KR830000606B1 - Process for preparing cephalosporin antibiotics - Google Patents

Abstract

Cephalosporins I (Ra,Rb = C1-4 alkyl, forms C3-7 cyclo-alkylidene with C; R4 = H, 3-or 4-carbamoyl; B =>S or >S→O; R5a = -COOθ, -COOR5; R5 = carboxyl protecting group; R6 = H, carboxyl protecting group; R7 = amino; R6a = carboxyl protecting group) and their salts were prepd. Thus, (6R,7R)-7-≮(Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxycyclopent-1-yl-oxyimino)-acetamido≉-3-(1-pyridiniummethyl)-ceph-e-em-4-carboxylate dihydrochloride salt was prepd. from (Z)-2-(1-tert.-butoxycar-bonylcyclopent-1-yl-oxyiminotritylamino)-2-(2-tritylaminothiazol-4-yl) acetic acid.

Description

Method for preparing cephalosporin antibiotic

The present invention relates to a cephalosporin antibiotic compound useful as an antibiotic and a method for preparing non-toxic salts and non-toxic easily metabolizable esters thereof.

The cephalosporin compound herein is described in J. Amer. Chem. Soc., 1982, 84, 3400, refers to the "sefam" described, "Sefem" refers to the basic sepam structure having one double bond.

Cephalosporin antibiotics are widely used to treat diseases caused by pathogenic bacteria in humans and animals, and are particularly useful for treating diseases caused by bacteria that are resistant to other antibiotics, such as penicillin compounds, and for treating 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 thus there has been considerable research on the development of various types of cephalosporin antibiotics.

For example, British Patent No. 1,399,086 describes a novel cephalosporin antibiotic containing a 7β- (α-etherized oximino) -acylamido group, wherein the oximino group has a syn configuration. . This class of antibiotic compounds is characterized by high stability against Gram-positive and Gram-negative bacteria, while being particularly stable against β-lactamase produced by various Gram-negative bacteria.

The discovery of compounds of this class has further spurred attempts in this field to find compounds with improved properties, such as improved properties for certain classes of bacteria, particularly Gram-negative bacteria.

British Patent No. 1,496,757 discloses a cephalosporin antibiotic containing a 7β-acylamido group of formula (A), wherein the compound is an isomer or a mixture of syn and anti isomers containing at least 90% syn isomers. Is described.

In the above general formula, R is thienyl or furyl group; ^Α R and R ^B is broad and, for example, or a C _1-4 alkyl group, or forms a group C _3-7 cycloalkyl alkylidene taken together with the carbon atoms to which they are attached; m and n are each 0 or 1, provided that the sum of m and n is 0 or 1.

The 3-position of the cephalosporin molecule may be unsubstituted or contain one of several possible substituents.

It has been found that these compounds have good activity, especially against Gram-negative bacteria.

British Patent No. 1,522,140 also describes cephalosporin antibiotics of formula (B), wherein the compound is a syn isomer or is present as a mixture of syn and anti isomers containing at least 90% syn isomers. .

In the above general formula, R ¹ is a furyl or thienyl group; R ² is a C _1-4 alkyl group, C _3-7 cycloalkyl group furylmethyl or thienylmethyl group; R ³ is hydrogen or carbamoyl, carboxymethyl, sulfo, or methyl group. These compounds exhibit high antimicrobial activity against a wide range of Gram-positive and Gram-negative bacteria, and are not only very stable against β-lactamase produced by various Gram-negative bacteria but also in vivo. Other compounds with similar structures have been developed from these compounds in an attempt to find antibiotics with enhanced broad spectrum antimicrobial activity and / or strong action against Gram-negative bacteria. This development led to several changes, such as introducing specific groups at the 3-position of the 7β-acylamido groups and cephalosporin molecules of the general formula. For example, Belgian Kingdom Patent No. 852,427 (the cephalosporin antibiotic compounds described herein are included within the scope of British Patent No. 1,399,086) has RD in formula (A), including 2-aminothiazol-4-yl. There are described cephalosporin antibiotic compounds in which various organic groups are substituted, oxygen atoms in oximino groups are attached to aliphatic hydrocarbon groups, and the aliphatic hydrocarbon groups themselves can be substituted with carboxy groups. In such compounds, the 3-position substituent is acyloxymethyl, hydroxymethyl, formyl or an optionally substituted heterocyclic thiomethyl group.

In addition, the Kingdom of Belgium Patent 836,813 discloses a hydroxyimino group in which R in the general formula (A) is substituted with 2-aminothiazol-4-yl, and an oximino group is hydroxyimino or blocked. Cephalosporin compounds, which are nogi, are described. In such compounds, the 3-position of the cephalosporin molecule is methyl substituted and the methyl group itself may be optionally substituted with various nucleophilic compound residues such as pyridinium which may be substituted with a carbamoyl group. The patent does not describe the activity of these compounds as antibiotics, and refers only to intermediates for producing antibiotics.

Belgian Kingdom Patent 853,545 discloses that the 7β-acylamido side chain is predominantly 2- (aminothiazol-4-yl) -2- (syn) -methoxyimino-acetamido group, and the substituent at 3-position is the Belgian kingdom. A broadly defined cephalosporin antibiotic as described in patent 836,813 is described. Exemplary compounds herein include compounds in which the 3-position is substituted with a pyridiniummethyl or 4-carbamoyl pyridiniummethyl group. The present inventors have found that cephalosporin compounds having a pyridiniummethyl group or a 3- or 4-carbamoyl pyridiniummethyl group at the 3 position and at the same time several groups specific at the 7β-position are particularly effective against a wide range of common pathogens (hereinafter In detail).

Examples of the compound of the present invention include the cephalosporin antibiotic compound of formula (I) and its non-toxic salts and non-toxic, easily metabolizable esters.

R ^a and R ^b in the general formula may be the same or different and each represent a C _1-4 alkyl group (preferably a straight alkyl group, ie a methyl, ethyl, n-propyl or n-butyl group and especially a methyl or ethyl group) Or R ^a and R ^b together with the carbon atom to which they are attached form a C _3-7 cycloalkylidene group, preferably C _3-5 cycloalkylidene group; R ⁴ represents a hydrogen 3- or 4- or carbamoyl group.

The compounds according to the invention are syn-isomers. The syn isomeric form is determined by the configuration of the group represented by the following general formula for the carboxamido group.

In the present specification, ssyn configuration refers to the following structurally.

Since the compounds according to the invention are geometric isomers, some may be produced in admixture with the corresponding anti isomers.

The compound of the present invention also includes a solvent compound (particularly a hydrate) of the compound of formula (I), and also includes a salt of an ester of the compound of formula (I).

The compounds according to the invention may also exist in the tomomo form (for example with respect to the 2-aminothiazolyl group), for example a tautomeric form such as the 2-iminothiazolinyl type is also within the scope of the invention. Included. The compound of general formula (I) may also be present in the zwitter ionic form (eg, 4-carboxyl groups are quantized and 7-sided carboxyl groups are de-quantized). When R ^a and R ^b represent different C _1-4 alkyl groups in the general formula, the carbon atoms to which they are attached become an asymmetric center.

Such compounds are diastereoisomers and the present invention includes each diastereoisomer of these compounds and mixtures thereof.

The compounds according to the invention exhibit a wide range of antibiotic activity. In general, the activity against Gram-negative bacteria is high. This high activity also affects Gram-negative bacteria, which produce numerous β-lactamases. This compound is also very stable against β-lactamase produced by Gram-negative bacteria.

The compounds according to the invention are Pseudomonas pathogens (e.g. Pseudomonas aeruginosa) and various Enterobacteriaceae (e.g. Escherichia coli, choleciella cofeimo) Klebsiella pheumoniae, Salmonella typhimurium, Shigella Sonnei, Enterobacter cloacae, Serratia marcescens, Providence, High activity against Proteus mirabilis and especially indole-positive proteus pathogens, such as Proteus vulgaris and Proteus morganii and Haemophilus influenzae strains Indicates.

The compounds according to the invention have antibiotic activity comparable to aminoglycosides such as amikacin or gentamicin, and are particularly active against various strains of Pseudomonas pathogens which are not sensitive to the majority of commercially available antibiotics. Unlike aminoglycosides, cephalosporin antibiotics are usually low in humans. Aminoglycosides have limited or complex therapeutic uses due to their high toxicity. The cephalosporin antibiotics according to the invention are thus very useful than amino-glycosides.

Non-toxic salt derivatives that may be formed by half of one or two carboxyl groups in the compound of formula (I) include inorganic metal salts such as alkali metal salts (e.g. sodium and potassium salts) and alkaline earth metals (e.g. calcium salts). Basic salts; Amino acid salts such as lysine and arginine salts; Organic base salts (e.g., prolocaine, phenylethylbenzylamine, dibenzylethyleneamine, ethanolamine, diethanolamine, and N-methylglucoseamine salt) Other non-toxic salt derivatives include hydrochloric acid, bromic acid, Acid addition salts formed by reaction with sulfuric acid, nitric acid, phosphoric acid, formic acid and trifluoroacetic acid, such as for example cross-linked lolistylenedivinylbenzenes containing polystyrene resins or amino or quaternary amino or sulfonic acid groups. It may be formed by the use of a copolymer resin or present in the form of a resinate containing a carboxyl group, for example a polyacrylic acid resin, soluble base salts of compounds of general formula (I) (e.g. alkalis such as sodium salts). Metal salts) can be used for treatment because they disperse rapidly at in vivo doses, however, insoluble salts of compounds of formula (I) may be used, for example, If you want to use a POE preparations, such salts may be formed by conventional methods, for example using an appropriate organic amine.

These and other salt derivatives, such as salts formed by reaction with toluene-p-sulfone and methanesulfonic acid, are used as intermediates in the preparation or purification of the compounds of the general formula (I). (The method is described above).

Non-toxic, easily metabolized ester derivatives that can be formed by esterifying one or more of the parent compounds of Formula (I) with unsubstituted carboxyl groups are acyloxyalkyl esters, such as lower alkanoyloxy-methyl or Ethyl esters such as acetoxy-methyl or -ethyl or pivaloyloxy methyl esters. In addition to the above ester derivatives, the present invention is within the scope of the compound of formula (I), other physiologically toxic equivalents, i.e., the parent antibiotic of formula (I) in an in vivo test such as an ester which can be easily metabolized It also includes physiologically toxic compounds that are converted to.

Preferred groups of the compounds according to the invention, which have high antibiosis, are compounds of the general formula (I) wherein R ⁴ is hydrogen, ie compounds of the general formula (Ia) and their non-toxic salts and non-toxic which can be easily metabolized Ester.

In the general formula, R ^a and R ^b are as defined above.

Specific among the compounds of formula (Ia) are (6R, 7R) -7-[(Z) -2 (2-aminothiazol-4-yl) -2- (2-carboxyprop of formula (Ib) -2-oxyimino) acetamido] -3- (1-pyridiniummethyl) -sef-3-m-4-carboxylate and its non-toxic salts (e.g. sodium salts) and non-toxic, can easily be metabolized It is an ester.

The compound of general formula (Ib) remarkably shows the antimicrobial property of the compound of general formula (I). In particular, it exhibits excellent antimicrobial activity against strains of Pseudomonas pathogens. This compound has an excellent antimicrobial activity that is not damaged by human serum, and furthermore, its inoculation effect is low. This compound exhibits rapid acid sterilization at concentrations close to the minimum inhibitory concentration. This compound disperses well in the body when a therapeutically effective amount is injected into small rodents. This compound, when injected intramuscularly in primates, maintains high serum levels for a long time. The half-life of serum in primates shows the potential for a relatively long half-life in humans, thus reducing the frequency of administration for insignificant infections. Tests for the infection of the lab-negative bacterium in mice were successful when treated with this compound, particularly with Pseudomonas aeruginosa strains resistant to cephalosporin antibiotics. This action is comparable with aminoglycosides such as amikacin. In acute toxicity studies of this compound in mice, LD _50> 1.0 g / kg. No renal toxicity in rats was observed at a dose of 2.0 g / kg.

Compounds having properties similar to those of the general formula (Ib) include (6R, 7R) -7-[(Z) -2 (2-aminothiazol-4-yl) -2 (1-carboxycyclobut-1 -Oxyimino) acetamido] -3 (1-pyridiniummethyl) -cep-3-m-4-carboxylate and its non-toxic salts and non-toxic easily metabolizable esters.

Other examples of preferred compounds according to the present invention include the following general formula (I) compounds and nontoxic salts thereof, and nontoxic, easily metabolizable esters.

(6R, 7R) -7-[(Z) -2 (2-aminothiazol-4-yl) -2 (2-carboxyprop-2-oxyimino) acetamido] -3- (4-carba Moyl-1-pyridiniummethyl) -cep-3-m-4-carboxylate; (6R, 7R) -7-[(Z) -2 (2-aminothiazol-4-yl) -2 (1- Carboxyprop-1-oxyimino) acetamido] 3- (1-pyridiniummethyl) -sef-3-m-4-carboxylate; (6R, 7R) -7-[(Z) -2- ( 2-aminothiazol-4-yl) -2- (1-carboxycyclopent-1-oxyimino) acetamido] 3 (1-pyridinium metal) -cep-3-m-4-carboxylate; ( 6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxycyclobut-1-oxyimino) acetamido] 3- (4-carba Moyl-1-pyridiniummethyl) -cep-3-m-4-carboxylate.

Other compounds according to the present invention include compounds in which R ^a , R ^b and R ⁴ in the general formula (I) are as follows.

Compounds of formula (I) are used to treat diseases caused by pathogens, such as respiratory and urinary infectious diseases, in humans and animals.

The present invention is a compound of the following general formula (Ic) compounds or non-toxic salts thereof or non-toxic easily metabolizable esters are prepared as follows. That is, a compound of formula (II) or a salt thereof (for example, an acid addition salt formed by reacting with an inorganic acid such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid or phosphoric acid or an organic acid such as methanesulfonic acid or toluene-P-sulfonic acid) Or an N-silyl derivative thereof is acylated with an acid of the following general formula (III) or an equivalent acylating agent and, if necessary, carried out in any suitable order by any of the following reaction steps.

i) converting the Δ ² -isomer to the desired Δ ³ -isomer.

ii) reduction of a compound in which B is> S → O to form a compound in which A is> S.

iii) converting carboxyl groups to non-toxic salts or non-toxic, easily metabolizable ester functionalities, and

iv) removing any carboxyl blockers and / or N-protecting groups.

를 갖는 -COO

또는 -COOR⁵기 [여기서 R⁵는 카복실 차단기, 예를 들어 에스테르-형성 지방족 또는 아르알리파틱 안콜 또는 에스테르-형성 페놀, 실란올 또는 스타난을(여기서 알콜, 페놀, 실란올 또는 스타난올은 1 내지 20개의 탄소원자를 함유하는 것이 바람직함)의 잔기이다]이고;R⁶는 수소 또는 R⁵에서 기술한 바와 같은 카복실 차단기이며; R7은 아미노 또는 보호된 아미노기이고; R^6a는 카복실 보호기이다.Wherein R ^a , R ^b and R ⁴ are as defined above; B is> S or> S → O (α- or β-); The dashed lines connecting the 2-, 3-, and 4-positions indicate that the compound is a cef-2-em or cef-3-em compound; R ^5a is an anion A such as a halide (e.g. chloride or bromide) or trifluoro acetate anion

-COO with

Or a -COOR ⁵ group wherein R ⁵ represents a carboxyl blocker, for example an ester-forming aliphatic or araliphatic anol or ester-forming phenol, silanol or stanan, wherein alcohol, phenol, silanol or stananol is 1 Preferably containing from 20 to 20 carbon atoms; R ⁶ is hydrogen or a carboxyl blocking group as described for R ⁵ ; R7 is an amino or protected amino group; R ^6a is a carboxyl protecting group.

In the above reaction, the compound of general formula (II), which is a starting material, is preferably a compound in which B is> S and a dotted line represents a Ceph-3-M compound, and the starting material of the present invention is N- (7-amino ce-3 -M-3-ylmethyl) pyridinium-4'-carboxylate dihydro-chloride is particularly suitable because it is prepared in high purity.

Acylating agents that can be used to prepare the compounds of formula (I) include acid halides, especially acid chlorides or bromide. Such acylating agents can be prepared by reacting an acid (III) or a salt thereof with a halogenating agent such as phosphorus pentachloride, thionyl chloride or oxalin chloride.

Acylation reactions with acid halides are effective to be carried out in aqueous and non-aqueous reaction media, typically at -50 to + 50 ° C, preferably at -20 ° to + 30 ° C, in the presence of an acid binder if necessary. Suitable reaction media include aqueous ketones such as aqueous acetone, esters such as ethyl acetate, halogenated hydrocarbons such as menthylene chloride, amides such as dimeltylacetamide, nitriles such as acetonitrile or mixtures of two or more of these solvents.

Suitable acid binders include tertiary amines (eg triethylamine or dimethylaniline), inorganic bases (eg calcium carbonate or sodium bicarbonate) and lower 1,2-alkylene oxides (eg ethylene oxide or propylene oxide); The same oxiranes and the like bind to the hydrogen halides liberated in the acylation reaction.

Acids of general formula (III) can be used as acylating agents to prepare compounds of general formula (I). Acylation reactions with acids (III) include condensing agents such as carbodiimides such as N, N'-dicyclohexyl carbodiimide or N-ethyl-N'-Y-dimethylaminopropyl-carbodiimide, Preference is given to carrying out in the presence of isoxazolium salts such as carbonyl compounds such as carbonyl-diimidazole or N-ethyl-5-phenylisoxazoliumperchlorate.

Acylation reactions can also be carried out by reaction with amide-forming derivatives of the general formula (III) acids, for example activated esters, symmetric anhydrides or mixed anhydrides (e.g., haloforms such as lower alkylhaloformates or by reaction with pivalic acid). It is effective to carry out using the (form formed in reaction with the mate).

Mixed anhydrides may also be formed using phosphoric acid (eg phosphoric acid or phosphorous acid), sulfuric acid or aliphatic aromatic sulfonic acid (eg toluene-P-sulfonic acid). Activated esters can typically be formed in situ using 1-hydroxybenzotriazole in the presence of a condensing agent. Alternatively, the activated ester may be preformed.

The acylation reaction using the free acid or its amidation derivative is preferably carried out in anhydrous reaction medium (e.g. methylene chloride, tetrahydrofuran, dimethylformamide or acetonitrile).

If necessary, the acylation reaction may be carried out in the presence of a catalyst such as 4-dimethyl-aminopyridine.

Acids of formula (III) and the corresponding acylating agents can be prepared and used in the form of their acid addition salts, if necessary. For example, acid chlorides are typically hydrochloride salts thereof, and acid bromide can be used in the form of hydrobromide salts.

The reaction product is separated into the reaction mixture by various methods such as recrystallization, iontophoresis, column chromatography and ion exchange resins (eg chromatography over the surface of ion exchange water) or the use of large network resins. Unreacted cephalosporin starting materials and other materials may be contained.

The Δ ² -cephalosporin ester derivatives prepared by the process of the invention can be converted to the corresponding Δ ³ -derivatives by treating the Δ ² -esters with a base such as pyridine or triethylamine.

The Cef-2-M reaction product is also oxidized by treatment with peracids such as peracetic acid or m-chloroperbenzoic acid to form the corresponding Cef-3-M-1-oxides, where necessary the sulfoxides described below. This can be followed by reduction to form the corresponding ceph-3-M sulfide.

Among the compounds obtained, compounds of which B is> S → O, for example, react the corresponding acyloxy sulfonium or alkoxysulfonium salts prepared in the same reactor (for example, in the case of acetoxysulfonium salts with acetyl chloride). This reaction can be accomplished by using sodium dithionite, or water-miscible with potassium iodide such as acetic acid, acetone, tetrahydrofuran, dioxane, dimethylformamide or dimethylacetamide. It is effective to use iodide in the form of a solution dissolved in a solvent. This reaction is carried out at about -20 ° C to +50 ° C.

Ester metabolites that can be easily metabolized of compounds of formula (I) are suitable esterification agents, such as acyloxy alkyl halides (e.g., iodides), of compounds of formula (I) or salts thereof or protected derivatives thereof. Can be prepared by reacting with an inert organic solvent such as dimethylformamide or acetone and, if necessary, removing the protective group.

Base salts of compounds of formula (I) are prepared by reacting an acid of formula (I) with a suitable base. For example sodium or potassium salts are prepared using the respective 2-ethyl-hexanoate or hydrogen carbonate. Acid addition salts are prepared by reacting a compound of formula (I) or an easily metabolizable ester derivative thereof with a suitable acid. If the compound of formula (I) is obtained as a mixture of isomers, the syn-isomers can be obtained by conventional methods such as crystallization or chromatography.

As starting materials for the preparation of compounds of formula (I) according to the invention, the compounds of formula (III) and their acid halides and the corresponding anhydrides contain syn isomers or at least 90% syn isomers, Preference is given to using mixtures of syn isomers and the corresponding anti isomers.

Acids of formula (III), provided that R ^a and R ^b do not form a cyclo-propylidene group with the carbon atoms to which they are attached, the compounds of formula (IV) It can be prepared by reacting with ether to remove the carboxyl blocker R ⁸ .

Wherein R ^a , R ^b , R ⁶ and R ⁷ are as described above and R ⁸ is a carboxyl blocker, T is halogen (eg chloro, bromo or urethra), sulfate or sulfonate (eg tosylate) )to be.

Isomers may be separated before or after etherification. The etherification reaction is carried out in the presence of a base such as potassium carbonate or sodium hydride, preferably in an organic solvent such as a cyclic ether such as dimethyl sulfoxide, tetorahydrofuran or dioxane, or N, N-disubstituted amide such as dimethylformamide. Perform on Under these conditions, the coordination of oxyimino groups is hardly changed by etherification. This reaction should be carried out in the presence of a base when using an acid addition salt of the compound of formula (IV) and the base should be used in an amount sufficient to rapidly neutralize the acid in question.

The acid of general formula (III) may be prepared by reacting a compound of general formula (VI) with a compound of general formula (VII), removing the carboxyl blocker R ⁸ , and separating the syn and anti isomers if necessary.

In the general formula, R ^a , R ^b , R ^6a , R ⁷ and R ⁸ are as defined above.

The reaction can in particular be used to prepare acids of the general formula (III) in which R ^a and R ^b together with the carbon atoms to which they are attached form a cyclo-propylidene group. In this case, the compound of general formula (VII) can be prepared using conventional methods, for example, the method of preparing tert-butyl 1-amino-oxycyclopropanecarboxylate of Belgian Patent No. 866,422.

The acid of general formula (III) can be converted into the corresponding acid halides, anhydrides and acid addition salts according to the conventional methods illustrated below.

Starting materials of formula (II) may also be prepared by conventional methods, for example by nucleophilic substitution of the corresponding 3-acetoxymethyl compound with an appropriate nucleophile (see, for example, British Patent No. 1,028,563).

In addition, a method for preparing the starting material of general formula (II) includes deprotecting the corresponding protected 7β-amino compound using conventional methods such as PC1 ₅ .

In any of the above transformations, it is necessary to protect certain sensitive groups in the compound molecule in question in order to prevent unnecessary side reactions.

For example, during the reaction, the NH 2 group in the amino thiazolyl residue needs to be protected by conventional methods such as trimethylation, acylation (eg chloro acetylation), quantization, and the like. The protecting group can then be removed by conventional means which do not rupture the target compound, for example in the case of trityl groups, optionally halogenated carboxylic acids (e.g. formic acid, chloroacetic acid or trifluoroacetic acid) or inorganic acids (e.g. Hydrochloric acid) or mixtures thereof, preferably in a protic solvent such as water, and in the case of chloro acetyl groups with thiourea.

It is preferred that the carboxyl blocker used in the preparation of the compound of formula (I) or in the preparation of the required starting materials can be easily separated in a suitable stage of the reaction, preferably in the final stage. In some cases, however, non-toxic, easily metabolizable such as acyloxy-methyl or -ethyl groups (e.g. acetoxymethyl or -ethyl or pivaloyloxymethyl) can be used and carboxyl blockers remain in the final product. To obtain ester derivatives of the general formula (I) compounds.

Suitable carboxyl blockers are described in the literature and representative examples are described in British Patent 1,399,086. Preferred blocked carboxyl groups include aryl lower alkoxycarbonyl groups such as p-methoxybenzyloxy carbonyl, p-nitrobenzyl-oxycarbonyl and diphenylmethoxycarbonyl; Lower alkoxycarbonyl groups such as tert-butoxycarbonyl and lower haloalkoxycarbonyl groups such as 2,2,2-trichloroethoxy-carbonyl. The carboxyl blocker can then be removed using any suitable method described in the literature. For example, in most cases acid or base catalyzed and enzymatically-catalyzed hydrolysis methods are used.

The antibiotic compound of the present invention can be used as a medicament or a veterinary medicine in a variety of convenient forms for administration, similar to other antibiotics. The present invention also includes pharmaceutical compositions containing the antibiotic compounds of the present invention. This composition is formulated in a conventional manner with the required pharmaceutical carrier and excipient.

The antibiotic compound of the present invention may be formulated as an injectable medicament and may be formulated in ampoules, in several dose containers, or with the addition of a preservative if necessary. The compositions may be formulated in the form of suspensions, solutions or emulsions dissolved in oily or aqueous excipients, and may contain suspending agents, stabilizers and / or dispersants, and the like.

Alternatively, the active ingredient may be in powder form and, prior to use, may be remixed with a suitable excipient such as sterile pyrogen-free water.

If necessary, such powders may also contain suitable non-toxic bases to increase the water solubility of the active ingredient or to make them physiologically toxic of the aqueous formulations produced when remixed with water. It may also contain a base in the water to be remixed with the powder. Such bases include inorganic bases such as sodium carbonate, sodium bicarbonate or sodium acetate, and organic bases such as lysine or lysine acetate.

The antibiotic compounds of the present invention may be formulated into suppositories using conventional suppository bases such as, for example, cocoa butter or other glycerides. Veterinary preparations may, for example, be formulated as an intramammary formulation in the substrate that is active or released rapidly for a long time. The composition may contain at least 0.1%, ie 0.1 to 99% of active substance, depending on the method of administration. It is preferred to contain 50 to 1500 mg of compound per unit, when configured in dosage units of the composition. The dose used for the treatment of an adult is preferably 500 to 6000 mg / day, depending on the route and frequency of administration. For example, in adults, 1,000 to 3,000 mg / day are usually used for intravenous or intramuscular administration. Higher daily doses are needed to treat Pseudomonas infection.

Antibiotic compounds of the present invention can be used in combination with other antibiotics such as penicillin or other cephalosporins. The following examples illustrate the invention. All temperatures are in degrees Celsius and "petrol" refers to petroleum ether (boiling point 40 to 60 ° C).

p.m.r. Spectra were measured at 100 MHz. The integral value was as expected, the coupling constant J was expressed in Hz and no sinn was measured. s = single line, d = double line, t = triple line, m = multiline, ABq = AB quartet.

Preparation Example 1

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

A solution of 180 g of sodium nitrite dissolved in 400 ml of water was added to a solution of 292 ml of ethylacetoacetate dissolved in 296 ml of 296 ml of glacial acetic acid, followed by stirring and ice cooling, and the reaction temperature was maintained at 10 ° C. or lower. After stirring and cooling for about 30 minutes, a solution of 160 g of potassium chloride in 180 ml of water is added.

The resulting mixture is stirred for 1 hour. The oil phase of the bottom layer is separated and the aqueous phase is extracted with diethyl ether. The extract is combined with oil and washed sequentially with water and saturated brine, then evaporated to dryness. Residual oil (which is left to solidify) is washed with petroleum and dried with potassium hydroxide under vacuum to afford 309 g of ethyl (Z) -2- (hydroxyimino) -3-oxobutyrate.

150 g of ethyl (Z) -2- (hydroxyimino) -3-oxobutyrate is dissolved in 400 ml of dichloromethane, and the solution which is stirred and cooled with ice is treated with 140 g of sulfuryl chloride. The resulting solution is left at room temperature for 3 days and evaporated.

The residue is dissolved in diethyl ether, washed with water until the wash is neutral, evaporated and dried. 177 g residual oil is dissolved in 500 ml ethanol and 77 ml dimethylaniline and 42 g 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: 180 ° (decomposition 0

Production Example 2

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

12.91 g of the product obtained in Preparation Example 1 was dissolved in 28 ml of dimethylformamide containing 8.4 ml of triethylamine, and stirred and cooled (-30 ° C.) to 1.675 g of trityl chloride in 2 hours. Add a little over. The mixture is warmed to 15 ° C. over 1 h, stirred for 2 h and then partitioned between 500 ml of water and 500 ml of ethyl acetate. The organic phase is separated and washed twice with 500 ml of water each time and shaken with 500 ml of 1N HC1. The precipitate is collected, washed sequentially with 100 ml of water, 200 ml of ethyl acetate and 200 ml of ether and dried under vacuum to afford the title solidification of a white solid.

Melting Point: 184 to 186 ° (Decomposition)

Preparation Example 3

Ethyl (Z) -2- (2-tert-butoxycarbonylprop-2-oxyimino) -2- (2-trityl aminothiazol-4-yl) acetate

34.6 g of potassium carbonate and 24.5 g of tert-butyl 2-bromo-2-methylpropionate were dissolved in 25 ml of dimethylsulfoxide, and 49.4 g of the product obtained in Preparation Example 2 was dissolved in 200 ml of nitrogen. It is dissolved in dimethyl sulfoxide and added to the stirred solution. The mixture is stirred for 6 hours at room temperature, poured into 2 liters of water, then stirred for 10 minutes and filtered. The solid is washed with water and dissolved in 600 ml of ethyl acetate. The solution is washed sequentially with water, 2N hydrochloric acid, water and saturated brine, evaporated and dried. The residue is recrystallized from petroleum ether (boiling point: 60-80 ° C.) to give 34 g of title compound. Melting point: 123.5-125 ° C.

Production Example 4

(Z) -2- (2-3-tert-butoxycarbonylprop-2-oxyimino) -2- (2-tritylaminothiazol-4-yl) acetic acid

2 g of the product obtained in Preparation Example 3 are dissolved in 200 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 added to a mixture of 500 ml of water, 7 ml of 2N hydrochloric acid and 500 ml of ethyl acetate, the organic layer is separated and the aqueous layer is extracted with ethyl acetate. The organic solutions are combined, washed sequentially with water and with saturated brine and then evaporated to dryness. The residue is recrystallized from a mixture of carbon tetrachloride and petrol to give 1 g of the title compound.

Melting Point: 152 to 156 ° C (Decomposition)

Production Example 5

Ethyl (Z) -2- (2-tritylaminothiazol-4-yl) -2- (1-tert-butoxycarbonylcyclobut-1-oxyimino) acetate

55.8 g of the product obtained in Preparation Example 2 are dissolved in 400 ml of dimethyl sulfoxide under nitrogen atmosphere and stirred with 31.2 g of potassium carbonate (fine particles) at room temperature. After 30 minutes, 29.2 g of tert-butyl 1-bromocyclobutane carboxylate are added. After another 8 hours, 31.2 g potassium carbonate was added. Add potassium carbonate for 3 days (six times 16 g at a time), then add 3,45 g of tert-butyl 1-bromocyclobutane carboxylate after 3 days. After 4 days, the mixture is poured into about 3 L of ice water, the solids are filtered off, washed well with water and petrol. The solid is dissolved in ethyl acetate and the solution is washed twice with brine, then dehydrated on magnesium sulfate and evaporated to form a blister material. The foamed material is dissolved in ethyl acetate-petrol (1: 2), filtered through 500 g of silica gel and evaporated to give 60 g of the foamed title compound.

ν _max (CHBr ₃ ): 3400 (NH) and 1730 cm ⁻¹ (ester).

Preparation Example 6

(Z) -2- (1-tert-butoxycarbonylcyclobut-1-oxyimino) -2- (1-tritylaminothiazol-4-yl) acetic acid

A mixture of 3.2 g of the product obtained in Preparation Example 5 and 1.65 g of potassium carbonate was refluxed in 180 ml of methanol and 20 ml of water for 9 hours and the mixture was cooled to room temperature. The mixture is concentrated and the residue is partitioned between ethyl acetate and water and 12.2 mL of 2N hydrochloric acid is added. The organic phase is separated and the aqueous phase is extracted with telacetate. The combined organic extracts are washed with saturated brine, evaporated and dried to give 2.3 g of the title compound.

λ _max (ethanol): 265 nm

Production Example 7

Ethyl (Z) -2- (1-tert-butoxycarbonylcyclopent-1-yloxyimino) -2- (2-tritylaminothiazol-4-yl) acetate

10 g of the product obtained in Preparation Example 2 together with 7 g of tert-butyl 2-bromo-cyclopentanecarboxylate was dissolved in 10 g of potassium carbonate in 40 ml of dimethyl sulfoxide for 21 hours at 21 ° C. under nitrogen atmosphere. Stir while. The mixture is poured into 500 ml of ice water and the gray solid is collected by filtration, washed with water and air dried.

This solid is recrystallized from 500 ml of methanol to give 11.7 g of the title compound. Melting point: 179 to 180 ° C.

ν _max (CHCr ₃ ): 3410 (NH), 1735 (ester), 1275 (ester) and 755 cm ⁻¹ (phenyl).

Preparation Example 8

(Z) -2- (1-tert-butoxycarbonylcyclopent-1-yloxyiminotritylamino) -2- (2-trityl aminothiazol-4-yl) acetic acid

625 mg of the product obtained in Preparation Example 7 was refluxed for 7 hours in 12 ml of methanol with 0.5 ml of 2N sodium hydroxide solution and 1 ml of water. The mixture is cooled overnight. Dilute with water and adjust the pH to 2 by adding orthophosphoric acid. The precipitate is extracted with ether and the combined extracts are washed with brine. Dehydration on magnesium sulfate and evaporation of the solvent gave 493 mg of the sample material which was then recrystallized from diisopropyl ether to give 356 mg of the title compound. Melting point: 171-173 degreeC.

ν _max (CHBr ₃ ): 250C-3500 (OH and NH), 1755 (ester), 1692 (acid) and 755 and 770 cm ⁻¹ (phenyl).

Preparation Example 9

(6R, 7R) -7-Amino-3- (1-pyridiniummethyl) -cep-3-m-4-carboxylic acid dihydrochloride a) 4.15 g of (6R, 7R) -7- (2-thienyl Acetamido) -3- (1-pyridiniummethyl) -sef-3-m-4-carboxylate; was added to 30 ml of dichloromethine and the stirred suspension was added to 5.09 ml of N, N-dimethylaniline and 2.52. Treat with ml of chlorotrimethylsilane. The mixture was stirred at 30-35 ° C. for 1 hour, cooled to -28 ° C., treated with 4.16 g of phosphorus pentachloride and again stirred at −25 to −30 ° C. for 1 hour, followed by 8.1 ml of butane-1,3 Diol and 20 ml of dichloromethane are mixed and poured into a stirred, cooled (-20 ° C.) solution. The solution is left at 0 ° C. for 30 minutes and the precipitated solid (A) is filtered off, washed with dichloromethane and dried under vacuum. It was redissolved in 17.5 ml of methanol, stirred, diluted with 87.5 ml of dichloromethane, the precipitated solid was filtered off, diluted with dichloromethane, the precipitated solid was filtered off, washed with dichloromethane and dried under vacuum to a white solid. 3.2 g of the title compound are obtained.

318);λmax (pH 6 buffer): 258 mm (E

318);

τ (D ₂ O) values: 0.95, 1.32 and 1.84 (pyridinium quantum), 4.10-4.46 (ABq, J 16 Hz, 3-CH _2- ), 4.56 (d, J5 Hz, 7-H), 4.70 (d, J5 Hz, 6-H), 6.14-6.50 (ABq, J17 Hz, C ₂ -H).

b) 8 g of solid (A) obtained in step a) is dissolved in 25 ml of 1N hydrochloric acid and 65 ml of isopropanol are added to obtain 4.95 g of the title compound crystals as a dihydrate.

τ (D ₂ O) values: 1.01, 1.36, and 1.78 (pyridinium quantum): 4.2-4.55 (ABg, J = 14 Hz, 3-CH ₂ −); 4.62 (d, J = 5 Hz, C ₇ -H); (; 47.4 (d, J = 5 Hz, C ₆ -H); 6.19-6.38 (ABq, J = 18 Hz, C ₂ -H).

% Water content by Karl Fischer method: 9.4%.

Example 1

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxycyclopent-1-1yl-oxyimino) -acetamido]- 3- (1-pyridiniummethyl) sef-3-m-4-carboxylate, dihydrochloride salt

0.46 g of phosphorus pentachloride was dissolved in 20 ml of methylene chloride at ambient temperature, the solution was cooled to 10 ° C. and 1.095 g of the product obtained in Preparation Example 8 were added at once. The mixture is warmed to -5 ° C and stirred for 30 minutes.

The solution is cooled to -10 ° C, 0.61 ml of triethylamine is added, and 6.7 ml of water is added with vigorous stirring to prevent the water from freezing below 0 ° C. The two phase mixture is stirred for 3 minutes and transferred to a tap funnel. The underlying phase was added 0.76 g of the product obtained in Preparation Example 9a to 10 ml of N, N-dimethylacetamide and 10 ml of acetonitrile containing 1.4 ml of triethylamine and added to a vigorously stirred suspension. Cool down to -20 ℃ in advance and make sure the temperature does not exceed -10 ℃. The mixture is stirred at −5 to −10 ° C. for 45 minutes and warmed to 21 ° C. over 1 hour. 0.3 ml of methanol is added and methylene chloride is evaporated under reduced pressure in a 30 ° C. bath. The residue is carefully partitioned between 30 ml of ethyl acetate and 30 ml of water and a small amount of sodium chloride is added. The organic layer was washed twice with 30 ml of water each time and the combined washings and further added sodium chloride were extracted with 20 ml of ethyl acetate. The combined organic layers are dehydrated on magnesium and evaporated to yield 1.79 g of foamy material which is then treated with diisopropyl ether to give 1.35 g of solid. 1.2 g of the solid is dissolved in 5 ml of formic acid and 0.38 ml of concentrated hydrochloric acid is added with vigorous stirring. After 1 hour at 21 ° C., the suspension is filtered and the residue is taken up by dissolution in a small amount of formic acid. The combined filtrates are concentrated by evaporation and the residue is treated with acetone to give 374 mg of the title compound.

]_D+8.6°(C1.02, H₂O);[

_D + 8.6 ° ( C 1.02, H ₂ O);

289);λmax (pH6 buffer): 255 nm (E

289);

273), λinfl 280(E

158).λinfl 295 (E

273) λinfl 280 (E

158).

Example 2

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyamino) acetamido] -3- (1 -Pyridiniummethyl) -cep--3-m-4-carboxylate, sodium salt

2.5 g of (R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyamino) acetamido] -3 -(1-pyridiniummethyl) -cep-3-m-4-carboxylate (which may be prepared by the method described in Example 7 of the pending splitting application) in water and the solution is dissolved in 1.52 g sodium 2 Ethylhexanoate is treated with a solution dissolved in 8 ml of methanol.

The mixture is added to stirred acetone for 15 minutes and the resulting suspension is filtered, washed and dried to afford 2.5 g of the title compound.

]_D ²³+0°(C1.02, H₂O);[

_D ²³ + 0 ° ( C 1.02, H ₂ O);

327, ε18630);λmax (pH6 phosphate: 255 nm (E

327, epsilon 18630;

305, 17,370) 및 280(E

172, ε 9,800);λinfl 240 (E

305, 17,370) and 280 (E

172, ε 9,800);

ν max (nusol): 1780 cm ⁻¹ (β-lactam);

C ₂₂ H ₂₁ O ₇ N ₆ S ₂ : Ha Ha 4.04%

Found 4.5%

Example 3

a) (6R, 7R) -7-[(Z) -2- (2-triphenylmethylaminothiazol-4-yl) -2- (2-tert-butoxy-carbonylprop-2- Oxyamino) acetamido] -2- (1-pyridiniummethyl) -cep-3-m-4-carboxylate

3.44 g of the product obtained in Preparation Example 4 was added to a stirred solution of 1.38 g of phosphorus pentachloride in 60 ml of methylene chloride, followed by cooling to -10 ° C. The fished solution is stirred at −5 ° C. for 30 minutes and cooled to −10 ° C.

1.33 g of triethylamine is added and 20 ml of water is added. The mixture was stirred at 0 ° C. for 3 minutes and the bottom layer was obtained from 2.19 g of the product obtained in Example 9a) of 30 ml N, N-dimethylacetamide and 30 ml of acetonitrile containing 3.03 g of triethylamine. It was dissolved in a mixture of and added to the stirred suspension over 10 minutes and then cooled to -10 ° C. The mixture is stirred at -10 to -5 [deg.] C. for 45 minutes, for 1 hour without cooling and 1 ml of methanol is added. Methylene chloride is evaporated off under reduced pressure and the remaining solution is added to 300 ml of water with stirring to precipitate 4.89 g of the title compound.

τ (CDCl ₃ ) value: 2.78 (S, [C ₆ H ₅ ] ₃ ; 3.37 (S-thiazole quantum); 0.35, 1.80, 2.12 pyridinium quantum); 4.18 (m, -7-H); 4.95 (6-H); 8.66 (S-tert-butyl); 8.50 (S, (CH ₃ ) ₂ ).

b) (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3- (1-Pyridiniummethyl) -cep-3-m-4-carboxylic acid, dihydrochloride

3.38 g of the product obtained in a) are dissolved in 20 ml of 98% formic acid with stirring. 1.2 ml of concentrated acid salt is added and the mixture is stirred for 1 hour. The precipitated solid is recovered by filtration under vacuum. The solvent is removed by evaporation under reduced pressure to give an oil phase which is treated with 30 ml of acetone to give 2.20 g of the title compound.

_{τ (D 2 O / N a} HCO 3) value: 3.08 (S, ^- thiazole proton); 0.06, 1.44, 1.93 (pyridinium quantum); 4.16 (d, J 5 Hz, 7-H); 4.74 (d, J 5 Hz, 6-H); 8.55 (S,-(CH ₃ ) ₂ ).

Acetone (measured in n.m.r.): 1 mole.

Water content: 5% (measured by the knife piquing method).

Chlorine, found 10.1% (C ₂₂ H ₂₄ N ₆ O ₇ S ₂ Cl ₂ + Acetone (1 mol) + Water (5%), Theoretical chlorine, 10.0%)

Example 4

a) (6R, 7R) -7-[(Z) -2- (2-triphenylmethylaminothiazol-4-yl) -2- (2-tert-butoxy-carbonylprop-2- Oxyamino) acetamido] -3- (1-pyridiniummethyl) sef-3-m-4-carboxylate

2.18 g of the product obtained in Preparation Example 9 b) were reacted in the same manner as in Example 3 a) to obtain 4.03 g of the title compound, the spectroscopicity of which was similar to that of Example 3 a).

b) (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyamino) acetamido] -3- (1-pyridiniummethyl) sef-3-m-4-carboxylic acid, dihydrochloride

3.8 g of the product obtained in a) were treated in the same manner as in Example 3 b) to obtain 2.17 g of the title compound, the spectroscopicity of which was similar to that of Example 3 b).

Example 5

a) (6R, 7R) -7-[(Z) -2- (2-triphenylmethyl-aminothiazol-4-yl) -2- (l-tert-butoxy carbonylcyclobut-1- Oxiimino) acetamido] -3- (1-pyridiniummethyl) sef-3-m-4-carboxylate

1.38 g of phosphorus pentachloride was dissolved in 60 ml of dichloromethane, the solution was cooled to -10 ° C, and 3.48 g of the product obtained in Preparation Example 6 were added at a time. The solution is stirred for 30 minutes at −5 ° C., 1.8 ml of triethylamine are added followed by 20 ml of water. After stirring the mixture at 0 ° C. for 9 minutes, the lower phase was dissolved in 2.18 g of the product obtained in Preparation Example 9 a) in 30 ml of dimethyl-acetamide, and added to the mixture which was cooled down, followed by 4.2 ml of triethylamine. Together 30 ml of acetonitrile are added at -10 ° C.

The reaction mixture is stirred for 45 minutes at -5 [deg.] To -10 [deg.] C. then stops cooling and the reaction is stirred for an additional hour at ambient temperature. The solvent is removed under reduced pressure and the residue is partitioned between ethyl acetate and water.

The organic phase is washed with brine and the aqueous extract is extracted with ethyl acetate. The combined ethyl acetate extracts are dried in the presence of charcoal and the solvent is removed under reduced pressure. The residue is treated with isopropyl ether to afford 3.80 g of the title compound.

ν max (nusol): 1780 cm ^-1 (β-lactam) τ (CDCL ₃ ) values: 2.74 (s, triphenylmethyl), 8.66 (s, tert-butyl)

b) (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxycyclobut-1-oxyimino) acetamido] -3- (1-pyridiniummethyl) sef-3-m-4-carboxylic acid, dihydrochloride

2.57 g of the product obtained in a) is added to the mixture in 15 ml of 98% formic acid and 0.9 ml of concentrated hydrochloric acid and stirred at ambient temperature for 1 hour. The mixture is filtered and the solvent is removed under reduced pressure. The resulting residue is treated with acetone to afford 1.79 g of the title compound.

ν max (nusol): 1785 cm ^-1 z (β-lactam) τ value (D ₂ O + NaHCO ₃ ): 1.05, 1.42, 1.91 (n, pyridinium quantum), 3.01 (s, aminothiazole quantum), 4.13 ( d, J 5 Hz, C ₇ proton), 4.68 (d, J 5 Hz, C-6 proton), 7.4-8.4 (wide m, cyclobutyl proton) dimethylacetamide (1/3 mol) and acetone (1/2 mol ) (measured by nmr) Water content: 7.4% (measured by Karl Fish method) Chlorine, found 9.2% (C ₂₃ H ₂₄ N ₆ O ₇ S ₂ Cl ₂ +1/3 mol dimethylacetamide + _1/2 mol acetone +7.4 water, theoretical chlorine, 9.5%).

Example 6

a) (6R, 7R) -7-[(Z) -2- (2-trityl-aminothiazol-4-yl) -2- (2-tert-butoxycarbonylprop-2-oxy Amino) acetamiro] -3- (1-pyridiniummethyl) cef-3-m-4-carboxylate, N, N-dimethyl-formamide solvate

4 g of the product powder obtained in Example 3a) are added to stirred 15 ml of N, N-dimethylformamide at 23 ° C. As soon as the solid is dissolved, crystals form. To the stirred mixture is added dropwise 20 ml of diisopropyl ether to dilute the mixture. The solid is collected by filtration to give 3.06 g of the title compound as a colorless needle.

N, N-dimethylformamide (measured by n.m.r.) = 21/2 mol

τ (DMSO-d ₆ ): 2.4-3.0 (m, trityl); 3.32 (s, aminothiazole ring protons); 0.47, 1.38, 1.82 (pyridinium protons); 4.34 (m, both C-7); 4.92 (d, J-5, C-6 quantum); 8.64 (s, both butyl); 8.62 (s,

=27.5°(C=1.1 메탄올중)

= 27.5 ° (C = 1.1 in methanol)

b) 6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) -acetamido] -3- (1-pyridiniummethyl) sef-3-m-4-carboxylic acid dihydrochloride

2.1 g of the product obtained in a) is dissolved in 10 ml of formic acid at 22 DEG C and 0.8 ml of concentrated hydrochloric acid is added. After 75 minutes the precipitated solid is filtered off. The filtrate is evaporated and 10 ml of industrial methylated alcohol is added. The solution is redevaporated and the residue is dissolved in methanol and the solution is then added to diiso propylether to give 1.35 g of the title compound.

-14.7°(C=0.95 pH6완충액중)

-14.7 ° (in C = 0.95 pH 6 buffer)

τ (DMSO-d ₆ ): 0.28 (d J9, -CO-NH), 0.77 (d, J6), 1.25 (t, J6), 1.70 (t, J6, pyridinium ring proton) 3.0 (s, aminothia Sol protons); 3.99 (d, d, 9.5, 7-H); 4.67 (d, J 5, 6-H); 8.42 (s,-(CH ₃ ) ₂ )

Formulation Examples

Example A-Injectable Anhydrous Powder

Vial sugar ingredient

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyamino) acetamido] -3- (1 -Pyridiniummethyl) sef-3-m-4-carboxylate 500mg

Lysine Acetate 189mg

Way

Cephalosporin antibiotics are mixed with lysine acetate and filled in glass vials. The top of the vial is purged with nitrogen and broken to seal it. At the time of administration, the product is dissolved by adding 2 ml of water for injection.

Example B-Anhydrous Powder for Injection

Sterilized 6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyamino) sterilized 6R, 7R acetamido ] -3- (1-pyridiniummethyl) cef-3-m-4-carboxylate and monosodium salt are filled in vials to contain 1.0 g of antibiotic acid per vial. Filling is performed aseptically under sterile nitrogen. Seal the vial with a rubber plate or plug fixed with aluminum foil to prevent gas ingress or microorganism ingress. The product is dissolved in injectable water or other suitable sterile carrier immediately prior to administration.

Example C-Tuwick-Pack Injection

a) Sterilized (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido]- 500 mg of 3- (1-pyridiniummethyl) sef-3-m-4-carboxylate are aseptically filled into glass vials in the presence of sterile nitrogen. Seal the vial with a rubber plate or plug fixed with aluminum foil to prevent gas ingress or microorganism ingress.

b) Sodium bicarbonate solution (3.84% W / V) was prepared, filtered and purified and filled with 2.15 mL in a clean ampoule. Carbon dioxide is introduced into the contents of each ampoule for one minute before sealing. Sterilize the ampoules with an autoclave and check for purification.

c) Immediately before administration, dissolve the popalosporin antibiotic in 2.0 ml of sodium bicarbonate solution.

Example D-Anhydrous Powder for Injection

Vial sugar

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxycyclobut-1-oxyimino) acetamido] -3- (1 -Pyridiniummethyl) sef-3-m-4-carboxylate 500mg

Sodium Carbonate, Anhydrous 47mg

Way

Cephalosporin antibiotics are mixed with sodium carbonate solution and filled into glass vials. The top of the vial is purged with nitrogen and broken to seal it. At the time of administration, the product is dissolved by adding 2 ml of water for injection.

Example E Veterinary Injection

ingredient

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxycyclobut-1-oxyimino) acetamido] -3- (1 -Pyridiniummethyl) cef-3-m-4-carboxylate 10% W / V

Aluminum distearate 2% W / V up to 100% W / V

Ethyl oleate 100% W / V

Way

The aluminum distearate is dissolved in ethyl oleate, heated with stirring at 150 ° C. for 1 hour and then cooled to room temperature. Sterile and ground antibiotics are aseptically added to the vehicle and stirred with a high speed mixer. The product is aseptically filled into injection vials and the vials are sealed using rubber plates or plugs fixed with aluminum foil.

Claims (1)

A cephalosporin of formula (Ic) characterized by acylation of a compound of formula (II) or a salt thereof or an N-silyl derivative thereof with an acid of formula (III) Antibiotic compounds, their non-toxic salts and non-toxic, easily metabolizable esters thereof.

In the above general formula R ^a and R ^b may be the same or different and each represent a C _1-4 alkyl group, or R ^a and R ^b together with the carbon atom to which they are attached form a C _3-7 cycloalkylidene group; R ⁴ represents hydrogen or a 3- or 4-carbamoyl group; B represents> S or> S → O; The dotted line connecting the 2-, 3- and 4-positions indicates that the compound is a cef-2-em or cef-3-em compound; R ^5a is a compound anion A

-COO with

Or a -COOR ⁵ group wherein R ⁵ is a carboxyl blocker and R ⁶ represents hydrogen or a carboxyl blocker; R ⁷ represents an amino or protected amino group and R ^6a represents a carboxyl protecting group.