KR830001592B1 - Process for preparing cephalosporin antibiotics - Google Patents

Abstract

Cephalosporins I(Ra, Rb = same or different, C1-4 alkyl; Y = carbon linked 5 or 6-membered heterocyclic ring contg. at least one N-atom opt. contg. one or more S-stoms and/or opt. substituted by C1-4 alkyl), having broad spectrum antibiotic activity and high stability to beta-lactamases, were prepd. by reacting compd. II (B = > S or > S →O; R1, R2 = H, carboxyl blocking group; R3 = (protected) amino group; X = substitutable nucleophile residue) with S-nucleophilic substance to form a group of CH2SY.

Description

[Name of invention]

Method for preparing cephalosporin antibiotic

Detailed description of the invention

The present invention relates to a compound of formula (I), a cephalosporin compound useful as an antibiotic, a nontoxic salt thereof (including an intramolecular salt thereof) and a method for preparing a nontoxic metabolic labile ester.

In the above formula, R ^a and R ^b are the same or different, each preferably having 1 to 4 alkyl groups (preferably straight-chain alkyl groups such as methyl, ethyl, n-propyl or n-butyl groups, especially methyl or ethyl groups). Or R ^a and R ^b together with the carbon atoms to which they are attached form a cycloalkylidene group of 3 to 7 carbon atoms, preferably a cycloalkylidene group of 3 to 5 carbon atoms; Y represents a 5- or 6-membered heterocyclic ring linked to carbon containing at least one nitrogen atom, which may contain one or more sulfur atoms in addition to the nitrogen atom and / or have from 1 to 4 carbon atoms Alkyl groups may be substituted.

The cephalosporin compound herein is named according to the method of J. Amer. Chem. Soc. 1962, 84, 3400 for "Sepam", and "Sepam" refers to a cepam structure having one double bond.

Cephalosporin antibiotics are widely used in the treatment of diseases caused by pathogens in humans and animals, and are particularly useful for the treatment of diseases caused by bacteria that are resistant to other antibiotics, such as penicillin pollen, and for the treatment of penicillin-sensitive patients. In many cases it is desirable to use cephalosporin antibiotics that are active against both Gram-positive and Gram-negative microorganisms, and intensive research has been done in developing various broad spectrum cephalosporin antibiotics.

For example, British Patent Specification No. 1,399,086 describes a novel cephalosporin antibiotic containing a 7β- (α-etherylated oxyimino) -acylamido group, wherein the oxyimino group has a new configuration. have. Antibiotic compounds of this kind are characterized by high antimicrobial activity against a wide range of Gram-positive and Gram-negative bacteria, in particular with high stability against β-lactamases produced by various Gram-negative bacteria.

The discovery of such compounds has spurred research in the field to find compounds with improved properties, for example against certain classes of microorganisms, especially Gram-negative bacteria.

British Patent No. 1,496,757 describes cephalosporin antibiotics containing the 7β-acylamido group of formula (A).

Wherein A is thienyl or furyl group; R ^A and R ^B can vary widely, for example an alkyl group of 1 to 4 carbon atoms or together with the carbon atoms to which they are attached form a cycloalkylidene group of 3 to 7 carbon atoms, m and n are each 0 or 1 and the sum of m and n is 0 or 1.

This compound is a neoisomer or a mixture of neo and anti isomers having at least 90% of the isomers. The 3-position of the cephalosporin molecule may be unsubstituted or substituted with various substituents. It has been found that these flowers exhibit good antimicrobial activity, in particular against Gram-negative bacteria. Efforts have been made to find antibiotics with broad spectrum antimicrobial activity and / or high activity against Gram-negative bacteria that have been revised from other compounds of similar structure by modification of these compounds. In such efforts, modifications have been made not only to the 7β-acylamido group of the general formula but also to specific groups introduced into the 3-position of the cephalosporin molecule.

For example, Belgian patent specification No. 852,427 describes cephalosporin antibiotic compounds falling within the scope of British Patent Specification No. 1,399,086 mentioned, in which group R of (AH) is 2-aminothia It may be substituted with various organic groups including zol-4-yl and the oxygen atom of the oxyimino group may be linked to an aliphatic hydrocarbon group, which may itself be substituted with carboxyl. In such compounds, the 3-position substituents can vary widely, including, among others, optionally substituted heterocyclicomethyl groups. Several examples of such groups are given here, wherein the heterocyclic moiety of the group is a 3- to 8-membered heterocyclic ring containing one to four nitrogen atoms (e.g. imidazolyl, pyrazolyl, pyridyl, Substitutable tetrazolyl groups such as pyrimidyl, or 1-1H-tetrazol-5-yl groups are included.

In addition, the Belgian Kingdom patent specification No. 836,813 may be substituted with the R group of the general formula (A), such as 2-aminothiazol-4-yl, and the oxyimino group is hydroxyimino or blocked hydroxyimino group ( Eg, a cephalosporin compound, which is a dioxyimino group). In this compound, the 3-position of the cephalosporin molecule is substituted with a methyl group which may optionally be substituted with residues for the various nucleophilic compounds described herein. Examples of residues include 5- or 6-membered heterocyclic rings (eg, pyridyl, pyrimidyl, pyrazolyl, or imidazolyl) which may contain 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen. There is a mercapto group which may be attached to, and the bicyclic may be substituted with a lower alkyl group if necessary. In the above-mentioned specification such compounds are mentioned only as preparation intermediates of the antibiotics described in the specification, and their antimicrobial activity is not described at all.

Belgian patent specification 853,545 discloses that the 7β-acylamido side chain is predominantly 2- (2-aminothiazol-4-yl) -2- (new) -methoxyimido acetamino group and the 3-position substituent is It describes a cephalosporin antibiotic defined similarly to the mentioned Belgian Kingdom patent specification 836,816.

Examples include compounds in which the 3-position is substituted with various heterocyclic-thio methyl radicals, including the methyltet tazolylthiomethyl radical.

With the present invention, by selecting a few specific groups with respect to the 7β-position and properly combining them with the 3-position heterocyclic-substituted thiomethyl group, particularly useful activities against a wide range of pathogens encountered are described in detail below. It was found that the cephalosporin compound can be obtained.

The general formula (I) compound according to the present invention is a neoisomer. The neoisomer type is determined by the coordination of the next group with respect to the carboxamido group.

In this specification, new coordination is stated as follows:

Since the compounds according to the invention are geometric isomers, it is to be understood that mixtures with the corresponding antiisomers may be present.

The present invention also includes solvates (particularly hydrates) and salts of esters of the general formula (I) compounds.

It will be understood that tautomers, such as the 2-iminothiazolinyl type, are also included in the present invention because the compounds according to the invention may exist in tautomeric forms for the 2-aminothiazolyl group. This compound may exist in various zwitterionic forms, for example, when group Y is quaternary form, such as an N-alkylpyridinium group. In this zwitterionic form, it is possible to deprotonate a 4-position carboxyl group or a 7-position side chain carboxyl group. These zwitterionic types and compounds thereof are also included in the scope of the present invention.

When R ^a and R ^b in the general formula (I) represent different alkyl groups having 1 to 4 carbon atoms, the carbon atoms to which they are attached become asymmetric centers and exist as diastereomers, and only these individual diastereomers But also mixtures thereof are included in the present invention.

In the general formula (I), the heterocyclic ring represented by Y may have 1 to 4 nitrogen atoms, and if necessary, may contain one sulfur atom in addition to nitrogen, and examples thereof include imidazolyl, pyrazolyl, and pyri. Dill, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl and thiazolidanyl. Heterocyclic rings may be substituted, if desired, with one or more alkyl groups (eg, methyl groups) having 1 to 4 carbon atoms on their heteroatoms (eg, nitrogen).

The compound according to the present invention exhibits broad spectrum antimicrobial activity, showing high activity against gram-negative bacteria including gram-negative strains producing β-lactamase. The compound also has a high degree of stability against β-lactamase produced by Gram-negative bacteria.

The compound is a variety of strains of enterobacteriaceae (e.g., E. coli, Klapsiella pneumoniae, Salmonella typhimurium, Shigella sonnei, Enterobacter cloase, Serratia marsons, Providen Excellent activity against Pseudomonas spp. It was confirmed that the.

The antibiotic properties of the compounds according to the invention are comparable to aminoglycoside antibiotics, such as amikacin or centamicin, in particular their activity against various Pseudomonas strains which are not sensitive to most of the currently available antibiotics. However, unlike aminoglycosides, cephalosporin antibiotics are generally less toxic to the human body. While aminoglycoside therapy for humans is limited or complicated by its high toxicity, the cephalosporin antibiotics of the present invention show superior advantages over aminoglycosides.

Non-toxic salt derivatives that may be produced by one or two reactions of two carboxyl groups present in the compound of formula (I) include, but are not limited to, alkylimetal salts (e.g. sodium and potassium salts) and alkaline earth metal salts (e.g. calcium salts). Inorganic base salts: Amino acid salts (e.g. lysine and arginine salts): Organic base salts (e.g. procaine, phenylethyl-benzylamine, dibenzylethylenediamine, ethanolamine, diethanolamine and salts with N-methylglucosamine ) Is included. Other nontoxic salt derivatives include acid addition salts such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid and trifluoroacetic acid. The salt may also be in the form of the resulting resinate with resins such as polystyrene resins or crosslinked polystyrene divinylbenzene copolymer resins containing amino or quaternary amino groups or sulfonic acid groups, or polyacrylic acid resins containing carboxyl groups. have. Therapeutic uses include soluble base salts of compounds of formula (I) (alkali metal salts such as sodium salts), since such salts are rapidly distributed in the body after administration. Insoluble salts are sometimes preferred, for example in the case of depot preparations, which salts can be produced by conventional methods with suitable organic amines.

Such salts and other derivatives (e.g., salts with toluene-P-sulfonic acid or methanesulfonic acid) can be used as intermediates in the preparation and / or purification of the compounds of general formula (I) of the invention according to the processes described below.

Nontoxic metastable labile ester derivatives that can be produced by esterifying one or both of the carboxyl groups of the parent compound of formula (I) include lower aceanoyls such as acetoxy-methyl or ethyl or -pivaloyloxy-methyl ester Acyloxyalkyl esters, such as -oxy-methyl or ethyl-ester, are included. In addition to the ester derivatives, the present invention also provides compounds of the general formula (I) in the form of other physiologically acceptable equivalents, i.e. physiologically acceptable compounds that are converted in vivo to the parent antibiotic compound of general formula (I) It is included too.

Preferred compounds according to the invention include, for example, aromatic heterocyclic rings containing 1 to 4 nitrogen heteroatoms (without sulfur heteroatoms), rings having 1 to 2 nitrogen heteroatoms (nitrogen heteroatoms 1). Compounds of the general formula (I) which represent a ring having a dog (a ring containing one nitrogen heteroatom are particularly preferred) include one or two methyl groups attached to the nitrogen hetero atom of the ring and the ring is methyl-substituted. It is advantageous to contain a quaternary nitrogen hetero atom, such as examples of the Y group being 1-methyl pyridinium, 1-methylpyrimidinium, and 1,2-dimethylpyrazolium.

Among the compounds according to the present invention, the following general formula (Ia) compounds and nontoxic metabolic labile esters are preferred in view of their high antimicrobial activity.

(Wherein R ^a and R ^b are as described above)

R ^a and R ^b in formula (Ia) preferably each represent a methyl group or together form a cyclobutylidene group at the carbon atom to which they are attached.

Among the compounds of general formula (a), excellent are (6R, 7R-7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxycyclobut-) of formula (Ib) Oxyimino) acetamido} -3-[(1-methylpyridinium-4-yl) thiomethyl] sef-3-m-4-carboxylate and its nontoxic salts (eg sodium) and nontoxic metabolic labile esters to be.

치는 1.0/kg을 초과하며, 2.0/kg의 용량에서도 신장독성은 관찰되지 않는다.Structural (Ib) compounds surprisingly have all of the general antibiotic properties described with respect to general formula (I) compounds, among which their marked activity, particularly against Pseudomonas strains. This compound also shows useful activity against Staphylococcus oreus strains. This compound exhibits excellent antimicrobial properties that are not damaged by human serum and increases the amount of inoculum and has little effect on the compound. As soon as the concentration of this compound reaches the minimum inhibitory paddle, it immediately shows sterilizing effect. Bovine rodents are evenly distributed in the body after subcutaneous injection, reaching a therapeutically effective concentration. In primates, high serum levels are sustained by intramuscular injection. The half-life of blood concentrations in primates suggests that the half-life in humans is relatively long, which may reduce the number of doses in mild infections. When mice were experimentally infected with Gram-negative bacteria, they were satisfactorily treated with the present compounds, and showed an excellent protective effect against Pseudomonas aeruginosa strains, a microorganism which is not usually sensitive to cephalosporin antibiotics. This protective effect is comparable to that of amino glycosides such as amikacin. From the acute toxicity test of mice

Values exceed 1.0 / kg and no renal toxicity is observed at doses of 2.0 / kg.

Other compounds having properties comparable to those of the structural formula (Ib) include (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxif-2 -Ropeoxyimino) acetamido] -3-[(1-methylpyridinium-4-yl) -thiomethyl] sef-3-m-4-carboxylate and its nontoxic salts (e.g. sodium salt) and nontoxic There is one metabolic labile ester.

Other examples of preferred compounds according to the invention include the following general formula (I) compounds and their nontoxic salts and nontoxic metabolic labile esters.

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3-[( 1-methylpyridinium-2-yl) -thiomethyl] cef-3-m-4-carboxylate;

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxycyclobut-oxyimino) acetamido] -3-[(1- Methylpyridinium-2-yl) -thiomethyl] cef-3-m-4-carboxylate;

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3- (1 -Methyltetrazol-5-ylthiomethyl) cefe-3-m-4-carboxylic acid;

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxycyclobut-1-oxyimino) acetamido] -3 (1- Methyltetrazole-5-yliomethyl) cef-3-m-4-carboxylic acid;

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3-[( 1-methylpyridinium-3-yl) -thiomethyl] cef-3-m-4-carboxylate;

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3-[( 1,2-dimethylpyrazolinium-3-yl) -thiomethyl] cef-3-m-4-carboxylate;

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3-[( 1,3-dimethylimidazolium-2-yl) -thiomethyl] cef-3-m-4-carboxylate; And

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3-[( 1-methylpyrimidin-2-yl) -thiomethyl] cef-3-m-4-carboxylate.

Examples of other compounds according to the present invention include compounds of general formula (I), wherein R ^a , R ^b and Y are as follows.

Formula (I) compounds can be used in the treatment of various diseases caused by pathogenic bacteria in the human body and in animals, for example, staphylococcal and urinary tract infections.

The compounds according to the invention, in particular the general formula, (Ic) compounds and their nontoxic salts and nontoxic metabolic labile esters

[Wherein R ^a , R ^b and Y are as defined above;

B is> S or> S → 0 (α- or β-);

R ¹ is hydrogen or a carboxyl blocking group (eg, ester-producing aliphatic)

Or a residue of an araliphatic alcohol or a residue of an ester-producing phenol, silanol or stananol (the carbon number of these alcohols, phenolsilanol or stananol is preferably 1 to 20);

R ^2a represents a carboxyl blocking group as described above for hydrogen or R ¹ ;

R ³ represents an amino or protected amino group;

Dashed lines connecting the 2-, 3-, and 4-positions indicate that this compound is a cef-2-em or cef-3-em compound.

Compound of formula (II)

Wherein R ^a , R ^b , R ¹ , R ² , B and the dashed line are as described above and X is a substitutable moiety of the nucleophile (e.g., acetoxy or dichloroacetoxy group or halogen atom such as chlorine, bromine or iodine) Or a salt thereof, characterized in that it reacts with a sulfur nucleophile which produces a group of the formula -CH ₂ SY wherein Y is as described above at the 3-position of formula (II).

In the above-described process, sulfur nucleophiles can be used to substitute various kinds of substituents X from cephalosporin of general formula (II). The ease of substitution is somewhat related to the pka of the acid HX from which the substituents are derived, ie atoms or groups X derived from strong acids are generally more readily substituted than atoms or groups derived from weaker acids. Ease of substitution is also somewhat related to the properties of sulfur nucleophiles and nucleophiles can be used, for example in the form of suitable thiols or thions.

Substitution of X by sulfur nucleophile can conveniently be carried out by keeping the reactant in solution or suspension. This reaction is advantageously carried out using 1 to 10 moles of nucleophiles.

The nucleophilic substitution reaction can be conveniently carried out in the case of the general formula (II) compound in which the substituent X is a halogen atom or an acyloxy group as described below.

[Acyloxy group]

Formula (II) compounds, wherein X is an acetoxy group, are convenient starting materials for nucleophilic substitution reactions using sulfur nucleophiles. Another starting material of this kind is a compound of formula II, wherein X is a residue of substituted acetic acid (eg, chloroacetic acid, dichloroacetic acid and trifluoroacetic acid).

When X is a substituent of this kind, in particular, the substitution reaction of the general formula (II) compound in which X is an acetoxy group can be promoted by the presence of iodide or thiocyanate ions in the reaction medium.

Substituent X may also be derived from haloformic acid or carbamic acid such as formic acid, chloroformic acid.

When using a compound of formula (II) in which X represents an acetoxy or substituted acetoxy group, it is generally preferred that group R ^{1 in} formula (II) is a hydrogen atom and B represents> S. In this case, the reaction proceeds advantageously in aqueous medium.

Under aqueous conditions, the pH of the reaction solution is advantageously maintained in the range of 6 to 8, and base is added if necessary. The base is conveniently a hydroxide or bicarbonate of an alkaline earth metal such as sodium hydroxide or sodium bicarbonate.

In the case of using the general formula (I) compound in which X is an acetoxy group, the reaction temperature range is conveniently 30 ° to 110 ° C, preferably 50 ° to 80 ° C.

[halogen]

Formula (II) compounds, wherein X is chlorine, bromine or iodine, may also be conveniently used as starting materials for the ring-reaction with sulfur nucleophiles. When using this general formula (II) compound, B can represent> S and R ¹ can represent a carboxyl blocking group. This reaction is conveniently carried out in a non-aqueous medium, which preferably comprises one or more organic solvents, advantageously polar organic solvents (e.g. ethers such as dioxane or tetrahydrofuran, esters such as ethyl acetate, formamide and Amides such as N, N-dimethylformamide, and ketones such as acetone). Other suitable organic solvents are described in detail in British Patent No. 1,326,531. The reaction medium should not be too acidic or basic.

In the case of general formula (II) compounds wherein R ¹ and R ² are carboxyl blocking groups and the resulting Y group contains quaternary nitrogen atoms, the product will be obtained in the form of a halide salt to be used as a result of the reaction, if necessary. Ion exchange reactions can yield salts with the desired anions.

The reaction in the case of using a general formula (II) compound in which X is halogen as described above is conveniently carried out at -20 ° to + 60 °, preferably 0 ° to + 30 ° C.

When the introduced nucleophile does not produce a compound containing quaternary nitrogen atoms, the reaction is generally carried out in the presence of an acid scavenger such as a base such as triethylamine or calcium carbonate.

The reaction product may be recrystallized, ionophoresis, column chromatography and the use of ion exchange groups (e.g. ion exchange resin column chromatography) or by various methods including macroreticular resins, for example unreacted cephalosporin starting materials and It can be separated from the reaction mixture which may contain other substances.

²-세팔로스포린 에스테르 유도체는,

²-에스테르를 피리딘 또는 트리 에틸아민 같은 염가로 처리하는 등의 방법에 의해 상용하는

³-유도체로 전활시킬 수 있다.Obtained according to the present invention

² -cephalosporin ester derivatives,

² - to commercial by a method such as to process ester inexpensively as pyridine or triethylamine

^3- Can be derivatized with derivatives.

The cefe-2-M reaction product may be oxidized to a compatible ceft-3-M 1-oxoxide by reaction with a concentrated acid such as peracetic acid or -chloro perbenzoic acid; The produced sulfoxide side can be reduced as described below, if necessary, to produce commercially available ceph-3-M sulfide.

When a compound of B is> S → 0 is obtained, for example, by reacting with acetyl chloride or the like (in the case of the ethoxysulfonium salt), a commercially available acyl oxysulfonium or alkoxysulfonium salt is reduced. Reduction reactions can be performed with the corresponding sulfides, with reduction in sodium dithionite, or with solutions of sodium iodide in water-miscible solvents (e.g. acetic acid, acetone, tetrahydrofuran, dioxane, dimethylformromamide or dimethylacetamide). Is made by the same iodide ion. The response temperature ranges from -20 ° to + 50 ° C.

Metabolic labile ester derivatives of compounds of formula (I) may be compounds of formula (I) or salts or protected derivatives thereof, conveniently acyloxyalkyl halides (e.g., iodide) in an inert organic solvent such as dimethylformamide or acetone. It can be prepared by reacting with a suitable esterification agent, such as by removing the protecting group if necessary.

Base salts of compounds of formula (I) may be produced by reacting an acid of formula (I) with an appropriate base. For example, sodium or potassium salts can be prepared using 2-ethylhexanoate or bicarbonate names. Acid addition salts can be prepared by reacting a compound of formula (I) or a metastable labile ester derivative thereof with an appropriate acid.

When the compound of general formula (I) is obtained as an isomer mixture, the neoisomers can be obtained by conventional methods such as crystallization or chromatography.

When X in the formula (II) compound is halogen (chlorine, bromine or iodine), the ceph-3-em starting compound is prepared by conventional means, for example 7β-protected amino-3-methylcep-3-m- Halogenation of 4-carboxylic acid ester 1β-oxides, removal of 7β-protecting groups, 7β-amino produced by a method analogous to the method of the present application and pending Korean Patent Application No. 79-1688 (hereinafter referred to as the original application) The desired 7β-acylamido of the compound can also be prepared by acylation to the group followed by reduction of the ionic 1β-oxide group. This is described in British Patent No. 1,326,531. The commercially available ceft-2-m compound is commercially available 3-bromomethylsef-2 by the reaction of the 3-methylcef-2-em compound with N-bromosuccinimide according to the method of JP 6,902,013. It can be prepared by generating an amp compound.

If X in general formula (II) is an acetoxy group, such starting materials can be prepared by acylating 7-amino cephalosporranic acid, for example, in a similar manner to the process described in the original application. Formula (II) compounds in which X represents another acyloxy group include the corresponding 3-hydroxymethyl compounds, which can be prepared by hydrolysis of the appropriate 3-acetoxymethyl compound, for example It may be prepared by acylation according to the method as described in 1,474,519 and 1,531,212.

In some of the above modification reactions it is necessary to protect sensitive groups in the molecule of the problem compound to avoid unwanted side effects. For example, at any stage of the above-mentioned reaction chain, it is desirable to protect the NH ₂ group of the amino thiazolyl moiety by, for example, tritylation, acylation (eg chloroacetylation), quantization or other conventional methods. You may need it. The protecting group can be removed by any convenient method that does not cause degradation of the desired compound, for example trityl group, preferably in the presence of a protic solvent such as water, acetic acid, formic acid, chloroacetic acid or trifluoro Using a halogenated carboxylic acid such as acetic acid or a mineral acid such as hydrochloric acid or a mixture of such acids, the chloroacetyl group can be removed by treatment with thioutea.

The carboxyl blocking group used for the preparation of the compound of general formula (I) or for the preparation of the necessary starting materials is preferably a group which can be easily removed at an appropriate stage in the reaction chain process, conveniently at the final stage. However, in some cases, nontoxic metastable labile carboxyl blocking groups such as acyloxy-methyl or -ethyl groups (e.g. acetoxy-methyl or -ethyl or pivaloyloxymethyl) can be used and left intact in the final product. It may be convenient to produce suitable ester derivatives of the compound (I).

Suitable carboxyl blocking groups are well known in the art, and exemplary blocked groups are described in British Patent No. 1,399,086. Preferred blocked carboxyl groups include alkoxy lower alkoxycarbonyl groups such as P-methoxybenzyloxycarbonyl P-nitrobenzyloxycarbonyl and diphenylmethoxycarbonyl; lower alkoxy carbonyl groups such as t-butoxycarbonyl and lower haloalkoxycarbonyl groups such as 2,2,2-trichloroethoxy carbonyl. The carboxyl blocking group can be removed by any suitable method described later in the literature, for example in many cases acid or base catalyzed hydrolysis can be used, as is enzyme-catalyzed hydrolysis.

Antibiotics of the present invention can be formulated in a form suitable for administration in a conventional manner similar to other antibiotics, and pharmaceutical compositions containing an antibiotic according to the invention, suitable for use in humans or veterinary medicine, are within the scope of the present invention. It is included in. Such compositions are prepared in conventional manner by the addition of the required pharmaceutical carrier or excipient.

Antibiotics according to the present invention can be formulated for injection and added with preservatives as needed, prepared in ampoules or in multiple dosage forms. The compositions may also be prepared in the form of suspensions, solutions or emulsions in oily or aqueous carriers and may contain adjuvants such as suspensions, stabilizers and / or dispersants. Alternatively, the active ingredient may be formulated in powder form for reconstitution by addition of a suitable carrier (eg, sterile water from which pyrogenic substances have been removed).

If necessary, a nontoxic base suitable for such powder formulations may be included to enhance the water solubility of the active ingredient and / or to ensure that the pH of the aqueous form produced when the powder is reconstituted with water is in a physiologically appropriate range. Alternatively, a base may be added to the water for dissolving the powder. Examples of bases include inorganic bases such as sodium carbonate, sodium bicarbonate, or sodium acetate, or organic bases such as lysine or lysine acetate.

Antibiotics may also be formulated into suppositories containing conventional suppository bases such as cocoa butter or other glycerides.

Veterinary compositions may be formulated into formulations for intramuscular administration using sustained or rapid-release mechanisms. The composition may contain 0.1% or more, for example 0.1% to 99% of the active material depending on the method of administration.

When the composition is a dosage unit, it is preferable to contain 50 to 1500 mg of the active ingredient in each unit. The dose used for adult treatment is preferably 500 to 6000 mg per day, depending on the route of administration and the number of times. For example, for adults, 1000 to 3000 mg per day, intravenously or intramuscularly, is sufficient. The daily dose needs to be increased to treat Pseudomonas infection.

Antibiotics according to the invention can be administered in admixture with therapeutic agents such as penicillin or other cephalosporins.

The following examples illustrate the invention. All temperatures are in degrees Celsius and "petal" is petroleum ether (boiling point, 40 to 60 °).

Quantum magnetic resonance (p.m.r) spectra were measured at 100 MHz. The integration result is the same as indicated, and the coupling constant J is in Hz. The meaning of each code is as follows. S = single line, d = dual line, dd = north duplex line, m = multiple line, q = quartz line, and ABq = AB quartet.

Preparation Example 1

Ethyl (Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetate

292 g of ethyl aceto acetate was dissolved in 296 ml of glacial acetic acid, and a solution obtained by dissolving 180 g of sodium nitrite in 400 ml of water was added to a stirred and ice-cooled solution while maintaining the reaction temperature at 10 ° C or lower. Stirring and cooling are continued for about 30 minutes and a solution of 160 g of potassium chloride dissolved in 800 ml of water is added. The resulting mixture is stirred for 1 hour, the lower oil phase is separated and the aqueous layer is extracted with diethyl ether. The extract is combined with oil and then washed with water, saturated brine, dehydrated and evaporated. The residue oil solidified by standing is washed with petroleum ether and dried in vacuo on potassium hydroxide to give 309 g of ethyl (Z) -2- (hydroxyimino) -3-oxobutyrate.

A solution of 150 g of ethyl (Z) -2- (hydroxyimino) -3-oxobutyrate dissolved in 400 ml of dichloromethane was stirred and ice-cooled, and 140 g of sulfuryl chloride was added dropwise thereto. The resulting solution is kept at room temperature for 3 days and then evaporated. The residue is dissolved in diethyl ether, washed with water until the washing solution is almost neutral, dehydrated and evaporated. 177 g of xanthine oil are dissolved in 500 ml of ethanol and 77 ml of dimethyl anitin and 42 g of thiourea is added with stirring. After 2 hours, the product is collected by filtration, washed with ethanol and dried to give 73 g of the title compound. Melting point 188 ° (decomposition).

Production Example 2

Ethyl (Z) -2-hydroxyimino-2- (2-tritylaminothiazol-4-yl) acetate, hydrochloride

16.75 g of trityl chloride was dissolved in 28 ml of dimethylformamide containing 8.4 ml of triethyl amine, 12.91 g of the product of Preparation Example 1 was added to the solution cooled to -30 ° in small portions over 2 hours. The mixture is warmed to 15 ° over 1 hour, stirred for 2 more hours and then partitioned between 500 ml of water and 500 ml of ethyl acetate. The organic phase is separated, washed with water (500 ml x 2) and shaken with 500 ml of 1N hydrochloric acid. The precipitates were collected and washed successively with 100 m of water, 200 ml of ethyl acetate and 200 ml of ether and dried under vacuum to afford 16.4 g of the title compound as a white solid. Melting point 184 to 186 ° (decomposition)

Preparation Example 3

Ethyl (Z) -2- (2-t-butoxycarbonylprop-2-oxyimino) -2- (2-tritylaminothiazol-4-yl) acetate.

Nitrogen was added to a solution in which 34.6 g of potassium carbonate and 24.5 g of -t-butyl 2-bromo-2-methylpropionate were dissolved in 25 ml of dimethyl sulfoxide, and 49.4 g of the product of Preparation Example 2 was dissolved in 200 ml of dimethyl sulfoxide. It is added under air stream and the mixture is stirred for 6 hours at room temperature. The mixture is poured into 2 l of water, stirred for 10 minutes and filtered. The solid material is washed with water and dissolved in 600 ml of ethyl acetate. The solution is washed successively with water, 2N hydrochloric acid, water and saturated brine, followed by dehydration and evaporation. The residue is recrystallized from petroleum ether (boiling point 60-80 °) to give 34 g of the title compound. Melting Point 123.5-125 °

Production Example 4

(Z) -2- (2-t-butoxycarbonylprop-2-oxyimino) -2- (2-tritylaminothiazol-4-yl) acetic acid

2 g of the product of Preparation Example 3 are dissolved in 20 ml of methanol and 3.3 ml of 2N sodium hydroxide is added. The mixture is refluxed for 1.5 hours and then concentrated. The residue is dissolved in a mixture of 50 ml of water, 7 ml of 2N hydrochloric acid and 50 ml of ethyl acetate. The organic phase is separated, the aqueous layer is extracted with ethyl acetate, the organic solutions are combined, washed successively with water and saturated brine, dehydrated and evaporated. The residue is recrystallized from a mixture of carbon tetrachloride and petroleum ether to give 1 g of the title compound. Melting point 152 to 156 ° (decomposition)

Production Example 5

Ethyl (Z) -2- (2-tritylaminothiazol-4-yl) -2- (1-t-butoxycarbonylprop-1-oxyimino) acetate.

55.8 g of the product of Preparation Example 2 are stirred with 31.2 g of potassium carbonate (finely ground) in 400 ml of dimethylsulfoxide in the presence of nitrogen at room temperature. After 390 minutes, 29.2 g of t-butyl 1-bromocyclobutane carboxylate was added, 31.2 g of potassium carbonate was further added after 8 hours, and six times of 16 g of potassium carbonate was added three days later. Add 3.45 g bromo-cyclobutanecarboxylate again. Four days later, the mixture was poured into about 3 l of ice water, the solids were collected by filtration, washed well with water and petroleum ether, dissolved in ethyl acetate, the solution was washed twice with brine, dehydrated with magnesium sulfate and evaporated to give a foamy form. Get the substance. This foamy substance was dissolved in ethyl acetate-petroleum ether (1: 2), filtered through 500 g of silica gel and evaporated to yield 60 g of the title compound as a foamy substance.

Production Example 6

max (에탄올) 265nm (E_1% ^1㎝24³).(Z) -2- (1-t-butoxycarbonylprop-2-oxyimino) -2- (2-tritylaminothiazol-4-yl) acetic acid Preparation 3.2 g of product 5 and carbonic acid A mixture of 165 g of potassium was added to 1800 ml of methanol and 20 ml of water to reflux for 9 hours, and then the mixture was cooled to room temperature. The mixture is concentrated and the residue is partitioned between ethyl acetate and water, to which 12.2 ml of 2N hydrochloric acid is added. The organic phase is separated and the aqueous layer is extracted with ethyl acetate. The combined organic extracts are washed with fused brine, dehydrated and evaporated to yield 2.3 g of the title compound.

max (ethanol) 265 nm (E _1% ^{1 cm} 24 ³ ).

Production Example 7

Diphenylmethyl (1S, 6R, 7R) -3-bromomethyl-7-[(Z) -2- (2-t-butoxycarbonylprop-2-oxyimino) -2- (2-tri Tylaminothiazole-4-) ylacetamido] sef-3-m-4-carboxylate, 1-oxide

Diphenylmethyl (1S, 6R, 7R) -7amino-3-bromomethyl-sef-3-m-4-carboxylate, 1.40 g of 1-oxide hydrobromide, 100 ml of dichloromethane and sodium bicarbonate half-saturated solution Shake with 100 ml. The filtered organic layer was dehydrated over anhydrous sodium sulfate and evaporated to yield 1.05 g of free 7-amine as a white solid. 1.015 g of solid material and 1.23 g of the product of Preparation Example 4 were dissolved in 21 ml of N, N-dimethylformamide, and 394 mg of 1-hydroxybenzotriazole monohydrate and N, N-dicyclohexylcarbodiimide 530 were dissolved in this solution. Mg is added. A precipitate is formed soon, which is stirred for 18 hours at 20 ° and then filtered, and the residue is washed with ethyl acetate (2 × 100 ml). The combined filtrate and washing solution were washed with 2N hydrochloric acid (2 × 100ml) and water (2 × 100ml) and the organic layer was dehydrated with anhydrous sodium sulfate and evaporated to give 2.645 g of a brown foamy substance. Polishing with 50 ml of ether (:) yields 2.3 g of solid material. The solid material is partially purified on a column using 50 g of silica gel (70 to 230 mesh) with chloroform as an eluent, and 75 ml fractions are collected. From fractions 3 and 4 1.085 g of foam were obtained, which was purified by thin layer chromatography using ethyl acetate: toluene (1: 3) to give 494 mg of product (Rf about 0.5) as a foam. A solution of the product dissolved in a small amount of ethyl acetate is added to stirred petroleum ether, the precipitate is filtered off and dried under vacuum to afford 424 mg of the title compound as a solid.

Example 1

a) t-butyl (6R, 7R) -3-acetoxymethyl-7-[(Z) -2- (2-t-butoxycarbonylprop-2-oxyimino) -2- (2-tri Ylamino thiazol-4-yl) acet amido] cef-3-m-4-carboxylate

572 mg of the product of Preparation Example 4 and 328 mg of t-butyl (6R, 7R) -3-acetoxymethyl-7-aminocef-3-m-4-carboxylate in 10 ml of dimethylformamide were stirred and stirred at 0 °. After cooling, 150 mg of 1-hydroxy benzotriazole is added followed by 225 mg of dicyclo hexylcarbodiimide. The mixture is allowed to warm to room temperature, stirred for 5 hours and left overnight. The mixture is filtered and the white solid is washed with a small amount of ether. The filtrate and washings are diluted with 50 ml of water and extracted with ethyl acetate. The organic extracts were combined, washed successively with water, 2N hydrochloric acid, water, sodium bicarbonate solution and saturated brine, followed by dehydration and evaporation. The residue is eluted with ether through a silica column. The eluate containing the product is collected and concentrated to give 533 mg of the title compound. Recrystallization of a portion of this with di-isopropylether gives a product having a melting point of 103 to 113 ° (decomposition).

b) (6R, 7R) -3-ethoxymethyl-7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acet Amido] sef-3-m-4-carboxylic acid

18 ml of trifluoroacetic acid is added to a solution of 2.4 g of the product in step a) in 18 ml of anisole at 0 ° and the mixture is stirred at room temperature for 2 hours and then concentrated. The residue is dissolved in ethyl acetate and extracted with saturated sodium bicarbonate solution. Adjust the pH of the fertilized extract to 6 and wash the solution with ethyl acetate. The aqueous layer is adjusted to pH 1.5 with ethyl acetate, saturated with sodium chloride and extracted with ethyl acetate. The combined organic extracts are washed with saturated brine, dehydrated and evaporated. The residue is dissolved in 20 ml of warm 50% formic acid and left for 2 hours. The mixture is diluted with 50 ml of water, filtered and the filtrate is concentrated. The residue was dissolved in 50 ml of water, refiltered and lyophilized to yield 920 mg of the title compound.

c) (6R, 7R) -7-[(Z) -2-2 (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acet amido] -3 -(1-methylpyridinium-2-ylthiomethyl) cefe-3-emcarboxylate, monosodium salt.

1.58 g of the product from step b) and 0.50 g of sodium bicarbonate were warmed with 2 ml of water, and the mixture was mixed with 564 mg of N-methylpyrid-2-thione, 2.7 g of sodium iodide and about 400 mg of sodium bicarbonate (the pH of the mixture was 7 To be continued). 0.4 ml of water is added and the mixture is heated at 65 ° for 5 hours in the presence of nitrogen. The mixture was cooled and eluted with water first in a column to fill 100 g of Amberlite XAD-2 resin to collect 100 ml fractions (fractions 1-10), followed by elution with water: ethanol (3: 1) to obtain 100 ml fractions (11-14). Collect. Combine fractions 10-12, evaporate to 250 ml, wash with ether (4 x 125 ml), and lyophilize to give 594 mg of a light brown residue. 500 mg of the residue was dissolved in 150 ml of water and the solution was washed with ethyl acetate (3 × 150 ml) and lyophilized in the presence of formic acid to obtain a foamy substance, which was triturated with ether and dried under vacuum to give the title compound as 464 mg of formate salt. To obtain.

Example 2

a) t-butyl (6R, 7R) -3-acetoxymethyl-7-[(Z) -2-2 (1-t-butoxycarbonylcyclobut-1-oxyamino) -2- (2- Tritylaminothiazol-4-yl) acet-amido] sef-3-m-4-carboxylate

A solution in which 24.2 g of the product of Preparation Example 6 and 13,6 g of t-butyl (6R, 7R) -3-acetoxymethyl-7-aminoce-3--3-methyl-4-carboxylate were stirred and dissolved in 300 ml of dimethylformamide. After cooling to 0 °, 4.5 g of 1-hydroxybenzotriazole monohydrate and 6.4 g of dicyclo hexylcarbodiimide were added, and the product was separated almost as in Example 1 (a) to give 12.8 g of the title compound. To obtain.

Melting Point 113.5-116.5 ° (Decomposition)

b) (6R, 7R) -3-acetoxymethyl-7-[(Z) -2-2-aminothiazol-4-yl) -2- (1-carboxycyclobut-1-oxyimino) acetami Dop-3-m-4-carboxylic acid

100 ml of trifluoro acetic acid is added to a mixture of 12.5 g of step product a) and 5 ml of anisole at 0 °. The mixture is treated in almost the same manner as in Example 1b) to give 4 g of the title compound.

c) (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxycyclobut-1-oxyamino) acetamido] -3- M (1-methylpyridinium-2-ylthiomethyl) sef-3-m-4-carboxylate, monotanium salt

1.60 g of the product of step a) and 0.50 g of sodium bicarbonate are warmed with 2 ml of water, 564 mg of 1-methylpyrid-2-thione is added to this suspension, and then about 350 mg of sodium bicarbonate is added to bring the pH of the mixture to about 6.5. 2.7 g of sodium iodide was added and the slightly turbid solution was heated at 65 ° for 5 hours and then cooled to apply to a column packed with 100 g of Amberlite XAD-2 resin. The column was eluted with water to collect 150 ml fractions (1 to 5), followed by eluting with water: ethanol (3: 1) to collect 150 ml fractions (6 to 10). Combine 4-7 fractions and remove ethanol by evaporation. The solution was washed with 3 x 300 ml of ethyl acetate and 200 ml of ether and then evaporated to remove the organic solvent. The brown foamy material obtained by lyophilization was washed with ether, filtered and dried in vacuo to give 816 mg of the title compound as a foamy material.

Example 3

a) (6R, 7R) -3-acetoxymethyl-7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyamino) acet Amido] sef-3-m-4-carboxylic acid, trifluoro acetate salt

31 g of the product of Example 1 a) are dissolved in trifluluo acetic acid in 90 ml with cooling with ice water. After 5 minutes the mixture is warmed to 20 ° and after one hour the solution is poured into 900 ml of water. After 5 minutes, 450 ml of ether is added and the mixture is stirred for 10 minutes. The ether layer is separated and further extracted with 5 ml of water. The combined aqueous layers are washed three times with ether, each time the organic layer is back extracted with water. The combined aqueous layers were evaporated to dryness and the residue was triturated with ether and dried to afford 15.4 g of the title compound.

b) (6R, 7R) -7-[(Z) -2 (-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3-[( 1-methylpyridinium-4-yl) -thiomethyl] sef-3-carboxylate

a) Add 21.11 g of step product to 3 ml of mol, add 1.06 g of sodium bicarbonate in small portions and warm until gas evolution ceases. The solution is treated successively with 4 g of sodium iodide and 0.75 g of N-methylpitide-4-thione in the presence of nitrogen and left at 70 ° for 4 hours.

The mixture is cooled and diluted with water and the resulting solution is poured into 800 ml of acetone with vigorous stirring. The precipitated material is isolated by filtration, washed with a small amount of acetone and ether and dried under vacuum to afford 2.97 g of powdered material.

The product is dissolved in 10 ml of water and the solution is purified on a column (about 330 mm × 25 mm) containing 100 g of Amberlite XAD-2 resin. Water was first used as the column's eluent (9 × 50 ml fraction collection) followed by 25% aqueous ethanol (7 × 50 ml fraction collection), the appropriate fractions were combined, the ethanol was removed under vacuum and the residue was lyophilized to obtain the title compound. Is obtained in two times as follows:

Iii) 0.253 g (isolated from aqueous fraction)

_max(pH6완충액) 231.5nm (E_1cm ^1%369) 및 303nm (E_1cm ^1%336),

_max (pH 6 buffer) 231.5 nm (E _{1 cm} ^1% 369) and 303 nm (E _{1 cm} ^1% 336),

_inf255nm (E_1cm ^1%268)

_inf 255nm (E _1cm ^1% 268)

Ii) 0.900 g (separated from an aqueous ethanol fraction)

_max(pH 6완충액) 231.5nm (E_1cm ^1%378) 및 303nm (E_1cm ^1%379).

_max (pH 6 buffer) 231.5 nm (E _{1 cm} ^1% 378) and 303 nm (E _{1 cm} ^1% 379).

_inf225nm (E_1cm ^1%275),

_inf 225nm (E _1cm ^1% 275),

(D ₂ O) 1.68 (d, J6 Hz) pyridyl quantum), 3.15 (S, thiazol-5-yl quantum), 4.30 (d, J5 Hz, 7-H), 4.84 (d, J5 Hz, 6-H) , 5.72 (obvious ABq, 3-CH ₂ ), 5.88 (S, NCH ₃ ), 6.44 (center of ABq, J15 Hz, 2-H ₂ ) and 8.55 (S, Ce ₂ ).

Example 4

a) t-butyl (6R, 7R) -3-acetoxymethyl-7-[(Z) -2- (1-t-butoxycarbonylcyclobut-1-oxyimino) -2- (2-tri Ylaminothiazol-4-yl) acet amido] cef-3-m-4-carboxylate

A solution obtained by dissolving 24.2 g of the product of Preparation Example 6 and 13.6 g of t-butyl (6R, 7R) -3-acetoxymethyl-7-amino cef-3-em-4-carboxylate in 300 ml of dimethylformamide was 0 °. After cooling, 4.5 g of 1-hydroxy mentotriazole monohydrate was added followed by 6.4 g of dicyclo hexylcarbodiimide. Warm up the mixture to room temperature and stir overnight. The mixture is filtered and the white solid material obtained is washed with a small amount of ether. The filtrate and washings are diluted with 1.5 L of water and extracted with ethyl acetate. The organic extracts are combined, washed successively with water and brine, dehydrated and evaporated. The residue is dissolved in ether, filtered and evaporated again. The desired product is separated by elution with ether through two silica columns and the appropriate fraction is concentrated. Recrystallization from residues of di-isopropyl ether gives 12.8 g of the title compound.

Melting Point 113.5-116.5 °

[α] _D ²⁰ + 15.0 ° (⊇1.0, DMSO)

b) (6R, 7R) -3-acetoxymethyl-7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxycyclobut-1-oxyimino) acet Amido] cef-3-em-4-t-buroxy carboxyl liver hydrochloride

T-butyl (6R, 7R) -3-acetoxymethyl-7-[(Z) -2- (1-t-butoxycarbonyl cyclobut-1-oxyimino] 2- (2-tri in 72 ml formic acid Ylamino thiazol-4-yl) acetamido] sef-3-m-4-carboxylate 17,9 g is cooled to 12 ° and 6 ml of concentrated hydrochloric acid is added to the mixture at 18 to 20 ° for 1 hour 30 minutes. After stirring, the mixture is cooled to 6 ° and the solid is filtered off, washed with formic acid and the combined filtrate is added to 2 liters of isopropyl ether to be stirred for 15 minutes. Washed with and then dried in vacuo at 40 ° to afford 11.47 g of the title compound.

T (DMSO d ₆ ) 0.29 (d, J9 Hz), 2.98 (S, thiazol-5-yl both), 4.10 (dd, J4 and 9 Hz, 7-H) 4.78 (d, J4 Hz, 6-H), 4.98 And 5.29 (ABq, J4 Hz, 3-CH _2- ), 6.38 (S, 2-H ₂ ), 7.2-7.8 and 7.8-8.3 (cyclobutyl quantum) 7.98 (S, OCDCH ₃ )

c) (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxycyclobut-1-oxyimino) acetamido] -3- (1-methylpyridinium-4-ylthio-methyl] sef-3-m-4-carboxylate

To 5 ml of water (6R, 7R) -7 [(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxycyclobut-1-oxyimino) -acetamido] sef- Add 2.30 g of 3-m-4-carboxylic acid hydrochloride in small portions and warm until gas evolution ceases. 4 g sodium iodide is added to the solution followed by 0.75 g N-methylpyrid-4-thione. The mixture is left for 4 hours at 70 ° in the presence of nitrogen. The resulting solution is cooled to room temperature and poured into 800 ml of acetone. The precipitated solid material was separated by filtration, washed with 100 ml of acetone and 10 ml of diethyl ether and dried under vacuum to obtain 2.7 g of a powdery substance.

The product is dissolved in 10 ml of water and the pH of the solution is adjusted to 4.5 with acetic acid. The solution is treated with a mixture of 10 ml of Amberlite LA ₂ resin, 10 ml of ethyl acetate and 0.75 ml of acetic acid and stirred at ambient temperature for 1 hour. The aqueous layer is separated and washed with 5 ml of ethyl acetate. Ethyl acetate dissolved in the aqueous extract is removed by rotary evaporator and the resulting solution is adjusted to pH 4.5 with acetic acid. The solution is applied on a column filled with Amberlite, XAD-2 resin (about 330 mm × 25 mm), and the column is eluted with water: ethanol (2: 1) in about 1.2 L of water. Combine about 1.2 L of suitable fraction and evaporate with a rotary evaporator until the volume is about 25 ml. The residue was lyophilized to yield 530 mg of the title compound.

λ _max (pH6 buffer), 231 nm (E _{1 cm} ^1% 351) and 303 nm (E _{1 cm} ^1% 428),

λ _inf 255 nm (E _{1 cm} ^1% 267).

υ (D ₂ O + NaHCO ₃ ) 1.64 (d, J6 Hz) and 2.21 (d, J6 Hz) (both pyridyl), 3.07 (S, thiazol-5-yl both), 4.21 (d, J4 Hz, 7-H ), 4.75 (d, J4 Hz, 6-H), 5.5-5.8 (unclear ABq, 3-CH ₂ ), 5.84 (S, NCH ₃ ), 6.4 (center of ABq J15 Hz, 2-Hz) 7.58 and 8.1 ( Cyclobutyl quantum).

EXAMPLE

a) dipenylmethyl (6R, 7R) -7-[(Z) -2-t-butoxycarbonylprop-2-oxyimino) -2- (2-tritylaminothiazol-4-yl) Acetamido] -3-bromomethylsep-3-m-4-carboxylate

8.8 g of phosphorus pentachloride is dissolved in 400 ml of methylene chloride with stirring. The solution was cooled to -20 ° and treated with 22.8 g of the product of Preparation Example 4, the resulting clear solution was stirred for about 30 minutes at -15 °, then 15.8 ml of triethylamine was added and the mixture was further added at -15 ° for 5 minutes. After standing, 19.8 g of diphenylmethyl (R7, 7R) -7-amino-3-bromomethylsef-3-m-4-carboxylate hydrochloride and 5.6 ml of triethylamine were added to 400 ml of methylene chloride, and- Add to solution maintained at 15 to -20 ° over 5 minutes. After 10 minutes the cooler is removed and the mixture is stirred to raise to ambient temperature for about 30 minutes. The mixture is poured into 400 ml of 1 L methylene chloride, shaken and the organic layers are collected. Backwash water with 100 ml of methylene chloride. The initial methylene chloride layer is washed with dilute sodium bicarbonate solution (up to pH 8) and the aqueous layer is then counter-chucked again. Combine the organic layers and wash with semi-saturated brine. The methylene chloride layer is dehydrated with sulfuric magnesium and the solvent is evaporated to obtain anhydrous foamy solid material. The material is collected in an evaporation flask and dried in vacuo at 40 ° to obtain 40.25 g of the title compound as a pale yellow solid.

b) diphenylmethyl ((6R, 7R) -7-[(Z) -2- (2-t-butoxycarbonylprop-2-oxyamino) -2- (2-tritylaminothiazole- 4-yl) acetamido] -3- (1-methylpyridinium-4-ylthiomethyl) sef-3-m-4-carboxylate bromide

Dissolve 40 g of the product of step a) in 500 mL of tetrahydrofuran and add 5.0 g of N-methyl pyrid-4-thione with stirring. After stirring at the circumferential wall temperature for 6 hours, 2.0 L of diethyl ether was added thereto. The mixture is stirred for 1 hour and then cooled at 0 ° for 16 hours. The solid material was removed by filtration, washed well with diethyl ether and dried under vacuum for 16 hours to read 39.9 g of the title compound.

ν (CDCl ₃ ) 1.1-1.3 (broad d, pyridinium proton adjacent to N-Me), 2.2-2.4 (broad d, pyridinium proton adjacent to CS), 3.07 (S, CH. Ph ₂ ), 3.27 (S , Thiazol-5-yl both), 3.36 (Broad S, Ph ₃ CNH), 3.9-4.2 (dd, J5 Hz + 9 Hz, 7-H), 4.90 (d, J5 Hz, 6-H), 5.84 (Broad SC ₃ -CH ₂ + NMe), 6.1-6.6 (broad m, 2-H ₂ ), 8.38 + 8.40 (2 × S, C-Me ₂ ): ν _max (Newsol) 1802 (β-lactam), 1708 cm ^{− 1} (CO ₂ H)

c) (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3- (Methylpyridinium-4-ylthiomethyl) sef-3-m-4carboxylate

b) Dissolve 40 g of the product in 320 ml of trifluoroacetic acid and 80 ml of anisole and stir in ice jade for 1 hour 30 minutes. The solution is poured into 3 l of water and 1.5 l of diethyl ether and stirred vigorously. The aqueous layer was separated, further washed with diethyl ether (3 x 1.5 L), evaporated and dried under vacuum at about 50 °. The resulting foamed material was triturated with about 500 ml of acetone, and then the solid material was filtered, washed with diethyl ether and dried under vacuum at 40 ° to obtain 12.25 g of the title compound. N.m.r. of this product. Spectroscopy is similar to that of Example 3 b) product.

The fluorine analysis (2.8%) indicates that the product contained some trifluoro acetic acid.

Example 6

a) diphenylmethyl (6R, 7R) -7-[(Z) -2- (1-t-butoxycarbonylcyclobut-1-oxyimino) -2- (2-tritylaminothiazole-4 -Yl) acetamido] -3-bromo methylsef-3-m-carboxylate

9.2 g of phosphorus pentachloride was added to 400 ml of methylene chloride, -20 g was added, cooled to -20 °, and 23.32 g of the product of Preparation Example 6 were added thereto. The solution was stirred at -20 for about 30 minutes, then 12.32 mL of triethylamine was added and held for 5 minutes at -20 °, followed by diphenylmethyl ((6R, 7R) -7-amino-3- in 400 mL of methylene chloride. Dissolve 19.8 g of bromomethylsep-3-em-4-carboxylate hydrochloride and 5.6 ml of triethylamine and add to the solution maintained at −20 ° over 5 minutes, after 10 minutes the cooler is removed and the temperature of the reactants is removed. Was raised to circumferential wall temperature over 30 minutes and poured into 400 mL of 1 L of methylene chloride, 42 g of the title compound were isolated in a similar manner as described in Example 5 a).

b) diphenylmethyl (6R, 7R) -7-[(Z) -2- (1-t-butoxycarbonylcyclobut-1-oxyimino) -2- (2-tritylaminothiazole-4 -Yl) acetamido] -3- (methylpyridinium-4-yliomethyl) cep 3-m-4-carboxylate bromide

42 g of step a) product in 500 ml of tetrahydrofuran was treated with 5.2 g of N-methylpyrid-4-thione and stirred at circumferential wall temperature for 3 hours. After standing at about 0 ° for 16 hours, the solution is stirred and 2.0 l of diethyl ether is added. The solid material was filtered off, washed well with diethyl ether and dried in vacuo at 40 ° to afford 50.5 g of the title compound.

c) (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxycyclobut-1-oxyimino) acetamido3-3- (1-methylpyridinium-4-ylthiomethyl) cef-3-m-4-carboxylate

40.5 g of the product of step a) are stirred with 320 ml of trifluoroacetic acid and 80 ml of anisole at about 0 ° for 1 h 30 min and the mixture is poured into 3 l of water and 1.5 l of diethyl ether. The title compound is isolated in the same manner as in Example 5 c), whose spectroscopic results are similar to those of Example 4 c). The fluorine analysis (about 4.2%) shows that the product contains some trifluoroacetic acid.

Example 7

a) Diphenylmethyl (1S6R, 7R) -7-[(Z) -2- (2-t-butoxycarbonylcyclobut-2-oxyimino) -2- (2-tritylaminothiazole-4 -Yl) acetamido] -3-[(1-methylpyridinium-2-yl) thiotylme] sef-3-m-carboxylate1-oxide, bromide

Preparation 1.02 g of 1,2-dihydro-1-thimer-pyrimidine-2-thi of the product of Example 7 in 10 ml of anhydrous tetrahydrohydrane was treated with 158 mg and the mixture was stirred at 25 ° for 1 hour 30 minutes. give. The resulting solution was slowly added to 150 mg of ether, with stirring, and the precipitate was filtered off and dried in vacuo to yield 1.043 g of the title compound as a solid.

b) diphenylmethyl (6R, 7R) -7-[(Z) -2-21-t-butoxycarbonylcyclobut-2-oxyimino) -2- (2-trityl aminothiazole-4- I) acet amido] -3-[(1-methylpyridinium-2-yl) thiomethyl] sef-3-m-4-carboxylate iodide

912 mg of the product of step a) was added to 10 ml of acetone, treated with 525 mg of potassium iodide, and the suspension was stirred at 25 ° for 5 minutes and then cooled to -10 °. 0.115 mL of acetyl chloride is added and the mixture is stirred for 50 minutes at 0 ° to 2 ° and then added to a solution of 600 mg of sodium metasulfite in 60 mL of water. The precipitate is filtered off, washed with water and dried over phosphorus pentoxide under vacuum to yield 880 mg of a solid material. To this was added 5 ml of acetone, treated with 525 mg of potassium iodide, cooled to -10 ° and 0.115 ml of acetyl chloride. The mixture was stirred at 0 ° to 2 ° for 40 minutes and then added to a solution of 1 g of sodium metasulfite dissolved in 60 ml of water. The precipitate is filtered off, washed with water and dried in vacuo over phosphorus pentoxide to give 940 mg of the title compound as a solid.

Melting point 142-156 ° (decomposition)

c) (6R, 7R) -7-[(Z) -2- (2-amino thiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3- [(1-methylpyrimidin-2-yl) thiomethyl] -cep-3-m-4-carboxylate, trifluoroacetate

To 800 mg of the product of step b) 0.5 ml of anisole is added to wet and treated with 2 ml of acetic acid. The mixture is stirred at 24 ° for 2.5 minutes and evaporated to triturate the resulting oil with ether. 560 mg of the solid material obtained by filtration is washed with ether and dried in vacuo. After treatment with 0.14 mL of anisole and 16 mL of trifluoro acetic acid at 25 ° for 15 minutes, the mixture is filtered and the residue is washed with 5 mL of trifluoro acetic acid. The combined filtrates are evaporated and the resulting oil is triturated with ether. The solid was filtered off, washed with ether and dried in vacuo to give 409 mg of the title compound as a solid.

Example 8

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) -acetamino-3-[(1 , 2-dimethylpyrazolium-3-yl) thiomethyl] sef-3-m-4-carboxylate, sodium salt

264 mg of the product of Example 3 a) and 135 mg of sodium bicarbonate are warmed with 0.3 ml of water until complete dissolution. 97 mg of 1,2-dimethylpyrazole-4-yn-3-thione, 450 mg of sodium iodide and 0.1 ml of water are added and the mixture is heated with occasional stirring at 70 ° for 4 hours. The mixture is left to cool, diluted with 0.5 ml of water and slowly added to 100 ml of stirred acetone. The precipitate is filtered off, washed with acetone and ether and dried in vacuo to give 318 mg of solid. 282 mg of solid material is dissolved in a small amount of water and passed through a column packed with 100 g of Amberlite XAD-2 resin. 66 mL of water (fractions 1 to 6), followed by 66 mL of water ethanol (3: 1) (fractions 7 to 12), combined 7 to 10 fractions, evaporated to about 150, and freeze-dried to give a white color. 158 mg of foamy material are obtained, which are triturated with ether to give 133 mg of the title compound as a white solid.

Example 9

Diphenylmethyl (1S, 6R, 7R) -7-[(Z) -2- (2-t-butoxycarbonyl-2--2-oxyxymino) -2- (2-tritylaminothiazole-4- Yl) acetamido] -3- (pyrid-3-ylthiomethyl) sef-3-m-4-carboxylate, 1-oxide

1.54 g of the product of Preparation Example 7 and 0.200 g of 3-mercaptopyridine are added to 12 ml of anhydrous tetrahydrofuran and treated with 0.224 ml of triethylamine. The gray suspension is stirred at 22 ° for 10 minutes and then partitioned between 150 ml of water and 150 ml of ethyl acetate. The organic phase was washed with water (2 x 50 mL), dehydrated and evaporated to yield 1.546 g of foamy material. This foamy substance is eluted with toluene: ethyl acetate (2: 1) on a silica column (Merck Kiesel gel 60, 70-230 mesh, 50 g). Collect the appropriate fractions and evaporate to give 1,385 g of the title compound in the foam form.

Example 10

a) Diphenylmethyl (1S, 6R, 7R) -7-[(Z) -2- (2-t-butoxycarbonylcyclobut-2-oxyimino) -2- (2-tritylaminothiazole -4-yl) acetamido] -3- [1,3-dimethylimidazolium-2-yl] thiomethyl] sef-3-m-4-carboxylate, 1-oxide, bromide salt

The product 0.8 of Preparation Example 7 was added to 4 ml of anhydrous tetrahydrofuran, treated with 0.108 g of 1,3-dimethylimidazole-4-yn-2-thione, and the mixture was stirred at 24 ° for 3 hours. . The resulting solution was added to 150 ml of stirred ether and the precipitate was filtered off and dried in vacuo to yield 0.834 g of the title compound as a solid. Melting point 150 degrees to 160 degrees (decomposition)

b) diphenylmethyl (6R, 7R) -7-[(Z) -2- (2-t-butoxycarbonylcyclobut-1-oxyimino) -2- (2-tritylaminothiazole-2 -(2--4-yl) acetamido] -3- [1,3-dimethylimidazolium-2-yl) thiomethyl] sef-3-m-carboxylate, iodide salt

0.725 g of the product of step a) was added to 5 ml of acetone and treated as in almost Example 7 b) to yield 0.759 g of the title compound as a solid.

Melting point 135 ° to 145 ° (decomposition)

c) (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3- [(1,3-dimethylimidazolium-2-yl) thiomethyl] cef-3-m-carboxylic acid, trifluoro acetate salt

b) 0.65 g of step product is treated with 0.5 ml of anisole and 2 ml of trifluoroacetic acid and the product is separated in almost the same manner as in Example 7c to give 0.273 g of the title compound as a solid.

Example 11

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxycyclobut-1-oxyimino) -acetamido] -3- ( Pyrid-4-yl-thiomethyl) sef-3-m-4-carboxylate

12 g of the product of Example 2b) were added to a solution of 21 g of sodium iodide in 20 ml of water at ambient temperature, and then 3.72 g of sodium bicarbonate was added over 40 minutes, and 3.5 g of 4-mercapto-pyridine was added. Heat at 70 ° C. for time. The mixture is cooled to ambient temperature and then 2 liters of acetone are added to give 14 g of solid material containing the title compound.

[Reformation Example]

Example A-Injected Powder

Vial composition

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2--carboxyprop-2-propoxyimino) acetamido] -3- (1-methylpyridinium-4-yl) thiomethyl-sef-3-m-4-

Carboxylate 500mg

Narium acetate (anhydrous) 69 mg

Way

The cephalosporin antibiotic is even mixed with sodium acetate to fill the vial. The upper space of the vial is purged with nitrogen and sealed with a combination seal. Before administration, 2 ml of water for injection is added to dissolve the product.

Example B

Intramammary Injection (Veterinary)

Furtherance

(6R, 7R) -7-[(Z) -2-aminothiazol-4-yl) -2- (2--carboxyprop-2-oxyimino) acetamido] -3- (1-methyl Pyridinium-4-yl) thiomethylsef-3-m-4-carboxylate,

The latter three components are heated together at 150 ° C. for one hour and then cooled to room temperature with stirring. Sterile antibiotics ground to the carrier are added aseptically and mixed with a high speed mixer. Aseptically fill a sterile plastic syringe with 5.00 g of product per syringe.

EXAMPLE

Injection powder

Vial composition

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1--carboxycyclobut-1-oxyimino) acetamido] -3- ( 1-methylpyridinium-4-yl) thiomethyl-sef-3-m-4-

500mg of carboxylate

Way

Meglumine 161 mgmg Cephalosporin antibiotics are mixed with meglumine and filled into vial vial. The upper space of the vial is purged with nitrogen and sealed with a combination seal. Before administration, 2 ml of water for injection is added to dissolve the product.

Example D

Injection powder

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxycyclobut-1-oxyimino) acet amido sterilized in vial Charge 3- (1-methylpyridinium-4-yl) -thiomethylsef-3-m-4-carboxylate, monosodium salt, equivalent to 1.000 g of antibiotic per vial. Filling is performed aseptically in the presence of a sterile nitrogen blanket. Seal the vial with a rubber disc or plug and fix it with an aluminum lid to prevent gas ingress or microbial ingress. Immediately before administration, the water for injection dissolves the product in another suitable sterile carrier. Plysorbate 60 is polyoxyethylene sorbitan mono-stealte containing about 20 ethylene oxide side units and meglumine is N-methylglucamine BD.

Claims (1)

Reacting a compound of formula (II) or a salt thereof with a sulfur nucleophile which forms a group of the formula -CH ₂ Y (where Y is as described below) at the 3-position of the formula (II) To prepare a general formula (Ic) compound, non-toxic salts thereof, and non-toxic, easily metabolic esters.

In the above formula R ^a R ^b and R ^a are the same or different and each represent an alkyl group having 1 to 4 carbon atoms, or R ^a and R ^b together with the carbon atom to which they are attached form a cycloalkylidene group having 3 to 7 carbon atoms; B is> S or> S → 0; Y represents a 5- or 6-membered heterocyclic ring linked to carbon containing at least one nitrogen atom, which may contain one or more sulfur atoms in addition to the nitrogen atom and be an alkyl group of 1 to 4 carbon atoms. May be substituted; R ¹ represents hydrogen or a carboxyl blocking group; R ² represents hydrogen or a carboxyl blocking group; R ³ represents an amino or protected amino group; The dotted line connecting the 2-, 3- and 4-positions indicates that this compound is a cef-2-em or cef-3-em compound; X represents a substitutable magnetism of a nucleophile.