JPS61165391A - Cephalosporin antibiotic - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Original F! This invention relates to improvements in AFi cefaxporins.

More particularly, the present invention relates to novel cef70 compounds and derivatives thereof that have valuable antimicrobial properties.

The cephalosporin compounds described herein are described in the Journal of the American Chemical Society J (:f, Amer*Chem, Boam).

+962.84,3400, and the usage of 'cephem' refers to the basic cephalic structure with one double bond.

Cephalosporin antibiotics are widely used in humans and animals to treat diseases caused by pathogenic bacteria, especially for example, t#-f-! : It is useful in the treatment of diseases caused by bacteria that are resistant to other antibiotics, such as Nicillin compounds, and in the treatment of patients who are sensitive to Nicillin.

In many cases, it is desirable to use cephalosporin antibiotics that are active against both Gram-positive and Gram-negative pathogens; however, the development of cephalosporin antibiotics, which are still widely available, is still a problem. Much research has been devoted to

That is, for example, UK Grant No. 1399 by inventor #
The specification of No. 086 describes a new group of cephalosporin antibiotics 'b 7f in which a 7β-(α-etherified oxyimino)anuramide group is combined and the oximino group has a syn configuration. There is. This rare antibiotic compound is characterized by differential antibacterial activity against late Gram-positive and Gram-negative bacteria, combined with particularly high stability against β-lactamases produced by various Gram-negative bacteria.

The discovery of this compound has stimulated further research in this field, for example in an attempt to find compounds with improved properties against certain groups of bacteria, especially Gram-negative bacteria. This interest is reflected in a large number of patent applications, in which cephalosporins bearing specific oxyiminoetherifying groups in combination with specific substituents both on the 7β-acylamide side chain and in the 3-position of the cephalosporin core are shown. Applications have been filed for Sporin antibiotics.

GB 1604971 VC discloses that the 7β-position side chain is inter alia 2-(2-ifthiazol-4-yl)-
A wide variety of cephalosporin antibiotics are generally disclosed, which can be selected from the 2-(etherified oxyiba))a-cetomido group, in which this etherified group has a large number of possibilities. In this sense, it can be an alkyl group, for example, a methyl group with +W% of halogen atoms,
However, there are no specific examples of compounds with such a 7% content (
- and the preferred etherification group is stated to be 11 methyl groups. Preferred halogen atoms are stated to be tetramine and bromine atoms. The group at the 3-position can also be selected from a large number of groups; examples of possible 3-substituents include, for example, alkoxymethyl, optionally substituted pyridiniummethyl, optionally substituted carbamoyl. Oxymethyl, hydroxymethyl, acetoxymethyl, halomethyl and hydrogen are mentioned. British Patent No. 1604971
Cephalosporins with sulfur in position are described, while similar sulfoxides are described in GB 1605212 FiA specification.

GB 1,576,625 contains a general definition of cephalosporin compounds having a 7β-(α-etherified oxyino) acedoamide pendant anchor, in which the etherified group has a suitable e substituent. (However, one suitable substituent specifically mentioned for illustrative purposes does not include a rogen atom, where @a inter alia Preferably it is an abanothiazolyl group, further substituted with nine α-substituted groups.

The group at the 3-position can also be substituted by a number of other groups; possible 5-substituents that fall within the general definition include hydroxymethyl, acetoxymethyl, halomethyl and optionally substituted carba-substituents. The moyloxymethyl group is mentioned.

In British Patent Application No. 2039890A, the side axis at the 7β-position is 2-(2-aminothiazol-4-yl)-2-
(etherified oxygen ξ)) Acetamido group multimodal cephalosporin antibiotics are generally disclosed. One possible etherification group that has been mentioned is a halo-lower alkyl group (the fluoromethyl group is specifically mentioned by way of illustration).According to general policy, the 3-position of the cephalosporin nucleus is inter alia a carbamoyl group. An oxymethyl group is preferable. However, among the specifically exemplified compounds, only a 2-bromomethyl group, a 2-chloroethyl group, and a 2.2.2-) II fluoroethyl group are included. is the only example of a halo-lower alkyl group.

According to General Rule 14, the corresponding oxyid-noetherified group is, in particular, a linear auto- to 4-alkyl group whose terminal is mono-substituted by a #-11 halogen atom. Something can happen. According to its general definition, the group in the 3-position of the cephalosporin nucleus is preferably a carbamoyloxymethyl group. However - in the specifically exemplified compounds only 2-bromoethyl and 2-iodoethyl groups are found as examples of haloalkyl groups.

European Patent Application No. 111935 describes 7β-
In particular, the side chain at position 2-(2-afthiazole-4
-yl)-2-(etherified oximino)acetamido groups are generally defined as seven phalosporin compounds, in which said etherified groups can be selected from a number of possibilities, e.g. halogen atoms. According to its general definition, the 5-position head group of the cephalosporin core can inter alia be a carbamoyloxymethyl, acetoxymethyl or halomethyl group; for these compounds no description of their utility as antibiotics is available. It is only described as being useful as an intermediate in the synthesis of final products, which are limited to 5-quinolinium methyl and 3-quinolinium methyl compounds. However, the specifically exemplified compounds are simply difluoromethyl and 2.2.2-
) Only lyfluoromethyl groups are found as examples of haloalkyl oxime groups and these are only present in the inquinolinium methyl and 4 - Methylquinolinium Only K present in combination with the methyl group.

France RF3% Permit No. 2499995 Specification #-1
Cephalosporin antibiotics having a 1:2-(2-7inothiazol-4-yl)-2-(etherified oximino)acetamide 7β-side chain are disclosed, in which the sim etherified group in In particular, the case can be a 01-6 alkyl group substituted from 9 to 9. It is said that possible substituents include, for example, halogen atoms such as chlorine, bromine or iodine;
There is no specific description of fluorine. Fi as etherification group
There is only a specific example of bromoethyl. The 3-substituent can in particular be 01-6 alkoxymethyl optionally interrupted by 1 heteroatom.

Japanese patent @58-167594 #-i7β
-Position [2-(2-aminothiazol-4-yl)-2-
Cephalosporin antibiotics with an acetamido group (etherified oxygen No specific KH compound is disclosed. The 3-ff substituent is lower alkyl spanning lower alkoxymethyl.

Also, British Patent No. 1600735, 1IIFVC
discloses a number of cephalosporin antibiotics encompassed within its general disclosure compounds in which the 7-substituent is a 2-(2-aminothiazol-4-yl)-2-(etherified oximino)acetamido group. The oxime etherification group is defined as an aliphatic hydrocarbon residue which can be substituted with halogen, among others. Although fluoromethyl is mentioned as an example of an etherification group, the specific illustration merely describes chloroethyl and 2,2.2-)lifluoroethyl groups. The 3-substituent can especially be hydrogen.

According to the invention, the 7β-position tf K(2)-2-(
By selecting the 2-aminothiazol-4-yl)-2-(etherified oximino)acetamide group and further selecting the 7-fluoromethoxyino group as the etherified oximino group, it is effective against a wide variety of commonly encountered pathogenic bacteria. It has now been discovered that cephalosporin compounds can be obtained that have a significantly advantageous aspect of activity.

That is, according to the present invention, the present inventors have developed the following general formula (I) [wherein R1 is a carboxyl group, C! OOe group or blocked carboxyl group'), R2h7 mino group or protected amino group, and R is hydrogen or 0.CO,NHR5 (where BS#i hydrogen, a C1-4 alkyl group optionally substituted with 1 to 3 halogen atoms is also a FiN-protecting group), a group of formula OR4 (where R4#i C1-4 alkyl group optionally substituted with dihalogen atom or 01-4
4 alkoxy group) or pyridinium, 3
-car/ζmoyl-pyridinium or 4-carbamoyl-pyridinium group], and B is -8-
or - Taichi (α- or β-) and 2-13
A dotted line bridging the - and 4-positions indicates that the compound is a cef-2-em compound or a cef-3-em compound] and salts thereof, and wherein X is pyridinium a 3-carbamoylpyridinium group or a 4-carbamoylpyridinium group and, when R1 is other than cooe, provides compounds of formula (I) which are bonded to one anion.

Where R4 is a blocked carboxyl group, the blocking group is, for example, the residue of an ester-forming aliphatic or aromatic alcohol or the residue of an ester-forming phenol, silano-A/or stannanol. (preferably the alcohols, phenols, silanols or stanthenols mentioned above have from 111 to 20 carbon atoms).

In the formula, when R2 is a retained amino group, the retained group f
It can be a trityl or acyl (eg chloroacetyl or formyl) group, or the amino group can be protonated.

The compounds according to the invention are syn isomers. This syn isomeric form is defined by the configuration fK of the 1o,aH2F group with respect to the carboxabad group. The thin configuration is designated herein structurally as N in S.

Since the compounds of this invention are geometric isomers, it will be appreciated that some mixing with the corresponding anti isomer will occur.

Compounds of formula (I) include both active antibiotics and intermediates for their production. This will be described in more detail later.

It is recognized that salts of these compounds for use in medicine should of course be non-toxic. Similarly, if R1 is a carboxyl blocking group in a compound used in medicine, it should represent a metabolically unstable non-toxic ester functional group.

Thus, the antibiotically active compounds according to the invention have the following general formula (Ia), where R is hydrogen, an acetoxymethyl group, or have the formula 0H20, OO, NHR5, where R3A is hydrogen. C!H2OR4 (wherein R4 has the above definition) or pyridiniummethyl; is a 5-carbamoylpyridiniummethyl or 4-carbamoylpyridiniummethyl group, and RIA is a carboxyl group,
or KF'1000- group when R is pyridiniummethyl, 3-carbamoylpyridiniummethyl or 4-carbamoylpyridiniummethyl group] and its non-toxic salts and its non-toxic metabolically unstable esters. can.

As mentioned above, some of the compounds according to the invention can be used as starting materials for the production of other cephalosporins with antibiotic activity.

In particular, compounds of formula (I) in which R is CH2X (where -aminothiazol-4-yl)-2-monofluoromethoxyiminoacetamide group, and 3
It can be used to prepare other cephalosporins with different substituents in the - position. More details on this later #BK
be written.

The compounds of formula (Ia) according to the invention and their non-toxic salts and metabolically unstable esters exhibit widespread anti-viral activity both in vitro and in vivo. They have high activity against both Durham-positive and Gram-positive bacteria, such as many β-lactamase producing strains. These compounds also have high stability towards β-lactamases produced by a range of Gram-positive and Gram-positive bacteria.

It has been found that the compounds of formula (Ia) according to the invention exhibit high activity against Gram-positive bacteria such as Staphylococcus aureus, Staphylococcus epideltasis and Streptococcus species strains (including venicillinase producing strains) K. . This includes strains of a wide variety of Enterobacteriaceae (e.g. Escherichia coli, Klebsiella pneumoniae, Citrobacter tehersus, Enterobacter cloacaeceresia marcescens, Ploteus mirabilis and indole-positive Proteus strains such as Proteus vulgaris,
The high activity against Gram-positive bacteria and the high activity against Gram-positive bacteria possessed by the compounds of the present invention combined with high activity against Proteus vulgaris and Providence alba) and Haemophilus influenzae and Acinetobacter calcoaceticus and good activity against Pnoidomonas sp. This combination is unusual and particularly advantageous.

The compound of formula (Ia), in which R is a pyridinium methyl group, showed particularly high activity against the above-mentioned organisms, especially Enterobacter, Acinetobacter and Zinidomonas.

Examples of non-toxic salt derivatives which can be produced by reaction of carboxyl groups present in compounds of formula (I) include, for example, inorganic bases such as alkali metal salts (e.g. sodium and potassium salts) and alkaline earth metal salts. (e.g. calcium salts), 7() acid salts (e.g. harizine salts and arginine salts), organic base salts (e.g. prochloride salts, phenylethylbenzylamine salts, dibenzylethylenediamine salts, ethanolamine salts, jetanolamine salts) salts and N-methylglucosamine salts).

Examples of other non-toxic salt derivatives include acid addition salts such as those formed with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid and trifluoroacetic acid.

These salts may also be produced, for example, in polystyrene resins, or cross-linked polystyrene divinylbenzene copolymer resins containing amino groups or quaternary amino groups or sulfone groups, or resins containing carboxyl groups, such as polyacrylic acid resins. It may also be in the form of a resinate. Soluble base salts (eg alkali metal salts, eg sodium salts) of compounds of formula (I) can be used therapeutically as they are rapidly distributed throughout the body upon administration. However, when an insoluble salt of a compound of formula (I) is desired for a particular application, e.g. for use in a depot formulation, such a salt may be prepared in a conventional manner, e.g. using a suitable organic salt. sell.

Examples of non-toxic, metabolically unstable ester derivatives that can be produced by esterification of the carboxyl group in the base compound of formula (I) include, for example, acyloxyalkyl esters, such as lower alkanoyloxymethyl esters or lower alkanoyloxyethyl esters. Esters such as acetoxymethyl ester or acetoxyethyl ester or piparoyloxymethyl ester can be mentioned. In addition to the above-mentioned ester derivatives, the present invention also includes within its scope other physiologically acceptable compounds, such as metabolically unstable esters, which can be used in vivo to produce the original antibiotic compound of formula +1). ! Compounds of formula fl) in the form of physiologically acceptable compounds are included.

These and other salts or ester derivatives, such as salts with toluene-p-sulfonic acid or methanesulfonic acid, or esters with 5-butyl or diphenylmethyl esterification groups, can be used, for example, in the preparation of the compound of the present invention of formula (I) in the production method described below. It can be used as an intermediate in the production and/or f'i purification.

In the formula, the compounds of the present invention in which R is a pyridinium methyl group, a 3-carbamoylpyridinium methyl group, or a 4-carbamoylpyridinium methyl group, and R1 is not a blocked carboxy group usually contain positively charged pyridinium groups and carboxylates. esters and salts with bases of the compounds of formula (I) containing the positive ! group on the pyridinium ring. It is recognized that anions may be combined to balance the load, and such anions are non-toxic and may be derived from any of the aforementioned acids to produce non-toxic salt derivatives.

The compounds of this invention can be used to treat a wide variety of diseases caused by pathogenic bacteria in humans and animals, such as sepsis, respiratory tract infections, skin and soft tissue infections, and urinary tract infections.

According to another embodiment of the invention, we provide a process for the preparation of compounds of general formula (I) having the above definitions. The method is (4) using salt forms such as betaine or Vi acid addition salts (
In this case, the anions are, for example, hydrochloric acid, bromide water'Jg acid,
where R, R1, B and the dotted line has the above definition) or its N-silyl derivative; acylated with an acylated derivative, or (B) general formula +1 in which R represents a CH2X (where xVipyridinium, 3-carbamoylpyridinium or 4-carbamoylpyridinium group) group;
) is a compound represented by the following formula (IV) (wherein R', R2, B and the dotted line have the above definitions, and Y is a nucleophilic substitutable residue. (for example, an acetoxy or dichloroacetoxy group, or a hydrogen atom, a bromine or an iodine atom), where R5 is hydrogen, 3-
or a pyridine compound represented by a carbamoyl group or a 4-carbamoyl group; In order to prepare a compound represented by the general formula (R5 has the above definition), a compound of the general formula (I1 or a salt thereof, in which R is a hydroquine methyl group) is prepared by or by reacting with an acylating agent which serves to convert the hydroxy group into a 7cetoxy group or a 10,CO,NHR5 group having the above definition, or (to) where R is a 10H2X group (wherein or In order to prepare a compound of formula (I) which is an OR4 group as defined above, a compound of the general formula [) in which R is a hydroxymethyl group, The group can be reacted with an etherification agent which serves to convert the group into a 0H20R4 group (where R4 has the above definition) or (n) or a 10H2X group (where X is a hydroxy group). ) of the general formula (Il), in which R or 10H2X group (where X is an acetoxy group),
3-hypothesis acetylation of the compound or its salt, and then,
Each of the above pigeon houses requires and/-! or as desired, in any suitable order; any of the following reactions () Reactions for converting the Δ2-isomer into the desired Δ3-isomer; 11) Compounds in which B is 18O; By reducing B, -
8-, 111) Reaction to convert a carboxyl group into a non-toxic and metabolically unstable ester functional group, IV) Reaction to generate a non-toxic salt functional group, and ■)
any carboxyl blocking group and/or F
It consists of carrying out a reaction which removes the 'iN-holding i group.

The above reactions 1) to v) #- can be carried out in the conventional manner as indicated below.

The above method (in which a starting material 1 represented by formula (n)
ii is the formula in which B is -8- and the dotted line is Cef-3-
Compounds representing dime compounds are preferred.

Examples of acylating agents that can be used in the preparation of compounds of formula (I1) include acid halides, in particular acid chlorides or acid bromides.Such acylating agents include acids of formula (III) or It can be prepared by reacting the salt with a heloquinating agent such as phosphorus pentachloride, thionyl chloride or oxalyl chloride.

Acylation with an acid halide, optionally in the presence of an acid binder, is conveniently performed with KVi-50 to +5aC1, preferably -4
It can be carried out in an aqueous to non-aqueous reaction medium at temperatures of 0 to +30°C. Examples of suitable reaction media include, for example, aqueous ketone solutions (e.g. aqueous acetone), aqueous alcohols (e.g. aqueous ethanol), esters (e.g. Fih#Mxfl), x-thiols (e.g. tetrahydrofuran), halogenated hydrocarbons. ! (e.g. methylene chloride), amides (e.g. dimethylacetamide), nitriles (e.g. acetonitrile) or
Mention may be made of mixtures of such solvents of al or higher. Examples of suitable acid binders include, for example, tertiary amines (e.g. triethylamine or dimethylaniline), inorganic bases (e.g. calcium carbonate or sodium bicarbonate), and oxirafs such as lower 1,2-alkylene oxides (e.g. ethylene oxide or propylene oxide). These bind the hydrogen halide liberated in the acylation reaction.

The acid of formula (I) can itself be used as an acylating agent in the preparation of compounds of formula (I).Acylation with the acid of formula (III) can be carried out using condensing agents such as carbodiimides (e.g. #-i'NIN'-Synchronized to Kinrucarbojiibadomata1iN-x Chill-N'
carbonyl compounds (e.g. carbonyl diimidazole), inxazolium salts (e.g. 1-jN-ethyl-5-phenyl inxazolium verchlorate), and Preferably, it is carried out in the presence of 2-dihydroquinoline.

Acylation can also be carried out with amide-forming derivatives of the acid of formula (III) such as activated esters, symmetrical anhydrides or mixed anhydrides (e.g. piparic acid),
or haloformates (e.g. produced with lower alkyl haloformates). Mixed anhydrides can also be produced using phosphorous acids (eg phosphoric acid or phosphorous acid), sulfuric acid or aliphatic or aromatic sulfonic acids (eg toluene-p-sulfonic acid). Activated esters are conveniently produced in a reaction system using, for example, 1-hydroxybenzotriazole in the presence of the condensing agent mentioned above.

The acylation reaction consisting of the above-mentioned free acids or their amide-forming derivatives is preferably carried out in an anhydrous reaction medium, such as methylene chloride, tetrahydrofuran, dimethyl acedoamide or acetonitrile.

An alternative method of acylation is, for example, by reacting an acid of formula (III) with a preformed solution or M suspension. This solution or suspension is prepared by adding % oxalyl chloride or phosgene, or a phosphoryl halide (e.g. oxy It is produced by adding phosphorus chloride). This active form of the acid of formula (m) is then dissolved in a suitable solvent or mixture of Fi solvents, such as alcohols such as alkanols (e.g. ethanol or methanol), halogenated hydrocarbons (e.g. dichloromethane).
, esters (e.g. ethyl acetate), nyfkM (e.g. dioxane or tetrahydrofuran), ketones (e.g. dioxane or tetrahydrofuran),
For example, acetone), amides (eg dimethylacedoamide), acetonitrile, water and mixtures thereof can be reacted with the 7-amine compound of formula (II). This acylation reaction line, optionally washed, for example in the presence of the aforementioned acid binders (e.g. triethylamine, dimethylaniline or sodium bicarbonate), gives a range of from -50° to +5a C1, preferably from -4o O to +5
It is convenient to carry out at a temperature of 0°C.

Optionally, the acylation reaction may be carried out in the presence of a catalyst such as 4-dimethylaminopyridine.

The acid represented by formula (III) and the corresponding acylating agent can be prepared and used in the form of their acid addition salts, if desired. Thus, for example, the chlorides are advantageously used as their hydrochlorides and the acid bromides as their hydrobromides.

In the reaction (BI), the pyridine compound of formula (7) can act as a nucleophile to replace various substituents Y from the cephalosporin of formula (IV).To a certain extent, the ease of its substitution It relates to the pKa Ic of the acid HY from which the substituent is derived.

That is, atoms or groups Y derived from strong acids are generally
Atoms or groups derived from weaker acids tend to be more easily substituted. In addition, the fR11R group R5 in the compound represented by formula (7) is easy to understand to some extent.
It is also related to the very nature of

The substitution of Y by the pyridine compound of formula (g) is conveniently carried out by maintaining each reaction component in solution or suspension.

The reaction Fi is preferably carried out using 1 to 10 mol of pyridine compound.

Nucleophilic ftt transposition reactions may conveniently be carried out on compounds of formula (IV) in which the substituent Y is, for example, a halogen atom or an acyloxy group as discussed below.

Compounds of the formula (Fl/) in which Y is an acetoxy group are convenient starting materials for use in nucleophilic substitution reactions with pyridine compounds of the formula (t). Other starting materials in this class include, for example, formulas (I
Examples include compounds represented by 'l/).

Substitution reactions of this kind in Y substituents, particularly in compounds of formula (■) where Y is an acetoxy group, can be promoted by the presence of iodide or thiocyanate ions in the reaction medium. This type of reaction is described in British Patent No.
Specifications of No. 32621 and No. 1171603-II
It is more detailed than FVC.

Also, the substituent Y is! ! ! chloroformic acid, octoformic acid (eg chloroformic acid)'' or carbamic acid.

When using compounds of formula (IV) in which Y represents a 7cetoxy or substituted acetoxy group, the R3 group in the formula (I/) should generally be a hydrogen atom and 5ti It is desirable that it should represent -s-. In this case, the reaction is carried out in an aqueous medium, preferably from 5 to
Advantageously, it is implemented in 8 states, particularly preferably in the range 5.5 to 70 voices.

Said method using a compound of formula (IV) in which Y is the residue of a substituted acetic acid is described in British Patent No. 124165.
It can be carried out as described in Specification No. 7 LK.

When using a compound of formula (■) in which Y is an acetoxy group, the reaction Fi is 30°C to 110°C, preferably 5
It is convenient to carry out at temperatures between 0° and 80°C.

Formula (IV) in which Y is a chlorine, bromine or iodine atom in the halogen formula
Compounds of the formula are also conveniently used as starting materials in nucleophilic substitution reactions with pyridine compounds of the formula . When using compounds of formula (IV) of this type, B can represent -80- and R3 can represent a carboxyl blocking group.

This reaction is conveniently carried out in a non-aqueous medium, said medium advantageously comprising 1ffi or more of polar organic solvents, such as ethers (for example dioxane or tetrahydrofuran), halogenated hydrocarbons, etc. (
PJ, t is dichloromethane), esters (e.g. ethyl acetate), amides (e.g. formamide and N,N
-dimethylformamide) and ketones (eg acetone). In some cases the pyridine compound itself can be a solvent. Other suitable organic solvents are detailed in GB 1,526,551. The reaction medium must not be extremely acidic or extremely basic. In the formula, R1
In the case of a reaction carried out on a compound of formula (IV) in which is a blocked carboxyl group, the 3-pyridinium methyl product is produced as the corresponding compound, which can be substituted with one or more than the desired reaction group. It can be subjected to an ion-exchange reaction to produce a loaded material with the desired anions.

When using a compound represented by the formula (■) in which Y is the above-mentioned norogen atom, the reaction occurs between -10° and +
It is conveniently carried out at a temperature of 50°C, preferably +10° to +30°C.

Carbamoylation of the 3-hydroxymethyl compound of formula (■) in Method OK may be carried out by conventional methods using a suitable acylating (i.e., carbamoylating) agent. As an example of a suitable carbamoylating agent, mention may be made, for example, of the isocyanate of the formula R5, NOO, in which R3 has the abovementioned definition; ) having a substituent at the 3-position.

This carbamoylation reaction can be performed on hydrocarbons (e.g. aromatic hydrocarbons, e.g. benzene and toluene), halogenated hydrocarbons (e.g. dichloromethane), amides (e.g. formabad or dimethylformamide), esters (e.g. ethyl acetate). , ethers (e.g. vermiform ethers such as tetrahydrofuran and dioxane),
Preferably it is carried out in the presence of a solvent or a mixture of solvents selected from ketones (eg acetone), sulfoxides (sidelight dimethyl sulfoxide) and mixtures of these solvents.

The reaction is carried out at a temperature between -80°C and the boiling temperature of the reaction mixture (e.g. up to 100°C), preferably -20°C.
It is convenient to carry out at temperatures between .degree. and +30.degree. R3 group is N
- If it is a protecting group, it may subsequently be cleaved, for example by hydrolysis, to generate a 3-carbazoyloxymethyl group. Easily 1crA@ with subsequent processing! N that can be
- Examples of protecting groups R3 include, for example, acyl groups, especially lower alkanoyl groups (e.g. acetyl), no- and -ro-substituted lower alkanoyl groups (e.g. monochloroa-7tyl, dichloroacetyl or trichloroacetyl), chlorosulfonyl t
Examples thereof include t, -h-y romosulfonyl or heroquinated alkoxycarbonyl groups (eg, t-2,2,2-trichloroethoxycarbonyl). It takes N
-Protecting groups can generally be cleaved by rR or by base-catalyzed hydrolysis (e.g., base-catalyzed hydrolysis using hydrogen carbonate). Also, halogenated groups such as chlorosulfonyl, dichlorophosphoryl, trichloroacetyl and 2.2.2-)lichloroethoxycarbonyl can be cleaved on reduction, while groups such as chloroa-7tyl can also be It can be cleaved by treatment with a thioabad (eg thiourea).

The carbamoylation agent is preferably used in excess (e.g. at least 1.1 mol with respect to the compound of formula (F/)), the carbamoylation being carried out with a base such as a tertiary organic base such as a tri(lower alkyl) Due to the presence of amino acids (e.g. triethylamine) or alkali metals (
Although this may be facilitated by using a compound of formula (IV) in the form of a salt (e.g. sodium),
Such auxiliaries are not necessary in more active incyanates, such as compounds where R5 is a strong electron-withdrawing group, such as chlorosulfonyl or trichloroacetyl. Therefore, carbamoylation consisting of the reaction of the free acid of formula (IV) with an excess of incyanate in which R5 is a group such as chlorosulfonyl or tricooacetyl is difficult due to the flaw in the reaction conditions. This is particularly advantageous in practice. Because there is no need for temporary blocking and deblocking of the cephalosporin's 4-position rpoxy group and the resulting N-protected 5-carbamoyloxymethyl cephalosporin product. This is because the electron-withdrawing R5 group therein can be easily removed, for example, with an aqueous sodium hydrogen carbonate solution.

Minimize undesirable side reactions involving carbamoyloxymethyl groups? It should be noted that it is advantageous to retain or even introduce the KN-fi substituent R5 during the conversion of the intermediate 5-carbamoyloxymethyl group.

Another useful carbamoylating agent is cyanic acid, which is conveniently formed from an alkali metal cyanate salt, such as sodium cyanate, in a reaction system at 0°C, and the reaction is quenched, e.g. Facilitated by the presence of strong organic acids (eg trifluoroacetic acid). Cyanic acid corresponds in practice to said incyanate compounds in which R5 is hydrogen and therefore directly converts compounds of formula (M) into their 3-carbamoyloxymethyl analogs ICf.

Alternatively, carbamoylation can be carried out by combining a compound represented by formula (fV) with phoscene or carbonyl diimidazole, optionally in an aqueous or non-aqueous reaction medium.
This can be carried out by subsequent reaction with ammonia or a suitable substituted amine.

Acylation of the 3-hydroxymethyl compound by method (0) can be carried out by a conventional method, for example, as described in British Patent No. 114129.
In a similar manner to that described in specification No. 3, i.e. 4-
Carboxy group (if this is not already blocked)
This can be carried out by blocking the 3-hydroxymethyl group of the protected compound, and optionally subsequently removing the blocking group at the tip of the button.

In the above method, various substituent groups cFI2x are converted into CH20R.
' can serve as a group that can be converted into a group.

General methods suitable for the production of ethers are described by Meerwein K.
ania-chen Chemie) J, edited by Muller, Georg Thiem
e Ver'lag) Publishing, 1965, vol■ (3
) pp7-137 and [The Chemistry of Ether Linkage
of the Ether Linkage, edited by Patai, published by Interscience (London), 196
7, pp. 445-498, where E.
Methods involving the effects of I+, OH-, Grignard reagents and dissipation are discussed. Another method consisting of using isourea is Dabriti
) by Mr. Angsw, Chem.
- Moon, 1966.5% 470 and Vowbinkel (Vow
"Chem, Ber" by Mr. inkel
, N., 1967.100.16, and a method comprising the use of alkyl phosphites is described in H.O.A., May 1967.50, by Mr. Ohopard. 1021 and Aarvey, Tetrahedron J, 1966.22.
2561.

Thus, for example, etherification can be carried out by initially preserving the 4-carboxyl group and reacting the appropriate 3-hydroxymethyl compound with a diazo compound, such as a lower diazoalkane (eg diazomethane). It is desirable to use mild conditions with respect to the diazo reagent. The reaction rate of the diazo compound can be accelerated by the addition of Lewis acids such as boron trifluoride or aluminum trichloride. The reaction with the diazo compound can be carried out using organic solvents such as heloquinated hydrocarbons (e.g. dichloromethane or carbon tetrachloride), ethers (e.g. diethyl ether,
(tetrahydrofuran or dioxane), esters (e.g. ethyl acetate) or petroleum ether fractions, the inverse ratio is -15° to +50°C.
, preferably at about 5°C. The etherification can also be carried out, for example, by converting a suitable 3-halomethyl compound (e.g. 3-bromomethylsulfoxide) into a suitable mercury(II) salt, e.g. mercuric perchlorate or, more conveniently, mercuric trifluoroacetate. This can be carried out by reacting with alcohol. The abovementioned alcohols are conveniently used on their own as reaction solvents, but also other solvents such as chlorogenated hydrocarbons (e.g. dichloromethane), ethers (e.g. dioxane), nitriles (e.g. acetonitrile) and sulfoxides (e.g. (dimethyl sulfoxide).

The reaction is carried out at -20 to +100°C, conveniently at a Fia of ~4°C.
It can be carried out at 0°C. Other methods which may be used in the above-mentioned method include, for example, British Patent No. 211.
No. 0688, Japanese Patent No. 57-192392 and [J, Ohem,
Soc, ) J Perkin l, 1983, pp22
Examples include the methods described in 81-2286.

The compound according to the present invention in which 1x represents a hydroxyl group can be produced by deacetylating the corresponding 5-acetoxymethyl compound according to the above-mentioned method (9),
For example, British rXA patent nos. 1474519 and 153
It can be produced by hydrolyzing the 3-acetoxymethyl compound as described in each specification of No. 1212.

A particularly convenient method for the deacetylation of 5-acetoxymethyl compounds is described in British Patents Nos. 1 and 5 by the inventors.
31.2j2, for example, by enzymatic hydrolysis as described in the specification of No. 31.2j2.
This is done using an esterase derived from Dosporidium toruloides).

In any of the aforementioned methods, the reaction product can be processed by various methods such as recrystallization, iontophoresis, column chromatography, etc. from the reaction mixture which may contain e.g. unchanged cephalosporin starting material and other substances. Separation can be achieved by graphical methods and the use of ion exchangers (for example by chromatography on ion exchange resins) or by the use of macroreticular resins.

The Δ2-cephalosporin ester derivatives obtained by the process of the invention can be converted into the more corresponding Δ3-derivatives, for example, by treating them with radicals such as pyridine or triethylamine.

The cef-2-em reaction product can also be reacted with, for example, a peracid (e.g. peracetic acid or m-chloroperbenzoic acid) to form the corresponding cef-3-em 1-oxide, the resulting sulfoxide then being can be reduced to the corresponding desired cef-3-em sulfide.

When a compound in which B is -5O- is obtained, f7j
-j f + I (I-f can be converted to the corresponding sulfide by reduction of the corresponding acyloxysulfonium salt or alkoxysulfonium salt produced in the reaction system in the reaction in the case of the acetoquinosulfonium interface, and the reduction is For example, Vf: is carried out with iodine ion as a potassium iodide solution by sodium dithionite in a solvent (for example acetic acid, acetone, tetrahydrofuran, dioxane, dimethylformamide or polymethylacetamide). ``First, it will be carried out at temperatures between -20°C and +50°C.

Metabolically unstable ester derivatives of compounds of formula tr+ can be prepared by esterifying the compound of (I) or a salt thereof or a protected derivative thereof, conveniently in an inert organic solvent such as dimethylformamide and acetone. It can be produced by reacting with an agent such as an acyloxyalkyl halide (eg, an iodide) and removing any carrier groups as necessary.

A base salt of a compound represented by formula fl> can be produced by reacting a powder represented by formula (I) with a suitable base. Thus, for example, sodium or potassium salts can be prepared using the respective 2-ethylhexanoate or bicarbonate groups. Acid addition salts may be prepared by reacting a compound of formula (I) or a metabolically unstable ester derivative thereof with a suitable acid.

If the compound of formula (I) is obtained as a mixture of isomers, the syn isomer can be obtained by conventional means, such as crystallization or chromatography.

K used as starting material for preparing the compounds of the general formula TI+ according to the invention is in the syn-isomeric form or in the form of a mixture of syn- and anti-isomers containing at least 90% of the syn-isomer. Preference is given to using compounds of the formula (Ill) and the corresponding acid halides and acid anhydrides.

In addition, the starting material represented by formula (II) can also be used in a conventional manner,
For example, as described in GB 1,028,563, it may be prepared by nucleophilic transformation of the corresponding 3-acetoxymethyl compound with a suitable nucleophile, or by the method described in GB 2,052a90A. Rir.

A further method for the preparation of starting materials of formula (') consists in deprotecting the corresponding protected 7β-amino compound in a conventional manner, for example using Ffpct5.

When R in the formula (n+ is l:!H2X group (where X is chlorine, bromine or iodine atom), cef-3-
The Em starting compound can be prepared in a conventional manner, for example by halogenation of the Fi7β-protected amino-3-methylcef-5-Em-4-carboxylic acid ester 1β-oxide and removal of its 7β-protecting group. This generated 7β-amino compound is acylated to form the desired 7-acylamido group in the above (AI method #C, vkVc, part 1).
The β-oxide group can be subsequently removed. This is covered by the British patent el! , No. 1,526,551.

The corresponding Cef-2-M compound can be prepared by the method described in Dutch Patent Application No. 6902013.
Reacting the 3-methylcef-2-em compound with N-promosuccinibide to form the corresponding 3-bromomethylcef-2
-Em compounds can be produced from a single button.

A starting material of the formula in+ in which R is a hydroxymethyl group can be obtained by deacetylating the corresponding 5-acetoxymethyl compound, for example, as described in British Patent Nos. 1,474,519 and 1,531,212. Manufactured by Vine.

In addition, the compound represented by II (II) is described in British Patent No. 16
It can also be produced by the method described in No. 00755 Specification i1.

Compounds represented by formula (m) and derivatives thereof are:
As such, they are novel compounds and constitute a further feature of the invention. They are also represented by the following formula (■)B: The compound or its salt has the following general formula (■) T, (H3P (■) (wherein T#-i is chloro, bromo or iodo)
It can be prepared from K by etherification by selective reaction in , followed by removal by any carboxyl blocking MR6. The separation of isomers can be carried out either before or after such etherification. The etherification reaction is conveniently carried out in the presence of a base, such as potassium carbonate or sodium hydride, and an organic solvent such as methyl sulfoxide, a cyclic ether (such as tetrahydrofuran or Fidioxane or N,
Preference is given to working in an N-disubstituted amide (eg dimethylformamide).

Under these conditions, the configuration of the oximino groups is not substantially changed by this etherification reaction. Formula (M)
The compound represented by is play! Acid form! When used in the form of a salt with a base or a base, the etherification reaction is generally carried out in the presence of strong dispersion, for example potassium tert-butoxide;
Adding enough base creates a dianion. Furthermore, this reaction should be carried out in the presence of a base when an acid addition salt of the compound of formula (M) is used, the amount of base being sufficient to rapidly neutralize the acid in question. It must be.

In addition, the acid represented by formula (Ill) is a compound represented by the following formula (■) (in which R2 and R6 have the above definitions). It can also be produced by reacting with a compound, followed by removal of the carboxyl blocking group R6, and further separation of the syn and anti isomers if necessary.

These acids of formula (Ill) can be converted into the corresponding acid halides and anhydrides and acid addition salts, for example by conventional methods as described above.

The starting materials of the formula (F/) (where these are not the compounds of 2 (I) which can be prepared by the above-mentioned methods (4) to (to)) are prepared using a method similar to the above-mentioned method (A). It can be prepared from K by acylating the corresponding 7-amino compound by method.

Compounds of the formula (F/) in which Y represents an acyloxy group other than an acetoxy group are, for example, K as described in the specifications of British Patent Nos. 1,474,519 and 1,551,212, for example, a suitable 3-acetoxymethyl compound. It can especially be prepared by acylating the corresponding 3-hydroxymethyl compound which can be prepared by hydrolysis of .

Other compounds of formula (M) can be obtained from the 3-hydroxymethyl compound by conventional transformation reactions such as acylation or halogenation.

It should of course be appreciated that in some of the foregoing transformation reactions it is necessary to protect any sensitive groups within the molecule of the compound to avoid undesirable side reactions. An example of a suitable protective group is “Protective Groups in Organic Synthesis” by Theodora W. Greene.
protectiveGroups in Organi
John Wileya
nd 5ons Publishing, 1981) K is described.

For example, during any of the aforementioned reaction steps, it may be necessary to protect the NH2 group of the aminothiazolyl moiety by, for example, tritylation, annulation (eg chloroacetylation or formylation), protonation or other conventional methods.

This protecting group is then optionally halocyanated in any convenient manner that does not cause degradation of the desired compound, e.g. in the case of trityl groups, preferably in the presence of a protic solvent, e.g. water. by using a carboxylic acid (e.g. acetic acid, formic acid, chloroacetic acid or trifluoroacetic acid) or a mineral acid (e.g. salt rR) or a mixture of such acids or, in the case of chloroacetyl groups, by treatment with thiourea. It will probably be removed from KotoK.

The carboxyl blocking group used in the preparation of the compound of formula +1) or the necessary starting materials is preferably a group that can be easily cleaved at an appropriate step of the reaction process, conveniently at the final step.

However, in some cases, in order to obtain a suitable ester derivative of the compound of formula It is advantageous to use metabolically labile carboxyl blocking groups and to retain these in the final product.

Suitable carboxyl blocking groups are well known in the art and a list of representative blocking carboxyl groups is given in GB 1,599,086. Examples of suitable blocking carboxyl groups include, for example, aryl lower alkoxycarbonyl groups (e.g. p-methoxybenzyloxycarbonyl, p-nitro(
Mention may be made of dimethyloxycarbonyl and diphenylmethoxycarbonyl groups, lower alkoxycarbonyl groups (eg Ht-butoxycarbonyl) and lower haloalkoxycarbonyl groups (eg Ht-2.2.2-trichloroethoxycarbonyl). This carboxyl blocking group can then be removed by any suitable method disclosed in the literature. For example, acid-catalyzed hydrolysis or reduction can be applied in many cases, but enzyme-catalyzed hydrolysis can also be applied.

The antibiotic compounds of the invention can be formulated for administration in a manner similar to that of other antibiotics, by any convenient means, and the invention therefore falls within its scope for use in human or veterinary medicine. Comprising pharmaceutical compositions containing antibiotic compounds according to the invention, which are suitable for use in the treatment of antibiotics. Such compositions may be prepared for use in conventional manner with any necessary pharmaceutical carrier or excipient adjuvants.

The antibiotic compound of the present invention is a must! They may be formulated for injection and presented in unit dosage form in ampoules or multi-dose containers, with an optional preservative. These compositions may also include, for example, suspensions in oily or aqueous vehicles;
It may take the form of a solution or an emulsion and may contain formulation agents such as additives, stabilizers and/or dispersants. Alternatively, the active ingredient Fi may be reconstituted with a suitable vehicle, such as sterile, viroquine-free water, before use. It may also be in powdered form.

Optionally, such powders can be used to modify the aqueous solubility of the active ingredient and/or when the powder is reconstituted with water, the state of the resulting aqueous formulation is physiologically acceptable. Suitable non-toxic bases may be included. Alternatively, the base may be present in the powder or reconstituted water. This base can be, for example, an inorganic base (eg sodium carbonate, sodium bicarbonate or sodium acetate) or an organic base (eg lysine or lysine acetate). These antibiotic compounds may also be formulated as herbal medicines in conventional bases such as cocoa butter or other glycerides.

The veterinary pharmaceutical composition may be formulated, for example, as a mammary gland preparation in either a long-acting base or an immediate-release base.

The composition depends on the administration method, but α1% or more, for example 11-9
If the composition, which may contain 9% of active substance, consists of dosage units, each unit contains 100 to 3000 units, for example 20
Preferably, it contains 0 to 2000 g of active ingredient.

The daily dose when treating adults depends, inter alia, on the nature of the infection and the route or frequency of administration: 200-12,000, for example Fi 1,000-900.
It is preferable to hit 0. Generally, when treating one adult, 400 to 6000 strokes per day, for example 500 to 40
Intravenous or intramuscular administration using 00q of active ingredients is used. Higher daily doses may be required for treatment of Zinidomonas infections. In some situations, for example in the treatment of neonates, smaller daily doses of extracts in smaller dosage units may prove desirable.

Antibiotic compounds according to the invention can be administered together with other therapeutic agents, such as antibiotics such as yesilins or other cephalosporins.

The present invention will be explained below with reference to Examples and formulation examples.

All temperatures are expressed in °C.

pMsoFi dimethyl sulfoxide and ItO! f
is ethanol and DMF is N,H-dimethylformamide. Kleselgrl
60 is from West Germany's E-Merck Company (K, lLe'rk).
It is a silica gel manufactured by Anl Co.) and Solvucil ■
(sorbslx) U30 is manufactured by British Joseph Crossfield and Son of Warrington (Joaeph 0
rosfield an4Son of Warring
It is a silica gel made by ton).

Intermediate 1 Ethyl(3)-2-fluoromethoxybanor2-(2
-) ethyl (2-hydroxyimino-2-(2-triphenylmethylaminothiazol-4-yl)acetate hydrochloride) at 21°C under nitrogen. a71) in dimethyl sulfoxide (50m) with potassium carbonate ('15.35
P). To this was added bromofluoromethane (approximately 32 g).

The nitrogen flow was stopped and stirring continued for 2 hours. The kernel mixture was poured into an ice-water mixture with stirring and the solids were collected by filtration and washed with water. The solid was dissolved in methylene chloride and the organic layer was separated and dried over magnesium sulfate. Evaporation gave a foam. This was dissolved in methylene chloride and Kieselgel [F] (
60 (50F). This was added to the top of a similar column of silica (I25M) set in 10% ethyl acetate in cyclohexane. This column was then washed with 10% chloride in cyclohexane.
, 20% and then 30% ethyl acetate. The appropriate fractions were combined and evaporated to give the title compound (a06F) as a foam. .

'max (EtOH) 302Rm (I1! 92),
λ1nfl is 227.5Rm ('B乃"46) and 2
59 nm (Kt221) k included.

νm, engineering (CHBr3) 3400 (NH), 1739
(ester) and 1533 cR-j (C=N).

Intermediate 2 [Z) -2-Fluoromethoxyimino-2-(2-triphenylmethylaminothiazol-4-yl)acetic acid Intermediate 1 (7,8F) was dissolved in ethanol (50,I!/) and water ( Sodium hydroxide (083
F) under reflux for 15 minutes. The mixture was cooled and the crystalline precipitate was collected by filtration, washed with ethanol and ether, and dried. While vigorously stirring this solid, methylene chloride (8M) and water (
40m) and 88% phosphoric acid (2-) was added. The remaining solids were collected by filtration.

The solid was suspended in tetrahydrofuran (75m) and then 2M hydrochloric acid (8-) was added when a solution formed. The volume of this solution was reduced by half by evaporation and methylene chloride (5Qm) was added. The aqueous layer was extracted with further methylene chloride and the combined organic layers were washed with water, dried over magnesium sulfate and evaporated to give the title compound (,s, 5zf) as a solid.

S1nfl is 224 nm (Kt bottle 564), 2s4.
5Rm (g73213) and 260Rm (K*320
5); T (+1.lDM80)1.02
(g; NH), 2.64 (s; phenyl proton)2.
91(a; thiazole 5-H), and 4.29((
I, J°56EIz; CH2F).

Example 1 a) (6R,7R) -7-C(Z) -2-Fluoromethoxyimino-2-(2-)life≧lmethylanothiazol-4-yl)acetamido-3-(I-
pyridinium methyl) cef-3-em-4-carboxy,
Methylene chloride (IM
) was added to the solution of N,N-dimethylformamide (α38-) while stirring, and the mixture was stirred for 10 minutes while cooling with ice water. This mixture was recooled for 120' and added to Intermediate 2 (
I,8RM) was added. While cooling this solution with ice water,
The mixture was stirred for 0 minutes and then cooled again to -20'K. This solution was mixed with triethylamine (2,35
(6R,7R)-7-Abano3 in industrial alcohol (I2yd> and water (3-) containing -)
-(I-pyridiniummethyl)cef-3-em-4-carpoxylate dihydrochloride dihydrate (I, 52t). The solution was allowed to warm to 21°. Water (50m) was added and the precipitate was collected by filtration, washed with water and methylene chloride and dried to give the title compound (I24f).

(b) Shi' -56,5° (C101, DM130), λmax (EtOH) 25
6.5Rm (K:! 239), λ1nfl ke 225R
m (Pr3436) and 262Rm (Fi:!22
5).

b) (6!'t, 7R)-7-C(E-2-(2-7<
21 The mixture was dissolved in formic acid (6 Wt) with stirring at 0.degree. C. and to this was added water (3 g). After 1.5 hours, the mixture was filtered and the filter cake was leached with 0.30% water in acid. The combined filtrates were evaporated and the residue was triturated with 77 tons. The precipitate was collected by filtration, washed with acetone and dried to give the title compound (650R9).

[S61 -79.54° (c 01.DMso), λl! laz
226.5nm (Tung! 579), 1% 256nm (Elcm 566)pλ1nf1296n
m (“1 bottle 128).

Example 2 (6R,7R) -7-[(2)-2-(2-abaphthiazol-4-yl)-2-fluoromethoxyiminoacetamide)-3-(I-pyridiniummethyl)cef-3
-Em-4-carboxylate bishydrochloride (6R,7R) -7-C(3)-2-(2-)cutylaminothiazol-4-yl)-2-fluoro, d) Kisii ξ Noah Seven Door i-do)-3-(I-pyridiniummethyl)cef-5-em-4-carboxylate (27F) was stirred in formic acid (I08ffi/) for 5 minutes. To this was added water (27 mg) and the mixture was stirred at 22° to 25° for 2 hours.
I stirred for a strange amount of time. This is dichloromethane (I55rnt
) was added and the two-phase solution was stirred for 3 minutes. The upper aqueous phase was separated and concentrated hydrochloric acid (alm) was added. This solution was dissolved in isopropyl ether (I35m and 1001
nt). The second isopropyl ether wash was extracted with water (2-). The aqueous extracts were combined and acetone (230 m) was added to the stirred solution K for 1.25 hours. This chew was prepared at ambient temperature for 30 minutes.
Stir for a minute. The solid was collected by filtration under nitrogen and washed with acetone (2X50m). 40 of the solid matter
Vacuum dry for 18 hours at 16. The title compound of IP was obtained.

νml! LX (Nujol) is 3200 (NH)
; 1778 (β-lactam carbonyl), 1720 (0
02E and 1668-N 558(-cow)α-
1 is included.

τ value (DM80-d6) tiO,82,1,30
and 1.75 (pyridinium ring proton); 2.
94 (aminothiazole a); 4.10 (c-7H)
s 4.26 (-0-CH2F', JHr=56
Hz) t 4.32 (ABq - collapsed one CH2-N"); 6.32 + 6.51 (0-2 methylene ABq e 18 Hz).

Example 3 a) Diphenylmethyl(6R,7R)-3-carbamoyloxymethyl-7-((20-2-fluoromethoxyimino-2-(2-)liphenylmethylaξnotiazol-4-yl)acedo methylene chloride (I0
N,N-dimethylformamide (0,38
-) was added with stirring to the solution of oxalyl chloride (α37-), and the mixture was stirred for 10 minutes while cooling with ice water. This mixture was recooled to -20° and intermediate 2
(I,85P) was added. This solution was stirred for 10 minutes while cooling with ice water, and then again at -20°lc'! Rejected. N
, diphenylmethyl ILI (6) in methylene chloride (I0m) containing N-dimethylaniline (t26-).
R97R)-7-amino-3-carbamoyloxymethylcef-3-em-4-carboxylate (I,76F
) was added and the solution was allowed to warm to 21° for 30 minutes. This @ solution was washed twice with dilute hydrochloric acid and water, and methylene chloride was back-extracted from each wash. The combined organic solutions were dried over magnesium sulfate and evaporated to dryness. The residue was dissolved again in methylene chloride and petroleum ether (boiling point 40-6
Filtered through nlubucil@<Sorbgn) U30 (I00t) in 10-60 °C of ethyl acetate (0°).

Combine appropriate fractions and evaporate to produce the title compound.
The product (I, 892) was obtained by foaming.

(a3 o' + I Q-97° (cl, 09.rioo form), W engineering, (CHBr5)34oO (NH)
, 1789 (β-lactam), 1729 (ester and carbamate) and 1690 and 152C1
cIL-1 (amide).

b) (6R,7R) -3-carbamoyloxymethyl-7-C (2-(2-aminothiazol-4-yl)-2-fluoromethoxyiminoacetamide) cef-3-M-4-carribonated trifluoro The product (I,79F) of acetate step a) is converted to anisole (4-)
To this was added trifluoroacetic acid (I6-). After 55 minutes at 21°, water (2-) was added. Further [After 5 minutes, this solution was dissolved in diisopropyl ether (2QO
tnl) and the precipitate was collected by filtration, washed with diisopropyl ether and dried to give the title compound (890Q).

@), +4515° (c 1.12.DMSO), ν
MA Engineering (Nujol) 3700-2300 (NH2eN
H1OH and ΦNT(), 1775 (β-lactam)
, 1705 (C00) and 1670 and 154
5α-1 (Abad).

Example 4 a) t-Butyl(6R,7R)-3-acetoxymethyA--7-C(2))-2-fluoromethoxyivano-2-(2-)liphenylmethylanothiazole-4
-yl)acetamido]-Sefu 3-Em-4-carboxylate The title compound (2,41 is prepared as a foam from t-butyl 7-amino 77 allosboranate (I6!M) according to the method of Example 3a). and showed the following characteristics.

(cr) n' + 21.0° (c2.12.chloroform) νmax (CE B r 5 ) 55
95 (NH), 1789 (β-lactam) 1728 (
ester) and 1692 and 1518cIR-1 (
amide).

b) (6R,7R)-5-acetoxymethyl-7
-[(car-2-(2-aminothiazol-4-yl)-2
-Fluoromethoxyiminoacetamide] Cef-3-M-4-carboxylic acid trifluoroacetate Step I! The product of L) (2,29F) was dissolved in trifluoroacetic acid (I7Fυ). After 45 min at 21°, the solution was diluted with diisopropyl ether (200 m) and the precipitate was collected by filtration. Solid. was washed with diisopropyl ether and dried to obtain the title compound (I,4(
I) was obtained.

("l D' +3a67 (c α79.DMS
O), νmal (nujo, z) 3700-2200 (
NH2, NH, NH69o! hOE), 1777 (β-
Lacfim), 1718 (acetate) and 1668
and 1540csc-1 (amide).

Example 5 a) Diphenylmethyl (6R,7R) -3-methoxymethyl-7-CCZ'1-2-fluoromethoxyimino-2-(2-triphenylmethylaminothiazole-4-
The title compound (8001 g)
6R,7R) -7-amino-3-methoxymethylcef-3-em-4-carboxylate hydrochloride (675Q)
was prepared according to the method of Example 3a) and exhibited the following properties:

Ca) ,” +7.11° (c O, 42, rio form) , v, , (CHBr5 ) 3380 (NH)
, 1783 (β-lactam), 1723 (ester)
and 1689 and 1520cR-1 (a-do).

b) (6R,7R) -7-CI car 2-(2-aminothiazol-4-yl)-2-fluoromethoxyiminoacetamide]-3-methoxymethylcef-3-em-4-carboxylic acid Title compound (3701F) was prepared from the product of step a) (750Q) according to the method of Example 3b) and showed the following %.

CUE D 2+ 472° (co, al, DMS
O),'max(pt16 buffer)227Qm(K
'%359) 252Qm (z' layer 27a) λ1nfl
296cR nm (Ff: Bottle 111).

Example 6 a) Diphenylmethyl (6R,7R) -7-C(
2) -2-Fluoromedoxyino2-(2-)liphenylmethylaminothiazol-4-yl)acedo[xi]cefu 3-M-4-poxylate title compound (2,85P)Fi diphenylmethyl (6R
,7R) -7-Abano7F 3-Emu 4-carboxylate tosylate loading (2,61F) from Example 3a
) and exhibited the following properties.

CaEi2+24. q° (c 0.72.CHC6s)
,y! flax (CHBr5) 3390 (NH), 1
790 (β-lactam), 1728 (ester) and 1690 and 1520cR−+ (Abad).

1)) (6R,7R) -7-C(2)-2-(2
-Abafthiazol-4-yl)-2-fluoromethoxyiminoacetamide]-cef-3-em-4-carboxylate The title compound (I, 32F) is an example! The product C2,75 of step a) was subjected to the method of b). ) and showed the following properties.

Cadi2=86.8° (c Q, 62 DMSO),
λmaw(pH6pa777-)225.5nm (H;
1450), 29a5nm (K; Bottle 131), λ1n
f1253nmU1bottle296).

Example 7 (61,7R) -7-((6)-2-(2-aminothiazol-4-yl)-2-fluoromethoxyinoacetamide)-3-(I-pyridiniummethyl)ceph-
5-M-4-carboxylate bishydrochloride trihydrate (6R,7R) -7-C (2 - 2 -
(-2-)-2-fluoromethoxyiminoacetamide)-3-(I-pyridiniummethyl)ceph-3-em-4-rupoxylate (I3?) 20
Formic acid (29mK) was added with stirring at . After 5 minutes, add water (7
-) was added and the mixture was stirred for a further 2 hours at 200 °C. To this was added dichloromethane (35 mg).

The aqueous phase was separated and after addition of concentrated hydrochloric acid (2-) it was extracted with isopropyl ether (2X35m).

The aqueous solution was mixed with acetone (69-) for about 1.5 hours.
diluted with The precipitated solid was collected by filtration and washed with acetone/water then acetone and dried in vacuo to give a solid (5t).

Add an appropriate amount of the above 2.50ff) to 20e' of DMF
(I5d) Ic added. The solids dissolved to give a clear solution and crystallization occurred over time. After 2 hours, the solid was collected by filtration, washed sequentially with DMF and isopropyl ether, and dried in vacuo to yield a crystalline solid of 2.55P. Stir this solid material at 2.5F at 20°.
．． Add 5N* acid (5d) K, and once dissolved, add acetone (59
TRt) was added for about 1.5 hours. The solids were collected by filtration, washed with A7T and dried to give 1.8
The title compound 8F was obtained.

Water content by Karl Fischer volumetric analysis: FL
2%m/mνmaX (nujol) is 3650-2
100(Nl(,NH,)JH2,H2O); 1773
(β-lactam); 166B+ 1548 (-C
ONH) cs+-1.

The τ value (D), a5o-a6) is 3.47+5.65(A
B4. T=18.2H); 5.28(d.

, 7=5, IH); 5.64+5.90 (A
Bq, J=12, 2H) ;5.78 (JMF=
48゜21(); 5.89(IH); 705(IT()
;a24(t,,T=8.2H);a69(t.

J=8.1H); 9.17Cd, :J=6.2H).

Preparation Example Dry powder vial for injection Active substance (as bishydrochloride trihydrate) 500
19L-fulginine 177g, sodium carbonate, anhydrous 54Rg, and each of the above components were individually weighed and placed in a glass vial. The headspace of each vial was flushed with carbon dioxide, a rubber stopper was fitted onto the neck, and the aluminum overseal was deflated and applied. This formulation is F′i1 for administration.
．． 5- K was dissolved by adding water for injection.

The pharmacological effects of the compounds of the present invention will be explained below.

1. Determination of Minimum Inhibitory Concentration (MIC) - Table I Isosentitθst with or without fortifiers Serial 2-fold dilutions of freshly prepared test solutions were placed in agar. R them
Pour it into the bird dish. Add a multi-point inoculator (mult) to each plate.
i-paint 1 noculator) and containing approximately 105 colony forming units of bacteria as shown in Table IK.
However, many of them are clinical isolates. The MIC in bacterial Zr1Lt was read after 18 hours of incubation at 37°C as the minimum hrx to inhibit growth. Bacterial antigens were administered intraperitoneally either as a suspension (Staphylococcus aureus) or as a suspension of 1.5 inactivated yeast (E. coli). 1 and 5 hours after challenge ic s l 2
Two treatment doses of test compound in wt*water were administered subcutaneously.

Five days after challenge, the number of surviving mice was determined and the activity of the test compound was expressed as 50% efficacy (KDso).

3) β-Lactamase Stability - Table 1 Values indicate β-lactamase stability in the presence of partially VcnI-generated enzyme.
- fA11 was determined using spectroscopic 7111 spectroscopy by examining the loss of UV absorption (usually in the region of 260-265 nm) of the lactam ring.

Test Compound Test Compound A (6R,7R)-3-carbamoyloxymethyl-7
-[(6)-2-(2-7minothiazol-4-yl)-
2-Fluoromethoxyiminoacedobatocosef-3-
Em-4-carboxylic acid trifluoroacetate.

Test compound B C6R,7R) -7-C(3)-2-(2-azufthiazol-4-yl)-2-fluoromethoxyiminoacetamide]-3-methoxymethylcef-3-em-4-
carboxylic acid.

Test compound 0 (6R,7R)-7-((prior-2-(2-7inotiazol-4-yl)-2-fluoromethoxyiminoacedoobado)-3-(I-pyridiniummethyl)-77 -3
- emu 4-carboxylate.

Test compound D
-Carboxylic acid trifluoroacetate.

Test Compound Z (6R,7R) -7-CIcar2-(2-aminothiazol-4-yl)-2-fluoromethoxyiminoacetamide]cef-5-em-4-carboxylate.

Table ■ Table ■ 4) Toxicity Cephalosporins are generally known to have a low level of toxicity. That is, for example, the above-mentioned test compound C during the mouse holding test was administered at its highest dose (40
None of the experimental animals that were dosed with 0 Mg/g for up to 97 days died.

Patent applicant: 2 people outside of Gracs Group Limited

Claims (1)

[Claims] 1) The following general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R^1 is a carboxyl group, a COO^■ group, or a blocked carboxyl group. , R^2 is an amino group or a protected amino group, and R is hydrogen or the formula CH_2X {where X is a halogen atom, a hydroxyl group, an acetoxy group, a formula O. C.O. A group of NHR^3 (where R^3 is hydrogen, a C_1_-_4 alkyl group or an N-protecting group optionally substituted with 1 to 3 halogen atoms), a group of formula OR^4 (where R^ 4 is a C_1_-_4 alkyl group or a C_1_-_4 alkoxy group optionally substituted with a halogen atom) or pyridinium, 3-carbamoyl-pyridinium or 4
-carbamoyl-pyridinium group}, B is -S- or -SO- (α- or β-) and the dotted lines bridging the 2-, 3- and 4-positions If the compound is a cef-2-em compound or cef-3-
[indicating that it is an M compound] and salts thereof, and when X represents a pyridinium group, 3-carbamoylpyridinium group, or 4-carbamoylpyridinium group and R^1 is other than COO^■ is a compound represented by formula (I) that is bonded to one anion. 2) The following general formula (I a) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I a) {In the formula, R^A is hydrogen, an acetoxymethyl group, or a formula C
H_2O. C.O. A group of NHR^3^A (where R^3^A is hydrogen or a C_1_-_4 alkyl group optionally substituted with 1 to 3 halogen atoms), a group of formula CH_2OR^4 (where and R^4 is a group (having the above definition) or a pyridiniummethyl, 3-carbamoylpyridiniummethyl or 4-carbamoylpyridiniummethyl group, and R^1^A is a carboxyl group, or R^A is pyridinium methyl,
3-carbamoylpyridinium methyl or 4-carbamoylpyridinium methyl group, COO^■ group}; and its non-toxic salts; and its non-toxic and metabolically unstable compounds. Esters. 3) The compound according to item 2 above, wherein R^A is a pyridinium methyl, 3-carbamoylpyridinium methyl, or 4-carbamoylpyridinium methyl group. 4) Pharmaceutical compositions containing as active ingredient, together with pharmaceutical carriers and excipients, at least one compound of general formula (Ia) as defined in paragraph 2 above. 5) In the method for producing a compound represented by the general formula (I) having the above definition, (A) in the form of a salt, such as betaine or an acid addition salt (the anion in this case is, for example, hydrochloric acid, hydrobromic acid, The following formulas can be derived from mineral acids such as sulfuric acid, nitric acid or phosphoric acid, or organic acids such as methanesulfonic acid or toluene-P-sulfonic acid ▲ Mathematical formulas, chemical formulas, tables etc. ▼(II) (In the formula, R, R^1, B and dotted line have the above definitions) The compound represented by the following formula (III) or its N-silyl derivative ▲There are mathematical formulas, chemical formulas, tables, etc. ▼(III) (wherein R^2 has the above definition) Acylated with an acid or a salt thereof or an acylated derivative thereof; or (B) in which R is CH_2X (where X represents a pyridinium, 3-carbamoylpyridinium or 4-carbamoylpyridinium group) general formula (I)
To produce a compound represented by the following formula (IV) ▲Mathematical formulas, chemical formulas, tables, etc.▼(IV) (wherein R^1, R^2, B and dotted lines have the above definitions) and Y is a nucleophilic substitutable residue, such as an acetoxy or dichloroacetoxy group, or a chlorine, bromine or iodine atom), or a salt thereof, according to the following formula (V) ▲ Numerical formula, chemical formula, table etc.▼(V
) (wherein R^5 is hydrogen, 3-carbamoyl group or 4-
is a carbamoyl group), or in the formula (C), R is a -CH_2X group {where X is an acetoxy group or -O. CO-NHR^3 group (where R^3 has the above definition)]
), a compound of general formula (I) in which R is a hydroxymethyl group or a salt thereof is substituted by replacing the hydroxy group with an acetoxy group or -O. C.O. or (D) in which R is a -CH_2X group, where X is an OR^4 group as defined above. In order to produce the compound represented by (I), the compound represented by the general formula (I) in which R is a hydroxymethyl group is converted into a CH_2OR^4 group (where R^
4 has the above definition) or (E) in which R is a -CH_2X group, where X is a hydroxy group (I ), in which R is a -CH_2X group (where X
is an acetoxy group) or a salt thereof is 3-deacetylated, followed by any of the following, as necessary and/or desired in each of the above cases, in any suitable order: Reaction i) Reaction of converting the Δ^2-isomer into the desired Δ^3-isomer, ii) Reduction of a compound in which B is -SO to convert B to -
iii) a reaction that converts a carboxyl group into a nontoxic, metabolically unstable ester functional group; iv) a reaction that produces a nontoxic salt functional group; and v) any carboxyl blocking group. and/or N-
A process consisting of carrying out a reaction that removes a protecting group. 6) Compounds represented by the following general formula (III) ▲Mathematical formulas, chemical formulas, tables, etc.▼(III) (in the formula, R^2 has the definition described in Section 1 above), their salts, and their Acylated derivatives. 7) In the method for producing the compound represented by the general formula (III), its salts, and its acylated derivatives defined in Section 6 above, (a) the following formula (VI) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼(VI) (wherein R^2 has the above definition and R^6 represents hydrogen or a carboxyl blocking group) or a salt thereof can be combined with the following general formula (VII) T,CH_2F ( VII) etherification by selective reaction with a compound of the formula (T is chloro, bromo or iodo) followed by removal of any carboxyl blocking group R^6, or (b) (VIII) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (VIII) The compound represented by the following formula (IX) H_2N. O. A process consisting of reaction with a compound of the formula CH_2F (IX) 2 followed by removal of any carboxyl blocking groups R^6 and then optional separation into the syn and anti isomers.