JPH07509455A - Cephalosporins and 1-carba-1-dethiacephalosporins - 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] Cephalosporins and 1-carba-1-dethiacephalosporins The present invention provides new New β-lactam compounds, their preparation and uses, especially new cephalosporins Regarding phosphorus. These compounds have antibacterial properties and are therefore widely used. Treatment of bacterial infections in humans and animals caused by environmental microorganisms It is useful in

EP 0487996 Al (Bayer Akchengesernjaft (B a yerAG) is the general formula (A) [wherein R'' and R'' are various substituents, R1 is a ring selected from , where A and D may be the same or different, and CH=CH , oxygen or sulfur, R″ and R″lt, various substituents] A cephem indicated by is disclosed.

The present inventors have discovered that a 5- or 6-membered cyclic ether or cyclic chain exists at position 3 of the cephem nucleus. Particularly superior cephems with bicyclic rIl substituents containing an oh-ether group and carbacephems.

The present invention relates to formula (I).

[In the formula, R1 is hydrogen, metquin or formamide.

R2 is an anol group, particularly an anl group of cephalosporin, which has antibacterial activity.

coiR3 is a carboxy/group or a carboquinrad anion, or is an L s, R3 is an easily removable carboxyl/protecting group, or a pharmaceutically acceptable is a salt-forming group or an ester group that can be hydrolyzed in vivo.

X is s, so, so, or CI (,.

R(ha, is a bicyclic group represented by m is 1 or 2.

One of Y or Z is ○, 5SSO or SOh, and the other is 1, CH2 and R4 is unsubstituted or alkyl, alkokino, hydro. Roxy, Noroken, Amine, Alekyl Amino, Anru Amino, Noalkylua Mihe CO2R, OCOR, CONR2, SOtNRZ (here, R is -艮 di- or alkyl), aryl and heterocyclic 1-norka\, etc. may have the same or different one or more substituents R5), and this substituent Group R'R. on any carbon atom of said bicyclic ring system; two may be present ( , (\The R5 alkyl substituents are also optionally bicyclic one or more positions selected from the list for selecting R5 instead of the hydrogen atom of Substituent (substituted by 2;) may be used] The present invention provides a compound represented by: or a salt thereof.

The bonding carbon atom of the heterocyclic portion of R″ that connects R″ to the Cefa 0 sporin nucleus is: Generally, it is an asymmetric carbon atom. The invention relates to stereoisomers and both isomers. Contains mixtures.

In the compound represented by formula (1) in which R1 is formamide, the formamide The group has a configuration in which the hydrogen atom of the -NH-CHO moiety is cis- or trans- can exist. Of these, the cis conformation is usually preferred.

The compounds of the invention are useful as therapeutic agents for antibacterial use in pharmaceutical compositions. Preferred compounds within formula (1) are pharmaceutically acceptable compounds. , that is, formula (Ia): [In the formula, R1, R2 and R4 are the same as defined in formula (1), and the group CO 2R is CO2R3, and Co2R3 is a carboquine group or a carboquine group. -Anion or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof 10 to ivo hydrolyzable ester.

Therefore, the present invention provides compounds of formula (Ia) or compounds useful as therapeutic agents. is a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof; In particular, its in vivo hydrolyzable esthetics useful as orally administered therapeutic agents. It provides the following information.

The present invention further provides compounds of formula (la) useful in the treatment of bacterial infections. compound or a pharmaceutically acceptable salt or in vivo hydrolyzable salt thereof nνivo hydrolyzable enzymes, particularly useful in the oral treatment of bacterial infections. It also provides stealth.

The present invention provides antibiotic compounds represented by formula (Ia) or pharmaceutically acceptable thereof. administration of a therapeutically effective amount of an in vivo hydrolyzable ester, particularly in Human and animal therapy consisting of oral administration of a therapeutically effective amount of an in vivo hydrolyzable ester. It also includes methods for treating bacterial infections in objects.

Furthermore, the present invention provides a compound of formula (Ia) for the manufacture of a medicament for the treatment of bacterial infections. compound or a pharmaceutically acceptable salt or in vivo hydrolyzable Use of esters, especially in vivo for the production of oral treatments for bacterial infections o Including the use of hydrolyzable esters.

As used herein, the term "aryl" refers to each optionally halogen , mercapto, (CI-s)alkyl, phenyl, (CI4)alkoxy, hydro Roxy(C,,)alkyl, mercapto(CI-a)alkyl, halo(CI-s ) alkyl, hydroxy, amino, nitro, carboquine, (C1,6)alkyl carbonyloxy, (CI-6)alcoquinocarbonyl, formyl, or (C I-6) Up to 5, preferably up to 3 selected from alkylcarbonyl groups phenyl and naphthyl which may be substituted with a group of

As used herein, the terms "heterocyclyl" and "heterocyclic" Preferably up to 4 heterozygous rings in each ring selected from oxygen, nitrogen and sulfur. Includes aromatic and non-aromatic monocyclic and fused rings containing atoms. The ring is For example, halogen, (C+-a) alkyl, (CI-6) alkyl quin, halo(CI-s) alkyl, hydroxy, carboquino, carboquine salt, carbon Luboquin esters, e.g. (CI-s)alcoquinocarbonyl, (CI-a) Alcoquine carbonyl (C,,) selected from alkyl, aryl, and oxo groups may be substituted with up to three groups. Each heterocyclic ring is preferably , having 4 to 7, preferably 5 or 6 ring atoms. "heteroaryl" means a heteroaromatic heterocyclic ring. The fused heterocyclic system is a carbocyclic ring containing only one heterocyclic ring. heterocyclyl group Compounds within the scope of the present invention which include, depending on the nature of the heterocyclyl group, can be classified into It occurs in the following tautomeric forms. All such tautomeric forms are within the scope of this invention. included.

As used herein, the term "heteroaryl" preferably refers to means a heteroaromatic heterocyclic ring or ring system having 5 or 6 ring atoms .

As used herein, "alkyl", "alkenyl", "alkynyl" and and the term "alcoquino" refers to methyl, ethyl, propyl and butyl. Includes straight and branched groups containing 6 carbon atoms. In particular, alkyl groups is methyl.

As used herein, the term "halogen" refers to fluorine, chlorine, bromine and iodine. It means urin.

R3 is a pharmaceutically acceptable in vivo hydrolyzable ester. is a releasable carboxine protecting group or is in a pharmaceutically unacceptable salt form. These compounds of formula (1) include, as a rule, compounds of formula (Ia) or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable in vivo Useful as an intermediate in the production of hydrolyzable esters.

Suitable easily removable carboxyne protecting groups for group R3 include inv iv.

Groups forming ester derivatives of carboxylic acids, including hydrolyzable esters, are listed. It will be done. The derivative is preferably one that is easily cleaved in vivo.

Exists as an optional substituent in the compound represented by formula (1) or (Ia) Calhoki 7-group salts and in vivo hydrolyzable esters Luboquine protected derivatives are also included within the scope of this invention. Also, formula (1) or (I Amino group or substitution present as an optional substituent in the compound represented by a) Acid addition salts of amino groups are also included within the scope of this invention.

Suitable ester-forming carboxyne protecting groups are those that are removed under conventional conditions. . Such groups for R3 include benzyl, p-methocinobenol, benozo ylmethyl, p-nitrobenol, 4-bilinormethyl, 2.2.2-tric loloethyl, 2.2.2-tribromoethyl, t-butyl, t-amyl, allyl , nophenylmethyl, triphenylmethyl, adamantyl, 2-penzyloxy Phenyl, 4-methylthiophenyl, tetrahydrofuran-2-yl, tetrahydro Ropyran-2-yl, pentachlorophenyl, acetonyl, p-toluenesulfonyl nylethyl, methchinmethyl, nilyl, tin- or phosphorus-containing group, formula -N=CH an oxytum group represented by R (where R? is aryl or heterocycle), Alternatively, an inviv□hydrolyzable ester group as defined below may be mentioned. can be lost.

The carboxyl group can be removed by conventional methods appropriate for the particular R3 group, e.g. acid and base contact. Catalytic hydrolysis, or enzymatic catalytic hydrolysis, or when the remainder of the molecule is substantially regenerated from said ester by hydrogenolysis under conditions not affected by .

Suitable pharmaceutically acceptable in vivo hydrolysable compounds mentioned as R3 An example of an ester group is that it easily decomposes in the human body and separates from the parent acid or its salt. There are things that do. Suitable ester groups of this type include subformula (1) , (ii), (iii), (1v) and (v): C0yCJ-+y-OR(trl) [In the formula, R" is hydrogen, (CI-g)alkyl, (C3-7)cycloalkyl, methyl or phenyl, Rb is (C+0g) alkyl, (CI-a) a Lucoquin, phenyl, hennol, (C,7)nochloroalkyl, (C3-7)/c loalkyloxy, (CI-s)alkyl(C3-7)nochloroalkyl, 1-a mino(CI-s)alkyl or 1-((CI-s)alkyl)amino(CI- a) alkyl, or Ro and R' - together, as desired; 1°2-phenylene optionally substituted with 1 or 2 methoxyno groups group, and Ro may optionally be substituted with a methyl or ethyl group ( CI-J represents alkylene, R6 and Ro are independently (CI-a)alkylene; Ro represents (C1-a)alkyl, Rg is hydrogen or as desired selected from halogen, (CI-6)alkyl or (C,-6)alcoyne by represents phenyl optionally substituted by up to 3 selected groups; Q represents an acid or NH, Ro is hydrogen or (CI-g)alkyl, and R1 is , hydrogen, (CI-s)alkyl optionally substituted by halogen (C2-6)alkenyl, (CI-s)alcoquinecarbonyl, aryl or or heteroaryl; alternatively, R" and R" - taken together, ( CI-a) forms alkylene, Ro is hydrogen, (C1-s)alkyl or ( CI-6) represents alkokinocarbonyl, R1 is (C1-s) alkyl, (C I-a) Alkoquino, (C, -,) Alkoquino ((CI-a)) Alkoqui/Also represents aryl] Examples include those shown below.

Examples of suitable in vivo hydrolyzable ester groups include, for example, aceto oxymethyl, pivaloyloxymethyl, α-acetoquinoethyl, α-pivaloyl Oxy/ethyl, 1-(chlorohexyl/ruponyloxy)proper-1-yl, and acyloxyalkyl such as (1-aminoethyl)carbonyloxy/methyl group, ethoxy/carbonyloxy/methyl, α-ethoxy/carbonyloxy/ethyl Alcoquinocarbonyloxyalks such as and propoxy/carponyloxyethyl Kyl group, /alkylaminoalkyl, especially trimethylaminomethyl, dimethylalkyl Di-lower such as minoethyl, noethylaminomethyl or noethylaminoethyl alkylaminoalkyl group, 2-(isobutoquinocarbonyl)pent-2-enyl 2-(alkoxol) and 2-(alkoxol) such as carbonyl)-2-alkenyl group, phthalidyl, dimethoxyquinophthalidyl, etc. lactones: and second β-lactam antibiotics or β-lactamase inhibitors. Examples include linking esters.

Further suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include: formula.

In the formula E, R' is hydrogen, (C1-4) alkyl or phenyl. It is something that

A preferred hydrolyzable ester group is pivaloyloxymethyl ester. It's stealth.

As a suitable pharmaceutically acceptable salt of the carboxine group of the compound represented by formula (1) metal salts, e.g. alkalis such as aluminum, sodium or potassium l1VA salts, especially alkalis such as sodium, cal/lam or magnesium earth metal salts, and ammonium or substituted ammonium salts, such as Tilamitub; Which lower alkylamine, 2-hydroxyethylamine, bisbenzene 2-hydroxyethyl)amine or tris-(2-hydroxyethyl)-amine Hydroxy-lower alkyl amines such as loalkylamino, or protylene, nobennoramine, N,N-nobenno ruethylenenoamino, 1-efhenamine, N-methylmorpholino, N-ethyl Lupiperitsuno, ＼-he/nor-β-phenethylamine, dehydroahiethylamine N, N.

N-bisdehydro-abiethylamine, ethylenediamine, or pyridine, Pyrinone-type bases such as cholinone or quinoline, or the known and other amines used to form salts in Cephasporin. Substituted ammonium salts may be mentioned. Other light salts include lithium salts and silver salts. Salt is an example. Salts of formula (1) are prepared in conventional manner by salt exchange.

In the compound represented by formula (1) or (Ia), group X is an oxidized sulfur group. may be a sulfoquinodo (So) or a sulfone (So, ) group. stomach.

When X is a sulfokid group, it is understood that α- and β-isomers exist; Both such isomers are included within the scope of the present invention.

Preferably, X is CH2.

Preferably R1 is hydrogen.

Suitable anol groups R2 include formulas (a) to (f).

A,■-(1111 Heichi 4i (g), Ino (d+ [wherein p is 0.1 or 2; m is 0.1 or 2; A1 is (CI-8) Alkyl, substituted where the substituent is the same as defined in R4 above (Cl -5) Alkyl, (C3-8) chloroalkyl, chlorohexenyl, /chlorohex Sanoenyl, phenyl, substituted phenyl, chenyl, pyrinol or as desired Aryl (including heteroaryl) groups such as optionally substituted thiazolyl groups , (CI-a) alkylthio group or (CI-s) alkylthio group; , hydrogen or norogen atom, cart'/acid, carboxylic acid ester, sulfone Acid, Azide, Tetrazolyl, Hydroxyl/, Anolamino, Aminoureido, Ano Ruamino, heterocyclylamine/, guanine or anolureido group. , A2 is an aryl group, such as phenyl, 2.6-7methoxy/phenyl, 2- Alcoquine-1-naphthyl, 3-ori-lysoxazinol, or 3-(2- chloro-6-fluorophenyl)-5-, d-thylisoxazol-4-yl 3-aryl-5-methylisoxazoryl group, such as ! substituted alkyl group, or and X2 is -CH0CH2-1CH+ SCH+- or is an alkylene group, X3 is oxygen or sulfur atom, and A3 is phenyl , substituted phenyl, furyl, aminothiazolyl or aminothiadiazolyl (here , the amine group may be an aryl or hetero group (optionally protected), etc. is a loweryl group, A4 is hydrogen, (C1,6) alkyl, (CI-s) chloro Loalkyl, (C3-8) chloroalkyl (C1-a) alkyl, (C, -6) Alcoquinocarbonyl (Cl-6)alkyl, (C2-6)alkenyl, carpho Sat/(CI,s)alkyl, (C+J alkynyl, aryl, or up to 3 (C1-a)alkyl monosubstituted by an aryl group] The following can be mentioned.

Suitably, when R2 is a group (a), A+ is (CI-a) alkyl, (Cs -a) Chloroalkyl, 7-cohexenyl, 7-cohexenyl, phenyl, Substituted phenyl (e.g. substituted in the same way as in the above-mentioned -aryl), e.g. Hydroxyphenyl, chenyl or pyl-11-nor is hydrogen or/ %rokene atom, or carhoki/, carboxylic acid ester, and, child trafuryl , hydroxy, anoloxy/, optionally substituted aminohaureido , guaninono or anolureido group.

Preferably, when R2 is a group represented by formula (d), A2 is phenyl, X is oxygen and p is 0.

Separately, when R2 is a group represented by formula (e) or (f), a suitable definition of group A is As a definition, hydroxyimide is present in the side chain attached to the 7-position of the cephalosporin core. Antibacterially active cephalosporins containing substituted hydroxyimino or vinyl groups those commonly found in -yl, fuller-2-yl, fuller-3-yl, pyrigou-2-yl, birigou-3-yl biligul-4-yl, 5-amino-1,2,4-thianoazol-3-yl and 2-aminothiazol-4-yl, each in which the amino group is optionally ) may be substituted.

Preferred groups for , to, phenyl, 2-aminothiazol-4-y 2-yl, fuller-2-yl, checy-2-yl, 2-(2-chloroacetamido)thia Zol-4-yl, 2-tritylamino-thiazol-4-yl, 5-amino- 1゜2.4-Thianoazol-3-yl and 4-aminobyrimig-2-yl are Can be mentioned.

In the compound represented by formula (Ia), a preferable anol group R2 is 2-amino It is of formula (e) having group A3 which is thiazol-4-yl.

Preferred definitions for group A include hydrogen, methyl, ethyl, chloropropylmethane, Chil, triphenylmethyl (trityl), chlorobutyl, chlorobentyl, noku lohexyl, chloroheptyl, chlorooctyl, phenyl, carboxinmethyl, Includes carboquinoprobil and t-butoquinocarbonylmethyl.

A preferred definition for A4 in the compound represented by formula (la) is: Methyl and hydrogen are mentioned.

In the bicyclic substituent R4, one of )' or Z is O or S. is preferred. Examples of such groups R4 include nohydrobenzofuranyl, nohydroyl Sobenonofuranyl, nohydrothianaphthyl and nohydroxanaphthyl are mentioned. and such groups are determined by the available apical position on the 5- or 6-membered heterocyclic apex of R4. It may also be linked to the Cephalosporin nucleus. For example, R4 is a heterocyclic ring The 1st position adjacent to the 0 or S atom of! may be connected to the nucleus. Such a group R A preferred example of 4 is dihydrobenzofuran-2-yl. Preferably, R4 is It has up to three substituents R5. Preferably, R’l! , is non-replaceable.

The compound of the present invention in which R2 is a group represented by formula (e) or (f) has syn and Can exist as anti (or E and Z) isomers or mixtures thereof Wear. Both isomers are included within the scope of this invention.

Preferably, the compound of the present invention in which R1 is a group represented by formula (e) has a syn configuration. (i.e. has the syn group OA4 to the amide bond), or , is rich in its isomers.

Similarly, when R2 is a group represented by formula (f), group A4 is is preferably cis, i.e. the group (f) is 2-amino-thiazole- When 4-yl, the Z-configuration is preferred.

The 5- or 6-membered ring of the heterocyclic moiety represented by R4 exists in a number of isomeric forms. It is understood that All isomeric forms, including mixtures of isomeric forms, are included within the scope of this invention. It will be done.

Certain compounds of the invention contain a protected amino group. The preferred amino protecting group is , which is removed under conventional conditions without disrupting the remainder of the molecule. It is well known.

Examples of amino protecting groups include (CI-6)alkanoyl:benzoyl; optionally (C,,)alkyl, (C1,,)alcoquino, triflu in the phenyl ring with one or two substituents selected from olomethyl, halogen, or nitro. Optionally substituted benol: (C1-t)alcoquinecarbonyl, the above-mentioned Pen/ruoxycarbonyl or trioxycarbonyl substituted as for benol methyl (i.e. triphenylmethyl), alkoxycarbonyl, trichloroethyl Toquinocarbonyl or chloroacetyl may be mentioned.

Some of the compounds of the invention can be crystallized or recrystallized from solvents such as organic solvents. It will be done. In such cases, solvates are formed. The present invention relates to chemistry containing hydrates. Water-containing solvates and materials containing variable amounts of water produced by methods such as freeze-drying Includes within its scope compounds that include.

The antibiotic compounds of the present invention have been shown to be useful in pharmaceutical compositions and therefore each in substantially pure form, e.g., at least 60% pure, more preferably be at least 75% pure, preferably at least 85% pure, especially with low at least 95% pure, in particular at least 98% pure (% is based on w/w). It is easily understood when provided. Impure preparations of the compound cannot be used in pharmaceutical compositions. used to produce more pure forms; Compound preparations containing a small amount (both 1 and 1) of the compound represented by formula (1) or a salt thereof %, more suitably at least 5%, preferably from 10 to 49%. be.

Detailed compounds within the scope of the present invention represented by formula (la) include the following pharmaceutical compounds: Acceptable carboxylic acids and their salts and in vivo hydrolyzable Examples include esters (6R,75)-7-[2-(2-aminothiazol-4-yl)-2-(Z) -Methoquinoiminoacetamide]-3-[(S)-dihydrobenzofuran-2- yl]cepha-3-m-4-carboxylic acid, (6R,7S)-7-[2-(2-aminothiazol-4-yl)-2-(Z) -methquinoiminoacetamide]-3-[(2S)-2,3-dihydrobenzof Ran-2-yl]-1-calper 1-butiacefer 3-nimo-4-carboquine lard.

The present invention provides that -CO2R3 is a carboquine group or a carboquine rad anion. or R3 is a pharmaceutically acceptable salt-forming group or an in vivo hydrolyzable group. Preparation of a compound represented by formula (1) or (Ia) as defined above, which is a functional ester group. This provides a method for manufacturing. Here, the above definition in which R3 is a carboquino group-protecting group The compound represented by the formula (T) has a carboquino group or a carboquinolade anion. or R3 is a pharmaceutically acceptable salt-forming group or an in vivo hydrolyzable group. the group CO2R3 replaced by the group CO, R' which is a functional ester group. have

The present invention further provides the formula (I l) [In the formula, X5R1, CO2R3 and R4 are the same as defined above, and any of Reactive groups may also be protected, and amine groups may optionally undergo acylation. [Optionally substituted with a group that can be substituted] or a salt thereof] Formula (II 1) R2-○H (III) [In the formula, R2 is the same anol group as defined in formula (1), and any reactivity The base may also be preserved] or an N-anolated derivative thereof, and then, if desired, lower process l) removing any protecting groups.

11) Converting the group Co2R' into another group C○2R3.

111) Converting the group R2 into another group R2.

1-.) group X and/or)' and/or Z to another group X and/or) ′ and/or a step of converting S into SO or SO2, for example; ■ ) carrying out one or more of the steps of converting the product into a salt or ester. It also provides a method for producing a compound represented by formula (1), characterized by .

The acid of formula CI +) can be prepared by methods known in the art, or It is manufactured by a method similar to this method. Suitable methods include, for example, U K Patent 2 107 307 B, UK Patent Specification No. 1.536.281 and U. includes the method disclosed in Patent Specification 1 No. 1.508.064.

of a starting material of formula (I+) which can undergo anoration and optionally has the formula (I+). Suitable groups that may be present on ami, 7 groups include N-noryl, N-tin, and and N-phosphorus groups, such as trialkylsilyl groups such as trimethylnoryl, trimethyl A trialkyltin group such as n-butyltin, a group represented by the formula -P, R'R'' (this Here, R7 is alkyl, haloalkyl, aryl, aralkyl, alkoxy, Haloalkyl, aryl, aralkyl, alcoquine, haloalcoquine, aryl oxy, aralkyloxy or noalkylamino group, and R6 is R? same as or halogen, or R7 and Rs together form a ring. A suitable phosphorus group is -P (OC2H5)! , P(C2H 5) 2:. If desired, an amine group in the compound represented by formula (I+) The group that may be introduced into is trimethylnoryl.

Conveniently, the norylation reaction requires the concomitant addition of a base prior to the anoration reaction. It is carried out with no norylation agent. Suitable norylation agents include, for example, N-( trimethylnoryl)-acetamide, N,O-bis-(trimethylnoryl)acetamide toamide, N, O-bis(trimethylnoryl)-trifluoroacetamide, N -Methyl-N-trimethylnolylacetamide, N-methyl-N-trimethylnolylacetamide Lyle-trifluoroacetamide, N, N'-bis(trimethylnoryl)urea , and N.

O-his(trimethylnoryl) carbamate is mentioned. Preferred frilling agent is N,O-bis(trimethylnoryl)acetamide. Norylation reaction is Suitably in an inert anhydrous organic solvent such as /chloromethane, at room temperature or at elevated temperature, e.g. For example, the temperature is 30 to 60°C, preferably 40 to 50°C.

The process optionally comprises a small amount, e.g. For example, tri(C11 alkyl)noryl halides, especially trimethylnoryl chloride. may be carried out in the presence of

The reactive N-arylated derivative denoted by acid (lII) is used in the above method. Ru.

The choice of reactive derivative is, of course, influenced by the chemical nature of the acid substituents. Ru.

Suitable N-acylated derivatives include acid halides, preferably acid chlorides or or bromide, or symmetric or mixed anhydrides. Acylation is An acid binder that binds the hydrogen halide liberated in the hydrogenation reaction, e.g. Tertiary amines (e.g. pyridine or dimethylaniline), molecular molecules , an inorganic base (e.g. calcium carbonate or sodium bicarbonate) or oxy It is carried out in the presence of orchids. Oki/ran is preferably ethylene oxide or oxidized Oxidation with propylene (C+-s) is 1,2-alkylene. acid halogenation The acylation reaction using a compound is carried out at -50°C to -50°C, preferably -20°C to -50°C. At a temperature of +20 °C, water, acetone, tetrahydrofuran, ethyl acetate, trimethyl Acetamide, /methylformamide, acetonitrile, /chloromethane, 1. carried out in an aqueous or non-aqueous medium such as 2-dichloroethano or mixtures thereof . Alternatively, the reaction may be carried out in a water-immiscible solvent, especially methyl isobutyl ketone or carried out in unstable emulsions of aliphatic esters or ketones such as butyl acetate. be exposed. Acylation with acid halides or anhydrides is preferably carried out with pyridine or or in the presence of a basic catalyst such as 2,6-lutidine.

Acid halides are acid (II+) or salts or reactive derivatives thereof. Halogenated (salts) such as phosphorus chloride, thionyl chloride, oxalyl chloride or phosgene (brominating or brominating) agents.

Suitable mixed anhydrides are, for example, carbonic monoesters, trimethylacetic acid, thioacetic acid, Nophenylacetic acid, benzoic acid, phosphoric acid (e.g., phosphoric acid, phosphorous acid, and phosphatide) phosphoric acid) or aromatic or aliphatic sulfonic acids (e.g. p-toluene sulfonic acid). acid or methanesulfonic acid).

Alternatively, the N-acylated derivative of acid (l I +) is an acid anodide or 2-Mercabutopyridine, /anomethanol, p-nitrophenol, 2.4- Halophenos, including nonitrophenol, thiophenol, and benchlorophenol monomethquinephenol, N-hydroxysufnonimide, N-hydroxy Active esters such as nobenzotriazole or esters with 8-hydroxyquinolino Stell, or N-Ryonorsasocalin, N-Ryonorthiazolinone-2-thione or amides such as N-a/lphthalimide, or acids (II+) and oxy It is an alkylidene imino ester produced by reaction with

Other reactive N-acylated derivatives represented by acid (II+) include, for example, N.

No-ethyl, nopropylene or isopropyl luposiimide, N.

No-di-7lyroheki/rucarbodiimide, or N-ethyl-N'-[3- (dimethylamino)propyl]carbodiimide; e.g. N , N'-carbonylneumidazole or N,N'-carbonyldi-tri Suitable carbonyl compounds such as azoles 1, e.g. N-ethyl-5-phenyl Sooxazolinium-3-sulfonate or N-1-butyl-5-methyliso Isoxazinonium salts such as oxazolinium verchlorate: or N- Ethoxycarbonyl 2-ethoquino-1,2-:; With a condensing agent such as lucoquine carbonyl 2-alcoquino-1,2-nohydroxyphosphorus Examples include reaction intermediates formed by in 5 in situ reactions. other contractions As a mixture, Lewis acid (for example, BBr3CsHg): or diethyl phosphorus Examples include phosphoric acid condensing agents such as phorylnoanide. The condensation reaction can be carried out, for example, using methane chloride. Tyrene, dimethylformamide, acetonitrile, alcohol, benzene, dioxin Preferably carried out in an organic reaction medium such as xane or tetrahydrofuran. .

Further methods for forming N-acylated derivatives of acids represented by formula (111) The method uses carbonyl halides, preferably oxalyl chloride, or oxy salts. A phosphoryl halide such as phosphorus chloride is substituted with a lower anol tertiary amide, preferably N .

A halogenated hydrocarbon solvent containing N-methylformamide, preferably a dimethylformamide. Formula (I) in a preformed solution or suspension by addition to chloromethane ll). Then, the derived formula (II ) is reacted with a compound represented by formula (I+). let The acylation reaction is carried out at -40° to +30°C, optionally with an acid such as pyridine. Conveniently it is carried out in the presence of a binding agent. Optionally, 4-dimethylamino A catalyst such as pyridine may also be added. Preferred solvent for the acylation reaction is dichloromethane.

Optional removal of protecting groups (1), optional conversion of CO2R3 (ii), R2 to another R2, from Co2R1 to another Co2R'' 1), and and/or Y and/or Z to another X and/or Y and/or Z Any conversion (iv) to (iv) and any formation of salts or esters (V) using methods well known in the art of cephalosporin and beni/phosphorus chemistry. It is done using

For example, if the group XSY or Z is S, SO or S'02, then the group Z is, for example, as disclosed in European Patent Application No. 0114752 , an oxidative compound well known in the art of cephalosporin and peninolino synthesis. or converted into another group Y by a reduction method. For example, sulfokids (X or Y is SO) is a suitable oxidizing agent, e.g. an organic compound such as m-chloroperbenzoic acid. By oxidation with peracid, the corresponding sulfide (X, '1' or Z is S ) is manufactured from.

The reduction step is generally carried out by methods well known in β-lactam chemistry. , for example, by using phosphorus trichloride in trimethylformamide. Ru.

For example, the removal of Ho:J7& is a technique that reduces unnecessary side reactions to 1-Kuta. This is done by conventional methods known in the art. For example, R3 is the protecting group p-methane. When toquinobenol, this group is preferably protected in the presence of anisole. It is removed by treating the compound with aluminum chloride. unnecessary by-products Separation of is performed using standard methods.

Compounds of formula CI +) in which X is S, SO or 502 are of formula (IV) In formula 1, R21 is an amino protecting group as described above] Manufactured starting from A preferred group R21 is phenoquinoacetyl. Formula (I \') is a compound represented by the formula R"-Co-CH2-X where R' is the above defined and X is a halogen, preferably chlorine] Upon reaction, a compound of formula (V) is formed. Formula R' Co CH2X The compound represented by is derived from a known compound represented by the formula R'C02H by removing such an acid. It is produced by reacting with oxalyl halides such as oxalyl chloride. Ru.

Similarly, a compound of formula (II) in which X is CH2 is a compound of formula (Vl): where R21 and Rco2 are the above-mentioned amino-protecting groups] Manufactured starting from a compound. A preferred group R21 is phenylacetyl, A preferred group R22 is 4-methoquinophenyl. Compound represented by formula (Vl) is the formula R'-CO, CH=PR1C, where R'' is the same as defined above, and R is By reacting with a compound of formula which is aryl, preferably phenyl, form a compound that The compound represented by the formula R" CO, CH=PR3, In the presence of nil lithium, the oxidation of the known compound R'C02H with / reacting the derivative with a compound such as [CHz, P (Rs)]”Br- Manufactured by The compound represented by formula (Vll), for example, Pd/C :H, and the protecting group R22 was removed to form a compound represented by the formula (Vlll): form a compound. Compounds represented by formulas (V) and (Vllll) are converted into compounds represented by formula (I X) [wherein RH is the group R3 or can be converted to R3, or R is a vine group substituted by 3] It is converted to the compound shown in Preferably, R31 is The boxyl protecting group is preferably 4-methocinobenzyl. Shown by formula (IX) For example, the compound (■) or (Vlll) can be combined with the corresponding R31-glycan. Produced by reaction with oxide/late.

The compound represented by the formula (IX) is converted into a halo of the hydroxy group represented by the formula (IX). Substitution by a gen, e.g. thionyl halide such as thionyl chloride of (IX) and then reaction with compound PR3 to form a compound of formula (X): [wherein R is an organic hydrocarbon group such as alkyl or phenyl, preferably n-butyl] It is converted to the compound shown in

Compound (X) is then treated, typically by heating, for example under reflux. Cyclized, formula ON): A compound represented by is formed.

By deprotection of the 7-amine group, i.e., removal of R21, the A compound is obtained. Deprotection was performed using the known Delft method. , for example using phosphorus pentachloride in the presence of N-methylmorpholine. 4 - Deprotection of the acyl group, i.e. removal of R31, is carried out using standard methods. known for the formation of compounds of formula (+) which are salts or esters. may be used.

Compounds of formula (1) in which Manufactured by RO.

During the synthesis step, the compound has a 5- or 6-membered heterocyclic ring represented by R4. Isomers are resolved when it is necessary to separate compounds containing the and S isomers.

This is conveniently carried out on compounds of formula (XI).

Formula (II), (V), (Vl), (Vll), (vrll), (IX), (X ) and (XI) are novel and as such represent a further aspect of the invention. Configure the following.

The present invention provides a compound represented by formula (Ia) or a pharmaceutically acceptable salt thereof; consists of an in vivo hydrolyzable ester and a pharmaceutically acceptable carrier. The present invention also provides pharmaceutical compositions containing the following. The composition of the present invention can be administered orally, topically or non-administered. For use in the treatment of bacterial infections in mammals, including humans, including oral tubes. By analogy with other antibiotics, the antibiotic compounds of the invention used in humans or Formulated for administration in any convenient manner useful in veterinary medicine.

The composition is suitable for administration by routes such as oral, topical or parenteral, especially by the oral route. It is formulated to The composition can be used in the form of tablets, capsules, powders, granules, lozenges, creams, etc. in the form of an oral or sterile parenteral solution or suspension; It is.

Topical formulations of the invention include, for example, ointments, creams or lotions, ophthalmic ointments, and as eye or ear drops, impregnated bandages and aerosols; Preservatives in ointments and creams, such as solvents and emollients to aid drug penetration. Contains suitable conventional additives.

The formulation may be prepared using a compatible conventional carrier such as a cream or ointment base and a may contain ethanol or oleyl alcohol. The darning carrier is Present from about 1% to about 98% of the formulation. More generally, they are Forms up to about 80% of the formulation.

Tablets and capsules for oral administration are in unit dosage form and may contain conventional excipients, e.g. , 70 knobs, gum arabic, gelatin, sorbitol, tragacanth, or port Binders such as lyhinylpyrrolidone, lactose, sugar, corn starch, 1 Fillers such as calcium monophosphate, sorbitol or glycine, stearate Tablet lubricants such as magnesium, talc, polyethylene glycol or linica; /- Disintegrants such as Kymodenbun or acceptable agents such as sodium lauryl sulfate It may also contain an ff1ifffl agent. Tablets are commonly used in normal pharmaceutical practice. It may be coated according to well known methods. Oral liquid preparations can also be aqueous or in the form of an oily suspension, solution, emulsion, or elixir. or water or %l before use! Dry for reconstitution with a suitable vehicle of It may also be present as a dried product. Such liquid preparations may contain customary additives such as Sorbitol, methyl, lurose, glucose 70. Bu, Seratin, Hitokuki/ Ethylcellulose, Urunaki/Methylcellulose, Aluminum stearate clouding agents such as oleate or hydrogenated edible fats: lentin, sorbita monooleate Emulsifiers such as gum or gum arabic: almond oil, oily esters, e.g. Non-aqueous vehicles such as serine, propylene glycol or ethyl alcohol ( (including edible oils): preservatives such as methyl or propyl p-hydroxybenzoate; If desired, conventional flavoring or coloring agents may be included.

Suppositories may contain conventional suppository bases, such as cocoa butter or other glycerides. Ru.

For parenteral administration, fluid unit dosage forms include the compound and a sterile vehicle, a preferred Preferably, it is prepared using water. The compound is dependent on the vehicle used and Depending on the concentration, it can be either suspended or dissolved in the vehicle. Prepare solution To prepare the compound, dissolve it in water for injection, filter sterilize it, and then add it to a suitable vial. Can be filled into bottles or ampoules and sealed.

Conveniently, agents such as local anesthetics, preservatives and buffering agents are dissolved in the vehicle. can be done. After filling the composition into vials to enhance stability , can be frozen and the water removed in vacuo. Then add the lyophilized powder to the vial. Configure the liquid before use by supplying a vial with water for injection, sealed inside. good. Parenteral suspensions are made by suspending the compound in a sterile vehicle instead of dissolving it. It is prepared in virtually the same way, except that it cannot be carried out by filtration.

The compound is sterilized by exposure to ethylene oxide and then transferred to a sterile vehicle. can be suspended in Conveniently the composition includes a surfactant or a wetting agent. to promote uniform distribution of the compound.

Depending on the method of administration, the composition may contain from 0.1% to 60% by weight, preferably from 10 to 60% by weight. % active substance. The composition is composed of dosage units, each unit containing , preferably contains 50 to 500 mg of active ingredient. Used for the treatment of adults The dosage given is 100 to 300 Q per day depending on the route and frequency of administration. Preferably, it is in the mg range, for example 1500 mg per day. such administration The amount corresponds to 15-50 mg/kg per day. Preferably the dosage is 1 day. 5-20 mg/kg.

A compound represented by formula (Ia) or a pharmaceutically acceptable salt thereof or in vjv.

When using hydrolyzable esters in the above dosage ranges, unacceptable toxicological No effect is expected.

The compound of formula (Ia) is the only therapeutic agent in the composition of the invention. or in combination with other antibiotics or β-lactamase inhibitors. You may also use

Conveniently, the composition is also disclosed in EP-A-0053893. Such a formula (,Xl1): [wherein A is hydroxyl, substituted hydroxyl, thiol, substituted thiol, a amine, mono- or non-hydrocarbyl-substituted amino, or mono- or is a no-anora-amino, an optionally substituted thiazolyl group, or an optionally substituted thiazolyl group. is an optionally substituted tetrazolyl group] or consisting of a pharmaceutically acceptable salt or ester thereof.

Further advantageous compositions are of the formula (Xll+) where B is hydrogen, halogen or Formula (wherein R'' and R'' are the same or different, each represents hydrogen, (C+-s) Alcoquinocarbonyl or carboxy/, or a pharmaceutically acceptable salt thereof ] A compound represented by or a pharmaceutically acceptable salt thereof or in vivo hydration A compound of formula (Ia) or its pharmaceutically acceptable compound together with a degradable ester It consists of a salt or an in vivo hydrolyzable ester.

Further suitable β-lactamase inhibitors include those described in EP-A-0041768. Formula (XIV) as disclosed.

[wherein R'' and R'' are the same or different and each represents hydrogen or optionally (C,...) represents a hydrocarbon or heterocyclic group which may be substituted with a functional group. death.

R' represents hydrogen or a group represented by the formula Rl 3 or -SR+3, where: R13 is an optionally substituted (C1-+) hydrocarbon or complex. 6-alkylidenepenem or its pharmaceutically acceptable salts or in vivo hydrolyzable esters.

Further suitable β-lactamase inhibitors include, for example, EP-A-04107 68 and EP-A-0154132 [both of Beecham Group (Beec 6β-promopeninelanic acid and its Pharmaceutically acceptable salts and in vivo hydrolyzable esters and 6 β-iodopeninolanic acid and its pharmaceutically acceptable salts and in vivo Hydrolyzable esters may be mentioned.

Such compositions of the invention comprising a β-lactamase inhibitory amount of a β-lactamase inhibitor are formulated in a conventional manner using techniques and methods known per se.

The antibiotic compounds of the present invention are suitable for Gram-negative bacteria such as E. coli and A wide range of microorganisms including Durham-positive bacteria such as S. aureus Active against living organisms.

The following examples illustrate methods for making compounds of the invention and their intermediates, as well as Explain the process.

Example 1 (6R,7R)-7-C2-(2-aminothiazol-4-yl)-2-(Z) -Methoquinoiminoacetamide 1-3-[(S)-dihydrobenzofuran-2- Sefer 3-emu 4-carboxylic acid sodium and (6R,7R)-7 -[2-(2-aminothiazol-4-yl)-2-(Z)-methoquinoiminoa Cetamido]-3-((R)-”Hydrobenzofuran-2-yl]Sefer 3- Sodium emu-4-carboxylate a) (R5)-2-chloroacetyl-2,3-dihydrobenzofuran 23-7hi Thorough 2-benzofurancarboxylic acid (3.28 g) and dichloromethane (48 g) Oxalyl chloride (2.68 ml) was added to the stirred mixture of +nl). dimethyl Formamide (C2rS) is added and the mixture is refluxed at room temperature for 50 min then with L1. The mixture was stirred for an additional 10 minutes while flowing. Evaporate the solvent and remove the remaining 1% chlorofluorocarbon. The lum was evaporated twice. The residue was dissolved in dichloromethane (200 ml). , then the solution was cooled in a water bath. until all acid chloride is consumed. A stream of noadimethane in argon was bubbled through the solution, and then air was bubbled through the solution. Excess noadimethane was removed by filtration. All cyazoketonka is consumed Salt (hydrogen scum) was bubbled through the solution until the solution was washed with water and saline. It was dried with magnesium sulfate and then evaporated. Column chromatography of residue Added to matrix (711 couples, 4 liters of hexane, ethyl acetate) and labeled The following compound (3.93 g) was obtained. Shi72, (CHCr3) 1744cm-' : δ (CDCI43) 3.40 (IH, dd.

I16.13.6.33Hz), 3.57 (LH, dd, J 16.15.10 ．． 57Hz), -1,4H11 (, d, J 17.12Hz), 4.61 (LH , d, J 17.20Hz), 5.26<LH, dd, J 10.75.6.3 01(z), 6.87-6.96(2H,m) and 715-7.21(21- 1, m).

b) (3R,4R) 4-(R3)-2,3-nohydroben/furan-2- ylcarbonylmethylthio]-3-phenoxylene, acetamitoacetin-2-o (R3)-2-chloroacetyl-2,3-dihydrobenzofuran under argon. (3,93g) and (3R14R)-4-mercapto-3-phenoquinoacetate Amidazetidin-2-one (5.0 g) in dimethylformamide (50 ml) Potassium carbonate (4.5 g) was added to the medium stirring solution. The mixture was heated at room temperature for 1.5 hours. Stir for a while then partition between ethyl acetate and water. The organic phase was washed three times with water and then was washed with brine, dried over magnesium sulfate, and then evaporated. Hula Chromatography (Nlica gel; hexane/ethyl acetate (1:1)) to pure ethyl acetate) to give the title compound (7.09 g) in the form of a gum, This was used without further purification. ν, , (CH(J’3) 3410.1 783 and 1690CI-'.

c) (RS)-2-[(3R,4R)-4-[(RS)-2,3-dihydroben Zofuran-2-ylcarbonylmethylthiocou 3-phenoquine acetamidoase Tidin-2-one-1-yl]-2-hydroxyacetic acid 4-methocinobenzyl 4-methquinbenol glyochiturate (3,10 g) in lolomethane (30 ml) ), inverse water entrainer ) for 1 hour at reflux. The mixture was cooled to room temperature and ( 3R,4R)-4-[(R5)-2,3-dihydrobenzofuran-2-ylcal [bonylmethylthio]-3-phenoxy/acetamidoacetitun-2-one (7, 09g) in dichloromethane (45ml) was added, and then triethyl alcohol was added. Min (0,22+nl) was added. The mixture was stirred at room temperature for 1 hour, then The solvent was evaporated and the product was purified by flattened chromatography. purification by subjecting to ethyl acetate (11 to pure ethyl acetate) The title compound (6.22 g) was obtained in the form of a gum, which was used without further purification. Niji used, (CHCfs) 3411.1783.1742 and 1691 cm-'.

d) 2-[(3R,4R)-4-4(R5)-2,3-hydropenzofuran- 2-ylcarbonylmethylthioko-3-phenoquinoacetamidoazetidine-2 -on-1-yl3-2-tri-n-butylenephosphoranilideneacetic acid 4-meth Kimbennor (R5')-2-:C3R,4R)-4C(R3)2.3-/Hydrobenzof lano-2-ylcarbonylmethylthio]-3-phenoquinoacetamidoazetidi 4-Methoquinobenzyl (6,2-2-of-1-yl)-2-hydroxyacetate 2 g, crude) and 2,6-lutidine (1,85 ml) in tetrahydrofuran Thionyl chloride (1.15 ml) was added to a stirred solution of tetrahydrofurane in (471 Il). (9 ml) was added. The mixture was stirred at room temperature for 2 hours, then the solid was filtered and washed with tetrahydrofuran. Evaporate the combined filtrates and remove the residue. The toluene was evaporated.

The residue was dissolved in dioxane (57111) and trilobyl Phosphine (5.7ml) was added. The mixture was stirred for 50 minutes, then vinegar diluted with ethyl acid and the solution was successively treated with sodium bicarbonate solution, water and brine. and washed. The solution was dried over magnesium sulphate and then evaporated. Residue The distillate was purified by furano/uchromatography (/rigal; hexane, ethyl acetate (1. 1) Pure! = ethyl acetate) to obtain the title compound (3.09 g). . ν1111 (CHCZ’1) 3420.1761.1689.1612 and 1600cm-'.

e) (6R,7R)-3[(RS)-2,3-enehydropenzofuran-2-yl ]-7-phenoxy/acetamidocepha-3-em-4-carboxylic acid 4-methoxy 7be2-4(3R,4R)-4[(R3)-2,3-7hydropenzofuran-2 -ylcarbonylmethylthio-3-phenoquinoacetamidoazetinone-2- [on-1-yl]-2-1-ly n-butylphosphoranilideneacetic acid 4-meth A solution of quinbenzil (3.09 g) in toluene (150 ml) was heated under reflux for 3 hours. I let it happen. Evaporate the solvent and apply column chromatography using gradient eluent. By (Norikakel, hexane ethyl acetate (31 to 11)), The product was separated. The (S)-isomer of the title compound (465 mg).

v, , (C1 (Cr3) 3409.1788.1720 and 1697c r'; δ (CDCr3) 3.02 (IH, dd, J 16.52.8.37H z), 3.32 (LH, a.

J18.80 to 1z), 3.59-3.75 (lH, m), 3.37 (IH, d , J16.65)1z), 3.81 (3H, s), 4.55 (2H, s), 5. 00 (II-1, 6, J4.92Hz), 5.23 (21-1, s), 5.88 -5.96 (2H, m) and 6.74-7.37 (14H.

m). Next eluted was a mixture of compounds containing the (R)-isomer of the title compound. (745 mg).

r) (6R,7R)-7-amino-3-[(S)-2,3-dihydrobenzofura 4-Methoquinbenzyl (6R ,7R)-3-[(S)-2,3-dihydrobenzofuran-2-yl]-7-ph Enoki/acetamidocepher 3-M-4-carboxylic acid 4-methquinbenzyl (465+ng) of nochloromethane:/　A solution in (5,5 ml) from 15″ to -2 Cool to 0°C, then add N-methylmorpholine (0,179ml) and then and 1 l pentachloride (6.4 ml of solution in chloromethane containing 40+ g/ml) ) was added. The solution was stirred at the same temperature for 05 hours, then methanol (1.6 m 1) was added and the mixture was stirred at room temperature for 05 hours. Next, water (2.19 ml ) was added and the mixture was stirred vigorously for 0.5 hours. aqueous phase IN ammonia water The pH was adjusted to 6.2 with a solution and the mixture was extracted with chloroform. Chloroform The solution was washed with water and brine, dried over magnesium sulfate, and then evaporated. I set it. The residue was subjected to column chromatography using a gradient eluent. Kagel; hexane: ethyl acetate (11) to pure ethyl acetate), title compound (98 mg); Llsnm (CHC13) 1780 and Bi2Qc m-': δ (CD (Js) 1.68 (2H, s), 3.04 (IH, del, J 16.51.8.41Hz), 3.32 (IH, d, J18.68Hz), 3 ．． 36-3.78 (LHlm), 3.65 (LH, d, J 18.79Hz), 3.81 (3H, s), 4.76 (IH, d, J5.02Hz), 4.92 (L H, d, J 5.05Hz) 1.5.19 (LH, d, J 11.88Hz), 5 ．． 24 (LH, d, J 11.85Hz), 5.89 (IH, dd, J9.66 ．． 8.63) (z), 6.76 (IH, d, J 7.89Hz), 6.84-6 ．． 91 (3H, m), 7.10-7.19 (2H, m) and 7.36 (2H.

d18.63Hz).

g) (6R,7R)-7-42-(2-aminothiazol-4-yl)-2-( Z)-methquinoiminoacetamide]-3-[(S)-2,3-dihydrobenzo Furan-2-yl] cef-7-3-em-4-carphonate 4-methquinobenzyl 2 -(2-Aminothiazol-4-yl)-2-(Z)-methocinoiminoacetic acid (5 Hmg) and N,N-noisopropylethylamine (0,043ml) Cool the stirred solution in chloroformamide (0.9 ml) to -40°C. and methanesulfonyl chloride (0.19ml) was added. The mixture was heated at the same temperature. stirring for an hour, then (6R,7R)-7-remino-3-[(S)-2,3-di Hydrobenzofuran-2-yl]cepha-3-em-4-carboxylic acid 4-methoxy A solution of nobenzyl (98 mg) in 7 methylformamide (1 ml) was added and then Then pyridine (0,018ml) was added. The mixture was then heated at 0°C for 1 hour. The mixture was stirred for 0.5 h and then at room temperature for 0.5 h. The mixture was dissolved in ethyl acetate and citric acid. The organic phase was washed with water and brine and dried over magnesium sulfate. It was then evaporated. Column chromatography of the residue using gradient eluent Pure ethyl acetate (Nrica gel, hexanoethyl acetate (11) ), the title compound (112 mg): 5f:: C, (CHCr+) 　3490　, 3398, 1783, 1720゜1683 and 1611cm- ' : δ (CDC et al.) 3.06 (IH, dd, J 16.53° 8.20) I z), 3.33 (1] (, d, J 18.87 Hz), 3.64 (IH, dd, J 1668.9.87Hz), 3.69 (LH, d, J 18.92Hz), 3.81 (3H, s), 404 (3H, s), 5.06 (it (, d, J4.9 1Hz), 5.19 (LH, d, Jll, 82Hz), 5.25 (LH, cl, J 11.81Hz), 5.60 (2H, s), 5.92 (IH.

t, J9.73), 6.05 (IH, dd, J9.02.4.89Hz), 6. 77 (IH, d.

J T, 95) (z), 6.84-6.92 (4H, m), 7.14 (IH , dd, J14.08゜6.75Hz>, 7.35 (LH, d, J8.61Hz ) and 7.62 (LH, d, J 9.03Hz).

h) (6R,7R)-7-:2-(2-aminothiazol-4-yl)-2-( Z)-Methoquinoiminoacetamide'')-3-i(s)-2,3-7 hydropene Zofran-2-/L: Cef7-3-22-4-calho/acid sodium Runni 7 lower , anisole (2.7 ml.) and nochloromethane (1.35 ml.) with stirring. The mixture was cooled to -20'C and aluminum chloride powder (70 mg) was added.

The mixture was stirred at -20°C for 15 minutes. Then, (6R,7R)-7 -(2-12-7mi,・"thia7・'-ru4-yl)-2-(Z')-methoxy neumino-acetamido]-3-[(S)-2,3-dihydrofuran-2-yl ] Sefer 3-Emu 4-carphonoate 4-methquinobenzyl (11211g) solution in chloromethane (9111) and the mixture was stirred at -20°C for 5 minutes. did. Then add sodium citrate solution (5.95111 05M), The mixture was stirred vigorously for 10 minutes at room temperature.

The aqueous phase was separated and washed twice with nochloromethane. Evaporate the aqueous phase and Chromatography (HP20SS, water with increasing proportion of acetone as eluent) The product was purified by subjecting it to Combine the fractions containing the product. The residue was dissolved in water (5 ml) and lyophilized to give the title compound. (61 mg); ν, , (KBr) 1763.1680 and 15 97cm-' ;6 [(CDI)2SO ko 2.98(L H, d d, month 6.3 2.9.1 6Hz), 3.1 8 (IH, d, J 17.32H z), 3.31-3.40 (IH, m), 3.43 (IH, d, J1732Hz ), 3.82 (3H, s), 5.04 (IH, d, J5.79Hz), 5.59 (IH.

dclj8. o5.4.71) (z), 6.01 (IH, t, J 9.23H z), 6.7l-683 (3H, m), 7.08 (IH, t, J7.45Hz) , 7.18-7.24 (3H, m) and 9.53 (LH, dd8.08Hz) +m/z (FAB, +ve ion, thioglycerol) 524 (MH”), 5 46 (MNa”).

1) (6R,7R)-7-amino-3-[(R)-2,3-enehydropenzofura -2-yl]cepha-3-em-4-carboxylic acid 4-methquinobennor impure (6R,7R)-3-C(R)-2,3-7hydropenzofuran-2-yl]- 7-Funinoquinoacetamitocefur 3-M-4-carboxylic acid 4-methoxybe A solution of methane (745 mg) in methane (10,4111) was heated to -15°. Cool to -20°C, add N-methquin morphol (0.28f3ml), Next, a solution of phosphorus pentachloride in nochloromethane (a solution containing 40 mg/ml) The mixture was stirred at the same temperature for 05 hours, and then methanol was added. (2.6 ml) was added and the mixture was stirred at room temperature for 0.5 hours. Water (3,5 m1) was added and the mixture was stirred vigorously for a further 105 hours. /Chlorometa 7 was removed with a rotary volator and the aqueous phase was stirred with ethyl acetate. , the pH was adjusted to 62 with IN aqueous ammonia solution. Evaporate the organic phase and add water and food. It was washed with brine, dried over 7 ml of sulfuric acid, and evaporated. Use gradient eluent and the residue was subjected to column chromatography (Norica gel, hexane, vinegar). ethyl acetate (1:1 to pure ethyl acetate), title compound (101 mg) 〇Gett: 　;　ν,, -(CHCIs) 1779 and 1726cl'; δ (CD (J!s) 1.77 (2H, s), 2.99 (LH, dd, Jl 5 , 84.7.96Hz), 3.35 (LH, dd, Jl5.88.9.89Hz ), 3.40 (IH, d, J 17.97Hz), 3.56 (LH, d, Jl8 ．． 07Hz), 3.80 (3H, s), 4.72 (LH, d, J4.78Hz) , 4.91 (IH, d, J 5. OIHz), 5゜16 (L H, d, J 11.82Hz), 5.26. (IH, d, 11.81H2), 6.03 (I H, dd, J9.64.8.20Hz), 6.80-6.90 (4H, m), 7 ．． 12 (2H.

d, J9.52Hz) and 7.33 (2H,d, J8.65Hz).

D (6R,7R)-7-[2-aminothiazol-4-yl)-2-(Z)- methquinoiminoacetamide]-3-[(R)-2,3-dihydrobenzofuran -2-yl]Sefa-3=Em-4-carboxylic acid 4-methoquinobennor 2-(2 -aminothiazol-4-yl)-2-(Z)-methocinoiminoacetic acid (51 mg ) and N,N-diisopropylethylamine (0,044ml) The stirred solution in lumamide (1 ml) was cooled to -30° to -40°C and methane chloride was added. Sulfonyl (0,020o1) was added. The mixture was stirred at the same temperature for 0.5 h. , then (6R,7R)-7-amino-3-[(R)-2,3-dihydroben Zofran-2-yl] cef-7-3-em-4-carboxylic acid 4-methoquinobenol (101 mg) in trimethylformamide (bnl) was added. Next, The mixture was stirred at 0° C. for 1 hour and then at room temperature for 0.5 hours. the reaction mixture was partitioned between ethyl acetate and citric acid solution. Wash the organic phase with water and brine , dried over magnesium sulfate and then evaporated. using gradient eluent The residue was subjected to column chromatography (1 hexane for Norikake, ethyl acetate). (1:1) to pure ethyl acetate) to give the title compound (93 mg): v-,, (CH(J’3)3491.3398.1783.1726.168 3 and 1607 cr'; δ (CDCr3) 2.99 (LH, dd, Jl5. 96.7.90Hz), 3.36-3.46 (L H, d d, Jl5.83 ．． 9.81Hz), 3.40 (IH, d, Jl7.29Hz), 3.61 (LH ,d.

J 18.15Hz), 3.80 (3H, s), 4.04 (3H, s), 5.0 5 (LH, d, J4.83Hz), 5.16 (LH, d, Jll, 85Hz), 5.26 (LH, d, Jll, 82Hz), 5.39 (2H, s), 5.99 ( LH, dd, J8.98.4.82Hz), 6.13 (LH, t, J8.1 2Hz), 6.79-6.90 (4H, m), 7.10-7.16 (2H, m) , 7.32 (2H, d, J 8.57 Hz) and 7.64 (IH, d, J8 ．． 96Hz).

k) (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-( Z)-methquinoiminoacetamide]-3-[(R)-2,3-dihydrobenzo Sodium furan-2-yl]cepha-3-m-4-carboxylate under argon, Stirring of anisole (2,25III) and nochloromethane (1,12ml) The mixture was cooled to -20°C and aluminum chloride (58mg) was added. the mixture was stirred at room temperature for 15 minutes, then (6R,7R)-7-[2-(2-amino thiazol-4-yl)-2-(Z)-methoxy/imino-acetamide]-3[ (R)-2,3-7hydroxybenzofuran-2-ylcomopher 3-M-4 -carboxylic acid 4-methocinobenol (93 mg) in chloromethane (7.5 ml) ) solution was added. The mixture was stirred for a further 5 minutes at -20°C and then Sodium phosphate solution gt (4.95ml of 0.5M) was added and the mixture was further stirred. Stir vigorously for 10 minutes. The aqueous phase was separated and washed twice with dichloromethane, then So I evaporated it. Column chromatography (HP20SS, acetic acid as eluent) The product was purified by subjecting it to water (with increasing proportions of water). the product The containing fractions were combined and then evaporated. The residue was dissolved in water (5 ml). The title compound (54 mg) was obtained by dissolving it in solution and lyophilizing it. Br) 1763 and 1597 cm-1; δ[(CD3)2S○] 2.99- 3.25 (2H, m), 3.10 (LH, d, Jl6.09Hz), 3.46 ( LH, d, J 16.83Hz), 3.83 (3H, s), 500 (IH, d, J4.75Hz), 5.55 (LH, dd, J8.00.4.65Hz), 62 7 (L H, t, J 9.03Hz), 6.71-6.82 (2H, m), 6 ．． 74 (LH, s), 7°07 (IH, t, J 6.66Hz), 7.17 (LH, d, J 7.36Hz), 7.23 (2H.

S) and 9.56 (IH, d, J8.07): m/z (FAB, +ve ion , triglycerol) 524 (MH').

Example 2 (6R,7S)-7-[2-(2-aminothiazol-4-yl)-2-(Z) -methquinoiminoacetamide]-3-[(2S)-2,3-dihydrobenzof Ran-2-yl)-1-calper-1-butiacefer 3-nimo-4-carboxylic acid Sodium a) 2-benzo 2.3-7hydropenzofuran-2-ylcarboxylate Furocarboxylic acid (9.66g, 59.6ml) was added to ethanol (10Qml ) and hydrogenated with 10% palladium on charcoal (900 mg) for 16 hours.

The catalyst was removed by filtration through Celite, the filtrate was concentrated in vacuo, Greeting combination? i (9.52g, 98%) obtained f: : v-, (CH2(J’z) 1731.1598.1481 and 1221cr' +6. , (CDC1 3) 3.40 (IH, d d, J 16° (16,6Hz), 3.64 ( LH, dd, J 16.0.10.8Hz), 5.25 (IH, d d.

J 10.8.6.6Hz), 6.86-6.97 (2H, m), 7.10-7 ．． 22 (2H, m) and 7.98 (IH, br, s, exchanged).

b) 23-dihydrohenzofuran-2-ylcarbonylmethylenetriphenyl- Phosphorane 2,3-dihydrobenzofuran-2-ylcarboxylic acid (5 00mg, 3.05m! Iol) in solution in chloromethane (20111) Oxalyl chloride (530 μm, 6.08 mmol) was added. After stirring for 2 hours , the mixture was concentrated, redissolved in nochloromethane, and concentrated again. During Methyltriphenylphosphonium bromide (2.18g, 6.11mmol) Ethyl ether (30ml) Nakano suspension 3ml of a 2.06M solution in ether, 18mmol). 2 hours at room temperature After stirring, a solution of the acid chloride in 7 ethyl ether (30 ml) was added and 5 Stir vigorously for a minute. Water (20ml) was added and stirring continued for a further 5 minutes. water The sexual phase was separated and re-extracted with ether. Combined organic layer with water (x3) and salt Washed with water, dried over magnesium sulfate, then smeared directly above. the residual The product was chromatographed on Norikakel to give Hexa/Ko 50.70 and Purification by elution with 10096 ethyl acetate yielded the Muji compound (8501 1 g, 66%). (Measurement value M”422 1433°C21H2302P Theoretical value of M422.1436): v-1-(CI(2CA'ri 1536.1 481.1438.1405.1268.1232 OJ: Hi 1106cm-'.

δ1噸(CDCj3) 3.36 (IH, dd, Jl6.0.7.9Hz), 3. 53 (LH, dd.

J 16.0.10.3Hz), 4.27 (IH, d, J25.2Hz), 6. 80-6.88 (2H, m), 7.06-7.20 (2H, m) and 7.40 -7.68 (15H, m); m/z (C1, +ve ion, ammonia) 4 23 (MH”).

c) (3S,4R)-1-(4-methquinphenyl)-4-[3-oxo-3- (2゜3-7hydropenzofuran-2-yl)probenyl-3-phenylacetate Toamide azetinon-2-one (3S, 45)-4-formyl-1-(4-methquinphenyl)-3-pheny -acetamidoacetinon-2-one (4.13g, 12.2mmol) Acetonitrile (100111) Nakano suspension was mixed with 2,3-dihydrobenzofuran-2 -ylcarbonylmethylenetriphenyl-phosphorane (5.20g, 12.3 mmol) and heated at 80° C. for 2 hours. Most of the product (3,75g) was collected by filtration and washed with acetonitrile. The remainder of the product is poured into silicage. Purified by chromatography on a column and eluting with ethyl acetate. , an additional 1.28 g of the title compound was obtained (total 503 g, 86%): (measured value + M-482, 1846°C25) ItsN205 theoretical value M482.1842 ): v, , (KBr) 1772.1703.1659.1512 and 12 53cm-1, δ, 1 (CDCj,) 3.22 3.47 (2H, m), 3. 03 (2H, s), 3.76 (3H, s), 4.87 (IH, t, J5.4Hz ), 5.18 (IH, ddjlo, 3.7.1Hz), 5.46 (LH, dd, J8.1.5.4Hz), 6.18 (IH, t, J8.IHz), 6.58-6 ．． 92 (5H, m) and 706-7.28 (8H, m); m/z (C1, +v e-ion, ammonia) 500 (MH).

d) (3S,4R)-1-(4-methocytophenyl)-4-[3-oxo-3 -(2,3-7hydropenzofurano-2-yl)propylcou-3-phenylacetate Toamide 7-2-one (3S, 4R)-1-(4-methoquinophenyl)-4-C3-oxo-3= (2,3-7Hitrobe/Zofrano-2-yl)propenyl]-3-phenylacetate Toamitoacetenon-2-one (5.0g, 10.37mmol) Notetrahy FO7 u:/　(250+11) solution in 10% palladium on charcoal (300mg) Hydrogenation was carried out for 3.5 hours. I through Celite! After filtering, concentrate the filtrate in vacuo. The title compound (5.04g, 100%) was obtained: (i11+1if1 1: M”484.1999°C24H24NzOs (7) Theoretical value: M48419 98): v, , (KBr) 1757.1721.1659.1513 and 1247 cm-': δH (CDCA3) 1.50 (IH, m), 2.24 (L H, m), 2.42-2, 62 (2H, m), 3.25 (L H, m), 3.4 5 (LH, m), 3.54 (2H, s), 3.73 (3H, s), 4.15 (I H, m), 4.98 (IH, m), 5.29 (IH, m), 6.66 (IH, d, J7.9Hz), 6.79 (2H, m), 6.89 (2H, m) and 7° 13-7.36 (9H, m): m/z (Cl+ve ion, ammonia) 48 5 (MH'), DO2 (MNH4').

e) (3S, 4R)-4-[3-oxo-3-(2,3-dihydrobenzofura) (2-yl)propyl-3-phenylacetamidoazetin-2-one ( 3S, 4R)-1-(4-methquinphenyl)-4-[3-oxo-3-( 2,3-dihydrobenzofuran-2-yl)-propyl]-3-phenylaceto Tetrahydride of amidazetinon-2-one (3.80g, 785ml1lol) The suspension in Lofuran (380 ml) was diluted with ammonium nitrate (2.5 g) at 0°C. 25.8 g, 47.08 mmol) in water (160 ml). 0 After stirring for 5 min at 0°C, the reaction mixture was diluted with ethyl acetate and the aqueous phase was Extracted four times with a mixture of lahydrofuran and ethyl acetate (21). Combined with The extract was mixed with 5% aqueous sodium bicarbonate solution, 10% aqueous sodium sulfite solution ( X2), washed successively with 5% sodium bicarbonate aqueous solution, water, and then saline. Ta. After drying over magnesium sulfate, the solvent was evaporated in vacuo to yield the crude title compound. (1.64 g, 55%) was obtained.

ν, , (CH2C12) 3412.1772.1683 and 1507c m-'.

f) (R3)-2-hydroxy-2-[(3S,4R)-4-[3-oxo-3 -(2゜3-7hydrobenozofuran-2-yl)probylto-3-phenylaceto Amidoacetino-2-one-1-yl]acetic acid 4-methocinobenol 1.2-/ p-methoxy/benzyl glyochiturate (1,13 g, 5.82 mmol) using a Dean and Stark apparatus. I added it for an hour while letting it flow. The solution was cooled in water and (3S,4R)-4 -[3-oxo-3-(2,3-dihydrobenzofuran-2-yl)propyl] -3-phenylacetamidoazetidin-2-one (1.64g, 4.34m mol) and triethylamine (60 μm, 0.43 mmol). I understood. After stirring overnight at room temperature, the reaction mixture was concentrated in vacuo. Remove the residue from the Chromatography on silica gel in hexane at 30,50 then 7 Purification by elution with 0% ethyl acetate gave the title compound (626 mg, 25%), ν1. .

(CH2C12) 1763.1743.1671.1612 and 15151 c++-'; m/z (FAB, +ve ion, 3-nitrobenzyl alcohol /sodium acetate) 533 (MNa-).

g) 2-[(3S,4R)-4-[3-oxo-3-(2,3-dihydrobenzo Furan-2-yl)propyl]-3-phenylacetamidoazetidine-2-o n-1-yl]-2-4-n-butylphosphoranylidene acetate 4-methquinben The hydroxy compound (763a+) in THF (20 ml) at 20 °C g, 1.33 mmol) and 2.6-lutidine (233 uL 2.OOmm Thionyl chloride (146 μl, 2.00 mmol) in THF (2 ml ) solution was added. After stirring for 1 hour, the reaction mixture was passed through a pad of Celite. and the filtrate was evaporated in vacuo. Add toluene and reevaporate to form an oily (R3)-2-chloro-2-[(3S,4R)-4-C3-oxo-3-(2, 3-hydropenzofuran-2-yl)propyl]-3-phenylacetamide 4-methoxybenonol acetin-2-one-1-yl]acetate was obtained.

The crude chloro compound was dissolved in oxane (10+al) and trilobed chloroform was added. Treated with sphine (731 μl, 2.93 mmol). Stir for 30 minutes at room temperature. After that, the reaction mixture was diluted with ethyl acetate, diluted with dilute sodium bicarbonate solution, water and Washed successively with saline. The organic solution was dried, concentrated, and then purified on silica gel. 30.50 in hexane then 70% ethyl acetate. Elution with chill gave the title compound as a foam (7:33 mg, 73%): ν, . , (CH2C6z)3418.1751.1679.1612.1514 and 1464cm-': m/z (C1, +ve, ammonium) 757 (MH ”).

h) (6R,7S)-7-phenylacetamide-3 [(S) and (R)-2 ,3-7hydropenzofuran-2-yl]-1-calper 1-dethiacepha-3 -M-4-Calphonacetic acid 4-methoquinobennorphosphorane (733 mg, 0 , 97 mmol) and benzoic acid (10 mg) in toluene (15 ml) The mixture was heated under reflux for 11 hours. The reaction mixture was cooled, concentrated and the residue Chromatography on silica gel in hexane followed by 50% vinegar. Purified by elution with ethyl acetate and labeled as separate diastereoisomers The compound was obtained. The (S)-isomer was obtained as a pale yellow title product (72 mg, 14%), (measured value M”538.2126°C5zHsoNtOa theoretical value ~ 1538.2104) Niji-, (CH2C12) 3418.1771.171 9.16・18.1612.1516.1480.1392 and 1232cm ”, δ□ (CDCr3) 1.07 (LH, m), 1.87 (IH, m), 2. 19-2.52 (2H.

m), 2.88 (LH, dd, Jl6.3.8.3Hz), 3.56 (IH, d d, Jl6.3°9.8Hz), 3.59 (2H, s), 3.78 (3H, s) , 3.82 (LH, m), 5.12 and 5.20 (2H, ABQ, J 11. 9Hz), 5.29 (LH, dd, J6.7.4.9Hz), 5.93 (IH, dd, J9.8.8.3Hz), 6.0 (IH, d, J 6.7Hz), 67 3 (IH, a, JT, 9Hz), 6.80-6.89 (3H, m) and and 7.06-7.39 (9H, m): m/’z (C1, +v e ion, ammonia) 539 (MH”), 556 (\1λH, °).

Further elution of the column gave the (R)-isomer (41 mg, 8%): ( Measurement 1ii: 5t-338, 2121°C3zH3oN206 theoretical value M53 8.2104) Elm,, (CH2C12) 3417.1772.1722. 1684.1612.1516.1480.1389 and 1232 ("lj δ11 (CDC13) 1.25 (LH.

m), 1.87CN(, m), 2.10(1)1. m), 2.58 (LH, m) , 2.96 (IH.

a d, J ID, 9.78 Hz), 3.33 (IH, dd, J 15. 9.10.0Hz), 358(2H,s8 3.74(3H,s), 3.76( IH, m), 5.19 (2H, s), 527 (IH, dd, J6.3.5.3 Hz), 5.94 (LH, d, J6.3Hz), 6.09 (LH, ddj 10 ．． 0.7.8Hz), 6.73-6.88 (4H, m) and 7.07-7°3 7 (9H, m): m/z (C1, +ve ion, ammonia) 539 (MH two , 556 (MNH4”).

1) (6R,7S)-7-amino-3-[(2S)-2,3-dihydrobenzof Ran-2-yl]-1-calper-1-dethiacepha-3-em-4-carboxylic acid 4-Methoquinobenol (6R,7S)-7-phenylacetamido-3-[(23)-2,3-dihyde lobenzofuran-2-yl]-1-calper 1-dethiacepha-3-M-4- Carboxylic acid 4-methocinobenol (70 mg, o, 13 mmol) and N -Methylmorpholine (3041,0,27mIIol) of nochloromethane (61 11) The medium solution was dissolved in phosphorus pentachloride in nochloromethane (1,11Il) at -25°C. (44ml+, 0.21+mol).

The reaction was stirred at -10±5°C for 45 minutes, then methanol (15ffil) was added and stirring continued for 45 minutes at room temperature. Then water (32 ml) was added and the The mixture was stirred vigorously for an additional hour. Evaporate the chloromethane in vacuo to remove the aqueous residue. The distillate was adjusted to pH 7 with 1 ammonia solution in the presence of ethyl acetate. the mixture was extracted twice with ethyl acetate, dried and concentrated in vacuo. the residue on silica gel Purified by chromatography and eluting with ethyl acetate to give a thin The title compound was obtained as a yellow foam (3611 g, 66%), (measured value M"420. Theoretical value of 1689°C24H24NzOs M420.1685) Niji... CH2C12) 1764.1718.1612.1516.1480 and 13 95cm day, δu (CDCz3) 1.49 (LH, m), 2.02-2.49 (5H, m, 2 exchange), 2.93 (LH, dd, Jl 6, 3.8.3 Hz) , 3.56 (IH, dd, Jl6.3.9.7Hz), 3.72 (IH.

m), 3.79 (3H, s), 4.52 (LH, d, J5.4Hz), 5.19 (2H9s), 5°93 (LH, dd, J9.7.8.3Hz), 6.74 (L H, d, J 7.9Hz), 680-6,90 (3H, m), 7,06 7.1 6 (2H, m) and 7.34 (2H, m): m/Z (C1, +ve ion, ammonia) 421 (MH"), 438 (MNH, -).

j) (6R,7S)-7-f2-(2-aminothiazol-4-yl)-2-( Z)-methquiniminoacetamide]-3-[(2S)-2,3-dihydroben Zofran-2-yl]-1-carper 1-butiacefer 3-nimo 4-carbo 4-Methoquinbenzyl acid 2-(2-thiazol-4-yl)-2- in DMF (2 ml) at -30°C. (Z)-Methoquinoiminoacetic acid (19D, 0.095 mmol) and N, N - diisopropylethylamino (16 μm, 0.092 aoaol) with meth chloride Sulfonyl (7 μm, 0°09 Qmmol) was added. -30±10℃ After stirring for 30 minutes, (6R,7S)-7-amino-3-[(2S)-2,3- dihydrobenzofuran-2-yl]-1-calper-1-butiacefu-3-nim -4-methoxybenzyl-4-carboxylate (35 mg, 0.083 mIIol) in DMF (3 ml) was added, followed by Piritsuno (7 μm, 0.087 μmmol) was added. The reaction mixture was transferred to a water bath and continued stirring for an additional hour. Ta. After dilution with ethyl acetate, the solution was diluted with saturated aqueous sodium bicarbonate, 5% Washed successively with aqueous citric acid solution, water (x2) and saline, dried and then , concentrated in vacuo. The residue was chromatographed on Nori gel at 20°C. Aluminum chloride in Nisole (0,9 ml) and dry dichloromethane (0,5 ml) (22 mg, 0.17 mmol) was added and stirred for 15 minutes. Then, After lowering the temperature of the cooling bath to -40°C, (6 R,73)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methane quiniminoacetamide]-3-[(2S)-2,3-dihydrobenzofuran -2-yl]-1-calper 1-butiacefer 3-nimo 4-carboxylic acid 4- Methoxybennol (33 mg, 0.055 ma+ol) was added. 15 minutes later, The solution was treated with trisodium citrate (0.5M, 1.7ml) and then Stir vigorously for 10 minutes at room temperature. Separate the aqueous phase and wash twice with dichloromethane. and then concentrated in vacuo.

The residue was chromatographed on HP2OSS and then in water. Eluted with 1.2.4.8.10.15 and 20% THF. contains a product Fractions (h, p, 1.c, analysis) were combined, concentrated, and freeze-dried. The title compound was obtained (20 mg, 77%): v., (KBr) 1751. 1664.1597.1530.1480.1388.1232 and 1039 cr'; δh (da DMS○) 1.48 (IH, m), 1.80 (LH, m ), 2.02-2.15 (2H, m), 2.92 (LH, dd, J16.2.8 ．． 4Hz), 3.38 (IH, dd, J 16.2.9.6Hz), 3.68 ( LH, m), 3.81 (3H, s), 5.28 (IH, dd, J8.6.4.9 Hz), 6.10 (IH, ddj9.6.8.4Hz), 6.66-6.83 ( 3H, m), 7.07 (L H, m), 7.14-7.26 (3H, m) and 9.22 (LH, dj8.6Hz): m/z (F, AB, +ve ion, trig 505 (MH'), 528 (MNa).

Continuation of front page (51) Int, C1,6 identification symbol Internal office reference number C07D405/12 205 7602-4C409/12 205 7602-4C (72) Inventor Gasson, Pryon Charles British R.H. 3.7E Igiei, Bethchworth, Brockham Park (no street address shown) Smith Cry Beecham Pharmacy Powers I (72) Inventor: Naylor, Antoinette UK Leigh R.H. 3 ・7 Agee, Betschworth, Brotscombe Park (no address displayed) Smith Klein Beecham Pharmacy Rikiles

Claims (14)

[Claims] 1. Formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R1 is hydrogen, methoxy or is formamide; R2 is an acyl group; CO2R3 is a carboxy group or a carboxylate anion, or R3 can be easily removed. a carboxy protecting group or a pharmaceutically acceptable salt forming group or an in vivo reaction. is a water-decomposable ester group; X is S, SO, SO2 or CH2; R4 is ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ is a bicyclic group represented by, m is 1 or 2; one of Y or Z is , O, S, SO or SO2, the other is CH2, and R4 is unsubstituted Alkyl, alkenyl, alkynyl, alkoxy, hydro xy, halogen, amino, alkylamino, acylamino, dialkylamino, CO2R, OCOR, CONR2, SO2NR2 (where R is hydrogen or one or more same or different selected from aryl and heterocycle The substituent R5 may have an optional substituent R5 on the bicyclic ring system. Any R5 alkyl substituent may be present on any carbon atom in , optionally selecting R5 in place of any hydrogen atom in the bicyclic system. optionally substituted with one or more substituents selected from the list compound or its salt. 2. The compound represented by formula (I) according to claim 1, wherein X is S or CH2, and R1 is hydrogen. compound. 3. R2NH is 2-(2-aminothiazol-4-yl]-2-(Z)-methoxy The compound represented by formula (I) according to claim 1 or 2, which is shiiminoacetamide. . 4. In the bicyclic substituent R4, one of Y or Z is O or S. A compound represented by formula (I) according to any one of claims 1, 2, and 3. 5. R4 is dihydrobenzofuranyl, dihydroisobenzofuranyl, dihydrothi selected from anaphthyl and dihydroxanaphthyl, such group being represented by R4. cephalometric ring by any available ring position in the 5- or 6-membered heterocyclic ring. 5. The compound of formula (I) according to claim 4, which binds to the sporin nucleus. 6. Formula (I) according to claim 5, wherein R4 is unsubstituted dihydrobenzofuran-2-yl. ). 7. (6R,7S)-7-[2-(2-aminothiazol-4-yl)-2-( Z)-methoxyiminoacetamide]-3-[(S)-dihydrobenzofuran- 2-yl]cepha-3-em-4-carboxylic acid, and (6R,7S)-7- [2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoer Cetamido]-3-[(2S)-2,3-dihydrobenzofuran-2-yl]- Claim selected from 1-carba-1-dethiacepha-3-em-4-carboxylic acid A compound represented by formula (I) according to item 1. 8. Formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) [In the formula, R1, CO2R3 and R 4 is the same as defined above, any reactive group may be protected, and amino The group may be optionally substituted with a group capable of effecting acylation. stomach] A compound represented by formula (III): R2-OH (III) [In the formula, R2 is the same acyl group as defined in formula (I), and any reactivity groups may also be protected] or its N-acylated derivative, and then, if desired, the following Below process: i) removing any protecting groups; ii) converting the group CO2R3 into another group CO2R3; iii) converting the group R2 into another group CO2R3; iv) converting the groups X and/or Y and/or Z into groups R2; to the groups X and/or Y and/or Z, for example S to SO or SO2 one or more of the following steps; v) converting the product into a salt or an ester; A compound of formula (I) according to claim 1, characterized in that the above steps are carried out. Production method. 9. A compound represented by formula (II) according to claim 8, or formula (V): ▲ Formula, There are chemical formulas, tables, etc. ▼ Compounds represented by (V) or formula (VI): ▲ Number There are formulas, chemical formulas, tables, etc.▼(VI) [In the formula, R21 and R22 are amino is a protecting group] or formula (VII): ▲ Numerical formula, chemical formula, table etc. ▼ Compound represented by (VII) or formula (VIII): ▲ Formula , chemical formulas, tables, etc. ▼ Compounds represented by (VIII) or formula (IX ): ▲ Contains mathematical formulas, chemical formulas, tables, etc. ▼ (IX) [In the formula, R31 is the group R3, or or a group that can be converted to R3 or substituted by R3] A compound represented by or formula (X): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(X ) [wherein R is an organic hydrocarbon group] or a compound represented by the formula (XI ): ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Compound shown by (XI). 10. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof or in A medicament consisting of a viVo hydrolyzable ester and a pharmaceutically acceptable carrier Composition. 11. A compound of formula (I) or a pharmaceutically acceptable compound thereof useful as a therapeutic agent salts or in vivo hydrolyzable esters. 12. Compounds of formula (I) or medicaments thereof useful for treating bacterial infections -acceptable salts or in-vivo hydrolyzable esters. 13. The compound represented by formula (I) or its pharmaceutically acceptable in vivo A method for administering a therapeutically effective amount of a hydrolyzable ester to a human and Methods for treating bacterial infections in animals. 14. Compounds represented by formula (I) or the like for the production of therapeutic agents for bacterial infections Use of pharmaceutically acceptable salts or in vitro hydrolyzable esters of .