HU205939B - Process for producing new cephalosporing derivatives and pharmaceutical compositions containing them - Google Patents

Abstract

Cephem derivs. of formula (I) and their pharmaceutically acceptable salts are new. R1 = opt. protected amino; R2 = opt. substd. lower alkyl; R3 = COO(-) or opt. protected carboxy; R4 = lower alkyl substd. by opt. protected hydroxy; R5 = opt. protected amino; R6 = H or lower alkyl; X = anion; n = 0-1; provided that when (1) R3 = COO(-) then n = O; and (2) R3 = opt. protected carboxy then n = 1; lower = 1-6C.

Description

The present invention relates to novel cephem compounds and their pharmaceutically acceptable salts.

More particularly, the present invention relates to a process for the preparation of novel cephem compounds and their pharmaceutically acceptable salts having antimicrobial activity and to a pharmaceutical formulation comprising the above compounds.

Accordingly, the present invention relates to a process for the preparation of novel cephem compounds and their pharmaceutically acceptable salts which are highly effective against a number of pathogenic microorganisms.

The present invention further provides a process for the preparation of a pharmaceutical formulation comprising the above cephem compound or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention relates to a process for the preparation of novel cephem compounds of the formula I wherein:

R ¹ is amino, or C 1 -C 6 alkanoylamino or triphenyl (C 1 -C 6) alkylamino,

R ² is C 1 -C 6 alkyl optionally substituted with 1 to 3 halogens,

R ³ is a carboxylate group (COCl 3), a carboxyl group or a diphenyl (C 1 -C 6) alkoxycarbonyl group,

R ⁴ is hydroxy (C 1-6) alkyl, C 1-6 alkanoyloxy (C 1-6) alkyl or carbamoyloxy (C 1-6) alkyl,

R ⁵ is amino or C 1-6 alkanoylamino,

R ⁶ is hydrogen or C 1-6 alkyl,

X 'is an anion and n is 0 or 1 with the proviso that (i) if R ³ is carboxylate (COCT) then n is 0 and (ii) if R ³ is carboxyl or diphenyl - (C 1-6) alkoxycarbonyl, then n is 1.

With respect to the compound of formula (I) obtained by the process of the invention, the following should be stated:

The compound of formula (I) of the present invention includes its syn and anti isomers as well as mixtures thereof. The term "isomer" refers to the isomer containing the structural unit of formula (VIII) (wherein R ¹ and R ² are as defined above) and the term "isomer" refers to the geometric isomer of formula (IX). unit (wherein R ¹ and R ² are as defined above). All of the above geometric isomers and mixtures thereof are included within the scope of the present invention.

In the description of the process according to the invention as well as in the claims, these geometric isomers and their mixtures are for the sake of simplicity represented by the general formula (X) (wherein R ¹ and R ² are as defined above).

It should also be noted that the pyrazole moiety of the needle compound of formula (I) may exist in tautomeric forms and the tautomeric equilibrium may be characterized by moieties (A) and (B) (wherein R ⁴ , R ⁵ and R ⁶ above).

Both of these tautomeric forms are included in the process of the invention, although for the sake of simplicity, the compound of formula (I) is disclosed in the description of the process of the invention and in the claims as the pyrazolyl group of formula (A).

The cephem compound of formula (I) of the present invention can be prepared according to the following reaction schemes.

/. process (II) or an amino group + (III) or a reactive derivative of a carboxylchloro reactive or a port ka or 'salt —-—> (I) or a salt thereof

Method 2 - deprotection of the amino group of Rj (la) or its salt -> (Ib) or its salt

Process 3 (IV) or salt + (V) or salt -> (I) or salt thereof

Method 4 - Removal of the carboxyl protecting group of the group R _b ³ (Ic) or a salt thereof -> (Id) or a salt thereof

5. The method of removing _the group R ⁴ hydroxy protecting groups (Ie) or a salt thereof -> (If) or a salt thereof

6. The process of the R _group ^{of 5-amino} protecting group removal (Ig) or a salt thereof -> (Ih) or a salt thereof wherein in the general formulas R ^1, R ^2, R ^3, R ^4, R ^5, R ^6, X ~ and n is as defined above,

R _a 'is a protected amino group,

R _a ³ is a carboxyl group or a protected carboxyl group,

R _b ³ is a protected carboxyl group,

R ^ represents a carboxylate group or a carboxyl group, R ^₄ is a protected hydroxy-lower alkyl,

R _b ⁴ is hydroxy-lower alkyl, R _a ⁵ is a protected amino group, and

HU 205 939 B

Y is a good cleavage group.

The starting compound (Π) or its salts, which are novel compounds, can be prepared according to the following scheme.

Process A) (V) or a salt thereof (VI) or a salt-> (VII) or a salt thereof

-> (Ha) or its salt-> (Ilb) or its salt

Process B (IIc) or a salt thereof (IId) or a salt thereof

C) Procedure (He) or sója-> (IIf), or salt thereof, wherein in the general formulas R ^3, R b ^3, R ^3, R ^4, R ^4, R b ^4, R ^5, R ^5, R ^6, X ~ and n is as defined above,

R ⁷ is a protected amino group, and

Z is a cleavage group.

Some of the starting compounds of formula (V) or salts thereof are novel and may be prepared by the methods described in the Preparation Examples or by analogous methods.

Suitable pharmaceutically acceptable salts of the compound of formula (I) include the conventional non-toxic mono- or di-salts and include, for example, alkali metal salts (such as sodium salt, potassium salt, etc.) and alkaline earth metal salts (e.g., calcium salt, magnesium salt, etc.), ammonium salt, an organic base salt (e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N-dibenzylethylenediamine salt, etc.), an organic acid addition salt (e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.), an acid addition salt with an inorganic acid (e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.), an amino acid salt (e.g., arginine salt, aspartic acid salt, glutamic acid salt, etc.) and the like.

The meaning of the symbols used in the above and in the following description of the process of the invention is given in the following detailed examples.

Suitable protecting groups for the term "protected amino" include, for example, ar-lower alkyl, such as mono-, di- or triphenyl-lower alkyl (e.g., benzyl, 1-phenylethyl, 2-phenyl). ethyl group, benzhydryl group, trityl group, etc.), acyl group as described below and the like.

Suitable acyl groups include aliphatic acyl groups, aromatic acyl groups, aryl aliphatic acyl groups and heterocyclic aliphatic acyl groups derived from carboxylic, carbonic, carbamic, sulfonic and the like acids.

Suitable acyl groups include, for example, lower alkanoyl groups (such as formyl, acetyl, propionyl, hexanoyl, pivaloyl, etc.), mono- (di- or tri) -halo-lower alkanoyl (e.g. e.g., chloroacetyl, trifluoroacetyl, etc.), lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl) , hexyloxycarbonyl, etc.), mono- (di- or tri) -haloalkoxycarbonyl (e.g., chloromethoxy) carbonyl, (dichloroethoxy) carbonyl. , (trichloroethoxy) carbonyl group, etc.], aroyl group (e.g., benzoyl group, toluoyl group, xyloyl group, naphthoyl group, etc.), lower alkanoyl group (e.g., phenylacetyl). group, phenylpropionyl group, etc.), aryloxycarbonyl group (e.g., phenoxycarbonyl group, naphthyloxycarbonyl group). powders, etc.), aryloxy-lower alkanoyl, such as phenoxy-lower alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl, etc.), aryl-glyoxoyl (e.g., phenyl-glyoxoyl). aryl, lower alkoxycarbonyl, which may have suitable substituent (s), such as phenyl, lower alkoxycarbonyl, nitro or lower alkoxy. substituents (e.g., benzyloxycarbonyl (phenylethoxy) carbonyl, (p-nitro-benzyloxy) carbonyl, (p-methoxybenzyloxy) carbonyl, etc.) thienylacetyl- a group, imidazolylacetyl, furylacetyl, tetrazolylacetyl, triazolylacetyl, thiadiazolylacetyl, thienylpropionyl, thiadiazolylpropionyl, lower alkylsulfonyl (e.g. methylsulfonyl) , ethylsulfonyl, p ropylsulfonyl group, isopropylsulfonyl group, pentylsulfonyl group, butylsulfonyl group, etc.), arylsulfonyl group (e.g., phenylsulfonyl group, tolylsulfonyl group 35, xylsulfonyl group, naphthyl group) sulfonyl group, etc.), ar-lower alkyl sulfonyl group such as phenyl-lower alkyl sulfonyl group (e.g., benzyl sulfonyl group, (phenylethyl) sulfonyl group, benzhydrylsulfonyl group, etc.). .] and similar groups.

Preferred "protected amino" groups include aryl-lower alkylamino and lower alkanoylamino, as described above, more preferably triphenyl-C 1-4 alkylamino and C 1-4 alkanoylamino and most preferably tritylamino, formylamino and acetamido.

Suitable "protected carboxyl groups" include esterified carboxyl groups or the like. The ester group of the esterified carboxyl group may be, for example, a lower alkyl ester group (e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl). ester, hexyl ester, (1-cyclopropylethyl) ester, etc.] which may have other substituent (s), for example, lower alkanoyloxy-lower alkyl esters (e.g., acetoxymethyl) propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, (160 acetoxyethyl) ester, (1-propionyloxyethyl) ester , (piva3

EN 205 939 Β loyloxymethyl) ester, (2-propionyloxyethyl) ester. (hexanoyloxymethyl) ester, etc.], lower alkanesulfonyl-lower alkyl ester (e.g., (2-methylethyl) ester, etc.), or mono- (di or tri) haloalkyl ester (e.g., 2-iodoethyl) ester, (2,2,2-trichloroethyl) ester, etc.], lower alkenyl ester (e.g., vinyl ester, allyl ester, etc.), lower alkynyl ester (e.g. for example, ethynyl ester, propynyl ester, etc.), ar-lower alkyl ester which may have suitable substituent (s) (e.g., benzyl ester, (4-methoxybenzyl) ester, (4-nitrobenzyl) - ester, (phenylethyl) ester, trityl ester, benzhydryl ester, (bis) methoxyphenyl (methyl) ester, (3,4-dimethoxybenzyl) ester, (4-hydroxy-3, 5-di-t-butyl (benzyl) ester, etc.]; aryl ester which may have suitable substituent (s) (e.g., phenyl ester, (4-chlorophenyl) ester, tolyl ester, (4-t-butylphenyl) ester, xyl 1-ester, mesityl ester) , cumenyl ester, etc.]; or a similar ester and is preferably a mono- or di- or triphenyl-C 1-4 alkyl ester, and most preferably a benzhydryl ester.

Suitable "C 1 -C 6 alkyl" groups include straight or branched chain groups such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, 2-ethylpropyl , hexyl, and the like, preferably C1-C4 alkyl, and most preferably methyl.

Suitable alkyl groups having 1 to 3 halogen substituents include, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloro-2-fluoroethyl, bromo-2-fluoropropyl, 1-chloromethyl-2-iodo-1-bromoethyl,

2-difluorobutyl, 1- (dichloromethyl) -1-methylethyl, 2-fluoro-4-chloro-5-bromopentyl, 1-difluoro-2-ethylpropyl, 2-fluoro-3-iodo-hexyl or the like, wherein the preferred group is the dihalo (C1-C4) alkyl group, the most preferred group being the difluoromethyl group.

Suitable "hydroxy (C 1 -C 6) alkyl" groups include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, 1- (hydroxy) methyl) ethyl, 1-hydroxybutyl, [1- (hydroxymethyl) -1-methylethyl], 3-hydroxypentyl, 3-hydroxy-2-ethylpropyl, 6-hydroxyhexyl and the like, with hydroxy-C 1-4 alkyl being the preferred group and 2-hydroxyethyl being most preferred.

Suitable "protected hydroxy-lower alkyl groups" include acyloxy-lower alkyl groups and the like, wherein the suitable "acyl group" may be the acyl group as defined above for the "protected amino group" and the "acyloxy-lower alkyl group". for example lower alkanoyloxy-lower alkyl group (e.g. formyloxymethyl group, 1-formyloxyethyl group, 2-formyloxyethyl group, 2-acetoxyethyl group, 3-acetoxypropyl group, 1- (propionyloxymethyl) ethyl, 1-butyloxy-butyl, 1-hexanoyloxy-butyl, 1- (pivaloyloxymethyl) -1-methylethyl, 3-phosphorus-4,9 + 3 9-pentyl-. group, 3-formyloxy-2-ethyl-propyl, 6-acetoxy-hexyl, etc.], carbamoyloxy-lower alkyl group (e.g., carbamoyloxymethyl, 1-carbamoyloxyethyl, 2- carbamoyloxyethyl group, 3-carbamoyloxypropyl group, 1- (carbamoyloxymethyl) ethyl group, 1-carbamoyloxy butyl group t, 1-carbamoyloxymethyl-1-methylethyl, 3-carbamoyloxy-pentyl, 3-carbamoyloxy-2-ethyl-propyl, 6-carbamoyloxy-hexyl, etc.] or the like group; the preferred group being C 1-4 alkanoyloxy-C 1-4 alkyl or carbamoyloxy-C 1-4 alkyl, and most preferred is 2-formyloxyethyl, 2-acetoxyethyl or 2-carbamoyloxyethyl.

Suitable anions include formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluene sulfonate, chloride, bromide, iodide, sulfate, phosphate or the like.

Suitable "cleavage" groups include halogen (e.g., chlorine, bromine, iodine, etc.), acyloxy such as sulfonyloxy (e.g. benzenesulfonyloxy, tosyloxy, mesyloxy, etc.), lower alkanoyloxy (e.g. acetyloxy, propionyloxy, etc.) and the like.

The process of the present invention for the preparation of the novel compounds of the invention is described in detail below.

Procedure 1

The compound of formula I or salts thereof may be prepared by reacting a compound of formula II or an amino-reactive derivative or salt thereof with a compound of formula III or a carboxyl-reactive derivative or salt thereof.

The reactive derivative of the compound of formula (II) at a suitable amino group may be a Shiff-base imino derivative or a tautomeric enamine thereof, which may be prepared by reacting a compound of formula (II) with a carbonyl compound such as an aldehyde, ketone or the like. a silyl derivative by reaction of a compound of formula II with a silyl compound such as bis (trimethylsilyl) acetamide, mono (trimethylsilyl) acetamide, bis (trimethylsilyl) urea or the like producing; and a derivative prepared by reaction of a compound of formula II with phosphorus trichloride or phosgene and the like.

Suitable salts of the compound of formula (II) and its reactive derivatives may be specified for the compound of formula (I).

Suitable carboxyl-reactive derivatives of the compound of formula (III) include acid halides, acid anhydrides, active acid amides, activated esters and the like. A suitable reactive derivative may be, for example, an acid halide; an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g.

EN 205 939 Β -kylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.,) with dialkylphosphoric acid, sulfuric acid, thiochloric acid, sulfuric acid (e.g. methanesulfonic acid), e.g. with propionic acid, butanoic acid, isobutanoic acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutanoic acid, trichloroacetic acid, etc.) or aromatic carboxylic acid (e.g., benzoic acid, etc.); a symmetric acid anhydride; an activated amide formed with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole, tetrazole, or 1-hydroxy-1H-benzotriazole; or an activated ester (e.g., cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl ester, [(CH ₃ ) ₂ N = CH-], vinyl ester, propalyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesyl phenyl ester, phenyl azophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl- thioester, carboxymethylthioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolylthioester, etc.}, or an ester with an N-hydroxy compound [e.g. hydroxy-1-2 (1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole and the like. skilled ester] and the like ester. These derivatives are selected according to the compound of formula (III) used.

Suitable salts of the compound of formula (I) and its reactive derivatives may be the same as those for the compound of formula (I).

The reaction is usually carried out in conventional solvents such as water, alcohol (e.g. methanol, ethanol, etc.), acetone, dioxane, acetonitrile, chloroform, dichloromethane, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethyl -formamide, pyridine, or any solvent which does not adversely affect the reaction. The above conventional solvents may also be used in admixture.

When the compound of formula (ΙΠ) is used in the free acid or salt form, the reaction is preferably carried out using conventional condensing agents such as Ν, Ν'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N- cyclohexyl-N '- [4- (diethylamino) -cyclohexyl] -carbodiimide, Ν, Ν'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide, N-ethyl-N' - [3- (dimethyl- amino) propyl] carbodiimide, N, N'-carbonylbis (2-methylimidazole), petamethylene ketene-N-cyclohexylimine, diphenyl ketene-N-cyclohexylimine, ethoxyacetylene, alkoxy-1-chloroethylene, trialkyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride, (phosphoryl chloride), phosphorus trichloride, thionyl chloride, oxalyl chloride, lower alkyl haloformate (e.g., ethyl chlorate) , isopropyl chloroformate, etc.), triphenylphosphine, 2-ethyl-7-hydroxybenzisoxazolium salt, 2-ethyl-5- (m-sulfophenyl) isoxazolium hydroxide inner salt, 1- (p- chlorobenzene-sulfonamide nyloxy) -6-chloro-1H-benzotriazole, so-called. Vilsmeier reagent prepared by reaction of N, N-dimethylformamide and thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, or methanesulfonyl chloride or the like, and in the presence of a similar condensing agent.

The reaction may also be carried out on an inorganic or organic base such as an alkali metal carbonate, an alkali metal bicarbonate, a tri-lower alkylamine, a pyridine, a N-lower alkylmorpholine, an N, N-dicis lower alkylbenzylamine or the like. even in the presence of a base.

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

Procedure 2

The compound of formula (Ib) or a salt thereof of the present invention may be prepared from the compound of formula (Ia) or a salt thereof by deprotection of the amino group in R _a '.

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

The hydrolysis is preferably carried out in the presence of a base or an acid, including Lewis acids. Suitable bases include inorganic bases and organic bases such as an alkali metal (e.g. sodium, potassium, etc.), an alkaline earth metal (e.g., magnesium, calcium, etc.), their hydroxide or carbonate or bicarbonate, a trialkylamine (e.g. triethyl). amine, trimethylamine, etc.), picoline, 1,5-diazabicyclo (4.3.0) non-5-ene, 1,4-diazabicyclo (2.2.2) octane, 1,8-diazabicyclo (5.4.0) undec -730 me or similar base.

A suitable acid may be an organic acid (e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.), an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, aqueous hydrobromic acid, hydrochloric acid, etc.).

The deprotection process using a Lewis acid such as trihaloacetic acid (e.g. trichloroacetic acid, trifluoroacetic acid, etc.) or the like is preferably carried out in the presence of a cationic binder (e.g. anisole, phenol, etc.).

The reaction is usually carried out in a solvent such as water, an alcohol (e.g. methanol, ethanol, etc.), dichloromethane, tetrahydrofuran, a mixture thereof, or any other solvent which does not adversely affect the reaction. A liquid base or acid may also be used as a solvent. The reaction temperature is not critical and the reaction is usually carried out under heating or cooling.

The deprotection method used is 50 weeks of chemical reduction and catalytic reduction.

Suitable reducing agents for the chemical reduction process include a metal (e.g., tin, zinc, iron, etc.) or a metal compound (e.g., chromium chloride, chromium acetate, etc.) and an organic or inorganic acid (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, a mixture of toluenesulfonic acid, hydrochloric acid, aqueous hydrobromic acid, etc.).

The catalysts used in the catalytic reduction process may be those conventionally used. For example, platinum catalysts (e.g.

EN 205 939 Β platinum plate, platinum sponge, black platinum, colloidal platinum, platinum oxide, platinum fiber, etc.), palladium catalyst (e.g. palladium, etc.), nickel catalyst (e.g., reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalyst (e.g., reduced cobalt, Raney cobalt, etc.), iron catalyst (e.g., reduced iron, Raney iron, etc.), a copper catalyst (e.g., reduced copper, Raney copper, Ullman copper, etc.) and the like.

The reduction is usually carried out in a conventional solvent which does not adversely affect the reaction, such as water, methanol, ethanol, propanol, Ν, Ν-dimethylformamide or a mixture thereof.

In addition, if the acids used in the above chemical reduction process are liquid, they may also be used as solvents. Further, the solvent used in the catalytic reduction may be one of the solvents listed above or other conventional solvents (such as diethyl ether, dioxane, tetrahydrofuran, etc.), or mixtures thereof.

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

The process of the present invention includes converting a protected amino group in R ³ into an amino group, a protected carboxyl group in R ³ into a carboxyl group, and a protected hydroxy lower alkyl group in R ^4. converting it to a hydroxy-lower alkyl group.

Procedure 3

The compound of formula (I) or salt thereof of the present invention may be prepared by reacting a compound of formula (IV) or a salt thereof with a compound of formula (V) or a salt thereof.

Suitable salts of the compound of formula (IV) may be the same as those for the compound of formula (I).

Suitable salts of the compound of formula V include organic acid salts (e.g., formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.), inorganic acid salts (e.g., hydrochloride). , hydrobromide, sulfate, phosphate, etc.) and the like.

The reaction is carried out in a solvent such as water, phosphate buffer, acetone, chloroform, acetonitrile, nitrobenzene, dichloromethane, ethylene chloride, formamide, Ν, Ν-dimethylformamide, methanol, ethanol, diethyl ether. , tetrahydrofuran, dimethylsulfoxide, or any other solvent which does not adversely affect the reaction, which solvents are preferably polar. Among the solvents, hydrophilic materials may be used in admixture with water. If the material of formula (V) is liquid, it may also be used as a solvent. The reaction is preferably carried out in the presence of a base such as an inorganic base such as an alkali metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, an organic base such as trialkylamine or the like. The reaction temperature is not critical and the reaction is usually carried out under cooling or heating. The reaction of the process is preferably carried out in the presence of an alkali metal halide (e.g., sodium iodide, potassium iodide, etc.), an alkali metal thiocyanate (e.g., sodium thiocyanate, potassium thiocyanate, etc.).

The anion X can be anion derived from the cleavage group Y or any other conventional anion.

Procedure 4

According to the invention, the compound of formula (Id) or its salt can be prepared from the compound of formula (Ic) or its salt by deprotecting the carboxyl group of the group R _b ³ .

The reaction can be carried out according to process 2 and thus the reaction mode and conditions (e.g. base, acid, catalyst, solvent, reaction temperature, etc.) are as described in process 2.

The process of the present invention includes converting a protected amino group of R ¹ and / or R ⁵ group and / or a R ⁴ group into a protected hydroxy-carbon alkyl group by the above reaction.

Procedure 5

The compound of formula (If) of the present invention or salt thereof may be prepared by removing the hydroxyl protecting group from the group R _a ⁴ of the compound of formula (le) or salt thereof.

The reaction is carried out as described in Method 2 above, and the reaction mode and conditions (e.g., base, acid, catalyst, solvent, reaction temperature, etc.) are the same as those described in Method 2.

The process of the present invention includes the process of converting a protected amino group of R ¹ and / or R ⁵ and / or a protected carboxyl group of R ^{3 into an} amino group and / or a carboxyl group by reaction.

Procedure 6

The compound of formula (Ih) or salt of the present invention may be prepared by removing the amino protecting group from the group R _a ³ of the compound of formula (Ig) or salt thereof.

The reaction is carried out according to the procedure of Process 2 and the reaction mode and conditions (e.g. base, acid, catalyst, solvent, reaction temperature, etc.) are the same as those described for Process 2.

The process of the present invention includes the case where the protected amino group of the R ¹ group and / or the protected carboxyl group of the R ³ group and / or the protected hydroxy lower alkyl group of the R ⁴ group are converted into an amino group and / or to a carboxyl group and / or a hydroxy lower alkyl group by reaction.

HU

The reactions of Processes A) -C) for the preparation of the starting compound of formula II or its salts are described in Examples 2-6. is carried out in accordance with the procedure for the preparation of the compound of formula (I) or its salts.

The efficacy of the compound of formula (I) obtained by the process of the present invention was demonstrated by testing MIC (minimum inhibitory concentration) of representative compounds of formula (I) as follows.

Test method

An in vitro antibacterial assay was performed using a double agar agar dilution method as follows.

A set of overnight incubated assay cultures prepared on tryptase (10 ⁸ viable cells per ml) was inoculated in strips on heart infusion agar (HI agar) containing the concentrations of the test drug gradient. The minimum inhibitory concentration (MIC) is expressed as micrograms / ml after 20 hours incubation at 37 ° C.

Test compound (1) 7β- [2- (2-Aminothiazol-4-yl) -2- (methoxyimino) -acetamido] -3 - {[(3-amino-2- (2-hydroxy) ethyl) -1-pyrazoloyl-methyl} -3-cephem-4-carboxylate (syn isomer) (compound prepared in Example 4).

Test result

MIC microg / ml

Bacterial test compound tested (1)

Pseudomonas aeruginosa 26 0.39

For pharmaceutical use, the compound of formula (I) produced by the process of the invention and pharmaceutically acceptable salts thereof may be used in conventional pharmaceutical forms containing the above compound as an active ingredient and containing pharmaceutically acceptable additives and carriers. Pharmaceutically acceptable carriers include inorganic or organic solid or liquid carriers suitable for oral, parenteral and topical administration. The pharmaceutical form may be solid, such as tablets, granules, powders, capsules, or liquids, such as solutions, suspensions, syrups, emulsions, lemonades, and the like.

Where appropriate, the aforesaid formulations may contain additional additives such as stabilizers, wetting agents and other commonly used additives such as lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, white earth, sucrose, wheat starch, talc, gelatine, agar, pectin, peanut oil, olive oil, cocoa butter, ethylene glycol and the like.

The dosage of the compound of formula (I) may vary, depending on the age of the patient being treated, the condition of the patient, the type of disease, the type of compound of formula (I) used, and so on. Generally 1 mg to 4000 mg daily

A dose of 939 B 2 or greater may be used. The average unit dose may be about 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg, 2000 mg of the compound of the invention in patients infected with pathogenic microorganisms.

The process of the invention is illustrated in detail in the following Preparations and Examples.

Preparation 1

A mixture of acetic anhydride (11.13 ml) and formic acid (5.93 ml) was stirred at room temperature for 30 minutes. To the solution was added 5 g of 5-amino-1- (2-hydroxyethyl) pyrazole under ice-cooling and the mixture was stirred for 1 hour at 30-40 ° C. The reaction mixture was poured into water, tetrahydrofuran and ethyl acetate and adjusted to pH 6 with aqueous sodium bicarbonate. The organic phase was separated and the aqueous phase was extracted three times with tetrahydrofuran and ethyl acetate. The organic phases were combined, dried over magnesium sulfate and concentrated in vacuo. 5.18 g of 5-formamido-1- (2-formyloxyethyl) pyrazole are obtained.

IR (Nujol): 3180,1705,1660 cmNMR (DMSO-d _O 8): 4.21-4.61 (4H, m), 6.11 and 6.34 (lH, each d, J = 3 Hz ), 7.47 (1H, d, J = 3Hz), 8.00 (1H, s), 8.33 (1H, s).

Preparation 2 Benzhydryl 7 P - [(t-butoxycarbonyl) amino] -3-chloromethyl-3-cephem-4-carboxylate g and 5.82 g sodium iodide in 20 ml Ν, Ν-dimethyl- of Formamide (21.34 g) at room temperature was added 5-formamido-1- (2-formyloxyethyl) pyrazole and the reaction mixture was stirred at the same temperature for 24 hours. The mixture was poured into a mixture of water and ethyl acetate. The organic layer was separated, washed with water, brine and dried over magnesium sulfate. The solution was concentrated in vacuo to give 29.6 g of benzhydryl-7β - [(t-butoxycarbonyl) amino] -3 - {[3-formamido-2- (2-formyloxyethyl) -1-pyrazolo] methyl } -3-cephem-4-carboxylate iodide is obtained.

IR (Nujol): 1780.1720 ^cm-1 NMR _(DMSO-d6, δ): 1.49 (9H, s), 3.43 (2H, br s), 4.14 to 4.38 (2H, m ), 4.52-4.73 (2H, m), 5.15 (1H, d, J = 5Hz), 5.40 (2H, broad s), 5.67 (1H, dd, J = 5) Hz and 8 Hz), 6.88 (1H, s), 7.02 (1H, d, J = 3 Hz), 7.187.52 (10H, m), 7.94 (1H, d, J = 8 Hz) ), 7.99 (1H, s),

8.27 (1H, d, J = 3Hz), 8.51 (1H, broad s).

Preparation 3

29.5 g benzhydryl-7β - [(t-butoxycarbonyl) amino] -3 {[3-formamido-2- (2-formyloxyethyl) -1-pyrazole] -methyl} 3-cephem-4- To a mixture of carboxylate iodide and 30 ml of anisole in 90 ml of dichloromethane was added 60 ml of trifluoroacetic acid under ice-cooling. After stirring for 1 hour at room temperature, the reaction mixture was poured into a mixture of 600 ml of diisopropyl ether and 600 ml of ethyl acetate. The precipitate was filtered off to give 22.7 g of the bis (trifluoroacetic acid) salt of 73-amino-3 - {[3-formamido-2- (2-formyloxyethyl) -1-pyrazoloylmethyl} -3-cephemethoxycarboxylate.

IR (Nujol): 1780,1715,1660 ^cm-1

HU 205 939 Β

NMR (DMSO-d δ _sixth): 3.53 (2H, br s), 4.28-4.56 (2H, m), 4.78 to 4.99 (2H, m), 5.29 ( 2H, br s), 5.53 (2H, br s), 7.14 (1H, d, J = 3Hz), 8.22 (1H, s),

8.46 (1H, d, J = 3Hz), 8.63 (1H, s).

Preparation 4 The bis (trifluoroacetic acid) salt of 7P-amino-3 - {[3-formamido-2- (2-formyloxyethyl) -1-pyrazolo] methyl} -3-cephem-4-carboxylate was prepared in 50 ml of methanol. Concentrated hydrochloric acid (5.67 mL) was added to the solution at room temperature and the reaction mixture was stirred at the same temperature for 3 hours. The mixture was then added dropwise to 500 ml of ethyl acetate. The precipitate was filtered off and 6.1 g of 7? -Amino-3 - {[3-amino-2- (2-hydroxyethyl) -1-pyrazoloylmethyl} -3-cephem-4-carboxylate trihydrochloride were obtained. and 5.85 g of N-trimethylsilylacetamide in 40 ml of tetrahydrofuran. The reaction mixture is stirred for 1 hour at 10-15 ° C and then poured into 500 ml of diethyl ether. The precipitate was filtered off and 2.55 g of 7β- [2- (2-formamidothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - {[3-amino-2- (2- hydroxyethyl) -1-pyrazolo] methyl} 3-cephem-4-carboxylate dihydrochloride (syn isomer).

IR (Nujol): 1770, 1660 cm -1

NMR _(DMSO-d6, δ): 3.30 (2H, m) 3.68 (2H, m), 3.92 (3H, s), 4.31 (2H, m), 5.29 (1 H , d, J = 5Hz), 5.32 (2H, m), 5.88 (1H, dd. J = 5Hz and 8Hz), 5.99 (1H, d. J = 3Hz), 7 , 48 (1H, s), 8.12 (1H, d, J = 3Hz), 8.59 (1H, s), 9.81 (1H, d, J = 8Hz).

The following compounds (Examples 2 and 3) were prepared according to the procedure of Example 1.

Example 2

7β- [2- (2-Απιϊηο ΙΪΗΖο1-4-ϊ1) -2- (ιηεΙοχΐ-ϊηηίηο) -3εεΐamido] -3- {[3-amino-2- (2-hydroxyethyl) -l-pyrazolio] - methyl} -3-cephem-4-carboxylate (syn isomer).

IR (Nujol): 3300, 1770, 1640 cm ^-1

Example 3

7β - {[2- (2-Αππηο ίΪ3ζο1-4-ΐ1) -2- (0ϊί1υθΓ-πιεΙοχί) -ίmino] acetamido} -3 - {[3-amino-2- (2-hydroxyethyl) - 1-pyrazolyl] methyl} -3-cephem-4-carboxylate (syn isomer).

IR (Nujol): 3300, 1760, 1660 cm -1

Example 4

2.5 g of 7β- [2- (2-hydroxyethyl) -2- (2-hydroxyethyl) acetamide] -3 - {[3-amino-2- (2-hydroxyethyl) -pyrazolyl] To a solution of methyl methyl -3-cephem-4-carboxylate dihydrochloride (syn isomer) in methanol (12.5 ml) was added concentrated hydrochloric acid (0.88 ml) at room temperature. After stirring for 2 hours at the same temperature, the reaction mixture was poured into 500 ml of ethyl acetate and the precipitate was filtered off. The precipitate was dissolved in water (100 mL) and adjusted to pH 2 with 5% aqueous sodium bicarbonate. The solution was subjected to column chromatography on a macroporous nonionic "Diaion HP-20" adsorption resin column (Mitsubishi Chemical Industries). The desired compound was eluted with 10% diisopropanol and then lyophilized and 0.43 g of 7β- [2- (2-3τηίηο-ΐί3ζο1-4-ϊ1) -2- (πιείοχΐ-Ηηπιο) -ΗεέΐΗπιί8 '<

do] -3 - {[3-amino-2- (2-hydroxy-ethyl) -1-pyrazolo] methyl} -3-cephem-4-carboxylate (syn isomer) is obtained.

IR (Nujol): 3300, 1770, 1640 cm ^-1

NMR _(DMSO-d6, δ): 3.00 and 3.30 (2H, AB q, J =

Hz), 3.60 (2H, m), 3.83 (3H, s), 4.37 (2H, m),

5.06 (1H, d, J = 5Hz), 5.18 (2H, broad s), 5.65 (1H, dd, J = 5Hz and 8Hz), 5.84 (1H, d, J = 3Hz), 6.71 (1H, s), 7.18 (2H, broad s), 7.38 (2H, broad s), 8.08 (1H, d, J = 3Hz), 9 , 52 (1H, d, J = 8Hz).

The following compound (Example 5) was prepared according to the procedure of Example 4.

Example 5

73 - {[2- (2-Amino-thiazol -4-yl) -2- (difluoromethoxy) imino] acetamido} -3 - {[3-amino-2- (2-hydroxyethyl) -1-pyrazoloyl-methyl) -3-cephem-4-carboxylate (syn isomer).

IR (Nujol): 3300, 1760, 1660 cm @ -1. Example g Benzhydryl-73- [2-difluoromethoxy-imino] -2 - {[2- (trityl-amino) -thiazol-4-yl] -acetamido} -3- (chloromethyl) -3-cephem-4- To a suspension of the carboxylate (syn isomer) and 0.856 g of sodium iodide in 5 ml of N, N-dimethylformamide is added 4.18 g of 5-formamidol- (2-formyloxyethyl) pyrazole at room temperature. The reaction mixture was stirred for 24 hours and then poured into a mixture of ethyl acetate and water. The organic layer was separated and washed with brine and dried over magnesium sulfate. The organic solution was concentrated in vacuo and the residue dissolved in tetrahydrofuran. The solution was subjected to column chromatography on Amberlit IRA 400 (CF ₃ COO ~) (Rohm and Haas Co.) ion exchange resin. The title compound was eluted with tetrahydrofuran and the solution was concentrated in vacuo. 4.80 g of benzhydryl- [2- (difluoromethoxy) -imino] -2 - {[2- (trityl-amino) -thiazol-4-yl] -acetamido} 3 - {[3-formamido-2- The (2-formyloxyethyl) -1-pyrazolo] methyl} -3-cephem-4-carboxylate trifluoroacetic acid salt (syn isomer) is obtained.

IR (Nujol): 1780, 1720, 1675 cmNMR _(DMSO-d6, δ): 3.50 (2H, m) 3.65 (2H, m), 4.35 (2H, m), 5.25 ( 1H, d, J = 5Hz), 5.50 (2H, broad s),

5.88 (1H, dd, J = 5 Hz), 6.91 (1H, s), 7.03 (1H, s),

7.04-7.70 (27H, m), 8.08 (1H, s), 8.33 (1H, d, J =

Hz), 8.67 (1H, s), 9.05 (1H, s), 10.05 (1H, d, J =

Hz).

The following compound (Example 7) was prepared according to the procedure of Example 6.

Example 7

7β- [2- (2-Αιηίηο Ιϊηζο1-4-ί1) -2- (πιε (οχί-ίηιίηο) -3εεΙainido] -3 - {[3-amino (2-hydroxyethyl) -l-pyrazolio] -methyl} 3-cephem-4-carboxylate (syn isomer).

IR (Nujol): 3300, 1770, 1640 cm ^-1

Example 8

4.7 g of benzhydryl-7β- [2- (difluoromethoxy) dmino] - {[2- (trityl-amino) -thiazol-4-yl] -acetamido} -3 - {[3-formamido-2- (2-formyloxy) -ethyl) -1-pyrazolyl] methyl} -3-cephem-4-carboxylate (syn isomer) 15 ml dichloromethane and 5 ml

To a solution of HU in anisole mixture was added 10 ml of trifluoroacetic acid under ice-cooling. The reaction mixture

After stirring for 1.5 hours, the reaction mixture was poured into diisopropyl ether. The precipitate was filtered off and dissolved in water, and the solution was adjusted to pH 12 with ice-cold 1N sodium hydroxide. The mixture was stirred at the same temperature for 10 minutes and then adjusted to pH 2 with 1N hydrochloric acid. The solution was column chromatographed on a macroporous nonionic "Diaion HP-20" adsorption resin. The desired compound is eluted with 10% diisopropyl alcohol and lyophilized. 0.80 g of 7β- [2- (2-Amino-thiazol-4-yl) -2 - {[(difluoromethoxy) -amino] -acetamido} -3 - {[(3-formamido-2) - ( 2-hydroxyethyl) -1-pyrazolo] methyl} -3-cephem-4-carboxylate (syn isomer) is obtained.

IR (Nujol): 3250,1770,1665 ^cm-1

NMR (D ₂ O and DMSO-d ₆ , δ): 3.11 and 3.50 (2H, ABq,

J = 18 Hz), 3.85 (2H, m), 4.60 (2H, m), 5.22 (1H, d,

J = 5 Hz), 5.36 (2H, broad s), 5.81 (1H, d, J = 5 Hz),

6.91 (1H, t, J = 71Hz), 7.05 (1H, d, J = 3Hz), 7.18 (1H, s), 8.24 (1H, d, J = 3Hz) , 8.44 (1H, s).

Example 9

0.7 g 7P- [2- (2-Amino-thiazol-4-yl)] - 2 - {[(difluoromethoxy) -amino] -acetamido} -3 - {[3-formamide-2- (2) To a suspension of hydroxyethyl) -1-pyrazolo] methyl} -3-cephem-4-carboxylate (syn isomer) in methanol (3.5 mL) was added concentrated hydrochloric acid (0.42 mL) at room temperature. The reaction mixture was stirred at the same temperature for 2 hours and then poured into ethyl acetate. The precipitate was filtered off and dissolved in water. The pH of the solution is adjusted to 2 with 5% sodium bicarbonate solution and the solution is subjected to column chromatography on a macroporous nonionic adsorption resin "Diaion HP-20". The desired compound was extracted with 10% diisopropanol and 0.41 g of 7β- [2- (2-aminothiazol-4-yl)] - 2 - {[(difluoromethoxy) imino] acetamido} -3 {[3-Amino-2- (2-hydroxyethyl) -1-pyrazolo] methyl} -3-cephem-4-carboxylate (syn isomer) is obtained.

IR (Nujol): 3300.1760.1660 cm ^-1

NMR (D ₂ O, δ): 3.02 and 3.35 (2H, ABq, J = 18 Hz),

3.78 (2H, m), 4.28 (2H, m), 4.95 and 5.16 (2H, ABq, J = 16Hz), 5.16 (1H, d, J = 5Hz), 5.76 (1H, d, J =

Hz), 5.92 (1H, d, J = 3Hz), 6.86 (1H, 5, J =

Hz), 7.16 (1H, s), 7.83 (1H, d, J = 3 Hz). ·

The following compound (Example 10) was prepared according to the procedure of Example 9.

Example 10

7p- [2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - {[3-amino-2- (2-hydroxyethyl) -i-pyrazolio] methyl} -3-cephem-4-carboxylate (syn isomer).

IR (Nujol): 3300,1770,1640 ^cm-1

Example 11

6.5 g 7P- [2- (2-Amino-thiazol-4-yl) -2- (methoxyimino) acetamido] -3 - ([3-amino-2- (2-hydroxyethyl) -1 To a solution of the pyrazolo] methyl} -3-cephem-4-carboxylate (syn isomer) in 6.5 ml of water at room temperature was added 6.5 ml of 2N sulfuric acid.

939 B 2 while crystalline material precipitates. The crystalline material was filtered off, washed with acetone and 5.92 g of 7β- [2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - {[3-amino- 2- (2-Hydroxyethyl) -1-pyrazolo] methyl} -3-cephem-4-carboxylate (syn isomer) is obtained as the sulfuric acid salt.

NMR _(DMSO-d6, δ): 3.13 to 3.83 (2H, m), 3.40 to 3.83 (4H, m), 5.15 (IH, d, J = 5 Hz); 5.05 and 5.30 (2H,

ABq, J = 13 Hz), 5.79 (1H, d-d, J = 5 Hz and 8 Hz),

5.88 (1H, d, J = 3Hz), 6.71 (1H, s), 7.28 (2H, broad s), 7.95 (1H, d, J = 3Hz), 9.57 (1H, d, J = 8Hz).

Preparation 5 7P-3 - {[3-amino-2- (2-hydroxyethyl) -1-pyrazolo] methyl} -3-cephem-4-carboxylate trihydrochloride (g) was dissolved in water (264 ml) and the aqueous solution The column is chromatographed on a Diaion HP-20 column using water as eluent. The fractions containing the desired material were combined and 1.15 L of isopropanol was added dropwise to the combined solution under ice-cooling. The mixture was stirred for 1.5 hours under ice-cooling, whereupon crystalline material precipitated. The crystalline material is filtered off, washed with isopropanol-water (10: 1) under ice-cooling and then dried over phosphorus pentoxide. 29.95 g of 73-amino-3 - {[3-amino-2- (2-hydroxyethyl) -1-pyrazoloylmethyl} -3-cephem-4-carboxylate hydrochloride dihydrate are obtained.

IR (Nujol): 3270.1790.1560-1635 cm ^-1

NMR _(DMSO-d6, δ): 3.43 to 3.77 (2H, m), 4.47 to 5.07 (4H, m), 5.07 (IH, d, J = 5 Hz); 5.12 and 5.38 (2H,

ABq, J = 16Hz), 5.92 (1H, d, J = 3Hz), 7.56 (2H, broad s), 8.11 (1H, d, J-3Hz).

Elemental analysis according to the formula C ₁₃ H ₁₇ N ₅ O ₄ S x HCl.x 2 H ₂ O:

Calculated: C, 37.90; H, 5.38; N: 17.00; Cl, 8.60; Found: C, 37.82; H, 5.56; N: 16.73; Cl, 8.60.

Preparation 6

A mixture of acetic anhydride (44.5 ml) and formic acid (22.3 ml) was stirred at room temperature for one hour. To the mixture was added 5-amino-1- (2-hydroxyethyl) pyrazole (30 g) at 0-10 ° C, and the reaction mixture was stirred for 30 minutes under ice-cooling. The mixture was then poured into ice water, and the pH was adjusted to 40% with sodium carbonate solution.

Adjust to 10.5 and stir the mixture for 30 minutes under ice-cooling. The mixture was then extracted six times with a mixture of tetrahydrofuran and ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated in vacuo. 30.8 g of 5-formamido-1- (2-hydroxyethyl) pyrazole are obtained.

M.p. 109-112 ° C

IR (Nujol): 3230, 1695, 1570, 1540 cm

NMR _(DMSO-d6, δ): 3.62 to 3.95 (2H, m), 3.98 1.32 (2H, m), 6.22 and 6.36 (lH, each d, J - 3 Hz), 7.42 (1H, d, J = 3 Hz), 8.32 and 8.36 (1H, all s).

Preparation 7 To a suspension of 5-formamido-1- (2-hydroxyethyl) -pyrazole (g) in acetonitrile (50 ml) was added dropwise chlorosulfonyl isocyanate (0.77 ml) at -15 to -20 ° C. THE

The reaction mixture was stirred under ice-cooling for 3 hours, then 1 ml of water was added and allowed to stand overnight. Adjust the pH of the solution with 5N sodium hydroxide solution

Adjust to 7.5 and basify to 8.5 with 1N sodium hydroxide solution. The organic layer was separated and the aqueous layer was extracted with tetrahydrofuran. The extract and the organic phase were combined and dried over magnesium sulfate. The solvent was distilled off and the residue was recrystallized from ethyl acetate to give 0.60 g of 5-amino-1- (2-carbamoyloxyethyl) pyrazole.

NMR (DMSO-d _é, δ): 3.83-4.35 (4H, m), 4.80 to 5.18 (2H, brs), 5.32 (IH, d, J = 3Hz) , 6.33-6.87 (2H, broad), 7.08 (1H, d, J = 3Hz).

Preparation 8

According to Preparation 6, 3.69 g of 5-formamido-1- (2-carbamoyloxyethyl) pyrazole are obtained starting from 3.3 g of 5-amino-1- (2-carbamoyloxyethyl) pyrazole.

NMR _(DMSO-d6, δ): 4.22 (4H, s), 6.17 to 6.40 (lH, m) 20

6.40-6.63 (2H, m), 7.30-7.53 (1H, m), 8.13-8.47 (1H, m).

Example 12

1.5 g of benzhydryl 7 P- [2- (2-formamidothiazol-4-yl) -2- (methoxyimino) acetamido] -3-chloromethyl-3-cephem-4-carboxylate (syn isomeric) To a solution of 3 ml of N, N-dimethylformamide in nitrogen was added 0.36 g of sodium iodide. After stirring for 30 minutes at room temperature, 1.42 g of 5-formamido-1- (2-carbamoyloxyethyl) pyrazole was added. After stirring for 24 hours at the same temperature, 50 ml of ethyl acetate and 50 ml of ice-water are added. The organic layer was separated and washed with water followed by aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo.

1.60 g of benzhydryl-7β- [2- (2-formamido-thiazol-4-yl) -2- (methoxyimino) -acetamido] -3- {formamide-2- (2-carbamoyloxyethyl) -1- pyrazoloyl-methyl} -3-cephem-4-carboxylate trifluoroacetate (syn isomer). 40

Example 13

By the procedure of Example 8, 1.6 g of benzhydryl-7β- [2- (2-formamidothiazol-4-yl) -4- (methoxyimino) acetamido] -3 - {[3-formamido- Starting from 2- (2-carbamoyloxyethyl) -1-pyrazolo] methyl} -3-cephem-4-carboxylate trifluoroacetate (syn isomer), 1.10 g of 73- [2- (2-formamidothiazole) 4-yl) -2- (methoxyimino) -acetamido] -3 - {[3-formamido-2- (2-carbamoyloxy-ethyl) -1-pyrazolyl] -methyl} -3-ces-metal-4 carboxylate (syn isomer) was prepared.

Example 14

By the procedure of Example 9, 7β- [2- (2-formamido-thiazol-4-yl) -2- (methoxyimino) acetamido] -3 - {[3-formamido-2- (2-carbamoyloxy) ethyl) -1-pyrazolo] methyl} 3-cephem-4-carboxylate (syn isomer) 0.10 g of 73- [2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(3-amino-2-) 2-carbamoyloxyethyl] -1- 60 pyrazolio] -ethyl} -3-cephem-4-carboxylate (syn isomer).

R (Nujol): 3200-3300, 1760, 1710, 1650 cm -1 NMR (DMSO-d ₆ , δ): 3.0-3.90 (2H, m), 3.90-4.27 (4H,

m), 3.82 (3H, s), 4.40-5.47 (5H, m), 5.47-5.77 (1H, m), 5.81 (1H, d, J = 3Hz). ), 6.71 (1H, s), 6.90-7.57 (4H, in), 7.97 (1H, d, J = 3Hz), 9.51 (1H, d, J = 8Hz) ).

Preparation 9

According to Preparation 1, 5-formamido-4-methyl-1- (2-formyloxyethyl) pyrazole was prepared.

IR (Nujol): 3180, 1715, 1660 cnr '

NMR _(DMSO-d6, δ): 1.81 and 1.86 (3H, each s);

4.01-4.48 (4H, m), 7.25 and 7.40 (1H, each s),

8.06 (1H, s), 8.22 and 9.13 (1H, all s).

Preparation 10

5 g of 5-anino-1- (2-hydroxyethyl) -pyrazole are added to 14.7 ml of acetic anhydride with stirring and ice-cooling. Pyridine (6.3 ml) was added and the mixture was stirred at 25 ° C for 2 hours.

The reaction mixture was added to a mixture of ethyl acetate (50 mL) and aqueous sodium chloride solution (50 mL), and then aqueous sodium bicarbonate solution was added and the pH was adjusted to 7.0. The aqueous phase was extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was dried over magnesium sulfate, the magnesium sulfate was filtered off and the filtrate was concentrated in vacuo. 5.98 g of 5-acetamido-1- (2-acetoxyethyl) -pyrazole are obtained.

M.p. 83-84 ° C

IR (Nujol): 3270, 1750, 1670, 1565 cm ^-1

NMR _(DMSO-d6, δ): 1.93 (3H, s), 2.03 (3H, s), 4.22 (4H, br s.), 6.13 (IH, d, J = 2 Hz), 7.32 (1H, d, J =

Hz), 9.76 (1H, s).

The following compounds (Preparations 11-13) were prepared according to the procedure of Preparation 2.

11. Production

Benzhydryl 7? - [(t-butoxycarbonyl) amino] -3 - [(4-methyl-3-formamido-2-) 2-formyloxyethyl] -l-pyrazolio] methyl} -3-cephem-4-carboxylate iodide.

IR (Nujol): 3250, 1780, 1710, 1680 cm @ -1

NMR _(DMSO-d6, δ): 1.53 (9H, s), 1.97 (3H, s), 3.51 (2H, br s), 4.04 to 4.42 (2H, m) , 4.52-4.78 (2H, m), 5.08 (1H, d, J = 5Hz), 5.39 (2H, broad s), 5.61 (1H, dd, J5Hz and 8Hz), 6.86 (1H, s), 7.08-7.52 (10H, m), 7.93 (1H, s), 8.18 (1H, s), 8.34 (1H, s), 9.12 (1H, s).

Preparation 12

Benzhydryl 7? - [(t-butoxycarbonyl) amino] -3 - [(3-acetamido-2-) 2-acetoxy-ethyl] -l-pyrazolio] methyl} -3-cephem-4-carboxylate iodide.

IR (Nujol): 1780, 1720, 1230 cm -1

NMR _(DMSO-d6, δ): 1.41 (9H, s), 1.86 (3H, s), 2.25 (3H, s), 3.40 (2H, br s), 4.0 -4.4 (4H, m), 5.12 (1H, d, J = 5Hz), 5.37 (2H, s), 5.60 (1H, dd, J = 8Hz)

Hz), 6.85 (1H, s), 7.24 (1H, d, J = 3Hz), 7.1-7.6 (10H, m), 7.90 (1H, d, J = 8 Hz), 8.21 (1H, d, J =

Hz), 11.17 (III, s).

HU 205 939 Β

13. Production

Benzhydryl-7β - [(t-butoxycarbonyl) amino] -3 [(ε-formamido-2-) 2-hydroxyethyl] -1-pyrazolo] methyl} 3-cephem-4-carboxylate iodide.

IR (Nujol): 3300, 1780, 1710, 1560, 1150 cm- '

NMR (DMSO-d6, δ): 1.43 (9H, s), 3.53 (2H, s s),

4.0-4.5 (4H, m), 5.15 (1H, d, J = 5Hz), 5.40 (2Η, s),

5.55 (1H, dd, J = 8Hz and 5Hz), 6.90 (1H, s), 7.01 (1H, d, J = 3Hz), 7.1-7.5 (10H, m), 7.97 (1H, d, J =

Hz), 8.28 (1H, d, J = 3Hz), 8.50 (1H, s).

The following compounds (Preparations 14-16) were prepared by the procedure of Preparation 3.

Preparation 14

7P-Amino-3 - [(4-methyl-3-formamido-2-) 2-formyloxyethyl] -1-pyrazolo] methyl} -3-cephem-4-carboxylate bis (trifluoroacetic acid) salt.

IR (Nujol): 1780,1710,1670 ^cm-1

NMR (DMSO-d6, δ): 1.98 (3H, s), 3.49 (2H, broad s),

4.22-4.48 (2H, m), 4.61-4.87 (2H, m), 5.18 (2H, broad s), 5.46 (2H, broad s), 8.05 ( 1H, s), 8.23 (1H, s), 8.35 (1H, s).

Preparation 15

7P-Amino-3 - [(3-acetamido-2-) 2-acetoxyethyl] -1-pyrazolo] methyl} -3-cephem-4-carboxylate bis (trifluoroacetic acid) salt.

IR (Nujol): 1780, 1660, 1190 cm ^-1

NMR (DMSO-d6, δ): 1.95 (3H, s), 2.23 (3H, s), 3.46 (2H, broad s), 4.1-4.4 (4H, m), 5.20 (2H, m), 5.46 (2H, s), 7.01 (1H, d, J = 3Hz), 8.27 (1H, d, J3Hz), 11.17 (1Η, s).

Preparation 16

7P-Amino-3 - {[3-formamido-2- (2-hydroxyethyl) -1-pyrazolo] methyl} -3-cephem-4-carboxylate bis (trifluoroacetic acid) salt.

IR (Nujol): 3400.1780.1680.1580.1200.11140 cm- ¹ NMR (DMSO-d6, δ): 3.70 (2H, bs), 4.2-4.7 (4H,

m), 5.23 (2Η, m), 5.50 (2H, s), 7.07 (1H, d, J =

Hz), 8.35 (1H, d, J = 3Hz), 8.53 (1H, s).

The following compounds (Preparations 17 and 18) were prepared according to the procedure of Preparation 4.

Preparation 17

7p-amino-3 - [(4-methyl-3-amino-2-) 2-hydroxy-ethyl] -lpirazolio] methyl} -3-cephem-4-carboxylate-tri-hydrochloride. NMR _(DMSO-d6, δ): 1.94 (3H, s), 3.39 (2H, br s);

3.47-3.78 (2H, m), 4.06-4.42 (2H, m), 5.21 (4H, broad s), 7.87 (1H, s).

Preparation 18

7? -Amino-3 - {[3-amino-2- (2-hydroxyethyl) -l-pyrazolio] methyl} -3-cephem-4-carboxylate-tri-hydrochloride.

IR (Nujol): 3300,3150,1780,1710,1640,1580 ^cm-1 NMR _(DMSO-D6, δ): 3.60 (2H, broad s.), 4.1-4.5 (4H, m )

5.23 (2H, m), 5.30 (2H, s), 5.92 (1H, d, J = 3Hz),

8.07 (1H, d, J = 3Hz).

The following compounds (Examples 15-18) were prepared according to the procedure of Example 1.

Example 15

7p- [2- (2-formamido-thiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(4-methyl-3-amino-2-) 2-hydroxy-ethyl] -1 pyrazoloylmethyl} -3-cephem-4-carboxylate (syn isomer). IR (Nujol): 3150,1770,1650 ^cm-1

NMR _(DMSO-d6, δ): .1,94 (3H, s), 3.32 (2H, br s);

3.52-3.68 (2H, m), 3.88 (3H, s), 4.12-4.39 (2H, m),

5.14 (2H, broad s), 5.19 (1H, d, J = 5Hz), 5.82 (1H, dd, J = 5Hz and 8Hz), 7.36 (1H, s), 7.83 (1H, s), 8.47 (1H, s), 9.63 (1H, d, J = 8Hz).

Example 16

73- [2- (2-formamido-thiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(3-acetamido-2-) 2-acetoxy-ethyl] -l-pyrazolio] - methyl} -3-cephem-4-carboxylate (syn isomer).

IR (Nujol): 1780, 1660, 1550 cm *

NMR (DMSO-d6, δ): 1.96 (3H, s), 2.27 (3H, s), 3.23.6 (2H, m), 3.87 (3H, s), 4.1 -4.5 (4H, m), 5.22 (1H, d, J = 5Hz), 5.43 (2H, s), 5.90 (1H, dd, J = 8Hz and 5Hz), 7.00 (1H, d, J = 3Hz), 7.33 (1H, s), 8.29 (1H, d, J = 3Hz), 8.43 (1Η, s), 9.62 ( 1H, d, J = 8Hz).

Example 17

73- [2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(4-methyl-3-amino-2-) 2-hydroxy-ethyl] - 1-pyrazoloyl-methyl} -3-cephem-4-carboxylate (syn isomer).

IR (Nujol): 3300.1765.1660.1605 cm @ -1. example

73- [2- (2-Amino-thiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(3-acetamido-2) 2-hydroxyethyl] -l-pyrazolio] -methyl} -3-cephem-4-carboxylate (syn isomer).

IR (Nujol): 3200,1770,1600 ^cm-1

Example 19

7p- [2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(4-methyl-3-amino-2-) 2-hydroxy-ethyl] - 1-Pyrazoloyl-methyl} -3-cephem-4-carboxylate (syn isomer) was prepared according to the procedure of Example 4.

IR (Nujol): 3300,1765,1660,1605 ^cm-1

NMR (D ₂ O, δ): 1.97 (3H, s), 3.06 and 3.37 (2H, ABq, J =

Hz), 3.73-3.93 (2H, m), 3.98 (3H, s), 4.19-4.43 (2H, s), 5.09 (2H, broad s), δ, 19 (1H, d, J = 5Hz), 5.89 (1H, d, J = 5Hz), 6.96 (1H, s), 7.71 (1H, s).

Example 20

1.46 g 7P- (2 -) - 2-Formamido-thiazol-4-yl (2- (methoxyimino) -acetamido] -3 - [(3-acetamido-2-) 2-acetoxy-ethyl] -1-pyrazole To a suspension of 1-methyl} -3-cephem-4-carboxylate (syn isomer) in methanol (7.3 ml) was added concentrated hydrochloric acid (0.51 ml) at room temperature, and the reaction mixture was stirred at room temperature for 5 hours.

Ethyl acetate was added to the reaction mixture with stirring and ice-cooling. The resulting amorphous precipitate was dried in vacuo and dissolved in water (40 mL). The pH of the aqueous solution was made basic with stirring at -3-0 ° C with 1N sodium hydroxide solution to 13 and the mixture was stirred at the same temperature for 2 hours. The aqueous solution was then acidified to pH 2 with 1N hydrochloric acid and the solution was

HU 205 939 B is column chromatographed on Diaion HP-20 '. Eluent is 10% aqueous isopropanol. The fractions containing the desired compound were combined and the isopropanol was distilled off and lyophilized. 159 mg 7P- [2- (2-Aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(3-acetamido-2-) 2-hydroxyethyl] -1 -pyrazoloylmethyl} -3-cephem-4-carboxylate (syn isomer) is obtained.

160 ° C (dec.)

IR (Nujol): 3200, 1770, 1600 cm ^- '

NMR (D ₂ O, δ): 2.26 (3H, s), 3.10 (1H, d, J = 18Hz),

3.47 (1H, d, J = 18Hz), 3.8-4.1 (4H, m), 3.95 (3H, s), 5.20 (1H, d, J = 5Hz), 5.32 (2H, s), 5.77 (1H, d,

J = 5Hz), 6.93 (1H, d, J = 3Hz), 6.94 (1H, s), 8.16 (1H, d, J = 3Hz).

The following compounds (Examples 21 and 22) were prepared according to the procedure of Example 6.

Example 21

73- [2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(4-methyl-3-amino-2-) 2-hydroxy-ethyl] - 1-pyrazoloyl-methyl} -3-cephem-4-carboxylate (syn isomer).

IR (Nujol): 3300, 1765, 1660, 1605 cm22. example

7p- [2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(3-acetamido-2) 2-hydroxyethyl] -l-pyrazolio] -methyl} -3-cephem-4-carboxylate (syn isomer).

IR (Nujol): 3200, 1770, 1600 cm ^-1

The following compounds (Examples 23-27) were prepared according to the procedure of Example 8.

Example 23

7p- [2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - ([3-amino-2- (2-hydroxyethyl) -l-pyrazolio] methyl} -3-cephem-4-carboxylate (syn isomer).

IR (Nujol): 3300, 1770, 1640 cm ^- '

Example 24

7p- [2- (2-aminothiazol-4-yl) -2 -) (difluoromethoxy) imino (acetamido) -3 - {[3-amino-2- (2-hydroxyethyl) -lpirazolio ] -methyl} -3-cephem-4-carboxylate (syn isomer). IR (Nujol): 3300.1760, 1660 cm ^-1 ,

Example 25

7É- [2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(3-amino-2-) 2-carbamoyloxy-ethyl] -l-pyrazolio] -methyl} -3-cephem-4-carboxylate (syn isomer).

IR (Nujol): 3200-3300, 1760, 1710, 1650 cm ^-1

Example 26

7p- [2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(4-methyl-3-amino-2-) 2-hydroxy-ethyl] - 1-pyrazole - (- methyl) -3-cephem-4-carboxylate (syn isomer).

IR (Nujol): 3300, 1765, 1660, 1605 cm ^-1

Example 7

73- [2- (2-aminothiazol-4-yl) -2- (methoxyimino) imidazolinyl] -3 - [(3-acetamido-2) 2-hydroxyethyl] -l-pyrazolio] -methyl} -3-cephem-4-carboxylate (syn isomer).

IR (Nujol): 3200.1770, 1600 cm ^-1 .

Claims (9)

PATENT CLAIMS A process for the preparation of a cephem compound of formula (I) or pharmaceutically acceptable salts thereof, wherein: R ¹ is amino, or C 1 -C 6 alkanoylamino or triphenyl (C 1 -C 6) alkylamino, R ² is C 1 -C 6 alkyl optionally substituted with 1 to 3 halogens, R ³ represents a carboxylate group (-COO ^-), a carboxyl group or diphenyl (Cl-C6) alkoxy-carbonyl group, R ⁴ is hydroxy (C 1-6) alkyl, C 1-6 alkanoyloxy (C 1-6) alkyl or carbamoyloxy (C 1-6) alkyl, R ⁵ is amino or C 1-6 alkanoylamino, R ⁶ is hydrogen or C 1-6 alkyl, X ^- is an anion and n is 0 or 1 with the proviso that (i) when R ³ is carboxylate (COO ^- ) then n is 0 and (ii) when R ³ is carboxyl or diphenyl (C1-C6) -alkoxycarbonyl, then n is 1, characterized in that a) a compound of formula II wherein R ³ , R ⁴ , R ⁵ , R ⁶ , X ^- and n are as defined above or an amino-reactive derivative or salt thereof of formula III with a compound wherein R ¹ and R ² are as defined above or with a reactive derivative or a salt thereof on a carboxyl group; obsession b) a compound of Formula Ia wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X ^- and n are as defined above and R _a 'is a protected amino group or R _a * is a salt thereof. the amino protecting group is removed to form a compound of formula Ib or a salt thereof wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X ^- and n are as defined above c) a compound of formula (IV) or a salt thereof, wherein R ¹ and R ² are as defined above and R _a ³ is a carboxyl group or a diphenyl (C 1 -C 6) alkoxycarbonyl group; Y is a cleavage group with a compound of formula (V) or a salt thereof wherein R ⁴ , R ⁵ and R ⁶ are as defined above, or d) a compound of Formula Ic or a salt thereof, wherein R is¹, R², R⁴, R⁵, R⁶, X and n is as defined above, and R _b ³ is a protected carboxyl group, the carboxyl group is removed from R _b ^{3 to} form a compound of formula (Id) or a salt thereof, wherein R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , X ^- and n are as defined above, and R _c ³ is a carboxylate group (COO ^- ) or a carboxyl group, or 1 HU e) a compound of formula (le) or a salt thereof, wherein R ¹ , R ² , R ³ , R ⁵ , R ⁶ , X 'and n are as defined above, and R _a ⁴ is a protected hydroxy (C 1 -C 6) alkyl, the hydroxy protecting group of R _a ^{4 is} removed by a compound of formula (If) or a salt thereof wherein R ¹ , R ² , R ³ , R ⁵ , R ⁶ , X and n are as defined above, and R _b ⁴ is hydroxy (C 1 -C 6) alkyl, or /) a compound of formula (Ig) or a salt thereof, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ , X ^- and n are as defined above, and _R ⁵ is a protected amino group, R is _the group ⁵ the amino group is deprotected to the compound or a salt thereof (Ih) - wherein in formula R ^1, R ^2, R ^3, R ^4, R ^6, X ~ and n are as defined above. (Priority: 09/14/1988) A process according to claim 1 for the preparation of a cephem compound of formula (I) or pharmaceutically acceptable salts thereof, wherein R 1, R 2, R 3, R 5, X- and n are as defined in claim 1, R 4 is hydroxy (I). (C 6 -C 6) -alkyl or (C 1 -C 6) -alkanoyloxy (C 1 -C 6) -alkyl, and R ⁶ is hydrogen a) a compound of formula (II) wherein R ³ , R ⁵ , X 'and n are as defined in claim 1, R ⁴ and R ⁶ are as defined above or an amino-reactive derivative or salt thereof of formula (III) with a compound wherein R ¹ and R ² are as defined in claim 1 or with a reactive derivative or salt thereof on a carboxyl group, or b) a compound of formula (Ia) wherein R ² , R ³ , R ⁵ , X ^- and n are as defined in claim 1, R ⁴ and R ⁶ are as defined above and Ra ¹ is a protected amino group, or a salt thereof. removing the amino protecting group from Ra ^{1 to} form a compound of formula (Ib) or a salt thereof, wherein R ² , R ³ , R ⁵ , X- and n are as defined in claim 1, and R ⁴ and R ⁶ either as specified above, or c) a compound of formula (IV) or a salt thereof, wherein R ¹ and R ² are as defined in claim 1 and R _a ³ is a carboxyl group or a diphenyl (C 1 -C 6) alkoxycarbonyl group; and Y is a cleavage group, with a compound of formula (V) or a salt thereof, wherein R ⁵ is as defined in claim 1, R ⁴ and R ⁶ are as defined above, or d) a compound of formula Ic or a salt thereof wherein R ¹ , R ² , R ⁵ , X ^- and n are as defined in claim 1, R ⁴ and R ⁶ are as defined above and R b ³ is protected carboxyl the carboxyl protecting group is removed from the group Rb ^{3 to} form the compound of formula (1d) or a salt thereof, wherein R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , X and n are as defined above , and R <. ³ represents a carboxylate group (COO ^- ) or a carboxyl group, or 939 B 2 e) a compound of formula (le) or a salt thereof, wherein R is¹, R², R³, R⁵, X and n are as defined in claim 1, R⁶ given above and Ra⁴is a protected hydroxy (C1-C6) alkyl group, Ra⁴ the hydroxy protecting group is removed from the compound of formula (If) or a salt thereof, wherein R¹, R², R³, R⁵, R⁶, X and n is as defined above, and R_b ⁴ is a hydroxy (C 1 -C 6) alkyl group, or f) a compound of formula (Ig) or a salt thereof, wherein R ¹ , R ² , R ³ , X ^- and n are as defined in claim 1, R ⁴ and R ⁶ are as defined above and Ra ⁵ is a protected amino alkyl, ⁵ the group Ra is an amino-protecting group is removed from the compound (Ih) or salt thereof, of formula - wherein in formula R ^1, R ^2, R ^3, R ^4, X and n are as in claim 1, and R ⁶ of the above -. (Priority: September 14, 1987) 3. A method according to claim 1 (I) cephem compound of formula or pharmaceutically acceptable salts thereof, wherein in formula R ^1, R ^2, R ^3, R ^5, X ^- and n are as defined in claim 1, R ⁴ is carbamoyloxy (Cl-C6) alkyl, and R ⁶ represents a hydrogen atom, characterized in that a) a compound of formula (II) wherein R ³ , R ⁵ , X- and n are as defined in claim 1, R ⁴ and R ⁶ are as defined above or an amino-reactive derivative or a salt thereof (H 1); ) wherein R 1 and R ² are as defined in claim 1 or a reactive derivative or salt thereof on a carboxyl group, or b) a compound of formula Ia wherein R ² , R ³ , R ⁵ , X 'and n are as defined in claim 1, R ⁴ and R ⁶ are as defined above and R _a ' is a protected amino group, or salt of R _a ^! removing an amino protecting group from a group to form a compound of formula (Ib) or a salt thereof, wherein R ² , R ³ , R ⁵ , X 'and n are as defined in claim 1, R ⁴ and R ⁶ are as defined above, obsession c) a compound of formula (IV) or a salt thereof wherein R ¹ and R ² are as defined above and R _a ³ is a carboxyl group or a diphenyl (C 1 -C 6) alkoxycarbonyl group; and Y is a cleavage group, with a compound of formula (V) or a salt thereof, wherein R ⁵ is as defined in claim 1 and R ⁴ and R ⁶ are as defined above, or d) a compound of formula (Ic) or a salt thereof wherein R ¹ , R ² , R ⁵ , X ^- and n are as defined in claim 1 and R ⁴ and R ⁶ are as defined above and R b ³ is protected a carboxyl group, the carboxyl group is removed from Rb ^{3 to} form a compound of formula (1d) or a salt thereof, wherein R ¹ , R ² , R ⁵ , X and n are as defined in claim 1, and R ⁴ and R ⁶ is as defined above, and R _c ³ is a carboxylate (COO) or carboxyl group, or e) (Ie) or a salt thereof, wherein in formula R ^1, R ^2, R ^3, R ^5, X ^- and n are defined as in claim 1, ^R6 is as defined above, and R ^₄ is a protected hydroxy (C 1 -C 6) alkyl-cis 13 HU 205 939 Β port. R _from ⁴ and the hydroxy protecting group is removed from a compound of formula (If) or a salt thereof wherein R 'is. R ² , R ⁶ , R ⁵ , X 6 and n are as defined in claim 1, R ⁶ is as defined above, and R _b ⁴ is hydroxy (C 1 -C 6) -alkyl, or f) a compound of formula (Ig) or a salt thereof, wherein R ¹ , R ² , R ³ , X and n are as defined in claim 1, R ⁴ and R ⁶ are as defined above and Ra ⁵ is a protected amino- the amino protecting group in Ra ^{5 is} removed from the compound of formula (Ih) or a salt thereof wherein R ¹ , R ² , R ³ , X- and n are as defined in claim 1, R ⁴ and R ⁶ for the production of the above. (Priority: June 28, 1988) A process for the preparation of a compound of formula (I) or salts thereof according to claim 1, wherein R ¹ is amino or triphenyl (C 1 -C 6) -alkylamino. and R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X 'and n as defined in claim 1, wherein the appropriately substituted starting materials are used. (Priority: September 14, 1988) A process for the preparation of a compound of formula (I) or 'salts thereof according to claim 4, wherein R' is amino, R ³ is a carboxylate (COO ') or carboxyl group, and R ^{2 is} R ⁴ , R ⁵ , R ⁶ , X- and na as claimed in claim 2, characterized in that the appropriately substituted starting materials are used. (Priority: September 9, 1988) A process for the preparation of a compound of formula (I) according to claim 5, wherein R ² is C 1-6 alkyl or dihalo (C 1-6) alkyl and R ¹ , R ³ , R ⁴ , R 1, R ⁶ , X 'and na, as claimed in claim 3, wherein the appropriately substituted starting materials are used. (Priority: September 14, 1988) A process for the preparation of a compound of formula (I) according to claim 6, wherein R ¹ , R ³ , X 'and n in claim 3, R ² are methyl or difluoromethyl, R ⁴ is 2-hydroxyethyl, 2-formyloxyethyl, 2-acetoxyethyl or 2-carbamoyloxyethyl, R ⁵ is amino, formamido or acetamido, and R ⁶ is hydrogen or methyl, characterized in that the appropriately substituted starting materials are used. (Priority: September 14, 1988) The process according to claim 7, wherein 7-beta- [2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - {[3-amino-2- ( 2-hydroxyethyl) -1-pyrazoloyl-methyl) -3-cephem-4-carboxylate (syn isomer) or a sulfuric acid salt thereof, characterized in that the appropriately substituted starting materials are used. (Priority: September 14, 1987) A process for the preparation of a pharmaceutical formulation comprising the active ingredient of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X And n being processed into a pharmaceutical form with pharmaceutically acceptable carriers and / or additives as claimed in claim 1.