-carboxylate (syn isomer), mp. 156 to 165 C (dec.). IR (Nujol) : 3300, 3150, 1770, 1660, 1605, 1530 c-m 1 NMR (DMSO-d6, #) : 1,23 (3H, t, J=7Hz), 3,1,2 and 3.54 (ZH, ABq, J+18Hz), 3.86 C3H, s), 3.15 (2H, #. J=7Hz), 50.2 (1H, d, J=5Hz), 5,02 and 5,18 (2H, ABq, J=14Hz), 5.66 (1H, 2d, J=5 and 9Hz), 7.65 (1H s), 7.97 (1H, s), 8.25 (2H, broad s), 9.32 (1H, s), 9,45 (1H, d, J=9Hz) Example 4 A mixture of diphenylmethyl 7-[2-ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3methyl-l-imidazoliomethyl)-3-cephem-4-carboxylate trifluoroacetate Csyn isomer)(3 g) and anisole (7.5 ml) in trifluoroacetic acid (20 ml) was stirred for 20 minutes under cooling in an ice bath. The mixture was poured into cold diisopropyl ether (120 ml) under stirring and resulting precipitates were collected by filtration. The powder was suspended in water (50 ml), adjusted to pH 4 to 5 with aqueous solution of sodium bicarbonate and an insoluble material was filtered off, The filtrate was subjected to column chromatography on a non ionic adsorption resin "Diaion HP-20"(Trademark: Prepared by Mitsubishi Chemical Industres ( (100 ml). After the column was washed with water5 the elution was carried out with 20% aqueous methanol. The eluates containing an object compound were collected, evaporated to remove methanol under reduced pressure and lyophilized to give 7-[2ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]3-(3-methyl-1-imidazoliomethyl)-3-cephem-4-carboxylate (syn isomer) (1.46 g), mp. 156 to 1650C Cdec.). IR (Nujol) : 3300, 3150, 1770, 1660, 1605, 1530 cm NMR (DMSO-d6, 6) : 1.23 (3H, t, J=7Hz), 3,12 and 3.54 (2H, ABq, J=18Hz), 3,86 (3H, s), 4.15 (2H, q, J=7Hz), 5.02 (1H, d, J=SHz), 5.02 and 5.18 [2H, AB#, J=14Hz), 5.66 (1H, 2d, J=5 and (Hz), 7.65 (1H, s), 7.97 (1H, s), 8.25 (2H, broad s), 9.32 C1H. s), 9.45 (1H, d, J-9Hz) Example 5 The following compounds were obtained according to a similar manner to that of Example 4. (1) 7-[2-Ethoxyimino-2-[5-amino-1,2,4-thiadiazol-3 yl)acetaido-3-[3-methyl-l-(1,2,3-triazolio)methyl] 3-cephem-4-carboxylate (syn isomer), mp. 141 to 1450C (dec.). IR (Nujol) : 3400-3100, 1770, 1660, 1610, 1530, 1035 cm 1 (2) 7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl) acetamido]-3-(5-methyl-l-pyrimidiniomethyl)-3 cephem-4-carboxylate (syn isomer), mp. 135 to 1400C (dec.). IR (Nujol) : 3250, 3150, 1770, 1660, 1610, 1520 cm (3) 7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadizol-3-yl) acetamido]-3-(2-methyl-1-pyrazoliomethyl)-3 cephem-4-carboxylate (syn isomer), mp. 148 to 1580C (dec.). IR (Nujol) : 3400-3100, 1770, 1665, 1610, 1530 cm 1 (4) 7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol- 3-yl)acetamido]-3-(l-pyridaziniomethyl)-3-cephem 4-carboxylate (syn isomer), mp. 155 to 1600C. (dec.). IR (Nujol) : 3400-3100, 1770, 1660, 1610, 1530, 1350, 1040 cm-Ú (5) 7-[2-Ethoxyimino-2-[5-amino-1,2,4-thiadiazol-3 yl)acetamido]-3-[l-pyraziniomethyl)-3-cephem 4-carboxylate Csyn isomer), mp. 165 to 1700C (dec.). IR (nujoul) : 3250, 3150, 1770, 1660, 1610, 1520 cm 1 (6) 7-[2-Methoximino-2-(5-amino-1,2,4-thiadiszol-3-yl) acetamido0-3-(l-pyridaziniomethyl)-3-cephem-4 carboxylate (syn isomer) , mp. 165 to 1700C (dec.). IR (Nujol) : 3400-3100, 1770, 1660-1580, 1530, 1040 cm 1 (7) 7-(2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3 yl)acetamido]-3-(2-methyl-l-pyrazoliomethyl)-3 cephem-4-carboxylate (syn isomer), mp. 100 to 110 C (dec.). IR (Nujol) : 3400-3100, 1770, 1660, 1610, 1530, 1285, 1035 cm 1 (8) 7-[2-Ethoxyimino-2-t5-amino-1,2,4-thiadiazol-3- yl)acetamido]-3-(2-ethyl-l-pyrazoliomethyl)-3 cephem-4-carboxylate (syn isomer), mp. 150 to 155 C (dec.). IR (Nujol) : 3300, 3100, 1770, 1670, 1610, 1525 -1 (9) 7-[2-Allyloxyimino-2-(S-amino-1,2t4-thiadiazol-3- yl)acetamido]-3-(2-methyl-l-pyrazoliomethyl)-3 cephem-4-carboxylate (syn isomer), mp. 165 to 175 C (dec.). IR (Nujol); 3200, 3100, 1770, 1670, 1610, 1520 cm1 (10) 7-[2-(2-Propynyloxyimino)-2-(5-amino-1,2,4 thiadiazol-3-ylZacetamido]-3-(1-pyridaziniomethyl)- 3-cephem-4-carboxyiate Csyn isomer), mp. 160 to 1650C (dec.). IR.(Nujol) : 3250, 3200, 3100, 1770, 1660, 1620, 1520 cm-Ú (11) 7-[2-(2-Propynyloxyimino)-2-(5-amino-1,2,4 thiadiazol-3-yl)acetamido]-3-(2-methyl-l pyrazoliomethyl)-3-cephem-4-carboxylate (syn isomer), mp. 160 to 1700C (dec). IR (Nujol) : 3250-3100, 1760, 1670, 1610, 1520 cm 1 (12) 7-[2-Methylthiomethoxyimino-2-(5-amino-1,2,4 thiadiazol-3-yl)acetamido]-3-(2-emthyl-l pyrazoliomethyl)-3-cephem-4-carboxylate (syn isomer), mp. 145 to 1500C (dec.). IR (Nujol) : 3280, 3100, 1770, 1665, 1605, 1525 cm 1 (13) 7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4 thiadiazol-3-yl)acetamido]-3-(2-methyl-l pyrazoliomethyl)-3-cephem-4-carboxylate (syn isomer), mp. 165 to 1700C (dec,). IR (Nujol) : 3400, 3290, 3160, 3110, 1770, 1670, 1615, 1525 ---Ú (14) 7-[2-(2-Cyclopenten-l-yloxyimino)-2-(5-amino 1,2,4-thiadiazol-3-yl)acetamido]-3-(z-methyl l- pyrazoliomethyl) -3-cephem-4-carboxylate (syn isomer), mp. 155 to 1600C (dec.). IR (Nujol) : 3250, 3100, 1770, 1660, 1605, 1525 cm-Ú (15) 7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3- yl)acetamido]-3-(2-allyl-l-pyrazoliomethyl)-3 cephem-4-carboxylate (syn isomer), mp. 130 to 140 C (dec.). IR (Nujol) : 3400-3100, 1770, 1660, 1610, 1530 cm 1 (16) 7- [2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3- yl)acetamido]-3-(3-chloro-l-pyridaziniomethyl)-3 cephem-4-carboxylate (syn isomer), mp. 145 to 1500C (dec.). IR (Nujol) : 3300-3 0, 1775, 1670, 1610, 1530 cm 1 (17) 7-[2-Ethxoyimino-2-amino-1,2,4-thiadiazol-3-yl) acetamido]-3-[3-methyl-l-(1,3,4-triazoliomethyl)] 3-cephem-4-carboxylate (syn isomer), mp. 153 to 1570C (dec.). IR.(Nujol) : 3400-3100, 1770, 1660, 1610, 1530 cm 1 (18) 7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3- yl)acetamido]-3-[4-methyl-l-(1,2,4-triazoliomethyl] 3-cephem-4-carboxylate (syn isomer), mp. 159 to 164 C (dec.). IR (Nujol) : 3400-3100, 1770, 1660, 1605, 1530 cm (19) 7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3- yl)acetamido]-3-(3-hydroxy-l-pyridaziniomethyl)-3 cephem-4-carboxylate (syn isomer), mp. 159 to 1630C (dec.). IR (Nujol) : 3400-3100. 1775, 1670, 1610, 1520 cm 1 Preparation 2 To a solution of phosphorus pentachloride (54.6 g) in methylene chloride (500 ml) was added 2-ethoxyimino 2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer (54.0 g) under stirring and cooling at -200C. The mixture was stirred for 30 minutes at -15 to -120C and for 2 hours at -50C. To the mixture containing precipitates of an object compound was added diisopropyl ether (500 ml) at -50C and the mixture was stirred for 30 minutes at -5 to 100C. The resulting precipitates were collected by filtration, washed with diisopropyl ether and dried to give 2-ethoxyimino-2-(5 amino-l,254-thiadiazol-3-yl)acetyl chloride hydrochloride (syn isomer) (60.17 g), mp. 125 to 1270C (dec.). I.R. (Nujol) : 1785, 1625, 1055 cm 1 Analysis for C6H8O2N4SCl2 C H N S C1 calc'd : 26.57 2.95 20.66 11.81 26.20 found : 26.13 2.99 20.49 11.77 26.41 Preparation w To a suspension of diphenylmethyl 7-amino-3chloromethyl-3-cephem-4-carboxylate hydrochloride (27 g) in methylene chloride (300 ml) was added N,N-dimethylaniline (36.2 g) under cooling in an ice bath at 5 C. To the solution was added portionwise 2-ethoxyimino2-(5-amino-1,2,4-thiadiazol-3-yl)acetyl chloride hydrochloride (syn isomer) (16.2 g) below 110'C and the mixture was stirred for 45 minutes at 50C. The reaction mixture was diluted with a mixed solvent of methylene chloride (100 ml) and water (200 ml) and adjusted to pH 2 with 1N hydrochloric acid. The organic layer was separated out, washed with water, dried over magnesium sulfate and evaporated to dryness. The residue was triturated in diethyl ether to give diphenylmethyl 7-[2-ethoxyimino-2-(5-amino-1,2,4 thiadiazol-3-yl)acetamido) -3-chloromethyl-3-cephem-4- carboxylate (syn isomer) (32.3 g ), mp. 120 to 125 C Cdec.). I.R. (Nujol) : 3300, 3150, 1780, 1725, 1675 1625, 1530, 1495 cm 1 N.M.R. (DMSO-d6, 6) : 1.28 C3H, t, J=7Hz), 3.68 (2H, broad s), 4.23 C2H, q, J=7Hz), 4.47 (2H,s) ,5.27 (1H, d, J=5Hz), 5.97 (1H, 2d, Je5 and 8Hz), 7.0 (1H, s), 7.2-7.7 (1OH, m), 8.17 C2H, broad s), 9.62 (1H, d, J=8Hz) Preparation 4 To a cold solution of diphenylmethyl 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3chloromethyl-3-ephem-4-carboxylate (syn isomer) (10 g) in a mixed solution of methylene chloride (100 ml) and acetic acid (10 ml) were added 30t hydrogen peroxide (1.84 ml) and sodium tungstate (0.3 g). The mixture was stir d for 45 minutes in an ice bath and poured into diet yl ether (300 ml). The precipitates were collect d by filtration and washed with diethyl ether to give diphenylmethyl 7-[2- ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3chloromethyl-3-cephem-4-carboxylalte-l-oxide (syn isomer) (8.9 g), mp 150 to 1550C (dec.). I.R. [Nujol) : 3280, 3170, 1785, 1723, 1667, 1628, 1530 cm 1 N.M.R. (DMSO-d6, 6) : 1.30 C3H, t, J=7Hz), 3.90 C2H, broad s), 4.23 C2H, q, J=7Hz), 4.58 C2H, broad s), 5.12 (1H, d, J=5Hz), 6.10 (1H, 2d, J=5 and 8Hz), 7.02 (1H, s), 7.20-7.73 (10H, m), 8.15 C2H, broad s), 9.00 (1H, d, J=8Hz) Preparation 5 To a cold solution of diphenylmethyl 7-[2-ethoxyimino2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3 chloromethyl-3-cephem-4-carboxylate-l-oxide (syn isomer) (9.85 g) in acetone (222 ml) was added sodium iodide (8.22 g) and the mixture was stirred for 2 hours under cooling in an ice bath. The solvent was evaporated under reduced pressure and the residue was dissolved in a mixture of methylene chloride (200 ml) and water (100 ml). The organic layer was separated out, washed with an aqueous solution of sodium thiosulfate and water successively, dried over magnesium sulfate and evaporated to dryness. The residue was triturated in diethyl ether to give diphenylmethyl 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3iodomethyl-3-cephem-4-carboxylate-l-oxide (syn isomer) (10.39 g), mp. 159 to 1630C (dec.). I.R. (Nujol) : 3250, 3150, 1780, 1720, 1670, 1620, 1520 cm-1 N.M.R. (DMSO-d6, #) : 1.29 (3H, t, J=7Hz), 3.95 (2H, m), 4.25 (2H, q, J=7Hz), 4.50 (2H, m), 5.12 (1H, d, J=5Hz), 6.05 (1H, 2d, J=5 and 9Hz), 7.00 (1H, s), 7.4 10H, m), 8.13 (2H, broad s), 8.96 (1H, d, J=9Hz) Preparation 6 EMI31.1 A mixture of diphenylmethyl 7-[2-ethoxyimino-2 (5-amino-1,2,4-thiadiazol-3-yl)acetamido3-3- iodomethyl-3-cephem-4-carboxylalte-l-oxide (syn isomer) (4 g) and l-methylimidazole (0.5 g) in tetrahydrofuran (7 ml) was stirred for 40 minutes at room temperature. The resulting precipitates were collected by filtration, washed with tetrahydrofuran and dried to give diphenylmethyl 7-[2-ethoxyimino-2-(5-amino-1,2,4 thiadiazol-3-yl)acetamido]-3-(3-methyl-1-imidazolio- methyl)-3-cephem-4-carboxylate-l-oxide iodide (syn isomer) (4.20 g), mp. 105 to 114 C (dec.). IR (Nujol) : 3250, 3150, 1790, 1720, 1670, 1610, 1520 cm-Ú NMR (DMSO-d6, 6) : 1.21 (3H, t, J=7Hz), 3.77 C3H, s), 4.10 (2H, m), 4i5 C2H5 q; J=7Hz), 5.1 C3H5 m), 6.07 (2d, 1H, J=5 and 8Hz), 6.87 (1H, s), 7.33 (llH, m), ,60 (1H, s), 8.00 (2H, broad s), 8.91 (1H, d, J=2Hz), 8.93 (1H, broad s) Preparation 7 To a mixture of diphenylmethyl 7-[2-ethoxyimino-2 (5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-)3 methyl-l-imidazoliomethyl)-3-cephem-4-carboxylate-1- oxide iodide (syn isomer) (4 g) and N,N-dimethylaniline (1,21 g) in acetonitrile (40 ml) was dropped phosphorus trichloride (1.37 g) below 80C under stirring and cooling in an ice bath. The mixture was stirred for 2.5 hours at the same temperature and diethyl ether (45 ml) was added thereto. The resulting precipitates were collected by filtration, washed with diethyl ether and dried to give diphenylmethyl 7-[2-ethoxyimino-2 (5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-methyll-imidazolioemthyl)-3-cephem-4-carboxylate iodide (syn isomer) (4.18 g), mp. 115.5 to 120.5 C (dec.). IR (Nujol) : 1780, 1720, 1680, 1630, 1530 cm NMR (DMSO-d6, 6) : 1.22 (3H, t, J-7Hz), 3.09 (3H, s), 3.86 (2H, m), 4.18 (2H, q, J-7Hz), 5.18 (3H, m), 6.05 (1H, 2d, J=5 and 9Hz)1 6.94 (1H, s), 7.4 (15H, rn), 9,60 (1H, d, J=9Hz) Preparation 8 A solution of diphenylmethyl 7-[2-ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-methyll-imidazoliomethyl)-3-cephem-4-carboxylate iokide (syn isomer) (3.9 g) in a mixed solvent (10 ml) of tetrahydrofuran and methanol (1:1) was subjected to a column packed with an ion-exchange resin [Amberlite IRA-400 (trademark: Prepared by Rohm and Haas Co.) trifluoro acetate-form) (40 ml). The elution was carried out with the same solvent (80 ml) and the eluate was evaporated to dryness. The residue was triturated in diethyl ether to give diphenylmethyl 7-[2-ethoxyimino-2-(5amino-1,2,4-thiadiazol-3-yl)acetamido)-3-(3-methyl-l imidazoliomethyl)-3-cephem-4-carboxylate trifluoroacetate (syn isomer) (2.74 g), mp. 110 to 119;50C (dec.). IR (Nujol) : 3250, 3150, 1790, 1720, 1690, 1670, 1630, 1530, 1500 cm-1 Preparation 9 The following compound was obtained according to 2 similar manner to that of Preparation 1. 7-[2-Methylthiomethoxyimino-2-(5-amino-1,2,4-thiadiazol- 3-yl)acetamido]cephalosporanic acid (syn isomer), nip. 95.5 to 103.5 C (dec.). IR (Nujol) : 3400, 3300, 3190, 1770, 1720, i670, 1620,1525 cm-Ú NMR (DMSO-d6, 6) : 2.00 (3H, s), 2.17 (3H, s), 3.50 (2H, broad s), 4.68 and 4.92 (2H, ABq, J=l3Hz), 5.10 (1H, d, J=5Hz), 5.20 (2H, s), 5.77 (1H, 2d, J=5 and 8Hz), 8,07 (2H, broad s), 9.53 (1H, d, J=8Hz) Example 6 The following compounds were obtained according to similar manners to those of aforesaid Examples. (1) 7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl) acetamido]-3-[2-(2-hydroxyethyl)-l-pyrazolioemthyl]-3 cephem-4-carboxylate (syn isomer), mp 140 to 1470C (dec.) IR (Nujol): 3400-3100, 1770, 1660, 1610, 1525, 1280, 1035cm-Ú NMR (D2O, #) : 1.35 (3H, t, J=7Hz),'3.17 and 3.55 (2H, ABq, J=18Hz), 3.99 (2H, t, J=5Hz), 4.37 (2H, q, J=7Hz), 4.72 (2H, t, J=5Hz)1 5.30'(1H, d, J=5Hz), 5.48 (2H, broad s), 5.92 (1H, d, J=5Hz), 6.89 (1H, m), 8.35 (2H, m) (2) 7-[2-Ethoxyimino-2-(5-amlno-1,2,4-thiadiazol-3-yl)- acetamido]-3-(2-amino-1-pyrimidiniomethyl)-3-cephem 4-carboxylate (syn isomer), mp 195 to 2000C (dec.). IR (Nujol): 3280, 3160, 1765, 1660, 1635, 1610, 1565, 1520, 1030cm 1 NMR (DMSO-d6, #) : 1.34 (3H, t, J=7Hz), 3.40 and 3.83 (2H, ABq, J=18Hz), 4.14 (2H, q, J=7Hz), 4.70 and 5.45 (2H, ABq, J=14Hz), 5.08 (1H, d, J=5Hz), 5.70 (1H, dd, J=5 and 8Hz), 7.0 (1H, m), 8.1 (2H, broad s), 8.5 (1H, m), 8.7 (1H, m), 9.46 (1H, d, J=8Hz)

Claims: What we claim is 1. A new cephem compound of the formula EMI35.1 wherein R1 is amino or a protected amino group; R2 is lower aliphatic hydrocarbon group which may be substituted with suitable substituent(s), or cyclo(lower)alkenyl; and a group of the formula EMI35.2 is a heterocyclic cation group containing more than one nitrogen atom, which may be substituted with suitable substituent(s); and pharmaceutically acceptable salts thereof. 2. Syn isomer of a compound of claim 1, wherein EMI35.3 group is EMI35.4 3. A compound of claim 2, wherein R1 is amino; R2 is lower aliphatic hydrocarbon group which may be substituted with lower alkylthio or carboxy, or cyclo(lower) alkenyl; and a group of the formula EMI35.5 is unsaturated 5 to 6-membered heteromonocyclic cation group containing more than one nitrogen atom, which may be substituted with lower alkyl, amino, lower alkenyl, halogen, hydroxy or hydroxy(lower)- alkyl. 4. A compound of claim 3, wherein R2 is lower alkyl, lower alkenyl or lower alkynyl, each of which may be substituted with one lower alkylthio or carboxy, or cyclo(lower)alkenyl; and a group of the formula : -N is triazolio, imidazolio, pyrimidinio, pyràzólio, pyridazinio or pyrazinio, each of which may be substituted with one lower alkyl, amino, lower alkenyl, halogen, hydroxy or hydroxy(lower)alkyl. 5. A compound of claim 4, wherein R2 is methyl, ethyl, allyl, 2-propynyl, carboxymethyl, methylthiomethyl or 2-cyclopenten-l-yl; and a group of the gormula : -N# is triazolio substituted with one methyl, imidazolio substituted with one methyl, pyrimidinio substituted with one methyl or amino, pyrazolio substituted with one methyl, ethyl, 2-hydroxyethyl or allyl, pyridazinio which may be substituted with one hydroxy or chlorine, or pyrazinio. 6. A compound of claim, 4, wherein ,- -" R2 is lower alkyl and a group of the formula : is triazolio substituted with one lower alkyl. 7. A compound of claim 4, wherein R2 is lower alkyl and a group of the formula : is imidazolio substituted with one lower alkyl. 8. A compound of claim 4, wherein R2 is lower alkyl and a group of the formula : -N.' is pyrimidinio substituted with one lower alkyl or amino. 9. A compound of claim 4, wherein R2 is lower alkyl, lower alkenyl, lower alkynyl, carboxy (lower) alkyl, lower alkylthio (lower) alkyl or cyclo(lower)alkenyl and a group of the formula : -N sj is pyrazolio substituted with one lower alkyl, hydroxy(lower)alkyl or lower alkenyl. 10. A compound of claim 4, wherein Rê is lower alkvl or lower alkvnvl and a group of the formula EMI37.1 is pyridazinio which may be substituted with one hydroxy or halogen. 11. A compound of claim 4. wherein Rê is lower alkl and a group of the formula : is pyrazinio. EMI37.2 12. A compound of claim 5, which is selected from the group consisting of 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl] acetamido]-3-(3-methyl-1-imidazoliomethyl)-3-cephem- 4-carboxylate (syn isomer), 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)- acetamido]-3-[3-methyl-l-(1,2,3-triazolio)methyl]-3 cephem-4-carboxylate (syn isomer), 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)- acetamido]-3-(5-methyl-l-pyrimidiniomethyl)-3 cephem-4-carboxylate (syn isomer), 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)- acetamido]-3- (2-methyl-l-pyrazoliomethyl)-3- cephem-4-carboxylate (syn isomer), 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)- acetamido]-3-(1-pyridaziniomethyl)-3-cephem-4- carboxylate (syn isomer), <RTI ID=37.6> 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)- acetamido)-3- (l-pyraziniomethyl)-3-cephem-4- carboxylate (syn isomer), 7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl) acetamido]-3-(1-pyridaziniomethyl)-3-cephem-4carboxylate (syn isomer), 7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3yl)acetamido]-3-[2-methyl-l-pyrazoliomethyl)-3cephem-4-carboxylate (syn isomer), 7-[2-ethoxyimino-2-(5; ;amino-1,2,4-thiadiazol-3- yl)acetamido]-3-(2-ethyl-l-pyrazoliomethyl)-3cephem-4-carboxylate (syn isomer), 7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3- yl)acetamido]-3-(2-methyl-l-pyrazoliomethyl)-3cephem-4-carboxylate (syn isomer), 7-[2-(2-propynyloxyimino)-2-(5-amino-1,2,4- thiadiazol-3-ylacetamido]-3-(1-pyridaziniomethyl)3-cephem-4-carboxylate (syn isomer), 7-[2-(2-propynyloxyimino3-2-(5-amino-1,2,4- thiadiazol-3-yl)acetamido]-3-(2-methyl-lpyrazoliomethyl)-3-cephem-4-carboxylate (syn isomer), 7- [2-methylthiomethoxyimino-2- (5-amino-i,2,4- thiadiazol-3-yl)acetamido]-3-(2-methyl-lpyrazoliomethyl)-3-cephem-4-carboxylate (syn isomer), 7-[2-carboxymethoxyimino-2-(5-amino-1,2,4- thiadiazol-3-yl]acetamido]-3-(2-emthyl-l <RTI ID=38.7> pyrazoliomethyl)-3-cephem-4-carboxylate (syn isomer), 7-[2-(2-cyclopenten-l-yloxyimino)-2-(5-amino1,2,4-thiadiazol-3-yl)acetamido]-3-[2-methyl-lpyrazoliomethyl)-3-cephem-4-carboxylate (syn isomer), 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3- yl) acetamido]-3-(2-allyl-l-pyrazoliomethyl)-3 cephem-4-carboxylate (syn isomer), 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3- yl)acetamido]-3-(3-chloro-l-pyridaziniormthyl)-3 cephem-4-carboxylate (syn isomer), 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl) acetamido]-3-[3-methyl-l-(1,3,4-triazoliomethyl)] 3-cephem-4-carboxylate (syn isomer), 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3- yl)acetamido]-3-[4-methyl 2s4-triazoliomethyl)a 3-cephem-4-carboxylate (syn isomer), 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3- yl)acetamido]-3-(3-hydroxy-1-pyridaziniomethyl)-3- cephem-4-carboxylate (syn isomer), 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl) acetamido]-3-[2-(2-hydroxyethyl)-1-pyrazoliomethyl]- 3-cephem-4-carboxylate (syn isomer), and 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3- yl)acetamido]-3-(2-amino-l-pyrimidinoomethyl)-3 cephem-4-carboxylate (syn isomer). 13. A process for preparing a new cephem compound of the formula EMI39.1 wherein R1 is amino or a protected amino group; R2 is lower aliphatic hydrocarbon group which may be substituted with suitable substituent(s), or cyclo(lower)alkenyl and a group of the formula EMI40.1 is a heterocyclic cation group containing more than one nitrogen atom, which may be substituted with suitable substituent(s); or a salt thereof, which comprises (a) reacting a compound of the formula EMI40.2 wherein R1 and R2 are each as defined above; and R3 is a group which can be substituted with a group of the formula EMI40.3 or a sait thereof, witn a compound or tne tormula EMI40.4 wherein the compound of the formula : is a heterocyclic compound containing EMI40.5 more than one nitrogen atom, which may be substituted with suitable substituent(s), or (b) subjecting a compound of the formula EMI40.6 wherein RÚ , Rê and a group of the formula : are each as defined above , R4 is a protected EMI41.1 carboxy group and X is an acid residue, to elimination reaction of carboxy-protective group. 14. A compound of the formula EMI41.2 wherein R1 is amino or a protected amino group; R2 is lower aliphatic hydrocarbon group which may be substituted with suitable substituent(s), or cyclo(lower)alkenyl; R4 is a protected carboxy group, X is an acid residue, Y is -S- or and a group of the formula EMI41.3 is a heterocyclic cation group containing more than one nitrogen atom, which may be substituted with suitable substituent(s); and salts thereof. 15. A process for preparing a compound of the formula EMI41.4 wherein R1 is amino or a protected amino group; R2 is lower aliphatic hydrocarbon group which may be substituted with suitable substituent (s), or cyclo (lower) alkenyl R4 is a protected carboxy group; X is an acid residue and a group of the formula EMI42.1 is a heterocyclic cation group containing more than one nitrogen atom, which may be substituted with suitable substituent(s); which comprises reducing a compound of the formula EMI42.2 wherein R1 R2 R4 x and a vroun of the formule EMI42.3 are each as defined above. 16. A pharmaceutical antibacterial composition comprising a compound of claim 1 in association with a pharma ceutically acceptable, substantially non-toxic carrier or excipient. 17. A compound as defined in any of claims 1 to 12 for use as a pharmaceutical. 18. A compound as defined in any of claims 1 to 12 for use in the treatment of infectious diseases.

Inventors: GOTO, JIRO, SAKANE, KAZUO, TERAJI, TSUTOMU
Applicants: FUJISAWA PHARMACEUTICAL CO., LTD.
Application year: 1982
Main classification: C07D501
IPC codes: C07D501, A61P31, A61K31