NL7906497A - 3,7-Substituted-3-CEFEM-4-CARBONIC ACID COMPOUNDS, METHODS FOR PREPARING THE SAME AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE COMPOUNDS. - Google Patents

Description

i *.

Η vo 8258

Fujisawa Pharmaceutical Co., Ltd.

Osaka, Japan.

3.7 "Disubstituted-3-cephem-1-carboxylic acid compounds, processes for their preparation as well as pharmaceutical preparations containing these compounds as an active component.

The present invention relates to novel 3-7-disubstituted-3-cephem-carboxylic acid compounds and pharmaceutically acceptable salts thereof. More particularly, the invention relates to novel 3,7-disubstituted-3-ephem-4-carboxylic acid compounds and pharmaceutically acceptable salts thereof having antibacterial activity and methods of preparation thereof, to pharmaceutical compositions containing these compounds as active component as well as a method for its therapeutic application to treat infectious diseases in humans and animals.

Thus, it is a primary object of the invention to provide 3,7-disubstituted-3-cephem-L-earboxylic acid compounds and pharmaceutically acceptable salts thereof which are highly active against a number of pathogenic bacteria.

It is another object of the invention to provide processes for preparing 3,7-disubstituted-3-cephem-carboxylic acid compounds and pharmaceutically acceptable salts thereof.

It is a further object of the invention to provide pharmaceutical preparations containing as active component said 3-7-disubstituted-3-cephemicarboxylic acid compounds and pharmaceutically acceptable salts thereof.

It is yet another object of the invention to provide a method of treating infectious diseases caused by pathogenic bacteria in humans and animals.

The 3,7-disubstituted-3-cephem-carbonsuric compounds are new and can be represented by formula 1 of the formula sheet, where H "is an amino or protected aminc group, 2 ...

?: is an aliphatic cocwazer substance group which may contain suitable substituents 7906457 * 3 2, R is a carboxy or protected carboxy group, and ...

R is an N-containing 5-heteromonocyclic ring containing lower alkenyl groups,

2. YOU

Provided R is not methyl when R is tetrazolyl with a lower alkenyl group.

The compounds according to the invention (1) are new compounds which can be prepared according to the methods 1 - b of 12 3 the reaction schemes A - D of the formula sheet, wherein R, R, R and k 1a 10 R have the aforementioned meanings, R represents a protected amino group, R represents a protected carboxy (lower) alkyl group, R represents a carboxy (lower) alkyl group, and X is a group that may be substituted k. b with a group of the formula R -S-, wherein R has the aforementioned meanings.

Of the starting compounds, some of the compounds of formula III are new and can be prepared by

methods (1) - (3) as suggested in reaction schemes E - G

1 1a 2 of the formula sheet, wherein R, R and R each have the aforementioned meanings, Z is a protected carboxy group and I is halogen.

The other starting compounds of formula 2 can be prepared by methods as illustrated in 3b reaction scheme H of the formula sheet, wherein R and R each have the aforementioned meanings.

With regard to the title compounds of formulas 1, 25 1b and 1d, and the starting compounds of formulas 1, 1, 3,3,3 ·, 7, 8, 10 - 12 and 16, it is noted that said title and starting compounds include tautomeric isomers with respect to their thiazole groups, ie, where the group represented by formula 18 (wherein R1 has the aforementioned meanings) in the formula of said title and starting compounds has formula 18A (wherein R is the has the aforementioned meanings), this group of formula 18A may alternatively be represented by the tautomeric formula 18B (wherein 11d R is an imino or protected imino group). I.e. that both said groups (A) and (B) are in equilibrium state as so-called tautomeric forms which can be represented by scheme I of 7906497 f «3 ν -] ¾ the formula sheet (where B1 and 5 ellc have the aforementioned meanings).

This type of tautomerism between 2-aminothiazole compounds and 2-iminothiazoline compounds as mentioned above is known in the literature, and it is clear that both tautomeric isomers are balanced and readily convertible; consequently, such isanation is included as such by the compound. Thus, both tautomeric forms of the title compounds and the starting compounds are clearly within the scope of the invention.

In the description and examples, the compounds of the invention and starting compounds including the group of such tautomeric ismers are conveniently presented using one of the expressions therefor, i.e. formula 10A of the formula sheet.

As for the title compounds 1, 1 ^ and and the starting compounds 1, 1, 3, 3_, 3. 3., ^ - 7, 10-12 and 16

cl C cL cL O

it is clear that these title and starting compounds contain the syn isomer, anti isomer and mixtures thereof. With respect to compound 1, the syn isomer can e.g. are represented by the partial structure of formula 20 in the molecule, while the anti-isomer is represented by the partial structure of formula 21, and if it is clearer to explain the invention, the syn isomer as well as the anti isomer is To indicate one general formula, this is represented by the partial structure according to formula 22 of the formula sheet.

With regard to the other title compounds and starting compounds as mentioned previously, as regards the syn isomer and the anti isomer, reference may also be made to the same geometric isomers as illustrated for compound 1.

Suitable pharmaceutically acceptable salts of the 3,7-disubstituted-3-cephem-k-carbonsure compounds 1 are known non-toxic salts including inorganic salts, e.g. metal salts such as the alkali metal salt (e.g. sodium salt, potassium salt) and the alkaline earth metal salt (e.g. calcium zcut, magnesium salt), ammonium salt etc., organic salts, e.g. an organic amine salt (e.g., tri-7906497 Λ-V.

methylamine salt, triethylamine salt, methanolamine salt, diethanolamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N.II-di-benzyl et ethylenediamine salt etc.), organic acid salts (eg acetate, maleate, tartrate, methanesulfonate toluene sulfonate), inorganic acid salts (eg hydrochloride, hydrobromide, sulfate, phosphate), or salts with an amino acid (eg arginine, asperic acid, glutamic acid).

Various definitions in the description are explained in more detail below.

The term "lower" refers to 1 to 6 carbon atoms unless otherwise indicated.

Suitable protected amino groups can include an acylamino and amino group substituted with a conventional protecting group other than the acyl group such as ar (lower) alkyl (e.g., benzyl, trityl).

Suitable protected imino groups may contain an acyl imino and imino group substituted with a conventional protecting group other than the acyl group, such as ar (lower) alkyl (e.g. benzyl, trityl).

A suitable acyl moiety in the terms "acylamino", "acylimino" and "kcyloxy" may include carbamoyl, an aliphatic acyl group and an acyl group having an aromatic or heterocyclic ring. Suitable examples of said acyl group are lower alkanoyl (eg formyl, acetyl, propionyl, butyryl, isobutyryl, vale-25, isovaleryl, oxalyl, succinyl, pivaloyl), preferably a group with 1 - 1 carbon atoms, more particularly with 1 - 2 carbon atoms; lower alkoxycarbonyl with 2 - 7 carbon atoms (eg methoxy-carbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, tert-pentyloxycarbonyl, hexyloxycarbonyl), lower alkanesulfo ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl); arenesulfonyl (eg benzenesulfonyl, tosyl); aroyl (eg benzoyl, toluoyl, naphthoyl, phthaloyl, indanecarbonyl); ar (lower) alkanoyl (eg phenylacetyl, phenyl) ropionyl); and ar (lower) alkoxy-35 carbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl).

7906497 * *. 5

The above-mentioned acyl unit can contain 1 - 3 suitable substituent such as halogen (eg chlorine, bromine, iodine or fluorine), hydroxy, cyano, nitro, lower alkoxy (eg methoxy, ethoxy, propoxy, isopropoxy), lower alkyl (eg methyl, ethyl , propyl, iso-5 propyl, butyl), lower alkenyl (eg vinyl, allyl), aryl (eg phenyl, tolyl) etc.

Suitable examples of acylamino are lower alkano-ylamino or halogen (lower) alkanoylamino (more particularly tri- (i a.gATp) al kannyi flinirn) and a preferred example of acyloxy is lower alkanoyloxy.

Aliphatic hydrocarbon groups refer to a straight, branched or cyclic aliphatic hydrocarbon groups of 1-6 carbon atoms and may include lower alkyl, cyclo (lower) alkyl, lower alkenyl and lower alkynyl. Said aliphatic hydrocarbon groups may contain 1 to 2 suitable substituents, such as carboxy, protected carboxy, arylthio, lower alkylthio, aryl, acyloxy, lower alkoxy, aryloxy or a heterocyclic group.

A suitable lower alkyl and lower alkyl moiety in the terms "lower alkylthio", "carboxy (lower) alkyl" and "protected carboxy (lower) alkyl" may include a branched group, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl.

A suitable cyclo (lower) alkyl group is a group of 3-6 carbon atoms and it may contain cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

A suitable lower alkenyl group is a group containing 2 -6 carbon atoms and it can be e.g. vinyl, allyl, isopropenyl, 1-propenyi, 2-butenyl, 3-pentenyl, preferably containing a group with 2 - k carbon atoms and.

A suitable lower alkynyl group is a group of 2 to 6 carbon atoms and it may comprise ethynyl, 2-propynyl, 2-butynyl, 3-pentynyi and 3-hexynyi, preferably a group containing 2 - h3, especially 2-3 carbon atoms.

A suitable protected carboxy growth? and a protected earboxy unit in the term "protected carboxy (lower) alkyl" may include esterified carboxy in which the ester unit may be represented by a lower alkyl ester (eg methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, tert-pentyl ester, hexyl ester, 1-cyclopropylethyl ester), wherein the lower alkyl moiety preferably contains 1 - h carbon 5 atoms, lower alkenyl esters (eg vinyl ester, allyl ester); lower alkynyl esters (e.g. ethynyl ester, propynyl ester); mono (or di or tri) halogen ("lower) alkyl esters (e.g. 2-iodoethyl ester, 2,2.2-tri-chloroethyl ester); lower alkanoyloxy (lower) alkyl esters (e.g., aceto-xy methyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeyloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester); lower alkanesulfonyl (lower) alkyl esters (e.g., mesylmethyl ester, 2-mesylethyl ester); ar (lower) alkyl esters, e.g. phenyl (lower) alkyl ester, which may contain one or more suitable substituents (eg benzyl ester, U-methoxybenzyl ester, 15-nitrobenzyl ester, phenethyl ester, trityl ester, diphenylethyl ester, bis (methoxyphenyl) methyl ester, 3-dimetboxybenzyl ester, k-hydroxy-3,5-ditert-butylbenzyl ester ); aryl ester which may contain one or more suitable substituents (e.g. phenyl ester, tolyl ester, tertiary butyl phenyl ester, xylyl ester, mesityl ester, cumenyl ester). The preferred examples of protected carboxy may be lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, tert-pentyloxycarbonyl, hexyloxycarbonyl) with 2-7 carbon atoms, preferably 2-5 carbon atoms.

A suitable aryl group and aryl moiety in the terms "arylthio" and "arloxy" may include phenyl, tolyl, xylyl, mesityl, cuminyl, naphthyl and the like, wherein the aryl group may contain 1 to 3 suitable substituents such as halogen (eg chlorine, bromine, iodine or fluorine) and hydroxy.

Suitable lower alkoxy can contain a group which can be branched, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy.

A suitable heterocyclic group can be a saturated or unsaturated monocyclic or polycyclic heterocyclic group with at least one heteroatom, such as oxygen, sulfur or nitrogen.

A particularly preferred heterocyclic group 7906497 m * τ may be a heterocyclic group such as an unsaturated hetero-monocyclic 3-8 (preferably 5-6) ring having 1 to 4 nitrogen atoms, e.g. pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl 5 (hv 4H-1.2.4-triazolyl, 1H-1.2.3-triazolyl, 2H-1.2.3-triazolyl) tetrazolyl (hv 1H-tetrazolyl or 2E-tetrazolyl); a saturated hot-romonocyelic 3-8 (preferably 5-6) ring with 1-4 nitrogen atoms, e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl; an unsaturated condensed heterocyclic group with 1-4 nitrogen atoms, e.g. indolyl, isoindolyl, indolizinyl, henzimidazolyl, quinolyl, isoquinolyl, indazolyl, henzotriazolyl; an unsaturated heteromonocyclic 3-8 (preferably 5-6) ring containing 1-2 oxygen atoms and 1-3 nitrogen atoms, e.g. oxazolyl, isoxazolyl, oxa-diazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl); a saturated heteromonocyclic 3-8 (preferably 5-6) ring with 1-2 oxygen atoms and 1-3 nitrogen atoms, e.g. morphoiinyl; an unsaturated condensed heterocyclic group with 1-2 oxygen atoms and 1-3 nitrogen atoms, e.g. henzoxazolyl, henzoxadiazolyl; an unsaturated heteromonocyclic 3-8 (preferably 5-6) ring having 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, e.g. thiazoyl, uhiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thia-diazolyl); a saturated heteromonocyclic 3-8 (preferably 5-6) ring having 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, e.g. thiazoli-dinyl; an unsaturated heteromonocyclic 3-8 (preferably 5-25) ring with a zvav atom, h.v. thienyl; an unsaturated condensed heterocyclic group with 1 - 2 zvav atoms and 1 - 3 nitrogen atoms, e.g. henzothiazolyl, henzcthiadiazolyl; wherein the heterocyclic group 1 to 2 may contain suitable substituents such as lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, hutyl, isohutyl, pentyl, cyclopentyl, hexyl, cyclohexyl); lower alkenyl (e.g. vinyl, allyl, 1-propenyl, 2-hutenyl); aryl, (e.g. vinyl, tolyl); halogen (e.g. chlorine, hrcom, iodine or fluorine); amino; di (lower) alkylamino (lower) -alkyl (h.v., dimethylamino-ethyl, dimethylaminoethyl, diethylamino-propyl, diethylaminohutyl).

A suitable U-containing 5-membered heteromonocyclic ring 7906497 ar <8 means a saturated or unsaturated 5-membered heteromonocyclic ring having at least one nitrogen atom such as an unsaturated 5-membered heteromonocyclic ring, e.g. pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, triazolyl (e.g. te-1,2.U-triazolyl, 1H-1.2.3-triazolyl, 2Ξ-1.2.3-triazolyl); tetrazolyl (e.g. TH-tetrazolyl or 2Ξ-tetrazolyl); or a saturated 5-membered heteromonocyclic ring containing 1 to nitrogen atoms, e.g. pyrrolidinyl, imidazolidinyl. Said N-containing heteromonocyclic 5-ring contains 1 or 2 lower alkenyl groups, examples of which have previously been given as substituents.

A suitable group which may be substituted with a group of the formula R -S- may contain an acid residue such as azido, halogen, acyloxy, whereof halogen and. acyloxy earlier examples were given.

A suitable halogen can include chlorine, bromine, fluorine and iodine.

Preferred examples of each of the groups of the title compounds as described above are as follows; a preferred example of r "* is amino or acylamino (most preferably lower alkanoylamino or halogen (lower) alkanoylamino (especially without trihalogen (lower) alkanoylamino)); a preferred example of R is lower alkyl, lower alkenyl lower alkynyl, lower alkylthio (lower) alkyl, ar (lower) alkyl (more particularly phenyl (lower) alkyl), which may contain one or two halogens, acyloxy (lower) alkyl (more particularly lower alkanoyloxy (lower alkyl), carboxy (lower) alkyl, protected carboxy (lower) alkyl (especially lower alkoxycarbonyl (lower) alkyl), isoxazolyl (lower) alkyl or cyclo (lower) al-3.

kyl; a preferred example of R is carboxy; and a preferred 1}.

image of R tetrazolyl with a lower alkenyl group or triazolyl with 2 a lower alkenyl group, provided that R is not methyl when R is tetrazolyl with a lower alkenyl group.

The methods of preparing the title compounds of the invention are more specifically described below. Method 1

The title compound of formula 1 or a salt thereof can be prepared by reacting the compound of formula 2 or the reactive derivative thereof to the amino group or a salt thereof with the compound of formula 3 or the reactive derivative thereof to the carboxy group or a salt thereof.

Suitable reactive derivatives on the minogroup of the compound of formula 2 include Schiff's base type imino or the tautomeric amine type isomeres thereof formed by the reaction of the compound of formula 2 with a carbonyl compound such as ac et oacetic acid; a silyl derivative formed by the reaction of the compound of formula 2 with a silyl compound such as trimethyl-10-silylacetamide, bis (trimethylsilyl) acetamide; a derivative formed by the reaction of a compound of formula 2 with phosphorus trichloride or phosgene.

Suitable salts of the compounds of formula 2 and 3 include acid addition salts such as organic acid salts (e.g.

Acetate, maleate, tartrate, benzene sulfonate, toluene sulfonate) or inorganic acid salts (e.g., hydrochloride, hydrobromide, sulfate, phosphate); metal salts (e.g. sodium salt, potassium salt, calcium salt, magnesium salt); ammonium salts; organic amine salts (e.g. triethyl amine salt, dicyclohexylamine salt).

Suitable reactive derivatives on the carboxy group of the compound of formula 3 include an acid halide, an anhydride, an activated amide, an activated ester. Suitable examples include an acid chloride, an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (eg di-25-alkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid), diaikyl phosphoric acid, sulfurous acid, thiosulfoic acid, alkylcarboxylic acid, aliphatic carboxylic acid, pentahydric carboxylic acid ethyl butyric acid or trichloroacetic acid) or an aromatic carboxylic acid (eg benzoic acid); A symmetrical anhydride, an activated amide with imidazole, H-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester (eg cyanomethyl ester, methoxymethyl ester, dimethyiminc methyi ((GH ^) 2 - '= CIi)) ester, vinyl ester, propargyester, n-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenyla - thioester, p-nitrophenylthicester, p-cresyithioester, carboxymethylthio ester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester), or an ester with a W-hydroxy compound (eg ÎT.N-dimethylhydro 1- hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-6-chloro-1H-benzotriazole These reactive derivatives can be selected according to the type of the compound of formula 3 which is applied.

The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, I.N-dimethylformamide, pyridine or any inorganic solvent that does not adversely affect the reaction. These conventional solvents can also be used in mixtures thereof.

When the compound of formula 3 is used in the reaction in free acid form or in the salt form in the reaction, the reaction 15 "is preferably carried out in the presence of a conventional condensing agent such as NN-dicyclohexylcarbodiimide; N-cyclohexyl-N1-morpho -linoethylcarbodiimide; 1-cyclohexyl-N '- (- - diethylaminocyclohexyl-ar-bodimide; W.H'-diethylcarbodiimide, W.W'-diisopropylcarbodiimide; N-ethyl-N' - (3-dimethylamino-propyl) -carboxylamide; WW-carbonyl bis-20 (2-methylimidazole); pentamethylene-ketene-W-cyclohexylimine; diphenyl-ketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkylphosphite; ethylpolyphosphoryl; ; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5- (m-25 sulfophenyl) isoxazolium hydroxide intra-molecular salt; 1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole; so-called Vilsmeier- reagent prepared by reaction of dimethylformamide me t thionyl chloride, phosgene phosphorus oxychloride.

The reaction can also be carried out in the presence of an inorganic or organic base such as an alkali carbonate, tri (lower) alkylamine, pyridine, (- (lower) alkylmorphine, ST. IT - di (lower) alkylbenzylamine. The reaction temperature is not critical and the reaction is usually carried out under cooling or at ambient temperature.

In the present reaction, a syn isomer of the 7906497 11 title compound of formula 1 can be obtained by preferably carrying out the reaction of the compound of formula 2 with the corresponding syn isomer of the starting compound of formula 3, e.g. in the presence of a Vilsmeier reagent as mentioned above, 5 and under practically neutral conditions.

Method 2

The title compound (11) or a salt thereof can be prepared by subjecting the compound of formula 1a or a salt thereof to an elimination reaction of the amino protecting group.

Suitable salts of the compound of formula 1a include a metal salt, ammonium salt and organic amine salt as previously mentioned.

The present elimination reaction is carried out by conventional methods such as hydrolysis, reduction; a method in which the compound of formula 1a, in which the protecting group is an acyl group, is reacted with an imino-halogenating agent and then subjected to hydrolysis with an imino-etherifying agent, and if necessary, the resulting compound.

The hydrolysis may comprise a method using an acid or base as hydrazine. These methods can be selected depending on the type of protecting groups to be eliminated.

In these processes, hydrolysis using an acid is preferred to eliminate the protecting groups, such as unsubstituted or substituted alkoxycarbonyl (eg tert-pentyloxycarbonyl), alkanoyl (eg formyl), cycloalkoxycarbonyl or unsubstituted aralkoxycarbonyl (eg bensyloxycarbonyl, substituted benzyloxycarbonyl), substituted phenylthio, substituted aralkylidene, substituted alkylidene, substituted cycloalkylidene. A suitable acid may include an organic or inorganic acid, such as nitric acid, trifluoroacetic acid, benzenesulfonic acid, p-fluoro sulfonic acid, hydrochloric acid, preferably an acid which can be easily removed from the reaction mixture in a conventional manner such as distillation under reduced pressure, e.g. formic acid, tri-7906497 12 fluoroacetic acid, hydrochloric acid. Suitable acids for the reaction are selected according to the type of protecting group to be eliminated. When the elimination reaction is carried out with an acid, the reaction can take place in the presence or absence of a solvent. Suitable solvents include organic solvents, water or a mixed solvent thereof. When using trifluoroacetic acid, the elimination reaction is preferably carried out in the presence of anisole.

The hydrolysis using hydrazine is usually used to eliminate the protecting group, e.g. succinyl or phthaloyl.

Hydrolysis with a base is preferably used to eliminate the acyl group, e.g. haloalkanoyl (e.g. trifluoroacetyl). Suitable bases include inorganic bases or organic bases. The hydrolysis using a base is often carried out in water or a hydrophilic organic solvent or a mixed solvent thereof. A preferred base is alkali acetate.

Of the protecting groups, the acyl group is generally eliminated by hydrolysis as described above or by other conventional hydrolysis. In case the acyl group is halogen substituted alkoxycarbonyl or 8-quinolyloxycarbonate, they are eliminated by treatment with a heavy metal such as copper or zinc.

The reductive elimination is generally used to eliminate the protecting group, e.g. halo-alkoxycarbonyl (e.g. trichloroethoxycarbonyl), substituted or unsubstituted aralkoxycarbonyl (e.g. benzyloxycarbonyl, substituted benzyloxycarbonyl), 2-pyridylmethoxycarbonyl. Such a reduction can e.g. reduction with an alkali borohydride (e.g. sodium 30 borohydride).

Of the protecting groups, the acyl group can be eliminated by treatment with an imino-halogenating agent (e.g., phosphorus oxychloride, phosphorus pentachloride) and an imino-etherifying agent, such as lower alkanol (e.g., methanol, ethanol), followed, if necessary, by hydrolysis. The reaction temperature is not critical and can be selected according to the type of the amino protecting group and the elimination method as described above, the reaction preferably being conducted under mild conditions such as under cooling, at ambient temperature or slightly elevated temperature. ture.

The invention encompasses within its scope those cases in which the protected carboxy group is converted into the free carboxy group under the reaction conditions in the course of the reaction or after-treatment.

10 Method 3

The title compound of formula 1d or a salt thereof is prepared by subjecting the compound of formula 1c or a salt thereof to an elimination reaction of the carboxy protecting group.

For examples of suitable salts of the compound of formula 1c, reference is made to that of the compound of formula 1a.

The present elimination reaction is carried out by conventional methods such as hydrolysis. The hydrolysis may comprise a method using an acid or base. These methods can be selected depending on the type of protecting groups to be removed.

Hydrolysis using an acid is one of the most common methods of removing the protecting groups such as phenyl (lower) alkyl, substituted phenyl (lower) alkyl, lower alkyl, substituted lower alkyl. Suitable acids can include organic or inorganic acids such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid.

The reaction can be carried out in the presence of anisole. Acids suitable for reaction can be selected depending on the protecting group to be eliminated and other factors.

The hydrolysis using an acid can be carried out in the presence of a solvent such as an organic solvent, water or a mixed solvent thereof.

35 2nd reaction temperature is not critical and can be selected according to the type of protecting group and elimination 7906497

1U

method, and the reaction is preferably conducted under mild conditions such as under cooling, at ambient temperature or under slightly elevated temperature.

The invention includes within its scope those cases 3.

5 wherein the protecting carboxy group R is converted to the free carboxy group; and wherein the protected amino group is converted to the free amino group during the reaction or post-treatment.

Method b

The title compound of formula 1 or a salt thereof can be prepared by reacting the compound of formula 16 or a salt thereof with a compound of formula 17 or its reactive derivative to the mercapto group.

Suitable salts of the compound of formula 16 are those listed for the compound 15 of formula 2.

Suitable reactive derivatives on the mercapto group of the compound of formula 17 may include a metal salt, such as an alkali metal salt (e.g., sodium salt, potassium salt).

The reaction can 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 organic solvent that does not adversely affect the reaction , preferably those with a strong polarity. Of the solvents, hydrophilic solvents can be used mixed with water. The reaction is usually carried out in a practically neutral medium. When the compound of formula 18 or the compound of formula 17 is used in free form, the reaction is preferably carried out in the presence of a base, such as an inorganic base, e.g. alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate and an organic base such as trialkylamine. The reaction temperature is not critical and the reaction is usually carried out at ambient temperature, or. . heating or a small amount of heating.

The reaction includes within its scope those cases where the protected amino group R is converted to the free amino group according to the type of the protecting group and the reaction conditions.

The methods of preparing the title compound of formula 2 are described in more detail below.

51. The compound of formula 15 or a salt thereof can be prepared by reacting the compound of formula 13 or a salt thereof with a compound of formula 14 or the reactive derivative to its mercapro group.

Suitable salts of the compound of formula 13 are those as previously reported for the compound of formula 1a.

Suitable reactive derivatives on the mercapto group of the compound of formula 1¾ may include a metal salt, such as an alkali metal salt (e.g., sodium salt, potassium salt).

The reaction can be performed in a solvent such as water, acetone, chloroform, nitrobenzene, methylene chloride, ethylene chloride, dimethylformamide, methanol, ethanol, ether, tetrahydrofuran, dimethyl sulfoxide, or any other solvent that does not adversely affect the reaction, preferably in those with strong polarity. Hydrophilic solvents mixed with water can be used with the solvents. The reaction is preferably conducted in weakly basic or near neutral conditions. When the compound of formula 13 and / or the thiol compound of formula 11 are used in free form, the reaction is preferably carried out in the presence of a base, e.g. an organic base, such as alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate, or an organic base, such as trialkylamine, pyridine. The reaction temperature is not critical and the reaction is usually carried out at ambient temperature or under heating. The reaction product can be isolated from the reaction mixture in a conventional method.

2. The compound of formula 2 or a salt thereof can be prepared by subjecting the compound of formula 15 or a salt thereof to an elimination reaction of the 5-aminc-5-carboxyvaleryi group.

The present elimination reaction can be carried out by (i) reacting the compound of formula 15 or a salt thereof with a silylating agent, (ii) reacting the resulting compound with an imino halogenating agent, and then ( iii) reacting the obtained compound with an imino ether ether agent 5.

For examples of suitable salts of the compound of formula 15, see those mentioned for the compound of formula 1a.

Suitable silylating agents include mono- or bis-trialkylsilylacetamide (eg trimethylsilylacetamide, bis (trimethylsilyi) acetamide, trimethyl chlorosilane, dimethyl dichlorosilane, hexamethyl disilazane. The reaction of the compound of formula 15 with a silylating agent is carried out in the presence of a base) .

Suitable imino halogenating agents include phosphorus trichloride, phosphorus pentachloride, phosphorus bromide, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride and phosgene. The reaction temperature is not critical and the reaction is usually carried out at ambient temperature or under cooling.

Suitable imino etherifying agents which have been reacted with the hitherto obtained reaction product include alcohol, metal alkoxide and the like. Suitable alcohols include alkanol (eg, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol) which may be substituted with alkoxy (eg methoxy, ethoxy, propoxy, isopropoxy, butoxy). Suitable metal alkoxides include alkali alkoxide (e.g. sodium alkoxide, potassium alkoxide), alkaline earth oxides (e.g. calcium alkoxide, barium alkoxide). The reaction temperature is not critical and the reaction is usually carried out under cooling or at ambient temperature.

The product thus obtained is subjected to hydrolysis if necessary. The hydrolysis can be easily carried out by pouring the reaction mixture obtained above in water, before which optionally a hydrophilic solvent (e.g. methanol, ethanol), a base (e.g. alkali bicarbonate, trialkylamine) or an acid (e.g.

Dilute hydrochloric acid, acetic acid) is added.

7906497 17

In the aforementioned reactions and / or post-treatment of the reactions of the invention, the aforementioned tautomeric isomers can incidentally be converted into the other tautomeric isomers and such cases are also included in the invention.

In case the title compound of formula 1 is obtained in the form of the free acid in the place and / or in case the title compound of formula 1 contains a free amino group, it can be described as previously described by a conventional pharmaceutical method acceptable salt thereof are converted.

The compound of formula 1 as well as a pharmaceutically acceptable salt thereof according to the invention are all new compounds exhibiting strong antibacterial activity, inhibiting the growth of a wide variety of pathogenic microorganisms including gram-positive and gram-negative bacteria and are suitable as antibacterial agents. In order to demonstrate the utility of the compounds of formula 1 with reference to some representative compounds of the invention, some data regarding the in vitro antibacterial activity follows.

Test compounds (1) 7- [2-cyclopentyloxyimino-2- (2-aminothiazole---yl) acetamido] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-ephem-U-carboxylic acid (syn isomer) (2) 7- [2-ethoxyimino-2- (2-aminothiazol-1-yl) acetate amido] —3— (1-allyl-25 H-tetrazcol-5-yl) thiomethyl- 3-cephem - ^ - carboxylic acid (syn isomer) (3) 7- [2-allyloxyimino-2- (2-aminothiazole - ^ - yl) ac eat amido] -3- (1-allyl-1 H-tetrazole- 5-yl) thiomethyl-3-cephem - ^ - carboxylic acid (syn isomer) (h) 7- [2- (2-propynyl) oxyimino-2- (2-aminothiazole - ^ - yl) ac edamido] -3- 30 (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) ί 5) 7- [2- (methkyithicmethcxyimino-2- (2-aminothiaz-col-1-yl) acetamido] -3-1-allyl-1H-tetrazocl-5-yl) thiomethyl-3-ephem-k-carboxylic acid (syn isomer).

7906497 18

In Vitro Antibacterial Activity Test Method

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

A pre-culture culture loop of each test S strain in Trypticase soy fluid (10 ° live cells per car) was streaked onto cardiac infusion agar (ΗΙ-agar) containing graded concentrations of the test compounds, the minimum inhibitory concentration 3 (MRC) was expressed in yUg / cnT after incubation at 37 ° C for 20 hours.

Trial results

Test bacteria o MRC (/ Ug / cm) 15 Test compounds

_ (1) Μ Μ Μ M

Bacillus subtilis ATCC 6633 0.39 0.78 0.78 1.56 1.56

Pseudomonas aeruginosa HCTC-10i; 90 3.13 12.50 6.25 12.50 12.50 For therapeutic administration, the compounds of formula 1 or the pharmaceutically acceptable salts thereof according to the invention are used in the form of a conventional pharmaceutical preparation that said compound as active component comprises admixed with a pharmaceutically acceptable carrier, such as an organic or inorganic solid or diluent suitable for oral, parenteral or topical administration. The pharmaceutical preparations can be in solid form, such as capsules, tablets, dragees, ointments or suppositories, or in liquid form for injection purposes such as solutions, suspensions or emulsions. If necessary, the aforementioned compositions may include adjuvants, stabilizers, wetting or emulsifying agents, buffers and other conventional additives.

Although the dose of the compounds may vary depending on the age, the condition of the patient, the type of the disease, the type of the compound to be administered according to formula 7906497 19, it has been shown that an average single dose of about 10, 50, 100, 250, 500 and 1000 mg of the title compound of formula 1 of the invention is effective for the treatment of diseases caused by pathogenic bacteria.

Generally, a daily dose of from 1 mg to about 6000 mg or even more can be administered to a patient.

The invention is now further illustrated by the following preparations and examples.

The preparation of the starting compounds. Preparation 1 (1) 1-Allyl-1 E-tetrazole-5-thiol (21.3 g) was added to a solution of sodium bicarbonate (10.6 g) in water at j6 -78 ° C. (220 cm ^). To this was added sodium 7- (5-amio-5-carboxyvaleramido) cephalosporanate (5-9 g) for 15 minutes and the mixture stirred at 76-78 ° C for 80 minutes. The reaction mixture was adjusted to pH 3.0 with 6 ΪΓ chlorine hydrochloric acid under ice cooling and filtered. The filtrate was subjected to column chromatography on nonionic adsorption resin "Diaion KP-20" (Trademark: Mitsubishi Chemical Industries Ltd.) and eluted with a 30 / 5's aqueous solution of 20 isopropyl alcohol. The eluate was adjusted to pH 6.5 with a 28/5 aqueous solution of ammonia, concentrated and lyophilized to give ammonium-7- (5-amino-5-carboxyvaleramido) -3- (1-allyl-1H- tetrazol-5-yl) thiomethyl-3-cephem-carboxylate (21.7 g).

I.R. (Hujols): 3175, 17 ^ 0.1590 cm -1.

25 ÏIMR (dg-DMS0, è): 1.23 - 2. ^ 2 (ÖH, m), 3.12 - 3.97 (BE, m), k, 3T (2H, broad s), U, 80 5.15 (3H, m), 5.15 - 5.51 (2H, m), 5.51 - 6.25 (2H, m), 8.77 (1H, d, J = 8 Hz).

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(2) HH-dimethylaniline (18.2 cm °) was added to a mixture of ammonium-7- (5-amino-5-earboxyvaleramido) -3- (1-allyl-1H-tetrazcol-5-yl) thiomethyl -3-cephem-k-carboxylate (10.0 g), trimethyl-

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silyl chloride (20.9 cm ') and methylene chloride (75 cm2), and the mixture was stirred at reflux for 2.5 hours. Then, phosphorus pentachloride (5.63 g) was added at -30 to -35 ° C and the mixture was stirred at the same temperature for 2 hours. At the-

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The same temperature was added dropwise 2-ethoxyeuhanol (38 cm 3) and the mixture was stirred for 1 hour at the same temperature. At -5 to -10 ° C, water (80 cm 3) was added for 10 minutes and the obtained The mixture was stirred at the same temperature for 5 minutes The water layer was separated and adjusted to pH b92 with 2% aqueous ammonia solution.

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collected by filtration, with 10% aqueous acetone (1 + 0 cnr) and

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methanol (50 cm3), dried, and 7-amino-3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephemicaronic acid (1 g) was obtained.

I.R. (Nujol): 3150, 1800, 1610, 1530 cm -1.

NMR (dg-DMS0.13): 3.65 (2H, AB2, J * 18Hz), 1.33 (2H, ABq, J = 13Hz), 6.38-170, (TH, m).

Preparation 2 (1) Ethyl 2- (2-propynyloxyimino) -3-oxohutyrate (syn isomer) (71.2 g) was obtained by ethyl 2-hydroxyimino-3-oxohutyrate (syn isomer) ( 56.7 g) in the presence of potassium carbonate

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(72.3 g) and reacting N.N-dimethylformamide (280 cm @ -1) with 2-propynylhromide (33 g \).

I.B. (film): 3280, 3220, 2120, 1735, 1670 cm -1.

(2) Ethyl 2- (2-propynyloxyimino) -3-oxo-chloro-hutyrate 20 (syn isomer) (61.6 g) was obtained by ethyl 2- (2-propynyloxyimino) -3-oxohutyrate ( syn isomer) (21.2 g) with sulfuryl chloride (50.2 g) in acetic acid (81 cm ').

I.R. (film): 3300, 2130, 17 ^ 5, 1720, 1675 cm -1.

(3) Ethyl 2- (2-propynyloxyimino) -2- (2-a-minothiazol-1-25 yl) acetate (syn isomer) (35.6 g) was obtained by ethyl 2- (2-propynyloxyimino) 3-oxo-11-chloro-butyrate (syn isomer) (61 g) in

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absence of sodium acetate trihydrate (35.8 g), water (150 cnr) and

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convert ethanol (180 cm @ 5) with thiourea (20 g).

I.R. (Nujol): 3290, 2220, 1729 cm -1.

(B) 2- (2-Propnyloxyimino) -2- (2-aminothiazole-^-yl) acetic acid (syn isomer) (1.92 ^ g) was obtained by ethyl 2- (2-propynyloxyimino) - 2- (2-aminothiazole---yl) acetate (syn isomer) (2.8 g) in the presence of 1N aqueous sodium hydroxide solution (22.17 cm),

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hydrolyze methanol (23 cm-5) and tetrahydrofuran (20 cm-2).

35 I.B. (Nujol): 2190, ITkOciT1.7906497 21

Preparation 3

Formic acid (107 g) was added to acetic anhydride (239 g) under ice cooling and the mixture was stirred at 50 ° C for 1 hour and then cooled to 20 ° C. 2-5 (2-propynyloxyimino) -2- (2-aminothiazol-1-yl) acetic acid (syn isomer) (135 g) was added to the mixture and the mixture was left at ambient temperature for 3 hours.

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stirred perature. To the mixture was added diisopropyl ether (1 * 00 cm '), the precipitated crystals were collected by filtration, washed with diisopropyl ether and dried and 2- (2-propynyl-10-oxyimino) -2- (2-formamidothiazol-1 * -) yl) acetic acid (syn isomer) (118.5 g) was formed.

I.R. (Nujol): 3250, 2130, 1685, 1600, 1560 cm -1.

MR (dg-DMSO, $): 3.53 (1H, m) h, 87 (2H, d, J = 2Hz), 7.63 (1H, s), 8.61 (1I, s), 12, 7 (1H, hreed s).

15 3 preparation 1 *

To a solution of 2- (2-foramidothiazol-4-yl) glyoicyl-

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acid (30 g) and sodium bicarbonate (12.6 g) in water (1300 cnr), allyloxyamine hydrochloride (19.8 g) was added and the mixture stirred at ambient temperature at pE 6 for 7 hours. To the reaction

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The mixture was added with ethyl acetate (500 cnr). After the mixture was adjusted to pH 1.9 with 10% hydrochloric acid, the ethyl acetate was separated by a layer. The ethyl acetate layer was washed with an aqueous sodium chloride solution, dried over magnesium sulfate and the solvent was distilled off. The residue was triturated in diisopropyl ether, collected by filtration and dried to give 2-allyloxyimino-2- (2-formamidothiazol-1-yl) acetic acid (syn isomer) (25.3 g). I.R. (Nujol): 3110, 173C, 1660, 15 ^ 0 cm -1.

HMR (dg-DMS0, ê): 1 *, 70 (2H, m), 5.13 - 5.60 (2H, m), 5.73 - 6.27 (1H, m), 7.57 (1H s), 8.35 (1H, s).

Preparation 5 (1) Sulfuryl chloride (35.2 g) was added in one time with room temperature to a stirred solution of ethyl 2-ethoxy * 5 imino-3-oxyhutyrate (syn isomer) (1 * 3, 9 g) is acetic acid (1 * 9 cm 2 ') and the mixture is stirred at the same temperature for 1 hour. After the resulting solution was added to water (200 cm 3), the solution was extracted with methylene chloride. The extract was washed with a saturated aqueous sodium chloride solution, neutralized with an aqueous sodium bicarbonate solution, and washed with water. The solution was dried over magnesium sulfate and concentrated under reduced pressure to give ethyl 2-ethoxy-imino-3-oxo-1-chlorobutyrate (syn isomer) (53.8 g) as a pale yellow oil.

2.) A mixture of etbyl-2-ethoxyimino-3-oxo-1-chlorobutyrate (syn isomer) (38, t g), thiourea (13.2 g), sodium acetate 10 (11.3 g) ), methanol (95 cm) and water (95 cm) was stirred at 18 ° C for 10 minutes. After the resulting solution was adjusted to a pH of 6.5 with an aqueous sodium bicarbonate solution, the precipitates were collected by filtration and re-washed with di-op opyl to give ethyl 2-ethoxyimino-2- (2-aminothiazole). 1-yl) acetate (syn isomer) (11.7 g), m.p. 130-131 ° C.

I.R. (Mujol): 3150, 3275, 3125, 1715, 1620 cm -1.

(3) Etbyl-2-ethoxyimino-2- (2-aminothiazol-1-yl) acetate (syn isomer) (5 g) was added to a mixture of 1 H sodium

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hydroxide (15.9 cm0) and ethanol (30 cm) and the mixture stirred at room temperature for 5 hours. After ethanol was removed from the resulting solution under reduced pressure, the residue was

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ter (60 cm) and the mixture adjusted to pH 2.0 with 10% hydrochloric acid. The solution was salted out and the precipitates were collected by filtration and dried to give 2-ethoxy-25-imino-2- (2-aminothiazol-1-yl) acetic acid (syn isomer) (2.9 g).

I.R. (ilujol): 3625, 3225 (shoulder), 3100, 165o, 16l5 cm -1.

MR (dg-DMS0, ê): 1.20 (3H, t, J = 7µz), 1.09 (2H, q., J = 7Hz), 6.82 (1H, s), 7.2! (2H, wide s).

(1) 2-Ethoxyimino-2- (2-aminothiazol-1-yl) acetic acid (syn isomer) (100 g), formic acid (85.5 g) and acetic anhydride (190.1 g) were treated according to preparation 3 and 2-ethoxyimino-2- (2-formamidothiazol-1-yl) acetic acid (syn isomer) was obtained (99.1 g).

I.R. (Nujol): 3200, 3110, 3050, 1700 cm -1.

MR (dg-DMSO, j): 1.18 (3H, t, J = 6Hz), 1.22 (2H, q., J = 6Hz), 7.56 (1Ξ, 35s), 8.56 ( 1H, s), 12.62 (1H, broad s).

7906497 23

Preparation 6 (1) 1 Ephchyl-2-hydroxyimino-2- (2-8iainothiazol-4-yl) acetate (syn-isoneer) (126.4 g), formic acid (81.3 g) and acetic anhydride (180) g) were treated according to "preparation 3 and 5 ethyl-2-hydroxyimino-2- (2-forinamido-thiazol-4-yl) acetate (syn-isomer) was obtained (109.6 g).

I.B. (Nujol): 3320, 3140, 3050, 1T10, 1555 cm -1.

NMR (dg-DWSO, ί): 1.30 (3H, t, J = 7Hz), 4.33 (2H, <*, J = 7iz), 7.54 (1H, s), 8.54 (1H s), 11.98 (1H, s), 12.58 (1H, s).

10 (2) A mixture of chloromethylthiomethane (7.97 g), potassium

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µm odide powder (15.1 g) and acetone (79 cm) was stirred at ambient temperature for 1 hour, then the resulting mixture was filtered and washed with a small amount of acetone. The washings and the filtrate were combined and added to a stirrer. The suspension of ethyl 2-hydroxyimino-2- (2-formamidothiazol-4-yl) acetate (syn isomer) (17.5 g) and potassium carbonate powder (15.5 g) in ace-

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tons (300 ear). The mixture was stirred at ambient temperature for 3 hours, filtered and washed with acetone. The washing liquids and the filtrate were combined and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed twice with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The oily residue was subjected to silica gel column chromatography and eluting with chloroform to form ethyl 2-methylthiomethoxyimino-2- (2-formamido-25 thiazcol-4-yl) acetate (syn isomer) (2.4 g). Mp. 130 -131 ° C.

I.R. (iTujol): 3160, 3125, 3050, 1740, 1095 cm "1.

MR (dg-DMSC, t?}: 1.32 (3H, t, J = 7Hz), 2.22 (3H, s), 4.38 (2H, σ, J = 7Hz), 5.33 (2H , s), 7.67 (1H, s), 8.5β (1H, s).

30 (3) A mixture of ethyl 1-2-methylthiomethoxyimino-2- (2-foramidothiaziaz-4-yl) acetate (syn isomer) (2.4 g), 1 T aqueous sodium hydroxide (23.8 cm) } and methanol (19.8 cm) was stirred at 30 ° C for 2.5 hours. The resulting solution was adjusted to pH 7 with 10% hydrochloric acid and distilled off in vacuo.

The precarious solution was adjusted to pH 1 with 10% hydrochloric acid under ice cooling and the mixture extracted three times with ethyl acetate.

The extracts were washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo to give 2-methylthiomethoxyimino-2- (2-formamidothi-5zol-4-yl) acetic acid (syn isomer) ( 1.13 g) was obtained. Mp. 157 ° C (dec.).

I.R.- (Nujol): 3210, 3160, 3075, 1700, 1555 cm -1.

NMR (dg-DMSO, i): 2.2k (3H, s), 5.31 (2H, s), 7.61 (1H, s), 8.57 (1H, s), 12.73 (1H , s).

10 Preparation 7

The following compounds were obtained in a manner similar to that of Preparations 2-6i (1) 2-isopropoxyimino-2- (2-formamidothiazole-yl) acetic acid (syn isomer), m.p. 168 DEG-109 DEG (dec.); 15 I.R. "(Nujol): 3200, 3130, 1710, 1600, 1560 cm" 1.

(2) 2-butoxyimino-2- (2-formamidothiazole-H-yl) acetic acid (syn isomer).

I.R. (Nujol): 3350, 3160, 3050, 1700, 168Ο, 1570 'cm “1.

(3) 2-Hexyloxyimino-2- (2-formamidothiazole-Ijyl) acetic acid (syn-iso-20 more).

Mp. 115-116 ° C (dec.); I.R. (Nujol): 3170, 3070, 1720, 1700, 1660 cm ”1.

H14R (dg-DMSO, i): 0.6 - 2.1 (11H, m), U, 15 (2H, t, J = 6Hz), 7.53 (1H, s), 8.56 (1H, s), 12.69 (1H, s).

(* 0 2- (2-formyloxyethoxy) imino-2- (2-formamidothiazol-k-yl) acetic acid (syn isomer).

I.R. (Nujol): 3200, 1710, 1690 cm -1.

(5) 2-benzyloxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer).

I.R. (Nujol): 3330, 3200, 3100, 1660, 1590 cm ”1.

30 (6) 2-ethoxycarbonylmethoxyimino-2- (2-formamidothiazole-γ-yl) acetic acid (syn isomer), m.p. 112 ° C (dec.), I.R. (Nujol): 3150, 17 ^ 0, 1670, 1550 cm -1.

(7) 2-tert-butoxycarbonylmethoxyimino-2- (2-formamidothiazole-U-yl) -acetic acid (syn isomer), m.p. 11T ° C (dec.).

35 I.R. (Nujol): 3180, 31 ^ 0, 1750, 1690, 1630 cm ”1.

7906497 25 (3) 2- (3-isoxazolyl) methoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer), m.p. 110 ° C (dec.). I.R. (ffujol): 3270, 3130, 1680, 1540 cm -1.

Preparation 8 5 (1) Ephchyl-2-hydroxyimino-3-oxobutyrate (syn isomer, 40.0 g), 4-fluorobenzyl chloride (43.6 g), ΪΓ. Π-di with methylformamide (60.0 cm3), q potassium carbonate (52.0 g) and ethyl acetate (60.0 cm3) were treated in the usual manner to give ethyl 2- (4-fluorobenzyloxyimino) -3 oxobutyrate (syn isomer, 64.4 g).

10 1.3. (film): 3000, 2940, 1730, 1690, 1600 cm ”1.

MR (DMSO-dg, S): 1.21 (3H, t, J = 7.0Hz), 2.34 (3H, s), 4.26 (2H, q., J = 7Hz), 5.32 (2Is, s), 6.97-7, T3 (4h, m).

(2) Ethyl 2- (4-fluorobenzyloxyimino) -3-oxobutyrate (syn-isomer, 64.0 g), and sulfuryl chloride (35.6 g) and acetic acid (70.0 cm) were prepared according to preparation 5- (1) treated to give ethyl 2- (4-fluorobenzyloxyimino) -3-oxo-4-chlorobutyrate (syn isomer, 29.55 g) · IR (film): 1720, 1600 cm -1.

MR (DMS0-dg, S): 1.20 (3H, t, J = 7.0Ez), 4.28 (2H, q., J = 7Hz), 4.87 (2H, s),, 536 ( 2H, s), 7.00-7.75 (4H, m).

20 (3) Ethyl 2- (4-fluorobenzyloxyimino) -3-oxo-4-chlorobutyrate (syn isomer, 29.0 g), thiourea (8.8 g), sodium acetate (7.9 g), qqq water (72.5 cm3), tetrahydrofuran (60 cm3) and ethanol (72.5 cm) were treated according to preparation 5- (2) and ethyl-2- (4-fluorobenzyioxyimino) -2- (2-aminothiazole) was obtained -4-yl) acetate (syn isomer, 28.0 g).

I.R. (jfujol): 3450, 3150, 3100, 1710, 1620 cm -1.

MR (BMSO-dg, J): 1.23 (3H, t, 7 = 7.0Hz), 4.30 (2H, q, J = 7Hz), 5.15 (2H, s), 6, 90 (1H, s), 6.95-7.60 (4h, m).

(4) Ethyl-2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-4-30 yl) acetate (syn isomer, 25.5 g), 1-methyl imidazole (1.3 g), 1 N Naqq trihydroxide decimation (118.3cm 3}, methanol (250cm 3) and tetrahydro furan (200cm 3) were treated according to preparation 5- (3) to give 2- (4-fluorobenzyloxyimino} -2- (2-aminothiazol-4-yl) acetic acid (syn isomer, 22.11 g).

35 I.H. 3650, 31130, 3300, 3150, 1630 cm "1.

7906497 26 MR (DMSO-dg, $): 5.16 (2H, s), 6.88 (1H, s), 7.04-7.66 (4h, m).

(5) 2- (4-Fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) -acetic acid (syn isomer, 23.4 g), bis- (trimethylsilyl) acetamide (32.2 g), 2.2. 2-trifluoroacetic anhydride (49.9 g) and dry ethyl acetate (234

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5 cm) were treated according to preparation 3 to obtain 2- (4-fluorobenzyloxyimino) -2- [2- (2,2,2-trifluoroacetamido) thiazol-4-yl] acetic acid (syn isomer, 18.9 g), mp. Mp 180-182 ° C.

I.R. (Kujol): 3200, 3150, 1730 cm ”1.

MR (DMSO-dg, $): 5.25 (2H, s), 7.02 - 7.60 (4H, m), 7.72 (1H, s).

Preparation 9 (t) The following compounds were obtained by ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer) in the usual manner with resp. convert cyclopentyl bromide or 3,4-dichlorobenzyl chloride; (1) Ethyl 2-cyclopentyloxymino-3-oxobutyrate (syn isomer), oil.

15 I.R. (film): 1740, 1670, 1495, 1430 cm -1.

MR (CCl ^, $): 1.32 (3H, t, J = 7Hz), 1.4 - 2.2 (8H, m), 2.33 (3H, s), 4.27 (2H, < 1, J = 7 Hz), 4.87 (12, m).

(ii) Ethyl 2- (3,4-dichlorobenzyloxyimino) -3-oxobutyrate (syn isomer), oil.

20 I.R. (film): 1730, 1690, 1600, 1470, l400, 1370, 1310, 1240, 1130, 1080, 1010 cm "1.

MR (CCl ^, $): 1.30 (3H, t, J = 6Hz), 2.30 (3Ξ, s), 4.30 (2H, q, J = 6Hz), 4.47 (2H, s 7.00-7.53 (3H, m).

(2) The following compounds were obtained according to preparation 5- (1): (i) Ethyl-2-cyclopentyloxyimino-3-oxo-4-chlorobutyrate (syn isomer), oil I.R. (film): 1750, 1735, 1 ^ 5, 1435 cm -1.

MR (CCl ^, ^): 1.33 (3H, t, J = 7Hz), 1.3 - 2.4 (8H, m), 4.28 (2I, q, J = 7Hz), 4, 46 (2H, s), 4.86 (1H, m).

(ii) Ethyl 2- (3,4-dichlorobenzyloxyimino) -3-oxo-4-chlorobutyrate (syn-isomer), oil.

I.R. (film): 1740, 1710, 1590, 1470, 1400, 1370, 1320, 1260, 1200, 1130, 1010 cm -1.

35 MR (CC1U,): 1.37 (3H, t, J = 6Hz), 4.23 (2H, q, J = 6Hz), 7906497 27 4.43 (2H, s), 5.27 (2H, s), 71.0-7.60 (3H, m).

(3) The following compounds were obtained according to preparation 5- (2}: (i) Etbyl-2-cyclopentyloxyimino-2- (2-aminothiazol-4-yl) acetate 5 (syn isomer), mp 134 - 136 ° C.

I.R. (Hujol): 3490, 3450, 3250, 3120, 1735, 15 ^ 0.1460 cm -1.

HMR (DMSO-dg, $): 1.25 (3H, t, J = 7Hz), 1.62 (8h, broad s), 4.28 (2H, q., J = 7Hz), 4.70 ( 1H, m), 6.85 (1H, s), 7.20 (2H, s).

(Ii) Ethyl-2- (3,4-dichlorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetate (syn isomer).

I.R. (Hujol): 3460, 1720, 1600, 1540, 1460, 1390, 1260, 1180, 1020, 1010, 880, 810 cm -1.

HMR (DMSQ-dg, $): 1.25 (3H, t, J = 7Hz), 4.30 (2H, q., J = 7Hz), 5.17 (2H, s), 6.93 ( 1H, s), 7.27-7.73 (3H, m).

(4) The following compounds were obtained in a manner similar to that of Preparation 5— (3): (i) 2-Cyclopentyloxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer), m.p. 186 ° C (dec.).

20 I.R. (Hiijol): 3330, 3120, 1635, 1450 cm "1.

HMR (DMS0-dg, S): 1.1-2.2 (8H, m), 4.68 (1H, m), 6.81 (1H, s), 7.18 (2H, broad s).

(ii} 2- (3,4-Dichlorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetic acid (syn isomer).

25 I.R. (Hujol): 3430, 1660, 1590, 1400, 1010 cm -1.

HMR (SMS0-dg, ^): 5.23 (2H, s), 6.93 (1H, s), 7.30-7.77 (3H, m).

(5) The following compounds were obtained according to preparation 3: 30 (i} 2-Cyclopentyloxyimino-2- [2- (2,2,2-trifluoroacetamidi) thiazol-4-yl] -acetic acid (syn isomer).

I.R. (Hujul): 3200, 3130, 1720, 1590, 1580 cm -1.

HME (DMS0-d6, S): 1.34-2.22 (3H, m), 4.81 (1H, m), 7.71 (1H, s).

(Ii) 2- (3,4-Dic hlcorbenzyloxyimino) -2- [2- (2,2.2-trifluoroacetamido) -tbiazocl-4-yl] acetic acid (syn isomer).

7906497 28 I.B. (Nujol): 1720, 1580, 1300, 1260, 1200, 1ΐβ0, 1150 cm "1. Mm (DMSO-dg, (S): 5, ^ 0 (2H, s), 7, ^ 7 - 7.93 ( UH, m).

Example I

2-Allyloxyimino-2- (2-formamidothiazol-t-yl) acetic acid (syn isomer) (0.80 g). and dry ethyl acetate (10 ml) were added to a suspension of Vilsmeier reagent prepared from dry dimethylformamide (0.25 g) and phosphorus oxy- under stirring at 0-5 ° C.

O

chloride (0.528 g) in dry ethyl acetate (0.75 cnr), the resulting mixture was stirred at the same temperature for 30 minutes and a yellow solution was obtained. The solution was added to a solution of 7-amino-3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-M-carboxylic acid (1.11 g) with stirring at -10 ° C. and

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trimethylsilylacetamide (2.96 g) in dry ethyl acetate (5 cmr) and the mixture stirred at the same temperature for 1.5 hours. After adding water (15 cm) to the reaction mixture, the ethyl acetate layer was separated and. with an aqueous solution of sodium

O

bicarbonate (30 cmJ) extracted. The aqueous extract was acidified to 10 pf 2.0 with 10% hydrochloric acid and extracted with ethyl acetate 3 (150 cm 3). The extract was washed with water, dried and evaporated. The residue was pulverized with diisopropylether to give a colorless powder of 7- [2-allyloxyimino-2- (2-formamido-thiazole-1-yl) ac edamido] -3- (1-allyl-1H-tetrazole-5-) yl) thiomethyl-3-cephem-h-carboxylic acid (sym isomer), (1.18 g).

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

25 NMR (dg DMS0, S): 9.68 (1H, d, J = 8Hz), 8.51 (1H, s), 7.0 (0H, s), 5.60 - 6.33 (3H , m), M5, 5.57 (TH, m), i *, 2T-U, 77 (UH, m), 3.70 (2H, ABq, J = 18Hz).

Example II

The Vilsmeier reagent was conventionally prepared from dry dimethylformamide (2.6 g), phosphorus oxychloride (5.1 g)

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and dry ethyl acetate (10, U cm-1). To this was dried ethyl acetate (100 cm-2) and then at 0 ° C 2-cyclopentyloxyimino-2- [2- (2.2.2-trifluoroacetamide) thiazol-4-yl Acetic acid (syn isomer) (10 µg) added The mixture was stirred at the same temperature for 30 minutes The resulting mixture was stirred at -10 ° C of T-amino-3 - (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (9.6 g) and trimethylsilylacetamide (24.8 g) in dry ethyl

O

acetate (192 era) was added and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture. The ethyl acetate layer was separated and extracted with aqueous sodium bicarbonate (pH 7.5). The water layer was washed twice with ethyl acetate and adjusted to pH 2.0 with 10 # * hydrochloric acid after addition of ethyl acetate and tetrahydrofuran. The organic layer was separated, washed with water, dried over magnesium sulfate, treated with active hay and concentrated to a dry product. The residue was triturated with diethyl ether and the powder collected by filtration and washed with diethyl ether to give 7- [2-cyelopentyloxyimino-2- (2,2.2-trifluoroacetamido) thiazol-4-yl) acet amido] -3 - (1-allyl-1 H-tetrazol-15 5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (18.18 g).

BMP. (DMSO-d ^, S): 1.28 - 2.26 (8H, m), 3.73 (2H, m), 4.39 (2H, ABq, J = 14Hz), 4.77 (1H, m), 4.88 - 5.47 (5H, m), 5.70 - 6.52 (2H, m), 7.50 (1H, s), 9.67 (1H, d, J = 8, 0 Hz).

Example III

The Vilsmeier reagent was prepared in the usual manner from dry dimethylformamide (0.4 g), phosphorus oxychloride (0.9 g) and dry ethyl acetate (1.6 cm). Dry ethyl acetate (18 cm ') was added and then 2-ethoxyimino-2- (2-formamidothiazol-4-yl) -acetic acid (synismer) (1.3 g) at 0 ° C. The mixture was stirred at the same temperature for 30 minutes. The resulting mixture was stirred at -10 ° C to a stirred solution of 7-amino-3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (1.8 g) and trimethyl silylacetamide (4.6 g) in dry ethyl acetate (36 cm ') and the mixture stirred at the same temperature for 1 hour. Water (30 enr) was added to the reaction mixture. The ethyl acetate layer was separated and extracted with a saturated aqueous sodium bicarbonate solution (pH 7.5). The water layer was washed three times with ethyl acetate and adjusted to pH 2.0 with concentrated hydrochloric acid after addition of ethyl acetate (100 cm @ -1). The ethyl acetate layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, treated with activated charcoal and concentrated to dryness to yield T- [ 2-ethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) 5 (2 56 g).

I.B. (iTujol): 3200, 1765, 1665 cm ”1.

HMR (dg-DMSO, $): 1.26 (3H, t, J = 7.0Hz), 3.68 (2H, m), 4.18 (2H, q, J = 7.0Hz), 3, 68 (2H, m), 4.1- (2H, q, J = 7.0Hz), 4.36 (2H, ABq, J = 14.0 Hz), 4.75 - 5.57 (5H, m ), 5.68 - 6.40 (2H, m), 7.37 (1H, s), 8.48 (1H, s), 9.60 (1H, d, J = 8.0Hz).

Example IY

The Vilsmeier reagent was prepared from dry dimethylformamide (0.5 g), phosphorus oxychloride (1.3 g) and dry ethyl acetate.

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15 (2.0 cm) according to the usual method. To this was dried o tetrahydrofuran (20 cm-3) and then 2- (2-propynynyl) oxy-imino-2- (2-foimamidothiazol-4-yl) acetic acid (syn isomer), (1.6) at 0 ° C g) added. The mixture was stirred at the same temperature for 30 minutes. The resulting mixture was added to 20 a at -10 ° C. stirred solution of 7-amino-3- (1-allyl-1H-tetrazol-5-yl) thio-methyl-3-cephem-4-carboxylic acid (2.0 g) and trimethylsilylacetamide (5.1 g)

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in dry ethyl acetate (40 cm -1), after which the mixture was stirred at -10 to -20 ° C for 1 hour. The reaction mixture was added in water (30 cm 3). The organic layer was separated and collected with a

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The aqueous solution of sodium bicarbonate (30 cm ') is extracted. The water layer was adjusted to pH 2.2 with concentrated hydrochloric acid. Ramps were collected by filtration, washed with water and dried to give a colorless powder of 7- [2- (2-propynyl) oxy-imino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1 all-1H-tetra-30-sole-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.40 g).

I.R. (Nujol): 3310, 2170, 1790, 168cm ”1.

mm (dg-DMS0, C *): 3.49 (1H, m), 3.72 (2H, m), 4.38 (2H, ABq, J = 14 µz), 4.57 - 5.52 (TH , m), 5.69 - 6.40 (2H, m), 7.46 (1H, s), 8.55 (1H, s), 9.75 (1H, d, J = 8Hz).

35 Example V

The Vilsmeier reagent was conventionally prepared 7906497 from dry dimethylformamide (0.209 g), phosphorus oxychloride (0.434

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31 g) and dry ethyl acetate (0.25 car). To this was added dry tetrahydrofuran (6.5 cm 3) and then 2-methylthiomethoxyimino-2- (2-pharmamidothiazol-4-yl) acetic acid (syn isomer) (0.65 g) at 0 ° C.

The mixture was stirred at the same temperature for 30 minutes. The resulting mixture was added dropwise at -5 to 0 ° C to a stirred solution of 7-amino-3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (1 , 25 g) in a mixture of 0-3 water (10 cm) and acetone (10 enr), keeping the pH at 7-5 by triethylamine 10, and the mixture at the same temperature at pH 7.5 for 30 minutes stirred. The reaction mixture was added

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ethyl acetate (60 enr) and the mixture adjusted to pH 2.5 with 10% hydrochloric acid. Insoluble material was filtered off and the filtrate extracted twice with ethyl acetate. The combined extracts were washed twice with a saturated sodium chloride solution and dried over magnesium sulfate. The solution was distilled off and the residue triturated with diethyl ether to give a yellowish powder of 7- [2-methylthiomethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-aliyl-1H-tetrazole-5) -yl) -20 thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.03 g).

I.R. (Nujol): 3250, 3200, 1780, 1670, 1540 caf1.

HMR (dg-DMS0, S): 2.23 (3H, s), 3.72 (2H, s), 4.38 (2H, ASq., J = 14Hz), 4.3 - 5.6 (TH , m), 5.7 - 6.4 (2H, m), 7.48 (1H, s), 8.55 (1H, s), 9.75 (1H, d, <Γ = 8Εζ), 12 69 25 (1H, broad s).

Example VI

The Vilsmeier reagent was conventionally prepared from dry dimethyiformamide (0.74 g), phosphorus oxychloride (1.56 g)

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and dry ethyl acetate (2.0 car). To this was added dry tetrahydrofuran 30 (15 cm 3} and then 2- (3-isoxazolyl) methoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer) (1.50 g) at 0 ° C.

The mixture was stirred at the same temperature for 30 minutes. The resulting mixture was added dropwise at -5 to 0 C to a stirred solution of 7-smino-3- (1-aliyl-1Ξ-35 tetrazoo-5-yi) thiomethyl-3-cephem-4-carbonsure (2.34 g) in a mixture of water (11.5 cm) and acetone (11.5 cm), keeping the pH at 7.5 with triethylamine, and the mixture at the same temperature and pH 7 for 30 minutes , 5 was stirred. To the reaction

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mixture, ethyl acetate (60 cm) was added and the mixture adjusted to pH 2.5 with 5 10% hydrochloric acid. Insoluble material was filtered off and the filtrate extracted twice with ethyl acetate. The combined extracts were washed twice with a saturated sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off and the residue triturated with diethyl-10 ether to give a yellowish powder of 7- [2- (2-isoxazolyl) methoxyimino-2- (2- forma.ml dothiazole-yl) -acetamido] - 3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). (2.15 g).

I.R. (jujol): 3250, 170x, 1670, 1550 cm -1.

15 ME (dg-DMSO, {$): 3.72 (2I, s), U, U0 (2H, ABq., J = 1UHz), M - 5.6 (7H, m), 5.6 - 6 .5 (2H, m), 6.67 (1H, d, J = 2Hz), 7.50 (1Ξ, s), 8.56 (1H, s), 8.92 (1H, d, Js2Hz), 9.80 (1H, d, J = 8Hz), 12.72 (1H, broad s).

Example VII

20 Phosphorus oxychloride (1.0 g) was added in one time at 2 ° C to a suspension of 2-benzyloxyimino-2- (2-aminothiazol-4- * 3 yl) acetic acid (syn isomer) (1.1 g) ) in dry tetrahydrofuran (1U cm * 5) and the mixture stirred at 2 - 0 ° C for 15 minutes. Trimethylsilylacetamide (1.0 g) was added dropwise and the resulting mixture was stirred at 2-6 ° C for 20 minutes. Phosphorus oxychloride (1.0 g) was added to this and the mixture was stirred for 20 minutes. Then dry dimethylformamide (0.5 g) was added all at once at k-6 ° C and the mixture was stirred for 1 hour to obtain the same solution. In addition, 30 trimethylsilylacetamide (5.3 g) was added to a stirred suspension of 7-amino-3- (1-allylfH-tetrazol-5-yl) thiomethyl-3-cephemicarboxylic acid (1.8 g) in dry ethyl acetate (27 cm) and the solution stirred at 40 ° C for 30 minutes. To this solution, the above-obtained tetrahydrofuran solution was added all at once at -30 ° C and the resulting mixture was stirred at -5 to -20 ° C for 1 hour. To 7906497 33

O O

the reaction mixture, water (30 cnr) and ethyl acetate (20 cnr) were added. An organic layer was separated and extracted with an aqueous sodium bicarbonate solution. The extract was adjusted to pH 3 * 0 with 10 µl hydrochloric acid. Precipitates were collected by filtration, washed with water to give 7- [2-benzyloxyimino-2- (2-sminothiazol-4-yl) acet amido] -3- (1-allyl-1H-te-trazole-5- yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.85 g) · IH (Nujol): 3350, 3230, 1780, 1675, 1635 cm -1.

NMR (dg-DMSO, ê): 3.67 (2H, m), 4.4θ (2i, ABq., J = 15.0Hz), 4.85-10 5.56 (6h, m), 5, 62-6.45 (2H, m), 6.77 (1H, s), 7.01-7.65 (7H, m), 9.71 (1H, d, J = 8Hz).

Example 7III

The Vilsmeier reagent was conventionally prepared from dry dimethylformamide (0.44 g), phosphorus oxychloride (0.9 g), and dry ethyl acetate (1.0 cm). To this was added dry ethyl acetate (20 cm 3) and then 2-methoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer) (1.1 g) at -5 to -10 ° C. The mixture was stirred at the same temperature for 10 minutes. The resulting mixture was added dropwise at 0-5 ° C and pH 6.5-7.5 with stirring to a solution of 7-amino-3- (4-allyl-4H-1,2,4-triazole-3 -yl) thiomethyl-3-cephem-4-carboxylic acid (2.12 g) and

• O

sodium bicarbonate (2 g) in a mixture of water (20 cnr) and acetone

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(20 cnr), and the mixture stirred at the same temperature for 20 minutes. The water layer was separated and acetone evaporated. The water layer was adjusted to pH 3.0 under ice cooling and stirring with 10% hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give 7- [2-methoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (4-allyl-4H-1,2,4-triazole- 3-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.94 g).

30 I.E. (Nujol): 3200, 1680, 1550 cm-1.

NMF. (dg-DMS0, S): 3.72 (2H, broad s), 3.93 (3H, s), 4.20 (2H, broad s), 4.65 (2H, m), 4.72 - 5.43 (3H, m), 5.55 - 6.45 (2H, m), 7.43 (IK, s), 3.55 (1H, s), 8.65 (1H, s), 9 .63 (1H, d, J = 3Ez), 12.32 (1H, m).

7906497 3h

Example IX

The following compounds were obtained according to Examples I - VIII: (1) 7- [2-isopropoxyimino-2- (2-formamidothiazole-1-yl) acetamido] -5 3- (1-allyl-1H-tetrazole-5- yl) thiomethyl-3-cephem-carboxylic acid (syn isomer); I.E. (Uujol): 3220, 1780, 1670 cm -1; MR (dg-DM30, i): 1.20 (3H * s), 1.32 (3H, s), 3.70 (2H, wide s), U, 07 - M7 (3H, m), k, 93 - 5.50 (te, m), 10 5.67 - 6.23 (2H, m), 7, HO (1H, s), 8.50 (1H, s), 9.58 (1H, d , J = 8Hz).

(2) 7- [2-Butoxyimino-2- (2-formamidothiazol-U-yl) acetamido] -3- (1-allyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-Uc carbonic acid ( syn isomer).

15 I.B. (Nujol): 3200, 1780, 1695, 1675, 1655 cm -1.

MR (dg-DMS0, $): 0.88 (3H, m), 1.10 - 201 (te, m), 3.71 (2H, m), k ^ k (2H, t, J = 7, 0Hz), U, 38 (2H, ABq, J = 1 ^, 0Hz), U, 83 -5.51 (5H, m), 5.63 - 6, (2H, m), 7, (1H , s), 8.56 (1H, s), 9.65 (1I, d, J = 9.0Hz), 20 (3) 7- [2-hexyloxyimino-2- (2-formamidothiazol-4-yl) acetic acid amido] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.H. (Hujol): 3175, 1780, 1757, 168U, 16th cm ”1.

MR (dg-DMSO, £): 0.8U (3H, m), 1.06 - 2.03 (8H, m), 3.73 (2H, 25m), U, 1U (2H, t, J = 6.0Hz), U, U0 (2H, ABq, J * lU, 0Hz), ^, 85 - 5.52 (5H, m), 5.75 - 6. U5 (2H, m), 6.97 (1H, broad s), 7, (1H, s), 8.5 ^ (1Ξ, s), 9.63 (1H, d, J = 8.0Hz).

(te 7- [2- (2-formyloxyethoxy) imino-2- (2-formamidothiazol-U-yl) ac eat- arnido] -3- (1-allyl-1 H-tetrazol-5-yl) thiomethyl-3 -eef em-U-car-30 bonznur (syn isomer).

I.R. (Eujol): 3265, 1780, 1720, 1680 cm -1.

MR (dg-DMSO, $): 3.7 ^ (2H, m), U, 13 - te70 (6h, m), k, 85 - 5.53 (5H, m), 5.70 - 6, te (2H, m), 7.88 (1H, s), 8.26 (1H, s), 8.56 (1I, s), 9.69 (1H, d, 35 J = 9.0Hz).

7906497 35 (5) 7- [2-ethoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) -aetamido] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cef em-4 -arbic acid (syn isomer).

I.R. (Sfajol): 3500, 3280, 1780, 1735, 1690 cm -1.

5 HMR (dg-DMSO, S): 1.24 (3Ξ, t, J = 7Hz), 3.74 (2H, s), 4.20 (2H, q, J = 7Hz), 4.42 (2H , s), 4.77 (2H, s), 4.5 - 5.6 (5H, m), 5.7 - 6.4 (3H, m), 7.50 (1H, s), 8, 57 (1H, s), 9.68 (1H, d, J = 8Hz), 12.69 (1H, broad s).

10 (6) 7- [2-tert-butoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) -acetamido] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-ce- fem-4-carboxylic acid (syn isomer).

I.R. (Hujul): 3250, 1780, 1720, 168O, 1540 cm-1.

HMR (d ^ -DMSO, ^): 1.44 (9H, s), 3.71 (2H, ABq, J = 18Hz), 4.37 (2H, ABq, J = 14Hz), 4.62 ( 2H, s), 4.8 - 5.4 (5H, m), 5.5 - 6.4 (25, m), 7.46 (1H, s), 8.52 (1H, s), 9 .53 (1H, d, J = 8Hz), 12.60 (1H, broad s).

(7) 7 ”[2-ethoxy imino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-ephem-4-carboxylic acid (sya isomer).

I.R. (Hujol): 3350, 1780, 1675, 1635 cm -1.

(8) 7- [2-Isopropxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl} thiomethyl-3-cephem-4-carbonur) (syn isomer).

25 I.R. (Hujol)! 3350, 3250, 1780, 1675, 1630 cm -1.

(9) 7 "[2-Butoxyimino-2- (2-aminothiazol-4-yl) acetate amido] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid ( syn isomer). I.R. (Nujol): 3360, 1780, 1672 cm -1.

(10) 7- [2-Hexyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1- 30 allyl-1H-tetrasol-5-yl) thiomethyl-3-ephem-4-earloic acid (synchronic).

1.3. (Hujol): 3350, 324ο, 1780, 1675, 1630 cm "1.

(11) 7- [2-allyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-1H-tetrazcol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn - 35 isomer).

7906497 9 36 I.B. (Nujol): 3350, 3210, 1778, 1675 cm-1 (12) 7- (2- (2-propynyl) oxyimino-2- (2-aminothiazol-4-yl) acetamido] - 3- (1-allyl -1H-tetr azol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

5 I.B. (Nujol): 3330, 2170, 1780, 1683, 1630 cm -1.

(13) 7- [2-eth.oxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acet-amido] -3- (1-allyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem- 4-carboxylic acid (syn isomer).

I.B. (Nujol): 3360, 3230, 1780, 1680, 1630 cm -1.

10 (14) 7- [2-tert-butoxycarbonylmethoxyImino-2- (aminothiazol-4-yl) acetamido] -3- (1-allyl-1 H-tetrazol-5-yl) -thiomethyl-3-cep em -4-carboxylic acid (syn isomer).

I.B. (Nujol): 3330, 1780, 1730, t680, 1630 cm -1.

(15) 7- C 2 -with hylthi omet hoxy imino-2 - (2-aminothiazol-4-yl) acet amido] - 15 3- (1-lallyl-1H-tetrazol-5-yl) thiomethyl-3-c ephem- 4-carboxylic acid (syn isomer).

I.B. (Nujol): 3270, 1760, 1650, 1520 cm -1.

(16) 7- [2- (3-isoxazolyl) methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-1 H-tetrazol-5-yl) thiomethyl-3 -cef em-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3300, 1770, 1660, 1530 cm-1.

(17) 7- [2-carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cep em-4-carboxylic acid ( syn isomer).

25 I.R. (Nujol): 3360, 1780, 168Ο, 1630 cm-1.

(18) 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) ac edamido] -3 - (^ - allyl-4H-1.2.U-triazol-3-yl) thiomethyl-3-cephem -4-carboxylic acid (syn isomer).

I.B. (Nujol): 3350, 1775, 1670, 1530 cm-1.

30 (19) 7- [2-Cyclopentyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

Mp. 1U0-145 ° C (dec.).

I.R. (Nujol): 3300, 1770, 1660, 1020cm "1.

35 (20) 7- [2- (4-fluorobenzyloxyimino) -2- (2- (2,2.2-trifluoroac edamido) - 7906497 37 thiazaol - ^ - ylJacetarnido] -3- (1-allyl-1 H-tetrazole -5-yl} thio-methyl-3-ephem-k-carbonic acid (syn isomer).

I.B. (Hujol): 3250, 3170, 1780, 1720, 1650 cm -1.

MR (DMSO-dg, $): 3.6¾ (2Ξ, m), 3¾ (2H, ABq., J = 14Hz), U, 79 - 5 5, ¾¾ (7H, m), 5.65 - 6, 27 (2H, m), 6.95 - 7.61 (hK, m), 7.51 (1H, s), 9.83 (11, d, J = 8).

(21) 7- [2- (Luorbenzyloxyimino) -2- (2-aminot hiazole-yl) ac ed arnido] - 3- (1-allyl-1 H-tetrazol-5-yl) thiomethyl-3-c ephem carboxylic acid (syn isomer), m.p. Mp 157-161 ° C (dec.).

10 I.R. (Bujol): 3500, 1770, 166Ο, 1630, 1600 cm-1.

(22) 7- (2- (3. ^ - dichlcorbenzyloxyimino) -2- (2- (2,2.2-trifluoroacetamido) -thiazole - ^ - yl) ac ed arnido] -3- (1-allyl-1H -tetrazol-5-yl) -thiomethyl-3-phase-carboxylic acid (syn isomer).

I.R. (Bujol): 1770, 1650 cm -1.

15 BMR (DMSO-dg, <$): 3.72 (2S, m), k, k0 (2H, m), 5.00 - 5, ^ 3 (7H, m), 5.73 - 6.60 (2H, m), 7.30-7.77 (,m), 9.90 (1H, d, J * 8Hz).

(23) 7- (2- (3 .beta. - dichlorobenzyloxyimino) -2- (2-aminotbiazol-4-yl) acet-amido] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn isomer), mp 155-175 ° C (dec.).

I.R. (Bujol): 1770, 1660-1620, 1 ^ 50 cm -1.

Example X.

Concentrated hydrochloric acid (0.33 g) was added to a solution of 7- [2-allyloxyimino-2- (2-formamidothia-25-zoo-4-yl) acetamido] -3- (1-alyl-1H-tetrazole-5 -yl) thiomethyl-3-ce-

O

fem-4-carboxylic acid (syn isomer) (1.30 g) in methanol (13 cm) and the mixture stirred at ambient temperature for 5 hours. The solvent was distilled off under reduced pressure and the residue was dissolved in a saturated aqueous solution of sodium bicarbonate (25 cm 3). The aqueous solution was washed with ethyl acetate (25 em 3) and 10 / 5's hydrochloric acid was adjusted to pH 2.0 The precipitates were collected by filtration, washed with water and dried to give a colorless powder of 7- [2-allylozyimino-2- (2-amincthiazcol-4-yi} aeeetamido] -3- (1-allyl-1H-) tetrazol-5-yl) thio-35 methyl-5-ephem-4-acetic acid (syn isomer) (0.95 g); 7906497 * 38 IH (Nujol): 3350, 3210, 1778, 1675 cm -1 .

HMK (dg-DMSO, &): 3.68 (2H, ABq, J = 18Hz), 1 +, 1 + 0 - 1 + 71 (1 + H, m), 1 +, 80 - 5.1 + 5 (7 «T, m), 5.61+ _ 6.21+ (3H, m), 6jk (1H, s), 7.35 (2H, treed s), 9.62 (1Ï, d, J = 8Hz).

5 Example XI

7- [2-Cyclopentyloxyimino-2- (2- (2,2,2-trifluoroacetamido) thiazol-1 + -yl) acetamido] -3- (1-allylH-tetrazol-5-yl) thio-methyl-3-cephem -1 + carboxylic acid (sun isomer) (18.0 g) and tetrahydrofu-

O

ran (36 cur) were added to a stirred solution of sodium

O

10 acetate trihydrate (35.6 g) in water (360 cm). The mixture was mixed. stirred at ambient temperature for 18 hours and then distilled tetrahydrofuran from the reaction mixture. The remaining solution was adjusted to pH 3.0 with 15 # fs hydrochloric acid and the precipitates were collected by filtration, washed with water and dried to give crude 7- [2-cyclopentyloxyimino-2- (2-aminothiazole) -1 + -yl) acetamido] -3- (1 -allyll'H-tetrazol-5-yl) thiomethyl-3-cephem-1 + -carboxylic acid (syn isomer) (20 g). The crude material was purified by column chromatography over alumina (60 cnr) using a 3-5% aqueous solution of sodium acetate as eluent to give the pure title compound (8.31 g), mp. 11 + 0-11 + 5 ° C (dec.).

I.H. (Nujol): 3300, 1770, 1660, 1620 cm1.

HMB (DMS0-dg, S): 1.16 - 226 (ÖH, m), 3.73 (2H, m), 1 +, 1 + 1 (2H, ABq, J = 11 + Hz), 1+, 68 (1H, m), 1 +, 89 - 5.52 (5H, m), 5.62 -25 6.1 + 3 (2H, m), 6.73 (1H, s), 9.51 ( 1Ξ, d, J = 8Hz).

Example XII

Concentrated hydrochloric acid (0.9 g) was added. ambient temperature added to a solution of 7- [2-ethoxyimino-2- (2-formamidothiazol-1 + -yl) acetamido] -3- (1-allyl-1 H-tetrazol-5-yl) -30 thiomethyl-3- eefem-1 + -carboxylic acid (syn isomer) (2.1+ g) in a mixture

O O

of methanol (16.8 cmJ) and tetrahydrofuran (1 +, 8 cm) and the mixture stirred at 30 ° C for 3 hours. The solvent was distilled off under reduced pressure and the residue dissolved in a saturated aqueous sodium bicarbonate solution. The aqueous solution was washed with ethyl acetate and adjusted to pH 2.8 with concentrated hydrochloric acid. The precipitates were collected by filtration, washed 7906497 with water and dried to give 7- [2-ethoxyimino-2- (2-aminothiazol-4-yl) -acetamido] -3- (1-allyl H-tetrazole) 5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.72 g).

I.H. (flujol): 3350, 1780, 1675, 1635 cm -1.

5 MR (dg-DMSO, &): 1.24 (3H, t, J = 3Hz), 3.71 (2E, m), 4.13 (2H, q., J = 7.3Ez), 4, 37 (2H, ABq., J = 13.5Hz), 4.80 - 5.53 (5H, m), 5.64 - 6.45 (2H, m), 6.77 (1H, s), 7 .25 (2H, broad s), 9.62 (1H, d, J = 8.0Hz).

Example XIII

10 To a solution of 7- [2- (2-propynyl) oxyimino-2- (2-formamidothiazol-4-yl) acetate amido] -3- (1-allyl-1H-tetrazol-5-yl) thio-

O

methyl 3-cephem-4-carboxylic acid (syn isomer) (2.0 g) in methanol (14 cm), concentrated hydrochloric acid (0.3 g) was added and the mixture was stirred at ambient temperature for 3.5 hours. The solvent was distilled off under reduced pressure and the residue dissolved in a saturated aqueous solution of sodium bicarbonate.

The aqueous solution was washed with ethyl acetate and adjusted to pH 2.8 with concentrated hydrochloric acid. The precipitates were collected by filtration, washed with water and dried, yielding 7- (2- (2-propynyl) oxyimino-2- (2-aminothiazocl-4-yl) ac edamido] -3- [1- allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.43 g).

I.R. (Uujol): 3330, 2170, 1780, 1680, 1630 cm -1.

MR (dg-SMSO, S): 3.46 (1I1, m), 3.70 (2H, m), 4.37 (2H, ABa, J = 13.5Hz), 25 4.57 - 5.47 (TH, m), 5.60 - 6.49 (2H, m), 6.77 (1H, s), 7.25 (2H, broad s), 9.64 (1H, d, <1 = 8 .0Hz).

Example XIV

A mixture of 7- [2-methylthiomethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -2- (1-allyl-1H-tetrazol-5-yl) thio-30 methyl-3-cephem-4- carboxylic acid (syn isomer) (0.95 g), concentrated hydrochloric acid (0.324 g), methanol (9.5 cm ') and tetrahydrofuran • 3 y (2 cm') was stirred at ambient temperature for 2 hours. The solvent was distilled off under reduced pressure and the residue dissolved in a saturated aqueous sodium bicarbonate solution.

2 3rd aqueous solution was washed with ethyl acetate (25 cm) and with 7906497

Uo 10 $ s hydrochloric acid is adjusted to pH 1.5. The precipitates were collected by filtration, washed with water and dried to give 7- [2-methyl-thiomethoxyimino-2- (2-aminothiazole-1-yl) -acetamido] -3- (1-allyl-1 H -tetr azol-5-yl) thiomethyl-3-cef carboxylic acid 5 (syn isomer) (0.78 g).

I.R. (lujol): 3270, 1760, 1650, 1520 cm -1.

IRM (dg-DMSO, <$): 2.21 (3H, s), 3.72 (2H, s), U, 38 (2H, ABq., J »1UHz), M - 5.6 (TH, m), 5.7-6, U (2H, m), 6.80 (1H, ft), 7.2β (2H, broad s), 9.66 (1H, d, J = 8Hz).

Example XV

A. mixture of 7- [2- (3-isoxazolyl) methoxyimino-2- (2-formamidothiazole - ^ - yl) acetate amido] -3- (1-allyl-1 H-tetrazol-5-yl) thio-methyl-3 -cephem-4-carboxylic acid (syn isomer) (1.5 g) concentrated

•O

chlorine what is acidic (0.97 g), methanol (15 cm) and tetrahydrofuran

•O

15 (3 cnr) was stirred at ambient temperature for 2 hours. The solvent was distilled off under reduced pressure and the residue dissolved in a saturated aqueous sodium bicarbonate solution.

O

The aqueous solution was washed with ethyl acetate (25 cnr) and adjusted to pH 1.5 with TO 2 hydrochloric acid. The precipitates were collected by filtration, washed with water and dried to give 7- [2- (3-isoxazolyl) methoxyimino-2- (2-aminothiazol-k-yl) ac-ed amido] -3- (1- allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.65 g).

I.R. (Hujol): 3300, 1770, 1660, 1530 cm -1.

25 Bffi (dg-DMSO, S): 3.71 (2H, s), MO (2H, d, J = 14Hz), U, 8 - 5.6 (7H, m), 5.6 - 6.5 (2H, m), 6.62 (1H, d, J = 2Hz), 6.83 (1H, s), 7.29 (2H, wide s), 8.92 (1H, d, J = 2Hz) 9.73 (1H, d, J = 8Hz).

Example XVI

A mixture of 7- [2-methoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (U-allyl-UH-1.2. U-triazol-3-yl) thiomethyl- 3-cephem-U-carboxylic acid (syn isomer) (0.9 g), concentrated chlorine

OO O

hydrochloric acid (0.3cm-5), methanol (7cm-3) and tetrahydrofuran (7cm-3) was stirred at ambient temperature for 5 hours. The solvent was distilled off under reduced pressure and the residue was dissolved. 7906497 Μ dissolved in a saturated aqueous solution of sodium bicarbonate The aqueous solution was washed with ethyl acetate (25 cm) and adjusted to pH 2.0 with 10% hydrochloric acid The precipitates were collected by filtration, washed with water and dried and ver-5 received 7- [2-methoimino-2- (2-aminothiazol-4-yl) acetamido] -3- (4-al-lyl-4S-1,2,4-triazol-3-yl) thiomethyl- 3-cephem-4-carboxylic acid (syn-isomer) (0.5 g).

I.H. (Hujol): 3350, 1775, 1670, 1530 cm ”1.

HMR (dg-DMS0.6): 3.65 (2H, broad s), 3.83 (3H, s), 4.15 (2H, broad 10 s), 4.58 (2H, m), 4, 77 - 5.5 (3H, m), 5.58 - 6.33 (2H, m), 6.73 (1H, s), 8.60 (1H, s), 9.58 (.1H, d , J-8Hz).

Example XVII

The following compounds were obtained according to Examples X-XVI: (1) 7- [2-benzyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-1H-tetrazole-5- yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.H. (Jfujol): 3350, 3230, 1780, 1675, 1635 cm -1.

20 (2) 7- [2-Isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid ( syn-iscmeer).

I.H. (Xujol): 3350, 3250, 1780, 1675, 1630 cm -1.

HMR (d ^ -DMS0, è): 1.20 (3H, s), 1.30 (3H, s), 3.70 (2H, wide 25 s), 4.30 (3H, m), 4, 97-5.40 (4h, m), 5.63-6.27 (2H, m), 6.70 (1H, s), 9.55 (1H, d, J-8Hz).

(3) 7-C2-Butoxyimino-2- (2-aminotbiazol-4-yl) acetamido] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn- isomer).

30 I.H. (liujol): 3360, 1780, 1672 cm ”1.

MIS (dg-BMS0, £): 0.91 (3H, t, J = 6.0Hz), 1.18 - 1.96 (4h, m), 3.73 (2H, a), 3.87 - 4.73 (4h, m), 4.83 - 5.57 (5H, m), 5.63 - 6.40 (2H, m), 6.74 (1H, s), 7.20 (2H, broad s), 9.55 (1H, d, J = 8.0 Hz).

35 (4) 7-L2-hexyloxyimino-2- (2-aminothiazol-4-yl} acetamido] -3- (1- 7906497 * ► ψ kz allyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem -1 + -carboxylic acid (syn isomer).

I.E. (Hujol): 3350, 321 + 0.1780, 1675, 1630 cm -1.

HMR (dg-DMSO, S): 0.85 (3H, m), 1.00 - 2.00 (8H, m), 3.68 (2H, 5 m), 1 + .05 (2H, m) , 1 +, 37 (2H, m), 1 +, 80 - 5.1 + 7 (5H, m), 5.60 - 6, U7 (2H, m), 6.69 (1H, s), 7 .20 (2H, broad s), 9.50 (1H, d, J = 8.0Hz).

(5) 7-f 2-ethoxycarbonylmethoxyimino-2- (2-aminothiazol-1 + -yl) acet-amido] -3- (1-ally 1-1 H-tetrazol-5-yl) thiomethyl-3-cefem-1 + -carboxylic acid (syn isomer).

I.E. Uujol): 3360, 3230, 1780, 1680, 1630 cm -1.

EME (dg-DMSO, i): 1.21 (3H, t, J = 7Hz), 3.68 (2H, s), 1 +, 11 + (2H, s), 1 +, 1 ^ (2ï, a, J = 7Hz), 1 +, 38 (2H, s), 1 +, 66 (2Ξ, s), i +, 8 - 5.5 (5H, m), 5.6 - 6.1+ (3Ξ , 15 m), 6.80 (1H, s), 7.20 (2H, wide s), 9.5 (1I, d, J = 8Hz).

(6) 7- [2-tert-butoxycarbonylmethoxyimino-2- (2-aminothiazol-1 + -yl) -acetamido] -3- (1-allyl-1 H-tetrazol-5-yl) thiomethyl-3-cef em-1 + carboxylic acid (syn isomer).

20 I.E. (Eujol): 3330, 1780, 1730, 1680, 1630 cm -1.

KME (dg-DMS0,): 1.1 + 3 (9H, s), 3.67 (2H, s), 1 +, 37 (2H? AB4, J = 11 + Hz), 1 +, 56 (2ï ,. s), U, 8 - 5.5 (5H, m), 5.6 - 6.1+ (2H, m), 6.78 (1H, s), 7.20 (2H, broad s) , 9.5 (1H, d, J = 8Hz).

(7) 7- [2-carboxymethoxyimino-2- (2-aminothiazol-1 + -yl) acetamido] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-1 + -carboxylic acid ( syn isomer).

I.E. (Eujol): 3360, 1780, 1680, 1630 cm ”1.

(8) 7- [2- (1 + -fluorobenzyloxyimino) -2- (2-aminothiazol-1 + -yl) acetone-amido] -3- (1-allyl-1 H-tetrazol-5-yl) th.iomethyl -3-cep em-1 + -carboxylic acid (syn isomer).

Mp. Mp 157-161 ° C (dec.).

I.E. (Eujol): 3500, 1770, 1660, 1630, 1600 cm -1.

HME (DMS0-dg, $): 3.69 (2H, m), 1 +, 39 (2H, ABq., J * ll + Hz), 1 +, 75 -35 5, ½ (7H, m), 5.63 -6.57 (2H, m), 6.76 (1H, 7906497 »* 43 s), 6.86 - 7.76 (4η, m), 9.67 (1Η, d, J = 8Hz ).

(9) 7- [2- (3,4-dichlorobenzyloxyimino) -2- (2-aminothiazol-4-yl) -acetamido] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-c ephem -4-carboxylic acid (syn isomer), mp. 155-175 ° C (dec.).

5 1.3. (Hujol}: 1TT0, 1o60-1620, 1450 cm -1.

MR (DMSO-dg, S): 3.63 (2H, m), 4.33 (2H, m), 4.93 - 5.37 (7H, m), 5.67 - 6.40 (2H, m), 6.73 (1H, s), 7.10-7.70 (3H, m), 9.73 (1H, d, J = 8Hz).

Example XVIII

O

Trifluoroacetic acid (20 cm) was added under ice cooling to a stirred suspension of 7- [2-tert-butoxycarbonylmethoxy-imino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-1H- tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.05 g) in anisole

O

(2 cm), and the resulting mixture stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and diethyl ether added. Rashes were collected by filtration, washed with diethyl ether, dried and dissolved in an aqueous sodium bicarbonate solution. Insoluble material was filtered off and the filtrate adjusted to oH 3.2 with concentrated chloro-20 hydrochloric acid. The precipitates were collected by filtration, washed with water and dried to give 7- [2-carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-1H-tetrazol-5-yl) ) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) (0.8 g).

I.H. (Hujol): 3360, 1780, 1680, 1630 csf1.

MR (d ^ -DMSO, S): 3.68 (2H, ABq., J = 19Hz), 4.36 (2H, ABq., J = 14Hz), w it, 60 (2H, s), 4 .60 - 6.2 (7H, m), 6.80 (1Η, s), 7.24 (2H, broad s), 9.51 (1H, d, J = 9Hz).

Example XIX

To a solution of 7- [2-allyloxyi.mino-2- (2-amino-30-thiazcci-4-yl) acetamido] cephaloscranic acid (syn isomer) (4.8 g) in

O

pH 6.4 phosphate buffer solution (100 cm; 1-allyl-1H-tetrazole-5-thiol (2.1 g) was added and the mixture was then stirred at 55 - 60 ° 0 for 2 hours. The reaction mixture was cooled and charged with 10 Hydrochloric acid adjusted to pH 4.0 The precipitates were collected by filtration, washed with water and dried to give 7- [2-aliyloxyinino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-1H-7906497-tetrazol-5-yl) thiomethyl-3-cepentearearic acid (syn isomer) (2.0 g).

I.R. (Nujol): 3350, 3210, 1778, 1675 cm-1.

KMR (DMSO-dg, <$): 3.68 (2H, ABq, J = 18Hz), k, k0 - kjï (te, m), U, 80 - 5, te (7H, m), 5.6 ^ - 6.2b (3H, m), 6.7 ^ (1H, s), 7.35 (2H, broad s), 9 * 62 (1H, d, J = 8Hz).

Example XX

The following compounds were obtained according to Example XIX: (1) 7- [2-allyloxyimino-2- (2-formami dothiazol-teyl) ac edamido] -3- (1 - 10 allyl-1 H-tetrazol-5-yl ) thiomethyl-3-cephemetarboxylic acid (syn isomer).

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

(2) 7- [2-ethoxyimino-2- (2-formamidothiazol-teyl) acetamido] -3- (1-allyl-1H-tetrazol-5-yl) thiometh.yl-3-cefemearearic acid (syn - 15 isomer).

I.R. (mgol): 3200, 1765, 1665 cm-1.

(3) 7- [2- (2-propynyl) oxymino-2- (2-formamidothiazol-teyl) acetyl amido] -3- (1-allyl-1 Ht et r azool-5-yl) thiometbyl-3 -cef em-tecar-b on acid (syn isomer).

20 I.R. (iTujol): 3310, 2170, 1780, 1680 cm ”1.

(te 7- [2 -with hylthi ome t hoxyimi no -2 - (2-formamidothiazol-teyl) acet amido] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cep em -tecar-bon acid (syn-is omer).

I.R. (Rujol): 3250, 3200, 1780, 1670, 15 cm -1.

25 (5) 7- [2- (3-isoxazolyl) methoxyimino-2- (2-formamidothiazol-teyl) -ac edamido] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem -to carboxylic acid (syn isomer).

I.R. (Hujol): 3250, 1780, 1670, 1550 cm -1.

(6) 7- [2-benzyloxyimino-2- (2-aminothiazol-4-yl) acetate amido] -3- (1- 30 allyl-1H-tetrazol-5-yl) thiomethyl-3-cephemetcarboxylic acid (syn - isomer).

I.R. (Nujol): 3350, 3230/1780, 1675, 1635 cm -1.

(7) 7- [2-Methoxyimino-2- (2-formamidothiazol-teyl) acetamido] -3- (te-allyl-te-1,2-tetriazol-3-yl) thiomethyl-3-cephem-carboxylic acid 35 (syn isomer ). ^ I.H. (Nujol): 3200, 1780, 1680, 1550 cm -1.

7906497 U5 (8) T- [2-Isopropoxyimino-2- (2-formamidothiazol-U-yl) acetyl amido] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-U -carboxylic acid (syn isomer).

I.R. (JSujol): 3220, 1780, 1670 cm -1.

5 (9) 7- [2-Butoxylmino-2- (2-formamidothiazol-yl) -acetamido] -3- (1-allyl-1E-tetrazol-5-yl) thiomethyl-3-cephem-k- carboxylic acid (syn isomer).

I.R. (ffiijol): 3200, 1780, 1695, 1675, 1655 cm -1.

(10) 7- [2-Hexyloxyimino-2- (2-formamidotbiazol-U-yl) acetate amido] —3— (1 - 10 allyl-1H-tetrazol-5-yl) thiometbyl-3-cephem - ^ - carboxylic acid (syn isomer).

I.R. (Hujol): 3175, 1780, 1757, 168¾. 16U0 cm-1.

(11) 7- [2-ethoxycarbonylmethoxyimino-2- (2-formamidoth.iazole-yl) -acetamido] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cepem-4- Carboxylic acid (sym isomer).

I.R. (Eujol): 3500, 3280, 1780, 1735, 1690 cm -1.

(12) 7- [2-tert-butoxycarbonylmethoxyimino-2- (2-formamidothiazol-yl) -acetamido] -3- (1-allyl-1 H-tetrazol-5-yl) thiomethyl-3-cep em- 1l-carboxylic acid (syn isomer).

20 I.R. (Eujol): 3250, 1780, 1720, 1680, 15 ^ 0 cm -1.

(13) 7- (2-ethoxyimino-2- (2-aminothiazole - ^ - yl) acetate amido] -3- (1-allyl-1H-tetrazol-5-yl) tniomethyl-3-cephem - ^ - carboxylic acid ( syn isomer) IR (Sujol): 3350, 1780, 1675, 1635 cm -1.

(1¾) 7- [2-isopropxyimino-2- (2-aminothiazol-1-yl) ac edamido] -3- (1 - 25 allyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-carbonzunr (syn isomer).

I.R. (Hujol): 3350, 3250, 1790, 1675, 1630 cm -1.

(15) 7- [2-butoxyimino-no-2- (2-aminothiazol-1-yl) acetamido] -3- (1-allyl-1 H-tetrazol-5-yl) thiometbyl-3-cephem - ^ - carboxylic acid (synthesis).

I.R. (Jfujol): 3360, 1780, 1672 cm -1.

(16) 7-1 l -hexyloxyiminc-2- (2-aminothiasole - ^ - yi) ac edamido] -3- (1-allyl-1H-tetrazocl-5-yl} thiomethyl-3-cephem-3-carboxylic acid ( syn-iscmeer).

35 I.R. (Eujcl): 3350, 32UG, 1780, 1675, 1630 cm -1.

7906497 k6 RV (1T) 7- [2- (2-propynyl) oxyimino-2- (2-aminothiazol-4-yl) ac eat amido] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl -3-cephem-4-carbonic acid (syn isomer).

I.E. (Hujol): 3330, 2170, 1780, 1683, 1630 cm ”1.

5 (18) 7- [2-ethoxycarbonylmethoxyimino-2- (2-aminothiazole---yl) acetamido] -3- (1-ally-1'-tetrazol-5-yl) thiomethyl-3-cephem- U-car-bonztiur (syn isomer).

I.E. (Eujol): 3360, 3230, 1780, 168O, 1630 cm-1.

(19) 7- [2-tert -butoxycarbonylmethoxyimino-2- (2-aminothiazole-yl) acetyl-amido-1-3- (1-allyl-1H-tetrazol-5-yl) thicmethyl-3-cep em - ^ - carboxylic acid (syn isomer).

I.E. (Eujol): 3330, 1780, 1730, 1680, 1630 cm -1.

(20) 7- [2-methylthimethoxyimino-2- (2-aminothi az 0 ol-i (-y 1) acetamido] - 3- (1-olyl-1 H-tetr azol-5-yl) thiomethyl-3- give em-U-carboxylic acid 15 (syn isomer).

I.E. (Hujol) r 3270, 1760, 1650, 1520 cm -1.

(21) 7- [2- (3-isoxazolyl) methoxyimino-2- (2-aminothiazole-1-yl) acet-amido] -3- (1-allyl-1 H-tetrazol-5-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn isomer).

20 I.E. (Uujol): 3300, 1770, 1660, 1530 cm -1.

(22) 7- [2-carboxymethoxyimino-2- (2-aminothiazol-U-yl) acetamido] - 3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cef em-ii- carboxylic acid (syn isomer).

I.E. (Eujol): 3360, 1780, 168Ο, 1630 cm-1.

25 (23) 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3 - (^ - allyl- ^ H-1.2. + Triazol-3-yl) thiomethyl-3-cephem -4-carboxylic acid (syn isomer).

I.R. (ifujol): 3350, 1775, 1670, 1530 cm-1, (2k) 7- [2-cyclopentyloxyimino-2- (2-aminothiazol-U-yl) acetamido] -3- 30 (1-allyl-1H-tetrazole -5-yl) thiomethyl-3-cephem-4-carbonz-hour (syn isomer).

Mp. 1U0 - 1U5 ° C (dec.).

I.R. (Tujol): 3300, 1770, 1660, 120 cm-1.

(25) 7— [2- (U-fluorobenzyloxyimino) -2- (2-aminothiazol-U-yl) acetamido] -35 3- (1-allyl-1H-tetrazol-5-yl) thiamethyl-3-cephem- U-carboxylic acid (syn- 7906497 47 ismere), Sup. 157-161 ° C (dec.) I.H. (Hujol): 3500, 1770, 1660, 1630, 1600 cm 1.

(26) 7- [2- (3,4-dichlorobenzzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3 -cephem-4-car-5 carboxylic acid (syn isomer), mp. 155-175 ° C (dec.).

I.H. (Nujol): 1770, 1660-1620, 1 ^ 50 cm -1.

Reference

Vilsmeier reagent was conventionally prepared from dry dimethylformamide (0.526g), phosphorus oxychloride (1.10g), and dry ethyl acetate (1.5cm). To this was added ethyl acetate (10 cm) and then 2-methoxyimino-2- (2-formamidothiazol-4-yl) -acetic acid (syn isomer) (1.50 g) at 0 ° C. The mixture was stirred at the same temperature for 30 minutes and added at -10 ° C to a stirred solution of 7-8nino-3- (1-allyl-1H-tetra-15-sol-5-yl) thiomethyl-3-cephem -4-carboxylic acid (2.32 g) and trimethylsilyl

O

acetamide (6.18 g) in dry ethyl acetate (30 cm), then the mixture was stirred at the same temperature for 1 hour and extracted by adding ethyl acetate (20 cm3) and water (30 cm).

The ethyl acetate layer was separated and with a saturated aqueous

O

20 sodium bicarbonate solution (20 cm) extracted. The water layer was adjusted to pH 2.0 with 10% hydrochloric acid. The precipitates. were collected by filtration, washed with water and dried to give 7- [2-methoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-ailyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-25 isomer) (2.60 g).

I.R. (Nujol): 3200, 1770, 1710, 1665 cm -1.

NMP. (dg-DMSO, ^): 3.72 (2H, broad s), 3.93 (3H, s), 4.40 (2H, ABq, J * l4iz), 4.87-5.50 (5H, m), 5.73-6.37 (2H, m), 7.45 (1H, s), 8.55 (1H, s), 9.70 (1E, d, J = 8Ez).

- a 0 6 4 9 7

Claims (38)

A syn isomer of a compound according to claim 1, wherein the group of formula 18 is a group of formula 19. 3. A compound according to claim 2, characterized in that R is a lower alkyl, lower alkenyl, lower alkynyl or cyclo (lower) alkyl group, each of which may contain suitable substituents, 3 * R a carboxy group and R is a tetrazolyl group with a lower alkenyl group or a triazolyl group with a lower alkenyl group, under 2.1 * provided that R is not a methyl group when R is a tetrazolyl group with a lower alkenyl group. 1 *. A compound according to claim 3, characterized in that 2 R is an alkyl group with 2-6 carbon atoms, a lower alkenyl, lower alkynyl, cyclo (lower) alkyl or lower alkyl group with 1 to 2 substituents, selected from carboxy, protected carboxy, lower alkythio, acyloxy, isoxazolyl and aryl groups which may contain 1-3 halogen-1+ atoms, and R is a tetrazolyl group having a lower alkenyl group. A compound according to claim k, characterized in that 1.2 R is an ammo or lower alkanoylamino group and R is an alkyl group with 2-6 carbon atoms. Compound according to claim 5, characterized in that 1.2 R is an ammo or formamido group, R is an ethyl, isopropyl, butyl or 1 * 30 hexyl group and R is a tetrazolyl group with an allyl group. 7. A compound according to claim 6, characterized in that it consists of 7- [2-ethoxyimino-2- (2-aminothiazol-L-yl) acetamido] - $ 6 6 9 9 h9 3- (1- allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-U-carboxylic acid (syn isomer). Compound according to claim 6, characterized in that it consists of 7- [2-isopropoxy-imino-2- (2-aminothiazole-1-yl) -acet-5 arnido] -3- (1-allyl-1-1-yl) tetrazol-5-yl) -thiomethyl-3-cephem-carboxylic acid (syn isomer). A compound according to claim 6, characterized in that it consists of 7- [2-butoxyimino-2- [2-aminothiazole-1-yl) acetone arnido] -3- (1-aliyl-1H-tetrazole-5- yl) thiomethyl-3-cephemic acid (acisomer), A compound according to claim 6, characterized in that it consists of 7- [2-hexyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-1H-tetrazole-5 -yl) thiomethyl-3-cephem-U-carboxylic acid (syn isomer). Compound according to claim, characterized in that 1. R is an amino or lower alkanoylamo group and R is a lower alkenyl group. 12. A compound according to claim 11, characterized in that 1.2 h R is an amino or formamide group, R is an allyl group and R is a tetrazolyl group with an allyl group. Compound according to claim 12, characterized in that it consists of 7- [2-allyloxyimino-2- (2-aminothiazol-h-yl) acetyl-amido] -3- (1-aliyi-1H-tetrazoic) 5-yl) thiomethyl-3-cephem-hc carbonic acid (syn isomer). 25 1 ^. A compound according to claim U, characterized in that 1. R is an anno or lower alkanoyl group and R is a lower alkynyl group. A compound according to claim 1U, characterized in that 1 ·. 2k R is an amino or formamido group, R is a 2-propynyl and R is a tetrazolyl group with an allyl group. Compound according to claim 15, characterized in that it consists of 7- [2- (2-propynyl) -oxyimino-2- (2-aminothiazole-1-yl) -acetamido] -3- (1-allyl- 1H-tetrazcol-5-yl) thiomethyl-3-cephem-4-carbonic acid (syn isomer). A compound according to claim 2, characterized in that 1, 2 R is an amino or halo (lower) alkanoylamino group and R is a cyclo (lower) alkyl group. 38497 «1 * V A compound according to claim 17, characterized in that 1.2 R is an amino or trifluoroacetamido group, R is a cyclopentyl and K R is a tetrazolyl group with an allyl group. 19. A compound according to claim 18, characterized in that it consists of 7- [2-cyclopentyl-oxyimino-2- (2-aminothiazol-4-yl) acet amido] -3- (1-allyl-1 H- tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid (syn-isomer). 20. A compound according to claim +, characterized in that R 1 is an amino, lower alkanoylamino or halogen (lower) alkanoylamino-2 group and R is a lower alkyl group with a substituent selected from carboxy, lower alkoxycarbonyl, lower alkylthio lower alkanoyl oxy, isoxazolyl and phenyl which may contain 1 or 2 halogens. Compound according to claim 20, characterized in that 1. . .2 R a amino, formamxdo or trifluoroacetamido group, R a carboxy methyl, ethoxycarbonylmethyl, tert-butoxycarbonylmethyl, methylthiomethyl, formyloxyethyl, isoxazolylmethyl, benzyl, U-fluoro. . k benzyl or 3,4-dichlorobenzyl group and R is a tetrazolyl group with an allyl group. 22. A compound according to claim 21, characterized in that it consists of 7- [2-carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-1 Ht etr azole -5-yl) thiomethyl-3-cephemicarboxylic acid (syn isomer). Compound according to claim 21, characterized in that it consists of 7- [2-ethoxycarbonylmethoxyimino-2- (2-amino-25 ΐ! Ιίηζοο1-1 ^ 1) ηοββΐ3ΐιπ ^ ο] -3- (1-allyl- 1H-t etr azol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 2h. A compound according to claim 21, characterized in that it consists of 7- [2-tert-butoxy-carbonylmethoxyimino-2- (2-aminothia-sole - ^ - yl) acetamido] -3- (1-allyl-1 Etr azol-5-yl) thiomethyl-3-cephem-30 U-carboxylic acid (syn isomer). 25. A compound according to claim 21, characterized in that it consists of 7- [2-methylthio-methoxyimino-2- (2-aminothiazole - + + - yl) ac edamido] -3- (1-allyl-1] - tetr azol-5-yl) thiomethyl-3-cep em-4-carboxylic acid (syn isomer). 26. A compound according to claim 21, characterized in that 7906497 ► it consists of 7- [2- (3-isoxazolyl) methoxyimino-2- (2-aminothiazol-1-yl) acetamido] -3- (1-allyl- 1 H-tetrazol-5-yl) thiomethyl-3-cep em-1 ^ -carboxylic acid (syn isomer). 27. A compound according to claim 21, characterized in that it consists of 7- [2-benzyloxyimino-2- (2-aminothiazol-1-yl) -acetamido] -3- (1-allylfH-tetrazole-5-) yl) thiomethyl-3-cephem-b-carboxylic acid (syn isomer). 28. A compound according to claim 21, characterized in that it consists of 7- [2- (luorobenzyloxyimino) -2- (2-aminothiazol-k-yl) -10 acetamido] -3- (1-allyl-1H tetrazol-1-yl) acetamido] -3- (1-allyl-1H-tetrazol-5-yl} thiomethyi-3-cephem-1-carboxylic acid (syn isomer). 29. A compound according to claim 21, characterized in that it consists of 7- [2- (3.It-dichlorobenzyloxyimino} -2- (2-amxnothia-sole-1-yl) acetamido] -3- (1-allyl -1-tetrazol-5-yl) thiomethyl-3-cephem-lt-carboxylic acid (syn isomer). A compound according to claim 3, characterized in that R is an amino or lower alkanoylamino group, R is a lower alkyl group k and R is a trxazolyl group with a lower alkenyl group xs. A compound according to claim 30, characterized in that 1, 2, 14. , 20. an amxno or formamido group, R is a methyl group and R is a 4H-1,2,4-triazolyl group with an allyl group. A compound according to claim 31, characterized in that it consists of 7- [2-methoxyimino-2- (2-aminothiazol-J-yl) acetamido] -3- (4-allyl-1H-1.2). 3-triazol-3-yl) thiomethyl-3-cephem-1-carboxylic acid (syn isomer). 33. Process for preparing 3,7-disubstituted-3-cephem-k-carboxylic acid compounds of formula 1, wherein R 1 is an amino. 2 · or protected amxno group, R is an aliphatic hydrocarbon group, which may contain 3 dxe suitable substituents, R may contain a carboxy or belt 30-shielded carboxy group xs, and R contains an N-containing heteromonocyclic 2 rxng xs dxe lower alkenyl groups, provided that R has no . b methyl xs when R tetrazolyl with a lower alkyl group xs, or pharmaceutically acceptable salts thereof, characterized in that a compound of formula 2, wherein RJ and R "each have the aforementioned meaning or a reactive derivative thereof to the minogroup or a 7906497 * t salt thereof, is attempted in reaction with a compound of formula 1 wherein R and R each have the aforementioned meanings or the reactive derivative thereof to the carboxyl group or a salt thereof. 5 3k. Process for preparing a compound according to 2. formula 1b, wherein R is an aliphatic hydrocarbon group, which may contain suitable substituents, R is a car boxy or protected cark boxy group and R is an F-containing 5-heteromonocyclic ring containing 2 lower alkenyl groups, provided that R is not methyl k when R is tetrazolyl with a lower alkenyl group, or pharmaceutically. acceptable salts thereof, characterized in that a compound vol. 2 3 k according to formula 1a, wherein R and R and R each have the aforementioned significance and R is a protected araino group or a salt thereof, to an elimination reaction of. the amino protecting group is subjected. 35. A method of preparing a compound of formula 1d, wherein R is an amino or protected amino group, Ά is a carboxy (lower) alkyl group, R is a carboxy or protected carboxyk ... group, and R is an N -containing heteromonocyclic 5-nng containing 20 lower alkenyl groups, or pharmaceutically acceptable salts thereof, characterized in that a compound of the formula 1c, 13k 2a wherein R, R and R each have the aforementioned meanings and R a protected carboxy (lower) alkyl group or a salt thereof, is subjected to an elimination reaction of the carboxy protecting group. 36. A method of preparing a compound of formula 1, wherein R is an ammo or protected amino group, R is an aliphatic hydrocarbon group which may contain suitable substituents, R is a carboxy or protected carboxy group, and R a 5- containing heteromonocyclic 5-ring containing lower alkenyl groups, provided that R is not methyl when R is tetrazolyl with a lower alkenyl group, or pharmaceutically acceptable salts thereof, characterized in that a compound according to formula 16, wherein 12 3 R, R and R each have the aforementioned meanings and X is a group k 35 which may be substituted with a group of the formula R -S-, where 7906497. k in R has the aforementioned meanings, or a salt thereof, m is reacted with a compound of the formula S-Si, wherein R has the aforementioned meanings or its reactive derivative to the mercapto group. A compound of formula 3, wherein R 1 is an amino or 2 protected aminc group and R is a cyclopentyl or 3k-dichlorobenzyl group. 38. A process for preparing a compound of formula 3, wherein R is a carboxy or protected carboxy group and R 10 is a 5-containing heteromonocyclic ring containing lower alkenyl groups, or a salt thereof, characterized that a compound of formula 13, wherein R has the aforementioned meanings, or a salt thereof, is reacted with a compound of formula R -SH, wherein R has the aforementioned meanings or the reactive derivative thereof to the mercapto group, and the obtained 3 Ij. bond of formula 15, wherein R and R each have the aforementioned meanings, or a salt thereof, is subjected to an elimination reaction of the 5-smino-5-carboxyvaleryl group. 39. Pharmaceutical antibacterial preparation, characterized in that it contains a compound according to claim 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable, substantially non-toxic carrier or non-toxic diluent. UO. A method of forming a pharmaceutical antibacterial preparation, characterized in that a compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active component is mixed with an inert carrier. Onion. Process for the preparation of a compound according to 1a 2 formula 3a, wherein R represents a protected amino group and R represents a cyclopentyl or 3.dichlorobenzyl group or salts thereof, characterized in that a compound of formula 3'a wherein R has the aforementioned meanings, or salts thereof, is reacted with an amino protecting agent. 7906497 R1 -ft "^ -C-CONH — I —f S -1 11 <N> ch, -sr * 5 2 0 R3 OR2 K REACTION SCHEME A 1 1 n ^ -rr8! 4 i» in ^ Nv ^ -CK ^ -S-R4 + R1- # \ -C-COOH -5 ** 0 X 2 R3 N 5 2 OR2 R1- ^ "^ jC-CONH —— fS> SN o ^ N ^ V5- * 4 5. r3 OR2 R _B_ 1a RlaJi Xc-CONH — p — rs η '__ Ts N & % - * - ** OR2 R ° 1L N - \ H, N -f% C-CONH-j — r'S'i ~ sT ll “v5- * OR3 R3 Fujisawa Pharmaceutical Co. Ltd. 7906497 JL A. JL CH co .cz-. cH3-c0.cz M .........> 3 H * WNN 5 * 2 OH Ok H7N-C-NH, i- JL S NTCZ Y-CH2CO-CZ-> H2N ^ s3} j} OR2 OR2 tkk N-rC-COOH NnC-COOH v <si— «A Sb2 Ir2 amino-protecting agent X 8 2 -i ~ R 2 O -NH 2 n R1- # 11-COCOOH -> R1- # \ C-COOH »^ or salt thereof x JJ 2 OR ^ 7906497 Fujisawa Pharmaceutical Co. Ltd. JL J8. amino-protective JL J2 n agent n H ^ s ^ CZ - R ^^ cZ N 5 5 OH OH OR2 it -eliminerin9> RC-COOH ^ II N 5 2 ORz ± Ji or salt thereof J4 or reactive mercapto thereof HOOC- CH- (CH2) 3-CONH-j-fs> yyg J-NyJ-CH2OCOCH3. + R4.sh- 2. R3 to J5. or salt thereof HOOC-CH- (CH 2) 3 -CONH-3-S 2 N -CKj-S-R 4 R 3 2 or salt thereof 4 CH 5 -S-R 4 Ο T 3 fo fojiMva Pharmaceutical Co. Ltd. 7906497 R ISA 18 B 11--11- Ji 18 A 18 B 19 J & 20. il '22. r1- # "-V £ -co- R1 - #" \ -c-co- r1- # "4- c -co- ^ ft-OR2 TS? || ~ S? I Rz0-N? OR2 ii 3a1 // T ^ -0002 H-rpS-COOE h2e 4 >> I 2 bHT | OR2 JL HOOC-CH- (CH- ) - CONH -! - 1jH2 cr — Ns' ^ ~ CH2 ~ S. “R4 R3 N Ji ^ -iTl-C-CONH-r — r" S> ^ Μ-Λ-ch2-x 79 0 6 4 9 7 ° R r3 Fujisawa Pharmaceutical Co. Ltd. i * ·· JL 1c. ^ - / "Vc-CONH — I — f Svl 3 * - * OR2a r3 Id Rl" / ^ rc * C0NHn — tSni 3 "^^ CVS-R * ^ R2" »'Ά J7 R1 # - ~ ^ r- 0-COHE-T — f δΊ, - ^ + E * -SH ^ 5. O 'X OR * Rr B1 OR2 2? 7906497 Fujisawa Pharmaceutical Co. Ltd.