JPH11514981A - Pyrrolidine and thiazole derivatives with antibacterial and metallo-β-lactamase inhibitory properties - Google Patents

Abstract

SUMMARY OF THE INVENTION The present invention provides a β-lactam antibiotic which comprises converting a therapeutically effective amount of a thiazolidine or proline derivative of formula (I) or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof to a β-lactam antibiotic. And a method for treating a bacterial infection in a human or animal. Compounds (IA) within the scope of formula (I) are also claimed. In formula (I), X is S, S (O) n or CH ₂ ; n is 1 or 2; R is hydrogen, a salt-forming cation, or an ester-forming group that hydrolyzes in vivo; R ₁ and R ₂ are each hydrogen or an organic substituent; R ₃ is hydrogen, (C _1-6 ) alkyl, (C _2-6 ) alkenyl optionally substituted with up to 3 halogen atoms, ( C _2-6 ) alkynyl, aryl, aryl (C _1-6 ) alkyl, heterocyclyl or heterocyclyl (C _1-6 ) alkyl; and R ₄ is hydrogen or an acyl group which is hydrolyzed in vivo Means In compounds (IA), R ₃ ¹ is substituted with a halogen atom up to three (C _1-6) alkyl, aryl, aryl (C _1-6) alkyl, heterocyclyl or heterocyclyl (C _{1- 6} ) is alkyl; and X means S.

Description

DETAILED DESCRIPTION OF THE INVENTION Pyrrolidine and thiazo with antibacterial and metallo-β-lactamase inhibitory properties Diol derivative   The present invention relates to compounds having metallo-β-lactamase inhibitory and antibacterial properties. I do. The present invention also provides a method for producing such compounds, pharmaceutical compositions containing them, and And their use.   Metallo-β-lactamases are numerous β-lactamases, including carbapenems. Adds resistance to tom-based treatments and threatens future use of all such substances Has become. Increased use of carbapenem and other β-lactam antibiotics As a result, the clinical situation is that clinical strains producing metallo-β-lactamase survive Metallo-β-lactamases are now available in Bacillus ・ Fragilis (Bacillus fragilis), Klebsiella, Pseudomona Pseudomonas aeruginosa and Serratia marcessens (Serratia marcescens) has been identified in common pathogens. New knowledge At first glance, metallo-β-lactamases represent a critical aspect for antimicrobial chemotherapy Emphasis on having the potential to   US4046889, US4105776, US4307113, US431 6906, BE868532, CH63587, J55057561, J55 009060, US4283407, EP0001978, Saunders et al., J. Comp. uter-Aided Molecular Design 1: 133 (1987) and Waller et al., J. Med.Chem. 36: 239. 0 (1993) describe various proline-substituted and thiazolidine compounds with antihypertensive activity. Disclosure.   According to the present invention, in combination with a β-lactam antibiotic, a therapeutically effective amount of the formula ( Compounds of I) or pharmaceutically acceptable salts, solvates or in vivo hydrolysis Bacterial susceptibility in humans or animals comprising administering those esters that Dye treatment methods are provided: [In the formula:   X is S, S (O)_nOr CH_TwoIs;   n is 1 or 2   R is hydrogen, a cation forming salt or an in vivo hydrolyzing ester forming Group;   R₁And R_TwoAre each hydrogen or an organic substituent;   R_ThreeMay be substituted by hydrogen, up to three halogen atoms (C_1-6) Alkyl , (C_2-6) Alkenyl, (C_2-6) Alkynyl, aryl, aryl (C_1-6) Archi , Heterocyclyl or heterocyclyl (C_1-6) Alkyl; and   R_FourIs hydrogen, or an acyl group that hydrolyzes in vivo.   The compounds of formula (I) exist in many isomeric forms, which are racemic and diastereomeric All including the teleoisomeric forms are within the scope of the invention.   The stereochemistry at the carbon atom marked with * is D-, ie S when X = S , X = CH_TwoAnd R₁, R_TwoWhen = H or alkyl, R is preferred. New   Racemic forms of the known compounds of formula (I) and (^*) Of the D- and L-diastereomers Although described for other mixtures, the antihypertensive activity of the compounds is Has been found to be significantly present in Little or no attempt has been made to isolate the major D-isomer.   R_ThreeAryl (C_1-6) Alkyl is optionally substituted benzyl, phenethyl and And phenylpropyl.   R_ThreeIs up to three halogen atoms, aryl, aryl (C_1-6) Alkyl, hetero Cyclyl or heterocyclyl (C_1-6) Alkyl-substituted (C_1-6) Archi And the compounds represented by R_Three ¹Where X is S Are novel and form part of the present specification. R_ThreeIs R_Three ¹And X is S To Compounds of formula (I) are referred to herein as compounds of formula (IA).   R_ThreeIs preferably an optionally substituted benzyl, more preferably benzyl It is.   The preferred stereochemistry at the carbon atom marked (+) is S.   R_FourIs hydrogen, lower alkylcarbonyl, optionally substituted benzoyl or Is preferably an optionally substituted phenyl lower alkylcarbonyl.   R_FourSuitable examples of include hydrogen and acetyl.   In general formula (I), R₁And R_TwoRepresents hydrogen or an organic group. This is via a carbon atom Can be properly connected. For example, R₁Or R_TwoIs hydrogen or a formula -R^Five(R^FiveIs replaced Or not (C_1-10) Which represents a hydrocarbon group).   Preferably, R₁Or R_TwoIs hydrogen or (C_1-10) Alkyl, aryl, hetero Cyclyl or substituted (C_1-10) Alkyl, wherein the substituent is aryl , Heterocyclyl, hydroxyl, (C_1-6) Alkoxy, (C_1-6) Alkanoyloxy , Halogen, mercapto, (C_1-6) Alkylthio, heterocyclylthio, amine No, (mono- or di-)-(C_1-6) Alkylamino, (C_1-6) Alkanoylamino , Carboxy, or (C_1-6) Alkoxycarbonyl.   A suitable organic group R₁And R_TwoExamples are methyl, ethyl, propyl, hydroxymethyl Methoxymethyl, ethoxymethyl, acetoxymethyl, (1 or 2)- Toxiethyl, aminomethyl, 2-aminoethyl, acetamidomethyl, 2-A Cetamidoethyl, carboxymethyl, phenyl, pyridyl, pyrimidyl, and And isoxazolyl.   Especially R₁And R_TwoMay be hydrogen or methyl.   The above (C_1-6) Alkyl, (C_2-6) Alkenyl, (C_2-6) Alkynyl, aryl And aryl (C_1-6Examples of suitable optional substituents of the alkyl substituents include (C)_{1- 6} ) Alkanoyl, (C_1-6) Alkanoyloxy, heterocyclyl, amino, (C_1-6 ) Alkanoylamino, (mono- or di-)-(C_1-6) Alkylamino, hydroxyl Group, (C_1-6) Alkylsulfinyl, (C_1-6) Alkylsulfonyl, heterocyclyl Kurylthio, arylthio, sulfamoyl, carbamoyl, amidino, guani Dino, nitro, halogen, carboxy, carboxy salt, carboxy ester, Includes reelcarbonyl and heterocyclylcarbonyl groups.   X is preferably S.   A carboxylic acid group of a compound of formula (I) (or other Suitable pharmaceutically acceptable salts of (carboxylic acid group) are those wherein R is a metal ion such as aluminum. Salts, alkali metal salts (e.g., sodium, lithium, or potassium salts), Alkaline earth metal salts (e.g. calcium or magnesium salts), ammonium salts, And ammonium salt substitutes such as lower alkylamines (e.g., triethylamine Min), hydroxy lower alkylamine (e.g., 2-hydroxyethylamine), Bis- (2-hydroxyethyl) amine, tris- (2-hydroxyethyl) amine With lower cycloalkylamines (e.g. dicyclohexyl-amine), Or procaine, dibenzylamine, N, N-dibenzyl-ethylenediamine, 1-ephenamine, N-methylmorpholine, N-ethylpiperidine, N-ben Jill-β-phenethylamine, dehydroabiethylamine, ethylenediamine, N , N'-bishydroabiethylethylenediamine, pyridine type bases (for example, Gin, collidine and quinoline), and quaternary ammonium salts And those with other amines that can be used or used.   Pharmaceutically acceptable salts are also optional with any amino or compound of formula (I). Amino-substituted or heterocyclic cyclic nitrogen atom capable of being substituted Acid addition salts may be used. Suitable salts include, for example, hydrochloride, sulfate, hydrogen sulfate, acetate, And other pharmaceutically acceptable salts, including phosphates and the like, will be apparent to those skilled in the art. . Suitable acid addition salts are hydrochlorides and bisulfates.   A preferred salt is the sodium salt.   Examples of suitable pharmaceutically acceptable in vivo hydrolyzing ester-forming groups R are Easily decomposes in the body to form esters liberated from the parent acid or its salts. Including. Suitable radicals of this type are the sub-formulas (i), (ii), (iii), (iv) and And (v) include: (Where R^aIs hydrogen, (C_1-6) Alkyl, (C_3-7) Cycloalkyl, methyl, or Phenyl and R^bIs (C_1-6) Alkyl, (C_1-6) Alkoxy, phenyl, ben Jill, (C_3-7) Cycloalkyl, (C_3-7) Cycloalkyloxy, (C_1-6) Archi Le (C_3-7) Cycloalkyl, 1-amino (C_1-6) Alkyl, or 1- (C_1-6Al Kill) amino (C_1-6) Is alkyl; or R^aAnd R^bAre 1 if desired Or forming a 1,2-phenylene group substituted by two methoxy groups;^cIs Optionally substituted with a methyl or ethyl group (C_1-6) Represents alkylene;^dYou And R^eSeparately (C_1-6) Represents alkyl;^fIs (C_1-6) Represents alkyl;^gIs Hydrogen or halogen, (C_1-6) Alkyl, or (C_1-6) Select from alkoxy Represents phenyl optionally substituted with up to three groups; Q is oxygen or NH R^hIs hydrogen or (C_1-6) Is alkyl;ⁱIs hydrogen or halogen (C_1-6) Alkyl, (C_2-6) Alkenyl, (C_1-6) Alkoxyka Or carbonyl, aryl, or heteroaryl; or^hAnd RⁱIs To (C_1-6) Forms an alkylene;^jIs hydrogen, (C_1-6) Alkyl, or (C_1-6) Represents alkoxycarbonyl; and R^kIs (C_1-8) Alkyl, (C_1-8A) Lucoxy, (C_1-6) Alkoxy (C_1-6) Represents alkoxy or aryl).   Examples of suitable in vivo hydrolyzing ester-forming groups include, for example, acetoxime Tyl, pivaloyloxymethyl, α-acetoxyethyl, α-pivaloyloxy Ethyl, 1- (cyclohexylcarbonyloxy) prop-1-yl, and (1 An acyloxyalkyl group such as -aminoethyl) carbonyloxymethyl; Ethoxycarbonyloxymethyl, α-ethoxycarbonyloxyethyl and Alkoxycarbonyloxyalkyl, such as ropoxycarbonyloxyethyl Groups: dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or Is dialkylaminoalkyl such as diethylaminoethyl, especially di-lower Alkylaminoalkyl group; 2- (isobutoxycarbonyl) pent-2-enyl and And 2- (alkoxycarbonyl) such as 2- (ethoxycarbonyl) but-2-enyl Bonyl) -2-alkenyl groups; and phthalidyl and dimethoxyphthalidyl Lactone groups.   Further suitable pharmaceutically acceptable, in vivo hydrolyzing ester-forming groups are: formula: (Where R^kIs hydrogen, C_1-6Alkyl or phenyl) Is a group represented by   Preferably, R is hydrogen.   As used herein, the term "aryl" refers to up to five, preferably three, Up to halogen, mercapto, (C_1-6) Alkyl, phenyl, (C_1-6) Alkoki Si, hydroxy (C_1-6) Alkyl, mercapto (C_1-6) Alkyl, halo (C_1-6A) Alkyl, hydroxyl, amino, nitro, carboxy, (C_1-6) Alkylcarbonyl Xy, alkoxycarbonyl, formyl, or (C_1-6) Alkylcarbonyl group From Includes phenyl and naphthyl which may be substituted with a selected group.   As used herein, the terms "heterocyclyl" and "heterocycle" refer to each ring. Suitably containing up to four heteroatoms selected from oxygen, nitrogen and sulfur; Includes aromatic and non-aromatic, single and fused rings, wherein the rings are, for example, halogenated , (C_1-6) Alkyl, (C_1-6) Alkoxy, halo (C_1-6) Alkyl, hydroxyl, Ruboxy, carboxy salt, (C_1-6) Alkoxycarbonyl, (C_1-6) Alkoxyka Rubonil (C_1-6) Carboxyes such as alkyl, aryl, and oxo groups It may or may not be substituted with up to three groups selected from tell. Each heterocycle is from 4 It suitably has 7, preferably 5 or 6 ring atoms. "Heteroaryl" The term refers to heteroatom heterocycles, suitably having 5 or 6 ring atoms in each ring. Or ring system. Fused heterocyclic systems can include carbocycles and include only one heterocycle. Must be included. Compounds within the scope of the present invention that contain a heterocyclyl group include: Can be in two or more tautomeric forms, depending on the nature of the heterocyclyl group All such tautomeric forms are within the scope of the present invention.   As used herein, “lower alkyl”, “lower alkenyl”, “lower alkyl” The terms "quinyl" and "aroxy" are methyl, ethyl, propyl and butyi. And straight and branched groups containing 1 to 6 carbon atoms such as When In particular, the alkyl group is methyl.   The term "halogen" as used herein refers to fluorine, chlorine, bromine and iodine. means.   Any carboxy group which may be present as an optional substituent in the compound of formula (I) Pharmaceutically acceptable salts and pharmaceutically acceptable salts, including esters that can be hydrolyzed in vivo Acceptable esters are also understood to be within the scope of the present invention.   Compounds of formulas (I) and (IA) may be crystallized or recrystallized from a solvent such as an organic solvent. Some can. In such cases, a solvate can be formed. Freeze drying Containing solvents, such as hydrates and varying amounts of water, which can be produced by the process Stoichiometric solvates, including compounds, are within the scope of the invention. Formulas (I) and ( The compounds of IA) can be prepared, for example, by dissolving the compounds in water, preferably in a minimum volume of water, Leverage Aqueous solution of di- (C_1-6) Lower aliphatic ketones such as alkyl ketones, or acetyl Tons or ethanol (C_1-6) Can be mixed with water such as alcohol By mixing with an organic solvent, it can be produced in a crystalline form.   The compounds of formulas (I) and (IA) are metallo-β-lactamase inhibitors, Intended for use in pharmaceutical compositions. Therefore, these are substantially pure forms, eg For example, at least 60% pure, more suitable at least 75% pure, preferred Or at least 85% pure, especially at least 95% pure, especially at least pure Preferably, each is provided at a 98% degree (% is based on weight / weight). It will be easily understood. The impure product of the compound is more purely used in pharmaceutical compositions Can be used to produce forms; these less pure products of the compound At least 1%, more suitably the compound of formula (I) or (IA) or a salt thereof, Should be contained at least 5%, preferably 10 to 59%.   Compounds of formula (I) are generally analogous to the methods described in the prior art articles mentioned above. It can be manufactured by a method.   The present invention also provides a process for preparing a compound of formula (IA) as defined above, The method comprises the compound of formula (II):   Is a compound of formula (III): Wherein W is a leaving group and Y is R_Four'S or a group that can be converted to it, R^xIs R Is a carboxylate protecting group;₁', R_Two', R_Three'And R_Four'Is R₁, R_Two, R_Three And R_FourOr a group that converts into it, R, R₁, R_Two, R_ThreeAnd R_FourIs the expression ( IA), if necessary, then Y is R_Four'S, R^x, R₁', R_Two ', R_Three'And / or R, R₁, R_Two, R_ThreeAnd / or R_FourTo the desired R, R₁, R_Two, R_ThreeAnd / or R_FourTo convert each other) Consists of   Suitable ester-forming carboxy other than ester-forming groups that hydrolyze in vivo Protecting group R^xIs a group that can be removed under conventional conditions. R^xSuch groups for Is methyl, ethyl, benzyl, p-methoxybenzyl, benzoylmethyl, p- Nitrobenzyl, 4-pyridylmethyl, 2,2,2-trichloroethyl, 2,2 , 2-Tribromoethyl, t-butyl, t-amyl, allyl, diphenylmethyl , Triphenylmethyl, adamantyl, 2-benzyloxyphenyl, 4-methyl Luthiophenyl, tetrahydrofur-2-yl, tetrahydropyran-2-yl , Pentachlorophenyl, acetonyl, p-toluenesulfonylethyl, meth A group containing xymethyl, silyl, stannyl or phosphorus or a formula -N = CH R⁶(Where R⁶Is aryl or heterocyclyl, or as defined below (An ester radical that can be hydrolyzed in vivo) Include.   Certain compounds of formula (II) and (III) can include an amino group that can be protected. . Suitable amino protecting groups are well known to those skilled in the art and, if necessary, It can be removed under conventional conditions without decomposition.   Examples of amino protecting groups are (C_1-6) Alkanoyl; benzoyl; (C_1-4) Alkyl , (C_1-4) Select from alkoxy, trifluoromethyl, halogen, or nitro Benzyl optionally substituted on the phenyl ring by one or two substituents ; (C_1-4) Alkoxycarbonyl; benzyl substituted as above benzyl Oxycarbonyl or trityl; allyloxycarbonyl, trichloroethoxy Includes cycarbonyl or chloroacetyl.   Compounds of formula (III) may be used such as triethylamine, pyridine or morpholine. It is preferable to provide an anion produced by treating the amine with an organic base. .   The reaction of the compounds of formulas (II) and (III) is carried out at ambient temperature, e.g. Tetrahydrofuran, dichloromethane, dioxane or dimethylformamide It is preferably carried out in an inert solvent such as   Suitable examples of leaving W groups include halo such as chloro and mixed sulfonic anhydrides. For example, in mixed sulfonic anhydride, W is methanesulfonyloxy, toluene -P-sulfonyloxy or trifluoromethanesulfonyloxy This is the case.   R_FourExamples of Y that can be converted to 'S include halo such as bromo and include thiobenzoic acid. Or thioacetic acid.   R₁, R_Two, R_ThreeAnd R_FourR that can be converted to₁', R_Two', R_Three', R_FourExamples of ' A carboxy or amino group is protected by a carboxy or amino protecting group Things.   R of the compound of formula (II)_Four'Is preferably other than hydrogen, for example, acetyl.   The acid derivative of formula (II) is a strong base such as sodium hydroxide, followed by oxa chloride. Treatment with a source of anion leaving group W such as ril to give the corresponding free acid It is preferred to manufacture from.   The reaction product of the compounds of formulas (II) and (III) is a compound of formula (IV):   And the variables are as defined in formulas (II) and (III). R₁', R_Two' , R_Three'And R_Four'Is R₁, R_Two, R_ThreeAnd R_FourIf R^xIs other than R, Novel intermediate products of formula (IV) are also part of the present invention.   R^xIs other than hydrogen, a carboxy group -COOR^xCan be deprotected, ie Free carboxy, carboxy salt or carboxy ester in a customary manner It can be converted to the group -COOR and is described, for example, in EP 0232966A.   It is desirable to obtain from the mixture of isomers the free acid or salt of the preferred isomer of formula (I). The diastereomers of the product can be separated by chromatography. it can. If this is an ester and / or R_Four'Is other than hydrogen The desired isomer can be deprotected to give the corresponding free acid or salt. I However, the isomer mixture is first deprotected to give the free acid or salt of formula (I) Of the desired acid or salt isomers, followed by fractional recrystallization to obtain the desired acid or salt isomer. May have been found to be convenient. X = S and of formula (I)^*S isomer When the body is desired, the corresponding intermediate of formula (III)^*Using the S isomer preferable.   When the enantiomerically pure form of (III) is used for the preparation of (I), the (+) of (I) Preferred diastereomers at positions can also be separated by chromatography . Enantiomerically pure forms of (II) can also be used.   The carboxyl group is a specific R^xThe usual methods suitable for the groups are, for example, acid and And base-catalyzed hydrolysis, or by enzyme-catalyzed hydrolysis, or By hydrogenolysis under conditions where the remaining portion is substantially unaffected. You can play from tell. For example, in the case of acetonyl, 0.1 M in acetonitrile Hydrolysis with aqueous potassium hydroxide solution.   Pharmaceutically acceptable salts may, if necessary, be subjected to the usual work-up, and It can be manufactured by processing with a base. Suitable bases include sodium bicarbonate, sodium Form salt.   The crystalline form of a compound of formula (I) wherein R is a salt-forming cation may be, for example, In a medium, the compound (I) is dissolved at an appropriate environmental temperature, and then ethanol or acetone is added. This time (C_1-6) Add an organic solvent that can be mixed with water such as alcohol or ketone Crystallization occurs at which time, for example, cooling or crushing I can help more.   The compounds of the formulas (II) and (III) are known compounds or It can be manufactured by a method similar to the method described in the technical literature.   Compounds of formula (I), especially (IA), may be used in pharmaceutical compositions together with a pharmaceutically acceptable carrier. It can be administered in the form. The compounds of formula (I) have metallo-β-lactamase inhibitory properties , Animals, particularly mammals, including humans, especially humans and livestock (including livestock). ) Is useful for the treatment of infections. The compounds are, for example, especially It can be used to treat tubal, ureteral, and soft tissue and blood infections.   The compound is an infection caused by a metallo-β-lactamase producing strain, in addition to For the treatment of infections included in the antibacterial spectrum of antibiotic partners, Can be used in combination with biomaterial partners. Metallo-β-lactamers The strain producing strains are: Pseudomonas aeruginosa, Kleb Sierra pneumoniae, Xanthomonas maltofi Rear (Xanthomonas maltophilia), Bacteroides fragilis (Bacteroides fr agilis), Serratia marcescens, Bacteroides Bacteroides distasonis, Pseudodom cepacia onas cepacia), Aeromonas hydrophila, Aeromonas sobria, Aeromonas salmonicida as salmonicida), Bacillus cereus, Legionella gorma Includes legionella (Legionella gormanii) and Flavobacterium species I do.   Compounds according to the present invention may be carbopenem, penicillin, cephalosporin, or It may be admixed with other β-lactam antibiotics or used in combination. Generally excellent, due to the metallo-β-lactamase inhibitory properties of the compounds of the invention. Can have a synergistic effect. In such a case, the compound of formula (I) or (IA) And β-lactam antibiotics can be used separately or as described in detail below. It can be administered in the form of a single composition containing the active ingredient. The composition of the present invention is oral, Including compositions in a form suitable for topical or parenteral use, and Can be used to treat bacterial infections. The compounds of the formulas (I) and (IA) Suitable for buccal administration.   Compounds of formula (I) or (IA) may be analogous to other antibiotics and other Similar to the combination of β-lactam antibiotics / β-lactamase inhibitors To be administered in any manner convenient for use in human or veterinary medicine. Can be prescribed.   The composition can be administered by any route, such as oral, topical or parenteral. Can be prescribed. The composition may be a tablet, capsule, powder, granule, dragee, cream or It can be in the form of a liquid preparation, such as an oral or sterile parenteral solution or suspension. You.   The topical formulations of the present invention include, for example, ointments, creams or lotions, eye ointments and It can be made into eye drops or ear drops, impregnated bandages and aerosols, preservatives, drug Commonly used solvents such as solvents to aid penetration and emollients in ointments and creams Such additives can be included.   The formulation may also be prepared with a cream or ointment base and ethanol or It can also contain compatible conventional carriers such as oleyl alcohol. Such charge The body can be from about 1% to about 98% of the formulation. More usually, up to about 80% of the formulation It is.   Tablets and capsules for oral administration can be presented in unit dosage form, with binders such as Gum, gum arabic, gelatin, sorbitol, tragacanth, or polyvinyl Lupyrrolidone; fillers such as lactose, sugar, corn starch, potassium phosphate Lucium, sorbitol or glycine; tableting lubricants such as Gnesium, talc, polyethylene glycol or silica; disintegrants such as di Potato starch; or an acceptable wetting agent such as sodium lauryl sulfate Excipients that are sometimes used can be included. Tablets are well-known in normal pharmaceutical manufacturing Coating can be performed according to the law. Oral liquid preparations include, for example, aqueous or oily suspensions. Can be in the form of a liquid, solution, emulsion, syrup or elixir or used Can be provided as a dry product prior to reconstitution with water or other suitable excipient You. Such liquid preparations may contain suspending agents such as sorbitol, methylcellulose, glue. Coarse syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose Lurose, aluminum stearate gel or hydrogenated edible fats, emulsifiers such as Lecithin, sorbitan monooleate or gum arabic; non-aqueous vehicle (edible oil For example, almond oil, glycerin, propylene glycol, Or oily esters such as ethyl alcohol; preservatives such as methyl or Ropyl p-hydroxybenzoate or sorbic acid and, if desired, commonly used Conventional additives such as flavoring agents or coloring agents.   Suppositories may be any conventional suppository base such as cocoa butter or other glycerides It contains.   For parenteral administration, liquid unit dosage forms are the compound and sterile vehicle, preferably Is prepared using water. Depending on the vehicle and concentration used, the compound may be Can be suspended or dissolved. When preparing solutions, dissolve the compound in water for injection and destroy. After bacterial filtration, the vial or ampoule can be filled and sealed.   Advantageously, substances such as a local anaesthetic, preservative and buffering agents are dissolved in the vehicle. can do. After filling the vial with the composition to increase stability, freeze Then, water can be removed under reduced pressure. The lyophilized powder is then sealed in the vial and poured. A vial of water for injection can be added and supplied to reconstitute the liquid prior to use. Parenteral Suspensions can be suspended in excipients instead of dissolving the compound and sterilized by filtration. Prepared in substantially the same way except without it. Before suspending in sterile vehicle, The compound can be sterilized by exposure to lenoxide. Advantageously, the interface An active agent or wetting agent is included in the composition to facilitate even distribution of the compound. .   The compositions may contain from 0.1% by weight of active substance, preferably from 10 to 6%, depending on the method of administration. 0% by weight can be contained. Where the composition comprises dosage units, each unit may contain 5 of the active ingredient. It is preferable to contain 0 to 500 mg. The dose used for treatment of adult humans is The dose is preferably in the range of 100 to 3000 mg, depending on the administration route and frequency. For example, 1500 mg per day. Such a dose is 1.5-5 per day This corresponds to 0 mg / kg. The dosage should be 5-20 mg / kg per day. That's right.   Compounds of formula (I) or (IA) or their pharmaceutically acceptable at the above dosage ranges No toxic effect was observed when the salt was administered.   The composition according to the present invention comprises one or more compounds of the formula (I) or (IA). Active ingredients or therapeutic agents, such as carbapenem, penicillin or cephalo Included with β-lactam antibiotics such as sporin or their prodrugs May be. Is unstable or so to metallo-β-lactamase Otherwise known to be sensitive, and metallo-β-lactamers Carbape, both of which are also known to have some resistance to ze Nem, penicillin, cephalosporins and other β-lactam antibiotics are Whether administered separately or included in a composition according to the present invention, Formula (I) or Is suitable for co-administration with a compound of (IA).   Serine β-lactam such as clavulanic acid, sulbactam or tazobactam The protease inhibitor may also be administered separately from the compound of the invention and the β-lactam antibiotic. Or one of the other of the compound of the present invention and a β-lactam antibiotic. Alternatively, they can be administered simultaneously by co-formulation with both.   Examples of carbapenems which can be co-administered with the compounds according to the invention include imipenem, melo Penem, viapenem, BMS181139 ([4R- [4α, 5β, 6β (R^*)]] − 4- [2-[(aminoiminomethyl) amino] ethyl] -3-[(2-cyanoethyl) thio E] -6- (1-Hydroxyethyl) -7-oxo-1-azabicyclo [3^*.2.0] Hept-2-ene-2-carboxylic acid), BO2727 ([4R-3 [3S, 5S^*(R^* )], 4α, 5β, 6β (R^*)]]-6- (1-Hydroxyethyl) -3-[[5- [1 -Hydroxy-3- (methylamino) propyl] -3-pyrrolidinyl] thio] -4- Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-en-2-cal Boric acid monohydrochloride), ER35786 ((1R, 5S, 6S) -6- [ 1 (R) -hydroxymethyl] -2- [2 (S)-[1 (R) -hydroxy-1- [pyrroli Zin-3 (R) -yl] methyl] pyrrolidin-4 (S) -ylsulfanyl] -1-me Tyl-1-carba-2-penem-3-carboxylic acid hydrochloride) and S 4661 ((1R, 5S, 6S) -2-[(3S, 5S) -5- (sulfamoylamido) Nomethyl) pyrrolidin-3-yl] thio-6-[(1R) -1-hydroxyethyl]- 1-methylcarbapene-2-em-3-carboxylic acid).   An example of a penicillin suitable for co-administration with a compound according to the invention is benzylpea. Nicilin, phenoxymethylpenicillin, carbenicillin, azidocillin, pro Picillin, ampicillin, amoxicillin, epicillin, ticarcillin, cycla Syrin, pyrbenicillin, azlocillin, mezlocillin, sulbenicillin, pepe Includes racillin, and other known penicillins. Penicillin Esters that hydrolyze in vivo in the form of lodrugs, such as ampicide Phosphorus, benzylpenicillin and amoxicillin acetoxymethyl, pivaloy Ruoxymethyl, a-ethoxycarbonyloxyethyl and phthalidyl ester Aldehyde of penicillin containing 6-α-aminoacetamide side chain Or ketone adducts (e.g., hetacillin, methampicillin and amoxicillin And carbenicillin and ticarcillin α-d Stels, such as phenyl and indanyl α-esters You.   Examples of cephalosporins which can be co-administered with the compounds according to the invention are cephatrizine Cephalorizine, cephalotin, cefazolin, cephalexin, cefaseline Tolyl, cefapirine, cefamandole nafate, cefradine, 4-hydro Xisephalexin, cephaloglysin, cefoperazone, cefsulosin, cef Tajidim, cefuroxime, cefmetazole, ceftoxime, ceftriaxone , And other known cephalosporins, all of which are It can be used in the form of a drug.   Other than penicillin and cephalosporin which can be co-administered with the compounds according to the invention Examples of β-lactam antibiotics are Aztreonam, Latamoxef (Moxalactam- Trademark), and other known β-lactam antibiotics, all of which are They can be used in the form of a prodrug.   Penicillins which are particularly suitable for co-administration with the compounds according to the invention are Sylin, amoxicillin, carbenicillin, piperacillin, azlocillin, mez Includes rocillin, and ticarcillin. Such penicillins are pharmaceutically acceptable Salts, for example, their sodium salts. In addition, Ampicillin and amoxicillin are in the form of zwitterionic fine particles (generally (As ampicillin trihydrate or amoxacillin trihydrate) To injectable or injectable suspensions in the manner described above in connection with the compounds according to Can be used to use. For example in the form of sodium salt or trihydrate Amoxicillin is particularly preferred for synergistic use with the composition according to the invention.   Cephalosporins particularly suitable for co-administration with the compounds according to the invention are cephalosporins. Pharmaceutically acceptable salts, including fotaxime and ceftazidime, such as These can be used in the form of their sodium salts.   The compound of formula (I) or (IA) is a synergistically effective amount of carbapenem, penicillin Or in combination with a β-lactam antibiotic such as cephalosporin Can be given.   Compounds of formula (I) or (IA) are treated at a daily dose of 0.7 to 50 mg / kg body weight. It is appropriate to administer to a person. In a human adult (about 70 kg in weight), 50-3000 mg, preferably 100-1000 mg, of the compound It can be administered daily in 6 divided doses, preferably 2 to 4 doses. However, high dose Or lower doses can be used depending on the clinical situation.   When the composition according to the present invention is provided in unit dosage form, each dosage unit is in accordance with the present invention. Suitably from 25 to 1000 mg of the compound Preferably it comprises 0 mg. Each dosage unit is, for example, a compound 6 according to the invention. It can be 2.5, 100, 125, 150, 200 or 250 mg.   Converting a compound of formula (I) or (IA) to penicillin, cephalosporin, carbapenem Or a compound according to the invention when co-administered with another β-lactam antibiotic The ratio of the amount to the other β-lactam antibiotic amount can vary widely. The ratio The ratio can be, for example, from 100: 1 to 1: 100, and more particularly, for example, 2: 1. From 1:30.   Carbapenem, penicillin, cef in a synergistic composition according to the invention The amount of arosporin or other β-lactam antibiotics is usually About 50 mg per unit dose, about 62.5 m g to about 3000 mg, more usually about 30 mg per unit dose. 125, 250, 500 or 1000 mg.   The invention further provides a compound of formula (I) or a compound thereof for use in the treatment of a bacterial infection. Their pharmaceutically acceptable salts, solvents or esters that hydrolyze in vivo, Thus, there is provided a compound of formula (IA).   The invention also relates to a method of preparing a medicament for use in treating a bacterial infection, comprising the steps of: Compounds of (I) or their pharmaceutically acceptable salts, solvents or water in vivo Including the use of esters which are cleaved.   The present invention also provides compounds of formula (I) as metallo-β-lactamase inhibitors Or a pharmaceutically acceptable salt, solvent, or in vivo hydrolysable ester thereof. Includes the use of   In a further aspect, the invention provides a carbapenem antibiotic, a therapeutically effective amount of meta Consisting of administration in combination with a b-beta-lactamase inhibitor, Provide methods for treating bacterial infections in animals.   The invention further provides a therapeutically effective amount in the manufacture of a medicament for the treatment of a bacterial infection. Use of a carbapenem antibiotic in combination with a metallo-β-lactamase inhibitor Provide for.   Further compositions according to the invention are carbapenem antibiotics and pharmaceutically acceptable A metallo-β-lactamase inhibitor together with a carrier.   Such methods and compositions may be administered as described above for use of the compounds of formula (I). it can.   All of the above compositions and methods may optionally include a serine β-la A cutamase can be included.   The compounds of the present invention include both Gram-negative and Gram-positive microorganisms Active against metallo-β-lactamase enzymes produced by a wide range of microorganisms You.   The following examples illustrate compounds useful in the present invention, and intermediate products in their preparation. It describes things. (All temperatures are in ° C.). Example Example 1 3- [S-acetyl-2 '(RS) -benzyl-3'-mercaptopropionyl] -4 (S) -carboxy-5,5-dimethylthiazolidine (E1)   Dry tetrahydrofuran (8 ml) containing dry dimethylformamide (1 drop) Medium, S-acetyl-2-benzyl-3-mercaptopropionic acid (EP0361 3 65) (476 mg, 2.0 mmol) was cooled (0 ° C.) and stirred with water Sodium iodide (88 mg of a 55% suspension in oil, 2.0 mmol) was added. reaction The mixture was allowed to reach room temperature and stirring was continued for a further 15 minutes. Then the suspension Cool again (0 ° C.), treat with oxalyl chloride (210 μl, 2.4 mmol) and allow Stirred at warm for 30 minutes. The mixture obtained is then evaporated under reduced pressure and the residue is dried. Suspended in dry tetrahydrofuran (5 ml). The filtered solution is dried again to give an oil The acid chloride was obtained.   4 (S) -Carboxy-5,5-dimethyl in dry tetrahydrofuran (10 ml) Ruthiazolidine (J. Am. Chem. Soc., 71: 1137 (1949)) (161 mg, 1.0 mmol) The suspension was stirred and cooled (0 ° C.), and triethylamine (278 μl, 2. 0 mmol), followed by dry tetrahydrofuran (5 ml) of the above acid chloride. ) Solution was added and treated for 5 minutes. The mixture was stirred at room temperature for 3 hours and then ethyl acetate And 1 M hydrochloric acid. Wash the organic layer with water and saturated saline solution, dry Dried over sodium sulfate. Evaporation of the solvent gave an oily crude product which was It was subjected to chromatography. 4% medium in chloroform containing 0.1% acetic acid Eluted with ethanol, displaced the propionic acid starting material, followed by a crisp foam (c The diastereomer mixture (1: 1) (312 mg, 82%) Received. σ_H(CDCl_Three) (Isomer 1) 1.12 (3H, s), 1.41 (3H, s), 2. 34 (3H, s), 2.8-3.2 (5H, overlapping m), 3.93 (1H, d , J 8.0 Hz), 4.35 (1 H, s), 4.61 (1 H, d, J 8.0 Hz), 7.2-7 .3 (5H, m). (Isomer 2) 1.43 (3H, s), 1.56 (3H, s), 2.34 (3H, s) , s), 2.8-3.2 (5H, overlapping m), 4.01 (1H, d, J8.4) Hz), 4.55 (1H, s), 4.59 (1H, d, J 8.4 Hz), 7.2-7.3 (5H , m) ppm. Example 2: 3- [2 '(RS) -benzyl-3'-mercaptopropionyl] -4 (S) -carboxy C-5,5-dimethylthiazolidine (E2)   The S-acetyl derivative E1 (203 mg, 0.53 mmol) was added to water (0.6 ml) and And concentrated aqueous ammonia (0.4 ml, specific gravity 0.88) and stirred at room temperature for 1 hour. . The reaction mixture is diluted with ethyl acetate, washed with sufficiently diluted hydrochloric acid, and the aqueous phase is acidified. I made it. Treat the two-phase system with saturated saline solution, separate the organic phase and wash with more saline solution Clean, dry over sodium sulfate and evaporate to a crisp foam mark. The title diastereomer mixture was obtained (170 mg, 94%). ν_max(CHCl_Three) 1 740, 1719, 1641, 1443, 1425cm^-1. σ_H(CDCl_Three) (Different 1) 1.20 (3H, s), 1.43 (3H, s), 1.91 (1H, dd, J11.5 And 6.3 Hz), 2.55 (1 H, m), 2.75-3.15 (4 H, overlap M), 4.04 (1 H, d, J 8.1 Hz), 4.38 (1 H, s), 4.84 (1 H, d , J 8.1 Hz), 7.2-7.3 (5H, m). (Isomer 2) 1.46 (3H, s), 1.5 8 (3H, s), 2.05 (1H, s), 2.55 (1H, m), 2.75-3.15 (4H, Overlapping m), 4.20 (1H, d, J 8.1 Hz), 4.62 (1H, s), 4.81 (1H, d, J 8.1 Hz), 7.2-7.3 (5H, m) ppm. EIMS M⁺ 339. DCIMS MH⁺340. 3- [2 '(RS) -benzyl-3'-mercaptopropionyl] -4 by HPLC Separation of diastereomers of (S) -carboxy-5,5-dimethylthiazolidine   The diastereomer mixture of Example 2 was prepared using Hypersil BDS C8 (250 mm × 4. 6%) column and 0.1% trifluoroacetic acid / 0.1% toluene in acetonitrile. Elution was carried out uniformly with trifluoroacetic acid 70/30 at a flow rate of 0.8 ml / min. 215n m. Under these conditions, the (2′R, 4S) -diastereomer R_tIs 31.3 minutes, and R of the (2 ′S, 4S) -diastereomer_tWas 35.1 minutes . These diastereomers correspond to compounds E19 and 19 of Examples 19 and 20, respectively. It was the same as E20. Example 3 N- [S-acetyl-3'-mercapto-2 '(RS) -methylpropionyl] -D- Proline (E3)   Dry tetrahydrofuran (8 ml) containing dry dimethylformamide (1 drop) Medium, S-acetyl-2-methyl-3-mercaptopropionic acid (US Pat. 8 9) A solution of (324 mg, 2.0 mmol) was cooled (0 ° C.) and stirred, Sodium bromide (88 mg of a 55% suspension in oil, 2.0 mmol) was added. Reaction mixture The mixture was allowed to reach room temperature and stirring was continued for a further 15 minutes. Then resuspend the suspension Cooled (0 ° C.), treated with oxalyl chloride (210 μl, 2.4 mmol), room temperature For 30 minutes. The resulting mixture is then evaporated under reduced pressure and the residue is dried Suspended in tetrahydrofuran (5 ml). The filtered solution is dried again and the oily An acid chloride was obtained.   D-proline (230 mg, 2.0 mm) in dry tetrahydrofuran (10 ml) Mol) was cooled and cooled (0 ° C.) to give triethylamine (556 μl). 4.0 mmol), followed by dry tetrahydrofuran of the above acid chloride ( 5 ml) solution and treated for 5 minutes. The mixture was stirred at room temperature for 18 hours, then Partitioned between ethyl acetate and 1M hydrochloric acid. Wash organic layer with water and saturated saline solution And dried over anhydrous sodium sulfate. The solvent was evaporated to give an oily crude product, Kagel was subjected to chromatography. Chloroform containing 0.1% acetic acid Eluting with 4% methanol in methanol, followed by substitution of the propionic acid starting material followed by a colorless oil The title compound (180 mg, 35%) was recovered. Example 4: N- [3'-mercapto-2 '(RS) -methylpropionyl] -D-proline (E4)   The S-acetyl derivative E3 (155 mg, 0.60 mmol) was added to water (0.6 ml) and And concentrated aqueous ammonia (0.4 ml, specific gravity 0.88) and stirred at room temperature for 1 hour. . The reaction mixture is diluted with ethyl acetate, washed with sufficiently diluted hydrochloric acid, and the aqueous phase is acidified. I made it. Treat the two-phase system with saturated saline solution, separate the organic phase and wash with more saline solution , Dried over sodium sulfate and evaporated to give the title compound as a colorless oil (11 0 mg, 85%). ν_max(CHCl_Three1749, 1720, 1635, 1590 cm^-1. σ_H(CDCl_Three) (Isomer 1) 1.21 (3H, d, J 6.8 Hz), 1.67 (1 H, dd, J 10.1 and 7.4 Hz), 2.05-2.15 (3H, overlap M), 2.4-2.55 (2H, overlapping m), 2.8-3.0 (2H, Overlapping m), 3.52 (1H, m), 3.84 (1H, m), 4.66 (1H, m dd, J7.7 and 2.6 Hz). (Isomer 2) 1.23 (3H, d, J 6.8 Hz), 1 .56 (1H, dd, J8.6 and 8.6 Hz), 2.05-2.15 (3H, over Wrapping m), 2.4-2.55 (2H, overlapping wrapping m), 2.8-3.0 ( 2H, overlapping m), 3.65 (2H, overlapping m), 4.6 1 (1H, dd, J8 and 3 Hz) ppm. EIMS M⁺217. DCIMS M H⁺218. Example 5: N- (S-acetyl-3'-mercapto-2 '(S) -methylpropionyl) -D- Lorin (E5)   Dry tetrahydrofuran (8 ml) containing dry dimethylformamide (1 drop) Medium, S-acetyl-3-mercapto-2 (S) -methylpropionic acid (Jansen Cool solution (0 ° C.) of Chemica, Gir, Belgium) (324 mg, 2.0 mmol) The stirred solution was charged with sodium hydride (88 mg of a 55% suspension in oil, 2.0 ml). Lmol) was added. The reaction mixture is left to reach room temperature and stirred for a further 15 minutes. Continued. The suspension was then cooled again (0 ° C.) and oxalyl chloride (210 μl, 2.4 Mmol) and stirred at room temperature for 30 minutes. The resulting mixture is then And the residue was suspended in dry tetrahydrofuran (5 ml). Filtered The solution was dried again to give an oily acid chloride.   D-proline (230 mg, 2.0 mm) in dry tetrahydrofuran (10 ml) Mol) was cooled and cooled (0 ° C.) to give triethylamine (556 μl). 4.0 mmol), followed by dry tetrahydrofuran of the above acid chloride ( 5 ml) solution and treated for 5 minutes. The mixture was stirred at room temperature for 18 hours, then Partitioned between ethyl acetate and 1M hydrochloric acid. Wash organic layer with water and saturated saline solution And dried over anhydrous sodium sulfate. The solvent was evaporated to give an oily crude product, Kagel was subjected to chromatography. Chloroform containing 0.1% acetic acid Eluting with 4% methanol in methanol, followed by substitution of the propionic acid starting material followed by a colorless oil The title compound (119 mg, 23%) was recovered. σ_H(CDCl_Three) 1.23 (3H, d, J6.5Hz), 2.0 (3H, overlapping) M), 2.34 (3H, s), 2.45 (1H, m), 2.92 (1H, m), 2.96 (1 H, dd, J13.0 and 6.5 Hz), 3.14 (1H, dd, J13.0 and 7. 3 Hz), 3.48 (1 H, s), 3.76 (1 H, m), 4.58 (1 H, m) ppm. D CIMS MH⁺260. Example 6: N- (3'-mercapto-2 '(S) -methylpropionyl) -D-proline (E6)   The S-acetyl derivative E5 (102 mg, 0.39 mmol) was added to water (0.6 ml) and And concentrated aqueous ammonia (0.4 ml, specific gravity 0.88) and stirred at room temperature for 1 hour. . The reaction mixture is diluted with ethyl acetate, washed with sufficiently diluted hydrochloric acid, and the aqueous phase is acidified. I made it. Treat the two-phase system with saturated saline solution, separate the organic phase and wash with more saline solution , Dried over sodium sulfate and evaporated to give the title compound as a colorless oil (71 mg, 85%). ν_max(CHCl_Three) 1751, 1719, 1636, 1586c m^-1. σ_H(CDCl_Three) 1.21 (3H, d, J6.7 Hz), 1.70 (1H, dd, J1) 0.2 and 7.3 Hz), 2.05-2.15 (3H, overlapping m), 2. 4-2.55 (2H, overlapping m), 2.8-3.0 (2H, overlapping m) Ping m), 3.53 (1H, m), 3.84 (1H, m), 4.76 (1H, dd, J7.8 And 3.5 Hz) ppm. EIMS M⁺217. DCIMS MH⁺218. Example 7: 3- [S-acetyl-3'-mercaptopropionyl] -4 (S) -carboxy-5, 5-dimethylthiazolidine (E7)   Dry tetrahydrofuran (8 ml) containing dry dimethylformamide (1 drop) Medium, S-acetyl-3-mercaptopropionic acid (according to the method of EP 0361365) (Prepared analogously to the starting material of Example 1) (148 mg, 1.0 mmol) The solution was cooled (0 ° C.) and stirred to add sodium hydride (55% suspension in oil). (44 mg, 1.0 mmol). Leave the reaction mixture to room temperature and For 15 minutes. The suspension was then cooled again (0 ° C.) and oxalyl chloride ( 105 μl, 1.2 mmol) and stirred at room temperature for 30 minutes. The resulting mixture The material was then evaporated under reduced pressure and the residue was suspended in dry tetrahydrofuran (5 ml). It became cloudy. The filtered solution was dried again to obtain an oily acid chloride.   4 (S) -Carboxy-5,5-dimethyl in dry tetrahydrofuran (10 ml) A suspension of luthiazolidine (161 mg, 1.0 mmol) was stirred and cooled (0 ° C). Was treated with triethylamine (278 μl, 2.0 mmol) followed by previous A solution of the above acid chloride in dry tetrahydrofuran (5 ml) was added and treated for 5 minutes. The mixture was stirred at room temperature for 3 hours, then partitioned between ethyl acetate and 1M hydrochloric acid. The organic layer was washed with water and a saturated saline solution, and dried over anhydrous sodium sulfate. Dissolution The medium was evaporated to give a crude oil which was subjected to silica gel chromatography. 0 Elution with 4% methanol in chloroform containing 0.1% acetic acid The starting material substitute was recovered, followed by 1% in chloroform containing 0.1% acetic acid. Elution with 0% methanol yielded the title compound (70 mg, 24%) as a colorless oil. . σ_H(CDCl_Three) 1.50 (3H, s), 1.59 (3H, s), 2.34 (3H, s), 2. 72 (2H, t, J 6.8 Hz), 3.14 (2 H, t, J 6.8 Hz), 4.50 (1 H, s ), 4.69 (2H, m) ppm. Example 8: 3- [3'-mercaptopropionyl] -4 (S) -carboxy-5,5-dimethyl Thiazolidine (E8)   The S-acetyl derivative E7 (70 mg, 0.24 mmol) was added to water (0.6 ml) and It was dissolved in concentrated aqueous ammonia (0.4 ml, specific gravity 0.88) and stirred at room temperature for 1 hour. Dilute the reaction mixture with ethyl acetate, wash with sufficiently diluted hydrochloric acid and acidify the aqueous phase. did. Treat the two-phase system with saturated saline solution, separate the organic phase and wash with more saline solution Dried over sodium sulfate and evaporated to give the title compound as a colorless oil (60m g, 100%). ν_max(CHCl_Three1744, 1722, 1651, 1410c m^-1. σ_H(CDCl_Three) 1.52 (3H, s), 1.60 (3H, s), 1.81 (1H, t, J8.2Hz), 2.7-2.9 (4H, overlapping m), 4.55 (1H, s) 4.75 (2H, ABq) ppm. EIMS M⁺249.0496; C₉H_FifteenNO_Three S_Two, 249.0493 required. Example 9: 3- [S-acetyl-3'-mercapto-2 '(S) -methylpropionyl] -4 (S) -Carboxy-5,5-dimethylthiazolidine (E9)   Dry tetrahydrofuran (8 ml) containing dry dimethylformamide (1 drop) Medium, S-acetyl-3-mercapto-2 (S) -methylpropionic acid (162 mg (1.0 mmol) was cooled (0 ° C.) and sodium hydride ( 44 mg of a 55% suspension in oil, 1.0 mmol) were added. Bring the reaction mixture to room temperature. And stirred for another 15 minutes. The suspension was then cooled again (0 ° C.) , Treated with oxalyl chloride (105 μl, 1.2 mmol) and stirred at room temperature for 30 minutes did. The mixture obtained is then evaporated under reduced pressure and the residue is dried in tetrahydrofuran. Suspended in run (5 ml). The filtered solution was dried again to obtain an oily acid chloride .   4 (S) -Carboxy-5,5-dimethyl in dry tetrahydrofuran (10 ml) A suspension of luthiazolidine (161 mg, 1.0 mmol) was stirred and cooled (0 ° C). Was treated with triethylamine (278 μl, 2.0 mmol) followed by previous A solution of the above acid chloride in dry tetrahydrofuran (5 ml) was added and treated for 5 minutes. The mixture was stirred at room temperature for 3 hours, then partitioned between ethyl acetate and 1M hydrochloric acid. The organic layer was washed with water and a saturated saline solution, and dried over anhydrous sodium sulfate. Dissolution The medium was evaporated to give a crude oil which was subjected to silica gel chromatography. 0 Elution with 4% methanol in chloroform containing 0.1% acetic acid The starting material substitute was recovered, followed by 1% in chloroform containing 0.1% acetic acid. Eluting with 0% methanol, the title compound (150 mg, 49%) was recovered as a colorless oil. Was. σ_H(CDCl_Three) 1.23 (3H, d, J 6.2 Hz), 1.52 (3H, s), 1.5 9 (3H, s), 2.34 (3H, s), 2.91 (2H, overlapping m), 3. 20 (1H, dd, J16.1 and 9.4 Hz), 4.53 (1H, s), 4.71 (1H , d, J 8.7 Hz), 4.96 (1 H, d, J 8.7 Hz) ppm. Example 10: 3- [3'-mercapto-2 '(S) -methylpropionyl] -4 (S) -carboxy- 5,5-dimethylthiazolidine (E10) Method A   The S-acetyl derivative E9 (150 mg, 0.49 mmol) was added to water (0.6 ml) and And concentrated aqueous ammonia (0.4 ml, specific gravity 0.88) and stirred at room temperature for 1 hour. . The reaction mixture is diluted with ethyl acetate, washed with sufficiently diluted hydrochloric acid, and the aqueous phase is acidified. I made it. Treat the two-phase system with saturated saline solution, separate the organic phase and wash with more saline solution , Dried over sodium sulfate and evaporated to give the title compound as a colorless oil (12 9 mg, 100%). ν_max(CHCl_Three1747, 1719, 1646, 146 1,1421cm^-1. σ_H(CDCl_Three) 1.22 (3H, d, J 6.5 Hz), 1.52 ( 3H, s), 1.61 (3H, s), 1.87 (1H, dd, J11.1 and 6.7 Hz) 2.41 (1H, dd, J11.1 and 8.3 Hz), 2.92 (2H, overlap M), 4.54 (1H, s), 4.72 (1H, d, J 8.5 Hz), 5.01 (1 H, d, J 8.5 Hz) ppm. EIMS M⁺263.0648; C_TenH₁₇NO_ThreeS_Two Calculated as 263.0650. Method B   The acetonyl ester of Example 21 in acetonitrile (4 ml) and water (1 ml) E21B (76 mg, 0.237 mmol) in 0.1 M potassium hydroxide solution (2. (4 ml, 0.237 mmol) was added in 0.5 ml at a time and treated for 2 hours. All reactions After a period of 4.5 hours, the reaction mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. Yes The organic layer was dried over magnesium sulfate, and the solvent was removed to obtain an oily substance. It was subjected to chromatography. 4% medium in chloroform containing 0.1% acetic acid Eluting with ethanol, recovering the substituted propionic acid starting material, (23 mg, 38%) was collected. The product is obtained in spectral properties from Method A. The same compound was used. Example 11: 3- [S-acetyl-2 '(RS) -benzyl-3'-mercaptopropionyl] -4 (R) -carboxy-5,5-dimethylthiazolidine (E11)   Dry tetrahydrofuran (8 ml) containing dry dimethylformamide (1 drop) In, S-acetyl-2-benzyl-3-mercaptopropionic acid (238 mg, (1.0 mmol) was cooled (0 ° C.) and stirred, and sodium hydride (oil Medium 5 (44 mg of a 5% suspension, 1.0 mmol) was added. Bring the reaction mixture to room temperature The mixture was allowed to stand, and stirring was further continued for 15 minutes. The suspension was then cooled again (0 ° C.) Treated with oxalyl (105 μl, 1.2 mmol) and stirred at room temperature for 30 minutes. The resulting mixture is then evaporated under reduced pressure and the residue is dried in tetrahydrofuran ( 5 ml). The filtered solution was dried again to obtain an oily acid chloride.   4 (R) -carboxy-5,5-dimethyl in dry tetrahydrofuran (10 ml) Ruthiazolidine (Howard-Lock et al., Can. J. Chem., 64: 1215 (1986)) (161 mg, 1 2.0 mmol) was stirred and cooled (0 ° C.) to give triethylamine (2. 78 μl, 2.0 mmol) followed by dry tetrahydro A furan (5 ml) solution was added and treated for 5 minutes. The mixture was stirred at room temperature for 3 hours. And partitioned between ethyl acetate and 1M hydrochloric acid. Organic layer with water and saturated saline solution Washed and dried over anhydrous sodium sulfate. Evaporation of the solvent gave an oily crude, It was subjected to chromatography on silica gel. Chlorophos containing 0.1% acetic acid Elution with 4% methanol in lume yields the recovered propionic acid starting material, followed by The title compound (217 mg, 57%) was recovered as a crisp foam . σ_H(CDCl_Three) (Isomer 1) 1.12 (3H, s), 1.41 (3H, s), 2.35 (3 H, s), 2.8-3.2 (5H, overlapping m), 3.93 (1H, d, J8. 1 Hz), 4.36 (1 H, s), 4.61 (1 H, d, J 8.1 Hz), 7.2-7.3 (5 H, m). (Isomer 2) 1.43 (3H, s), 1.57 (3H, s), 2.35 (3H, s), 2.8-3.2 (5H, overlapping m), 4.02 (1H, d, J8.4Hz), 4.55 (1H, s), 4.60 (1H, d, J 8.4 Hz), 7.2-7.3 (5H, m) p pm. Example 12: 3- [2 '(RS) -benzyl-3'-mercaptopropionyl] -4 (R) -carboxy C-5,5-dimethylthiazolidine (E12)   The S-acetyl derivative E11 (217 mg, 0.57 mmol) was added to water (0.6 ml) and water. And concentrated ammonia water (0.4 ml, specific gravity 0.88) and stirred at room temperature for 1 hour. Was. The reaction mixture is diluted with ethyl acetate, washed with sufficiently diluted hydrochloric acid, and the aqueous phase is acidified. Sex. The two-phase system is treated with a saturated saline solution, the organic phase is separated off and further treated with a saline solution Wash, dry over sodium sulphate and evaporate to a crisp foam The title compound, (2′RS, 4S) diastereomer mixture was obtained (189 mg, 87 %). ν_max(CHCl_Three1739, 1720, 1643, 1432 cm^-1. σ_H( CDCl_Three) (Isomer 1) 1.18 (3H, s), 1.43 (3H, s), 1.93 (1H, d d, J11.4 and 6.0 Hz), 2.53 (1H, m), 2.75-3.15 (4H, Overlapping m), 4.03 (1H, d, J 8.1 Hz), 4.37 (1H, s), 4.84 (1H, d, J 8.1 Hz), 7.2-7.3 (5H, m). (Isomer 2) 1.46 ( 3H, s), 1.58 (3H, s), 2.11 (1H, t, J 16.5 Hz), 2.53 (1H , m), 2.75-3.15 (4H, overlapping m), 4.19 (1H, d, J8 .1Hz), 4.62 (1H, s), 4.81 (1H, d, J8.1Hz), 7.2-7.3 ( 5H, m) ppm. EIMS M⁺339.0966. C₁₆H_{twenty one}NO_ThreeS_TwoAs a total Calculated 339.0963. Example 13: 3- [S-acetyl-3'-mercapto-2 '(RS) -methylpropionyl] -4 ( S) -Carboxy-5,5-dimethylthiazolidine (E13)   Dry tetrahydrofuran (8 ml) containing dry dimethylformamide (1 drop) Medium, S-acetyl-3-mercapto-2 (RS) -methylpropionic acid (162 m g, 1.0 mmol) was cooled (0 ° C.) and stirred and added sodium hydride. (44 mg of a 55% suspension in oil, 1.0 mmol) was added. Bring the reaction mixture to room temperature The mixture was allowed to stand until stirring, and stirring was continued for another 15 minutes. The suspension was then cooled again (0 ° C), oxalyl chloride (105 μl, 1.2 mmol) and stir at room temperature for 30 minutes. Stirred. The resulting mixture is then evaporated under reduced pressure and the residue is dried Suspended in furan (5 ml). The filtered solution is dried again to obtain an oily acid chloride. Was.   4 (S) -Carboxy-5,5-dimethyl in dry tetrahydrofuran (10 ml) A suspension of luthiazolidine (161 mg, 1.0 mmol) was stirred and cooled (0 ° C). Was treated with triethylamine (278 μl, 2.0 mmol) followed by previous A solution of the above acid chloride in dry tetrahydrofuran (5 ml) was added and treated for 5 minutes. The mixture was stirred at room temperature for 3 hours, then partitioned between ethyl acetate and 1M hydrochloric acid. Organic The layer was washed with water and saturated saline solution and dried with anhydrous sodium sulfate. Solvent Evaporation gave an oily crude which was subjected to chromatography on silica gel. 0.1 Eluted with 4% methanol in chloroform containing 5% acetic acid, starting with propionic acid Substitution of material was recovered, followed by 10% in chloroform containing 0.1% acetic acid. Elution with methanol yielded the title compound (178 mg, 58%) as a white solid. σ_H(CDCl_Three) 1.23 and 1.25 (3H, d, J 6.2 Hz), 1.51 and 1 .52 (3H, s), 1.59 and 1.61 (3H, s), 2.34 (3H, s), 2.85 -3.2 (3H, overlapping m), 4.52 and 4.57 (1H, s), 4.7 0 and 4.72 (1H, d, J8.6 Hz), 4.83 and 4.96 (1H, d, J8. 6 Hz) ppm. Example 14: 3- [3'-mercapto-2 '(RS) -methylpropionyl] -4 (S) -carboxy -5,5-dimethylthiazolidine (E14)   The S-acetyl derivative E13 (178 mg, 0.58 mmol) was added to water (0.6 ml) and And concentrated ammonia water (0.4 ml, specific gravity 0.88) and stirred at room temperature for 1 hour. Was. The reaction mixture is diluted with ethyl acetate, washed with sufficiently diluted hydrochloric acid, and the aqueous phase is acidified. Sex. The two-phase system is treated with a saturated saline solution, the organic phase is separated off and further treated with a saline solution Wash, dry over sodium sulfate and evaporate to give the title compound as a colorless oil, (2′RS (4S) diastereomer mixture was obtained (152 mg, 99%). ν_max(CHCl_Three) 1745, 1717, 1648, 1459, 1418cm^-1. σ_H(CDCl_Three) 1 .23 (3H, d, J 6.4 Hz), 1.53 (3H, s), 1.62 (3H, s), 1.86 ( 1H, dd, J11.0 and 6.7 Hz), 2.46 (1H, m), 2.91 (2H, Wrapping m), 4.54 and 4.64 (1H, s), 4.73 (d, J8.5H z) and 4.76 (1H, d, J 8.3 Hz), 4.93 (d, J 8.3 Hz) and 5. 02 (1H, d, J 8.5 Hz) ppm. EIMS M⁺263.0648; C_TenH₁₇N O_ThreeS_TwoCalculated value 263.0650. Example 15: N- [S-acetyl-2 '(RS) -benzyl-3'-mercaptopropionyl] -D -Proline (E15)   Dry tetrahydrofuran (8 ml) containing dry dimethylformamide (1 drop) In, S-acetyl-2-benzyl-3-mercaptopropionic acid (238 mg, (1.0 mmol) was cooled (0 ° C.) and stirred, and sodium hydride (oil (44 mg of a 55% suspension in 1.0 mmol) was added. Bring the reaction mixture to room temperature And kept stirring for another 15 minutes. The suspension was then cooled again (0 ° C.) Treat with oxalyl chloride (105 μl, 1.2 mmol) and stir at room temperature for 30 minutes Was. The mixture obtained is then evaporated under reduced pressure and the residue is dried with tetrahydrofuran. (5 ml). The filtered solution was dried again to obtain an oily acid chloride.   D-proline (115 mg, 1.0 mm) in dry tetrahydrofuran (10 ml) Mol) was cooled and cooled (0 ° C.) to give triethylamine (278 μl 2.0 mmol), followed by drying of the above acid chloride in dry tetrahydrofuran ( 5 ml) solution and treated for 5 minutes. The mixture is stirred at room temperature for 3 hours, then Partitioned between ethyl acid and 1M hydrochloric acid. Wash the organic layer with water and saturated saline solution , And dried over anhydrous sodium sulfate. Evaporation of the solvent gave an oily crude product, silica The gel was subjected to chromatography. In chloroform containing 0.1% acetic acid Elution with 4% methanol, recovery of the propionic acid starting material replacement, followed by The title compound (87 mg, 26%) was recovered as a crisp foam. σ_H(C DCI_Three) 4.50 (1H, m), 1.85 (2H, overlapping m), 2.35 (3 H, s), 2.50 and 2.66 (1H, m), 2.9-3.3 (7H, overlap M), 4.38 and 4.57 (1H, dd, J 8.0 and 2.0 Hz), 7.2- 7.3 (5H, m) ppm. Example 16: N- [2 '(RS) -benzyl-3'-mercaptopropionyl] -D-proline (E1 6)   The S-acetyl derivative E15 (87 mg, 0.26 mmol) was added to water (0.6 ml) and And concentrated aqueous ammonia (0.4 ml, specific gravity 0.88) and stirred at room temperature for 1 hour. . The reaction mixture is diluted with ethyl acetate, washed with sufficiently diluted hydrochloric acid, and the aqueous phase is acidified. To did. Treat the two-phase system with saturated saline solution, separate the organic phase and wash with more saline solution Dried, dried over sodium sulphate and evaporated to give a crisp foam The compound was obtained as a mixture of diastereomers (70 mg, 92%). ν_max(CHC l_Three) 1753, 1720, 1630, 1579, 1452 cm^-1. σ_H(CDCl_Three ) 1.6 (2H, overlapping m), 1.85 (2H, overlapping m) , 2.28 and 2.43 (1H, m), 2.5-3.1 (6H, overlapping m ), 3.41 and 3.54 (1H, m), 4.45 (dd, J8.3 and 2.7Hz) And 4.65 (1H, dd, J8.3 and 2.3Hz), 7.2-7.3 (5H, m) pp m. EIMS M⁺293.1085; C_FifteenH₁₉NO_ThreeAs S, calculated value 293.1 086. Example 17: 3- [S-acetyl-2 '(RS) -benzyl-3'-mercaptopropionyl] -4 (S) -carboxythiazolidine (E17)   Dry tetrahydrofuran (8 ml) containing dry dimethylformamide (1 drop) In, S-acetyl-2-benzyl-3-mercaptopropionic acid (238 mg, (1.0 mmol) was cooled (0 ° C.) and stirred, and sodium hydride (oil (44 mg of a 55% suspension in 1.0 mmol) was added. Bring the reaction mixture to room temperature And kept stirring for another 15 minutes. The suspension was then cooled again (0 ° C.) Treat with oxalyl chloride (105 μl, 1.2 mmol) and stir at room temperature for 30 minutes Was. The mixture obtained is then evaporated under reduced pressure and the residue is dried with tetrahydrofuran. (5 ml). The filtered solution was dried again to obtain an oily acid chloride.   In dry tetrahydrofuran (10 ml), 4 (S) -carboxythiazolidine (How Ard-Lock et al., Can. J. Chem. 64: 1215 (1986)) (133 mg, 1.0 mmol). Was stirred and cooled (0 ° C.), and triethylamine (278 μl, 2.0 mmol) was added. ), Followed by the addition of a solution of the above acid chloride in dry tetrahydrofuran (5 ml). In addition, it was treated for 5 minutes. The mixture was stirred at room temperature for 3 hours, then ethyl acetate and Partitioned between 1M hydrochloric acid. The organic layer is washed with water and a saturated salt solution, and dried over anhydrous sodium sulfate. Dried with lium. Evaporation of the solvent gave an oily crude product which was chromatographed on silica gel. It was subjected to tomography. 4% methanol in chloroform containing 0.1% acetic acid And the substituted propionic acid starting material (120 mg, 50%) was recovered. The title compound (103 mg, 29%) was recovered in a crisp foam Was. σ_H(CDCl_Three) 2.35 (3H, s), 2.75-3.25 (7H, overlap M), 3.74 (d, J 8.1 Hz) and 3.86 (1 H, d, J 8.5 Hz), 4. 39 (d, J 8.1 Hz) and 4.55 (1 H, d, J 8.5 Hz), 4.88 (dd, J 6.7 and 2.7 Hz) and 5.04 (1H, dd, J 6.8 and 4.0 Hz), 7 .2-7.3 (5H, m) ppm. Example 18: 3- [2 '(RS) -benzyl-3'-mercaptopropionyl] -4 (S) -carboxy Citithiazolidine (E18)   The S-acetyl derivative E17 (103 mg, 0.29 mmol) was added to water (0.6 ml) and And concentrated ammonia water (0.4 ml, specific gravity 0.88) and stirred at room temperature for 1 hour. Was. The reaction mixture is diluted with ethyl acetate, washed with sufficiently diluted hydrochloric acid, and the aqueous phase is acidified. Sex. The two-phase system is treated with a saturated saline solution, the organic phase is separated off and further treated with a saline solution Wash, dry over sodium sulphate and evaporate to a crisp foam The title compound was obtained as a mixture of diastereomers (87 mg, 96%). ν_max(C HCl_Three) 1742,1722,1642,1612,1423cm^-1. σ_H(CD Cl_Three) 1.56 (dd, J8.2 and 9.2 Hz) and 1.82 (1H, dd, J6. 8 and 10.9 Hz), 2.5-3.2 (6H, overlapping m), 3.25 ( dd, J12.0 and 3.0 Hz) and 3.36 (1H, dd, J12.0 and 3.36 Hz). 5 Hz), 3.87 (d, J 8.0 Hz) and 3.94 (1 H, d, J 8.3 Hz), 4. 59 (d, J 8.0 Hz) and 4.67 (1 H, d, J 8.3 Hz), 4.92 (dd, J 6.8 and 3.0 Hz) and 5.09 (1H, dd, J 6.8 and 3.5 Hz), 7 .2-7.3 (5H, m) ppm. EIMS M⁺311.0660; C₁₄H₁₇NO_ThreeS_Two Calculated value 311.0650. Example 19: 3- [2 '(R) -benzyl-3'-mercaptopropionyl] -4 (S) -carboxy -5,5-dimethylthiazolidine (E19)   The carboxylic acid isomer (E1) of Example 1 (1.84 g, 4.83 mmol) was dried in DM Potassium carbonate (0.334 g, 2.42 mmol) and chloroa in F (20 ml). Treat with seton (0.80 ml, 0.93 g, 10.0 mmol) and stir at room temperature overnight did. The reaction mixture is then diluted with ethyl acetate and washed with 1M hydrochloric acid, followed by water Washed 6 times. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. To give the acetonyl ester of compound E1 as a diastereomer mixture (1.9 7g). Silica gel chromatography, 25% ethyl acetate / hexane To give the colorless oily (2′R, 4S) -isomer (E19A) (0.87 mg, 41%). ν_max(CHCl_Three) 1757, 1734, 1687, 1645, 141 7cm^-1. σ_H(CDCl_Three) 1.47 (3H, s), 1.61 (3H, s), 2.18 (3 H, s), 2.34 (3H, s), 2.85-3.15 (5H, overlapping m) , 4.02 (1H, d, J8.6 Hz), 4.55 (1H, s), 4.60 (1H, d, J8. 6Hz), 4.62 (1H, d, J16.8Hz), 4.74 (1H, d, J16.8Hz) 7.25 (5H, m) ppm. EIMS M⁺437.1337; C_{twenty one}H₂₇NO_FiveS_Two , 437.1331 required. Elution was continued and the oily (2'S, 4S) -isomer (E19 B) was obtained (0.98 mg, 46%). ν_max(CHCl_Three) 1757, 1734, 1 687, 1645, 1417cm^-1. σ_H(CDCl_Three) 1.17 (3H, s), 1.4 4 (3H, s), 2.19 (3H, s), 2.36 (3H, s), 2.85-3.15 (5 H, overlapping m), 3.93 (1H, d, J 8.1 Hz), 4.38 (1H, s ), 4.60 (1H, d, J8.1Hz), 4.65 (1H, d, J16.8Hz), 4.74 (1H, d, J 16.8 Hz), 7.25 (5H, m) ppm. EIMS M⁺437.13 37; C_{twenty one}H₂₇NO_FiveS_TwoCalculated value 437.1331.   Acetonitrile E19A (72 mg, 0.165 mmol) was added to acetonitrile. (4 ml), water (1 ml) and 0.1 M potassium hydroxide solution (3.30 ml). 1, 0.330 mmol) and stirred at room temperature for 5 hours. Dilute hydrochloric acid to the reaction mixture And partitioned between ethyl acetate and the salt compound. Salt solution of organic layer The mixture was washed with liquid and dried over anhydrous magnesium sulfate. Removal of the solvent gives an oil, Siri Kagel was subjected to chromatography. 10% methano containing 0.1% acetic acid Eluting with toluene / chloroform to give the desired product, but with incomplete hydrolysis. A few S-acetyl compounds were narrowed. This product is combined with water (0.6 ml) and The mixture was treated with concentrated aqueous ammonia (0.4 ml, specific gravity 0.88) and stirred at room temperature for 1 hour. Dilute the reaction mixture with ethyl acetate, wash with sufficiently diluted hydrochloric acid and acidify the aqueous phase. did. Treat the two-phase system with saturated saline solution, separate the organic phase and wash with more saline solution Dried over sodium sulfate and evaporated to give the title compound as a colorless oil (40m g, 73%). ν_max(CHCl_Three) 1751,1722,1643,1418cm^{- 1} . σ_H(CDCl_Three) 1.48 (3H, s), 1.60 (3H, s), about 1.6 (1H, m, 2.59 (1H, m), 2.75-3.15 (4H, overlapping m), 4.21 (1H, d, J8.0 Hz), 4.64 (1H, s), 4.82 (1H, d, J8. 0 Hz), 7.2-7.3 (5H, m) ppm. EIMS M⁺339. DCIMS M H⁺340. Example 20: 3- [2 '(S) -benzyl-3'-mercaptopropionyl] -4 (S) -carboxy -5,5-dimethylthiazolidine (E20)   Acetonitrile ester E19B of Example 19 (0.82 g, 1.88 mmol) Was dissolved in acetonitrile (40 ml) in 0.1 M aqueous potassium hydroxide solution (37.6 ml, (3.76 mmol) and stirred at room temperature for 5.5 hours. Post-treatment and purification before Performed as for the (R) isomer above. Crisp foam by chromatography The title compound (372 mg, 58%) of (crisp foam) was obtained. ν_max(CHCl_Three) 17 49,1720,1640,1421cm^-1. σ_H(CDCl_Three) 1.18 (3H, s) 1.43 (3H, s), 1.94 (1H, dd, J11.8 and 6.2 Hz), 2.50 (1H, ddd, J11.8, 11.8, 2.4 Hz), 2.88 (2H, overlap Ping m), 3.12 (2H, overlapping m), 4.03 (1H, d, J8.1 Hz), 4.38 (1H, s), 4.85 (1H, d, J 8.1 Hz), 7.2-7.3 (5H , m) ppm. EIMS M⁺339. DCIMS MH⁺340. Example 21: 3- [3'-mercapto-2 '(R) -methylpropionyl] -4 (S) -carboxy- 5,5-dimethylthiazolidine (E21)   The S-acetyl derivative E13 obtained in Example 13 (450 mg, 1.47 mmol ) In dry DMF (5 ml) was stirred and potassium carbonate (102 mg, 0.738) was added. Mmol) and chloroacetone (0.235 ml, 273 mg, 2.95 mmol) ) And the mixture was stirred overnight at room temperature. The reaction mixture is then diluted with ethyl acetate And washed with 1M hydrochloric acid, followed by 6 washes with water. The organic layer is treated with anhydrous magnesium sulfate. And the solvent was removed under reduced pressure to give the acetonyl ester of compound E13. Obtained as an astereomeric mixture (0.53 g).   The acetonyl ester mixture (388 mg, 1.07 mmol) was then concentrated. Methanol solution (0.8 ml, specific gravity 0.88) and water (1.2 ml) Dissolved in nitrile (2 ml) and stirred for 1 hour. Acidify the reaction mixture with 5M hydrochloric acid And extracted with ethyl acetate. The organic layer is washed with water and saturated saline solution, Dry over nesium and remove the solvent to give an oil, which is chromatographed on silica gel. I was served. Elution with ethyl acetate / hexane (1: 2) (2 ′S, 4S) -isomer The form E21B (56 mg, 16%) was obtained. ). ν_max(CHCl_Three) 1756,173 6, 1648, 1459, 1417 cm^-1. σ_H(CDCl_Three) 1.20 (3H, d, J 6.4 Hz), 1.56 (3H, s), 1.64 (3H, s), 1.81 (1H, dd, J10 .9 and 6.6 Hz), 2.18 (3H, s), 2.41 (1H, dd, J10.9 and 8.4Hz), 2.90 (2H, overlapping m), 4.55 (1H, s), 4.6 2 (1H, d, J16.8Hz), 4.71 (1H, d, J8.7Hz), 4.85 (d, J1 6.8 Hz) and 5.00 (1 H, d, J 8.7 Hz) ppm. EIMS M⁺319. 0909; C₁₃H_{twenty one}NO_FourS_TwoCalculated value 319.0912. Continue elution, (2 The 'R, 4S) -isomer E21A (65 mg, 19%) was obtained. ν_max(CHCl_Three) 17 56, 1737, 1648, 1461, 1417 cm^-1. σ_H(CDCl_Three) 1.2 0 (3H, d, J 6.4 Hz), 1.55 (3H, s), 1.55 (1H, m), 1.64 (3 H, s), 2.17 (3H, s), 2.47 (1H, dd, J 9.5 and 8.4 Hz), 2. 90 (2H, overlapping m), 4.61 (1H, d, J16.8 Hz), 4.6 4 (1H, s), 4.76 (1H, d, J 8.3 Hz), 4.81 (d, J 16.8 Hz) and And 4.91 (1H, d, J 8.3 Hz) ppm. EIMS M⁺319.0909; C₁₃H_{twenty one}NO_FourS_Twoage Calculated value 319.0912.   Acetonitrile was added to acetonyl ester E21A (87 mg, 0.273 mmol). (4 ml) and 0.1 M potassium hydroxide solution in water (2.7 ml, 0.27 mm Mol) was added at once and the mixture was treated for 2 hours. After 6 hours total reaction time, mix the reaction The product was acidified with diluted hydrochloric acid and extracted with ethyl acetate. Dry the organic layer with magnesium sulfate Drying and removal of solvent gave an oil which was subjected to silica gel chromatography. . Elution with 4% methanol in chloroform containing 0.1% acetic acid gave a gummy The title compound (34 mg, 47%) was obtained. ν_max(CHCl_Three) 1752, 1719, 1647, 1457, 1419cm^-1. σ_H(CDCl_Three) 1.21 (3H, d, J6.) 3Hz), 1.51 (3H, s), 1.51 (1H, unclear), 1.60 (3H, s), 2.4 7 (1H, dd, J9.3 and 8.5 Hz), 2.92 (2H, overlapping m ), 4.61 (1H, s), 4.75 (1H, d, J8.3 Hz), 4.91 (1H, d, J8. 3 Hz) ppm. EIMS M⁺263.0648; C_TenH₁₇NO_ThreeS_TwoAs calculated Value 263.0650. Example 22: 3- [S-acetyl-3'-mercapto-2 '(S) -methylpropionyl] -4 (R) -Carboxy-5,5-dimethylthiazolidine (E22)   Dry tetrahydrofuran (8 ml) containing dry dimethylformamide (1 drop) Medium, S-acetyl-3-mercapto-2 (S) -methylpropionic acid (162 mg (1.0 mmol) was cooled (0 ° C.) and sodium hydride ( 44 mg of a 55% suspension in oil, 1.0 mmol) were added. Bring the reaction mixture to room temperature. And stirred for another 15 minutes. The suspension was then cooled again (0 ° C.) , Treated with oxalyl chloride (105 μl, 1.2 mmol) and stirred at room temperature for 30 minutes did. The mixture obtained is then evaporated under reduced pressure and the residue is dried in tetrahydrofuran. Suspended in run (5 ml). The filtered solution was dried again to obtain an oily acid chloride .   4 (R) -carboxy-5,5-dimethyl in dry tetrahydrofuran (10 ml) A suspension of luthiazolidine (161 mg, 1.0 mmol) was stirred and cooled (0 ° C). Was Was treated with triethylamine (278 μl, 2.0 mmol) followed by A solution of the acid chloride in dry tetrahydrofuran (5 ml) was added and treated for 5 minutes. Mixed The mixture was stirred at room temperature for 3 hours, then partitioned between ethyl acetate and 1M hydrochloric acid. Yes The organic layer was washed with water and a saturated saline solution, and dried over anhydrous sodium sulfate. solvent Was evaporated to give an oily crude which was subjected to silica gel chromatography. 0. Elution with 4% methanol in chloroform containing 1% acetic acid yields propionic acid. The replacement of the starting material was recovered, followed by 10% in chloroform containing 0.1% acetic acid. % Methanol to recover the title compound (164 mg, 54%) as a colorless oil. . σ_H(CDCl_Three) 1.24 (3H, d, J 6.4 Hz), 1.51 (3H, s), 1.61 ( 3H, s), 2.34 (3H, s), 2.95 (2H, overlapping m), 3.10 ( 1H, dd, J13.0 and 7.6 Hz), 4.56 (1H, s), 4.72 (1H, d, J 8.5 Hz), 4.83 (1 H, d, J 8.5 Hz) ppm. Example 23: 3- [Mercapto-2 '(S) -methylpropionyl] -4 (R) -carboxy-5, 5-dimethylthiazolidine (E23)   The S-acetyl derivative E22 (164 mg, 0.54 mmol) was added to water (0.6 ml) and And concentrated ammonia water (0.4 ml, specific gravity 0.88) and stirred at room temperature for 1 hour. Was. The reaction mixture is diluted with ethyl acetate, washed with sufficiently diluted hydrochloric acid, and the aqueous phase is acidified. Sex. The two-phase system is treated with a saturated saline solution, the organic phase is separated off and further treated with a saline solution Wash, dry over sodium sulfate and evaporate to give the title compound as a colorless oil (1 39 mg, 100%). ν_max(CHCl_Three) 1748, 1720, 1650, 14 59,1421cm^-1. σ_H(CDCl_Three) 1.23 (3H, d, J 6.4 Hz), 1.5 3 (3H, s), 1.53 (1H, unclear), 1.61 (3H, s), 2.49 (1H, dd, J 9.5 and 8.5 Hz), 2.88 (2H, overlapping m), 4.63 (1 H, s), 4.75 (1H, d, J 8.3 Hz), 4.92 (1 H, d, J 8.3 Hz) ppm . EIMS M⁺263.0648; C_TenH₁₇NO_ThreeS_TwoAs calculated value 263.06 50. Example 24: N- [S-acetyl-2 '(RS) -benzyl-3'-mercaptopropionyl] -L -Proline (E24)   Dry tetrahydrofuran (8 ml) containing dry dimethylformamide (1 drop) In, S-acetyl-2-benzyl-3-mercaptopropionic acid (238 mg, (1.0 mmol) was cooled (0 ° C.) and stirred, and sodium hydride (oil (44 mg of a 55% suspension in 1.0 mmol) was added. Bring the reaction mixture to room temperature And kept stirring for another 15 minutes. The suspension was then cooled again (0 ° C.) Treat with oxalyl chloride (105 μl, 1.2 mmol) and stir at room temperature for 30 minutes Was. The mixture obtained is then evaporated under reduced pressure and the residue is dried with tetrahydrofuran. (5 ml). The filtered solution was dried again to obtain an oily acid chloride.   L-Proline (115 mg, 1.0 mm) in dry tetrahydrofuran (10 ml) Mol) was cooled and cooled (0 ° C.) to give triethylamine (278 μl 2.0 mmol), followed by drying of the above acid chloride in dry tetrahydrofuran ( 5 ml) solution and treated for 5 minutes. The mixture is stirred at room temperature for 3 hours, then Partitioned between ethyl acid and 1M hydrochloric acid. Wash organic layer with water and saturated saline solution And dried over anhydrous sodium sulfate. The solvent was evaporated to give an oily crude product, Kagel was subjected to chromatography. Chloroform containing 0.1% acetic acid Eluted with 4% methanol in methanol to recover the substituted propionic acid starting material, followed by The crisp foam of the title compound was recovered (80 mg, 24%). σ_H( CDCl_Three) 1.50 (1H, m), 1.85 (2H, overlapping m), 2.35 ( 3H, s), 2.50 and 2.66 (1H, m), 2.9-3.3 (7H, overlap Ping m), 4.38 and 4.57 (1H, dd, J 8.0 and 2.0 Hz), 7.2 -7.3 (5H, m) ppm. Example 25: N- [2 '(RS) -benzyl-3'-mercaptopropionyl] -L-proline (E 25)   The S-acetyl derivative E24 (80 mg, 0.24 mmol) was added to water (0.6 ml) and water. And concentrated aqueous ammonia (0.4 ml, specific gravity 0.88) and stirred at room temperature for 1 hour. . The reaction mixture is diluted with ethyl acetate, washed with sufficiently diluted hydrochloric acid, and the aqueous phase is acidified. To did. Treat the two-phase system with saturated saline solution, separate the organic phase and wash with more saline solution Dried, dried over sodium sulphate and evaporated to give a crisp foam The compound was obtained (70 mg, 100%). ν_max(CHCl_Three1749, 1716, 1 633, 1583, 1450cm^-1. σ_H(CDCl_Three) 1.6 (2H, overlap) Ping m), 1.85 (2H, overlapping m), 2.28 and 2.43 (1 H, m), 2.5-3.1 (6H, overlapping m), 3.41 and 3.54 ( 1H, m), 4.45 (dd, J 8.3 and 2.7 Hz) and 4.65 (1 H, dd, J 8.3 and 2.3 Hz), 7.2-7.3 (5H, m) ppm. EIMS M⁺293. 1085; C_FifteenH₁₉NO_ThreeAs S, the calculated value is 293.1086. Example 26: 3- [2 '(S) -benzyl-3'-mercaptopropionyl] -4 (S) -carboxy -5,5-dimethylthiazolidine-1-oxide (E26) (sulfoxide Sex A)   S-acetylacetonyl derivative E19B (42 mg, 0.096 mmol, working A solution of the compound (prepared as described in Example 19) in dichloromethane (3 ml) was stirred and Treated with loperbenzoic acid (21 mg, 0.096 mmol) and additional 1 hour at room temperature Stirred. The reaction mixture is then washed with saturated sodium bicarbonate and magnesium sulfate. The solvent was removed to obtain a crude product, which was subjected to silica gel chromatography. Provided. Elution with ethyl acetate / hexane (1: 1) gave sulfoxide isomer A (3 2 mg, 72%). ν_max(CHCl_Three1758, 1734, 1685, 1 656, 1413, 1063cm^-1. σ_H(CDCl_Three) 1.33 (3H, s), 1.5 6 (3H, s), 2.19 (3H, s), 2.35 (3H, s), 2.85-3.15 (5H, Overlapping m), 4.08 (1H, d, J11.9 Hz), 4.59 (1H, d, J16.8Hz), 4.69 (1H, d, J11.9Hz), 4.73 (1H, s), 5.0 4 (1H, d, J 16.8 Hz), 7.25 (5H, m) ppm. APCI-MS MNH_Four ⁺ 471. Continued elution provided sulfoxide isomer B (12 mg, 28%). ν_max(CHCl_Three1762, 1734, 1685, 1656, 1417, 106 3cm^-1. σ_H(CDCl_Three) 0.95 (3H, s), 1.42 (3H, s), 2.19 (3H, s) , s), 2.37 (3H, s), 2.85-3.15 (5H, overlapping m), 4. 14 (1H, d, J11.2 Hz), 4.25 (1H, d, J11.2 Hz), 4.58 (1 H, s), 4.62 (1H, d, J 16.8 Hz), 4.79 (1 H, d, J 16.8 Hz), 7.25 (5H, m) ppm. APCI-MS MNH_Four ⁺471.   Sulfoxide isomer A (31 mg, 0.068 mmol) was added to acetonitrile (1 0.5 M) in 0.1 M potassium hydroxide (1.37 ml, 0.137 mmol) Then, the mixture was stirred at room temperature for 4 hours. Dilute the reaction mixture with ethyl acetate and acidify with dilute hydrochloric acid did. The organic layer was washed with water and a saturated saline solution, and dried over magnesium sulfate. The solvent was removed to give an oil, concentrated ammonia solution (0.4 ml) and water (0.6). ml) and stirred for 1 hour. The above post-treatment was repeated to obtain a crude product. K Subjected to chromatography to give the title compound in a crisp foam. 12 mg, 49%). ν_max(CHCl_Three) 1631cm^-1. σ_H(CDCl_Three+ MeO D drops) 1.25 (3H, s), 1.29 (3H, s), 1.95 (1H, s), 2.43 (1 H, d, J 11.4 Hz), 2.8-3.1 (4H, overlapping m), 4.02 ( 1H, d, J11.0Hz), 4.38 (1H, s), 4.91 (1H, d, J11.0Hz) 7.2-7.3 (5H, m) ppm. ESMS MH⁺356. Example 27 3- [2 '(S) -benzyl-3'-mercaptopropionyl] -4 (S) -carboxy -5,5-dimethylthiazolidine-1-oxide (sulfoxide isomer B) ( E27)   The title compound was prepared by a method generally described herein. Example 28 3- [2 '(S) -benzyl-3'-mercaptopropionyl] -4 (R) -carboxy -5,5-dimethylthiazolidine (E28)   The title compound was purified using the method outlined in Examples 19 and 20 using E11 Manufactured from. NMR was identical to E19. Example 29 3- [2 '(R) -benzyl-3'-mercaptopropionyl] -4 (R) -carboxy -5,5-dimethylthiazolidine (E29)   The title compound was prepared from E11 using the method outlined in Example 19. Was. NMR was identical to E20. Example 30 3- [2 '(R or S) -benzyl-3'-mercaptopropionyl] -4 (S) -ca Ruboxithiazolidine (E30)   The title compound was converted to E17 using the methods outlined in Examples 19 and 20. Manufactured from. C₁₄H₁₇NO_ThreeS_Two, 311.0650, EI MS M + 311.0654. Example 31 3- [2 '(S or R) -benzyl-3'-mercaptopropionyl] -4 (S) -ca Ruboxiathiazolidine (E31)   The title compound was converted to E17 using the methods outlined in Examples 19 and 20. Manufactured from. C₁₄H₁₇NO_ThreeS_Two, 311.0650, EI MS M⁺311.0650. Example 32 3- [2 '(RS) -mercaptomethyl-4'-phenylbutanoyl] -4 (S) -cal Boxy-5,5-dimethylthiazolidine (E32) a) 2-acetylthiomethyl-4-phenylbutanoic acid   2-phenylethylmalonic acid (1.8 g), 40% aqueous dimethylamide solution (1.0 8 ml, 1 equivalent) and 37% aqueous formaldehyde solution (0.64 ml, 1 equivalent). The mixture in water (10 ml) was stirred at room temperature overnight. After cooling at 0 ° C, the solid was filtered off And washed with water and dried. Heat white solid at 170 ° C for 10 minutes and cool to room temperature did. The resulting gum was dissolved in ethyl acetate (20 ml) and 10% hydrogen sulfate was added. Wash with lithium (10 ml), water (2 × 10 ml), saturated saline (10 ml) and dry (MgSO_Four) And evaporated to give crude 2-methylene-4-phenylbutanoic acid . σ_H(CDCl_Three) 2.55-2.90 (4H, m, 2xCH_Two), 5.65, 6.85 ( 2H, 2xs, =_H), 7.25 (5H, m, Ph). Dissolve the solid in thioacetic acid (1 ml) Understand, 10 Heated at 0 ° C. for 1 hour. After evaporation, the gum was dissolved in ethyl acetate (10 ml). Dissolved and extracted with saturated sodium bicarbonate solution (2 × 10 ml). The collected extract Wash with ethyl acetate (2 × 10 ml) and acidify with 10% potassium bisulfate solution (pH 3). The aqueous layer was extracted with ethyl acetate (2 × 10 ml) and the combined extracts were extracted with water (2 × 10 ml). 10 ml), dried (MgSO 4_Four), Evaporated to give the title compound as a yellow oil (0.52 g, 24%);_H(CDCl_Three) 2.00 (2H, m, CH_Two), 2.71 ( 3H, m, CH_Two, CH), 3.14 (2H, m, CH_Two), 7.24 (5H, m, Ph) . EIMS M⁺252 DCIMS MNH_Four ⁺270. b) 3- [2 '(RS) -mercaptomethyl-4'-phenylbutanoyl] -4 (S)- Carboxy-5,5-dimethylthiazolidine   The title compound was prepared using the procedure outlined in Examples 17 and 18 using 2-A Prepared from cetylthiomethyl-4-phenylbutanoic acid. EIMS M⁺353E SMS MH 352. Example 33 3- [2 '(RS) -mercaptomethyl-5'-phenylpentanoyl] -4 (S) -ca Ruboxiathiazolidine (E33) a) 2-acetylthiomethyl-5-phenylpentanoic acid   According to the method described in Example 32a), 3-phenylpropylmalonic acid (6.14). g) was converted to 2-methylene-5-phenylpentanoic acid (2.1 g, 40%). ; Σ_H(CDCl_Three) 1.88 (2H, m, CH_Two), 2.37 (2H, t, J7.6Hz) , CH_Two), 2.67 (2H, t, J 7.6 Hz, CH_Two), 5.68 and 6.33 (2 H, 2xs, =_H), 7.26 (5H, m, Ph). Dissolve the solid in thioacetic acid (5 ml) And heated at 100 ° C. for 2 hours. Evaporation gave the title compound (2.9 g, 100 %); Σ_H(CDCl_Three) 1.71 (4H, m, 2xCH_Two), 2.33 (3H, s, CO CH_Three), 2.64 (3H, m, CH, CH_Two), 3.08 (2H, m, CH_Two), 7.2 7 (5H, m, Ph). b) 3- [2 '(RS) -mercaptomethyl-5'-phenylpentanoyl] -4 (S) -Carboxythiathiazolidine   Using the method outlined in Examples 17 and 18, the title compound was Prepared from tylthiomethyl-5-phenylpentanoic acid. C₁₆H_{twenty one}NO_ThreeS_Two, Calculating for 339.0963, EIMS M⁺339.0966.   The following compounds have been described in the literature as ACE inhibitors: E4 Saunders et al., J. Computer-Aided Molecular Design, 1: 133                   (1987) E6 Waller et al., J. Med. Chem. 36 (16): 2390 (1993). E8 JP55009060 E14 JP55009060 E24, E25 US4046889 Biological activity I₅₀screen   The inhibitory activity of the compounds of the present invention was measured using nitrocefin (final concentration) as the reporter substrate. (91 μM) using 25 mM PIPES pH7 buffer at 10 step concentrations (10 μM). 00, 333, 111, 37, 12.3, 4.1, 1.4, 0.46, 0.15, And 0.05 μM) at 37 ° C. Pre-incubate enzyme and inhibitor for 5 minutes Assay, performed the assay, and performed in the presence of added zinc sulfate. Final concentration, Zn²⁺100 μM). The method is described in detail in the following reference: P ayne et al., J. Antimicrob. Chemother. 28: 255 (1994), Payne et al., Antimicrob.Agents and Chemother. 38: 767 (1994). result   Examples 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 23, 25, In the compounds of 26, 28, 29, 30, 31, 32 and 33, B. fragili I against B. fragilis CfiA metallo-β-lactamase₅₀Values are <500 μM Met. I for compounds E2, E20 and E26₅₀The value must be <1 μM Was found. Compounds of Examples 19, 21, and 27 and captopril (N- (3 '-Mercapto-2' (S) -methylpropionyl) -L-proline) is xanthomo Xanthomonas maltophilia L-1 and Bacillus selenium Us Weak but significant activity against (Bacillus cereus) II metallo-β-lactamase Was presented. Bacteroides fragilis producing metallo-β-lactamase fragilis) against a carbapenam antibiotic. Antibacterial activity:   [MIC = minimum inhibitory concentration (μg / ml)]   Carbapenam's antibacterial activity was enhanced as follows:

────────────────────────────────────────────────── ─── Continuation of front page    (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, L U, MC, NL, PT, SE), OA (BF, BJ, CF) , CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (KE, LS, MW, SD, S Z, UG), UA (AM, AZ, BY, KG, KZ, MD , RU, TJ, TM), AL, AM, AT, AU, AZ , BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, G E, HU, IL, IS, JP, KE, KG, KP, KR , KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, P L, PT, RO, RU, SD, SE, SG, SI, SK , TJ, TM, TR, TT, UA, UG, US, UZ, VN (72) Inventor Paine, David John             United States 19426-0989 Pennsylvania             College Building, Post Office             Box 5089, South Collegeville             No. 1250, Smith Kline Beecham (72) Inventors Bateson, John Hargreaves             UK, RH 3.7A             Lee, Sally, Betchworth, Blockham             Park, SmithKline Beecham Hu             Armaturicals

Claims (1)

[Claims]   1. A therapeutically effective amount of formula (I): [Where,   X is S, S (O) n or CH_TwoIs;   n is 1 or 2;   R is hydrogen, a salt-forming cation, or an ester-forming group that hydrolyzes in vivo. Yes;   R₁And R_TwoAre each hydrogen or an organic substituent;   R_ThreeMay be substituted by hydrogen, up to three halogen atoms (C_1-6) Alkyl , (C_2-6) Alkenyl, (C_2-6) Alkynyl, aryl, aryl (C_1-6) Archi , Heterocyclyl or heterocyclyl (C_1-6) Alkyl; and   R_FourRepresents hydrogen or an acyl group that is hydrolyzed in vivo. Or a pharmaceutically acceptable salt, solvate or in vivo thereof Whether the hydrolyzing ester is administered in combination with a β-lactam antibiotic A method of treating a bacterial infection in a human or animal.   2. Formula (IA): [Wherein, R_Three ¹Is substituted with up to three halogen atoms (C_1-6) Alkyl, ally Le, aryl (C_1-6) Alkyl, heterocyclyl or heterocyclyl (C_{1- 6} ) Is alkyl; and X represents S] Or a pharmaceutically acceptable salt, solvate or in vivo compound thereof. Those esters that hydrolyze.   3. R_Three ¹Is optionally substituted benzyl, phenethyl or phenylpro The compound according to claim 2, which is a pill.   4. R_FourIs hydrogen, lower alkylcarbonyl, optionally substituted benzoy Or phenyl lower alkylcarbonyl which may be optionally substituted. Or the compound according to 3.   5. R₁Or R_TwoIs hydrogen, (C_1-10) Alkyl, aryl, heterocyclyl Or substituted (C_1-10) Alkyl, wherein the substituent is aryl, heterosa Acryl, hydroxyl, (C_1-6) Alkoxy, (C_1-6) Alkanoyloxy, halogen , Mercapto, (C_1-6) Alkylthio, heterocyclylthio, amino, Or di)-(C_1-6) Alkylamino, (C_1-6) Alkanoylamino, carboxy, Or (C_1-65.) Any one of claims 2 to 4, which is an alkoxycarbonyl The compound according to the above.   6. The compound according to any one of claims 2 to 5, wherein R is hydrogen.   7. Asterisk(^*The stereochemistry at the carbon atom with () is D- and the carbon with (+) The compound according to any one of claims 2 to 6, wherein the stereochemistry at the elementary atom is S. .   8. 3- [S-acetyl-2 '(RS) -benzyl-3'-mercaptopropio Nyl] -4 (S) -carboxy-5,5-dimethylthiazolidine.   9. 3- [2 '(RS) -benzyl-3'-mercaptopropionyl] -4 (S)- Carboxy-5,5-dimethylthiazolidine.   10. N- [S-acetyl-3'-mercapto-2 '(RS) -methylpropio Nyl] -D-proline.   11. N- [3'-mercapto-2 '(RS) -methylpropionyl] -D-pro Rin.   12. N- (S-acetyl-3'-mercapto-2 '(S) -methylpropioni Ru) -D-proline.   13. N- (3'-mercapto-2 '(S) -methylpropionyl) -D-proli N.   14． 3- [S-acetyl-3'-mercaptopropionyl] -4 (S) -cal Boxy-5,5-dimethylthiazolidine.   15. 3- [3'-mercaptopropionyl] -4 (S) -carboxy-5,5 -Dimethylthiazolidine.   16. 3- [S-acetyl-3'-mercapto-2 '(S) -methylpropioni Ru] -4 (S) -carboxy-5,5-dimethylthiazolidine.   17． 3- [3'-mercapto-2 '(S) -methylpropionyl] -4 (S) -ka Ruboxy-5,5-dimethylthiazolidine.   18. 3- [S-acetyl-2 '(RS) -benzyl-3'-mercaptopropi Onyl] -4 (R) -carboxy-5,5-dimethylthiazolidine.   19. 3- [2 '(RS) -benzyl-3'-mercaptopropionyl] -4 (R) -Carboxy-5,5-dimethylthiazolidine.   20. 3- [S-acetyl-3'-mercapto-2 '(RS) -methylpropio Nyl] -4 (S) -carboxy-5,5-dimethylthiazolidine.   21. 3- [3'-mercapto-2 '(RS) -methylpropionyl] -4 (S)- Carboxy-5,5-dimethylthiazolidine.   22. N- [S-acetyl-2 '(RS) -benzyl-3'-mercaptopropi Onyl] -D-proline.   23. N- [2 '(RS) -benzyl-3'-mercaptopropionyl] -D-p Lorin.   24. 3- [S-acetyl-2 '(RS) -benzyl-3'-mercaptopropi Onyl] -4 (S) -carboxythiazolidine.   25. 3- [2 '(RS) -benzyl-3'-mercaptopropionyl] -4 (S) -Carboxythiazolidine.   26. 3- [2 '(R) -benzyl-3'-mercaptopropionyl] -4 (S)- Carboxy-5,5-dimethylthiazolidine.   27. 3- [2 '(S) -benzyl-3'-mercaptopropionyl] -4 (S)- Carboxy-5,5-dimethylthiazolidine.   28. 3- [3'-mercapto-2 '(R) -methylpropionyl] -4 (S) -ka Ruboxy-5,5-dimethylthiazolidine.   29. 3- [S-acetyl-3'-mercapto-2 '(S) -methylpropioni Ru] -4 (R) -carboxy-5,5-dimethylthiazolidine.   30. 3- [mercapto-2 '(S) -methylpropionyl] -4 (R) -carbo Xy-5,5-dimethylthiazolidine.   31. N- [S-acetyl-2 '(RS) -benzyl-3'-mercaptopropi Onyl] -L-proline.   32. N- [2 '(RS) -benzyl-3'-mercaptopropionyl] -L-p Lorin.   33. 3- [2 '(S) -benzyl-3'-mercaptopropionyl] -4 (S)- Carboxy-5,5-dimethylthiazolidine-1-oxide. (Sulfoxy De-isomer A)   34. 3- [2 '(S) -benzyl-3'-mercaptopropionyl] -4 (S)- Carboxy-5,5-dimethylthiazolidine-1-oxide. (Sulfoxy De-isomer B)   35. 3- [2 '(S) -benzyl-3'-mercaptopropionyl] -4 (R)- Carboxy-5,5-dimethylthiazolidine.   36. 3- [2 '(R) -benzyl-3'-mercaptopropionyl] -4 (R)- Carboxy-5,5-dimethylthiazolidine.   37. 3- [2 '(R or S) -benzyl-3'-mercaptopropionyl]- 4 (S) -carboxythiazolidine.   38. 3- [2 '(S or R) -benzyl-3'-mercaptopropionyl]- 4 (S) -carboxythiazolidine.   39. 3- [2 '(RS) -mercaptomethyl-4'-phenylbutanoyl] -4 (S) -carboxy-5,5-dimethylthiazolidine.   40. 3- [2 '(RS) -mercaptomethyl-5'-phenylpentanoyl]- 4 (S) -carboxythiazolidine.   41. Formula (II): With a compound of formula (III): 3. The compound of formula (IA) according to claim 2, comprising reacting with a compound represented by the formula: Manufacturing method of compound. Wherein W is a leaving group, Y is R_Four'S or a group convertible thereto,^x Is R or a carboxylate protecting group;₁', R_Two', R_Three'And R_Four'Is R₁ , R_Two, R_Three ¹And R_FourOr a group that can be converted into them (where R, R₁, R_Two , R_Three ¹And R_FourIs as defined in formula (IA)), and if necessary, Y is R_Four'S, R^x, R₁', R_Two', R_Three'And / or R, R₁, R_Two, R_Three ¹and / Or R_FourTo R, R₁, R_Two, R_Three ¹And / or R_FourEven if Good]   42. Formula (IV): [Wherein, R^xIs R or a carboxylate protecting group;₁', R_Two', R_Three'O And R_Four'Is R₁, R_Two, R_Three ¹And R_FourOr a group that can be converted into them,₁' , R_Two', R_Three'And R_Four'Is R₁, R_Two, R_Three ¹And R_FourIf R^xIs other than R is there] A compound represented by the formula:   43. A compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof. , A solvate or an in vivo hydrolysable ester with a synergistically effective amount of Pharmaceutical composition comprising a β-lactam antibiotic and a pharmaceutically acceptable carrier .   44. A medicament comprising the compound of claim 2 and a pharmaceutically acceptable carrier. Drug composition.   45. Claims further comprising a synergistically effective amount of a β-lactam antibiotic. 44. The pharmaceutical composition according to 44.   46. β-lactam antibiotics are imipenem, meropenem, biapenem, BM S181139 ([4R- [4α, 5β, 6β (R^*)]]-4- [2-[(aminoimino Methyl) amino] ethyl] -3-[(2-cyanoethyl) thio] -6- (1-hydroxy Ethyl) -7-oxo-1-azabicyclo [3.2.0] hept-2-en-2-ca Rubonic acid), BO2727 ([4R-3 [3S^*5S^*(R^*)] 4α, 5β, 6β (R^*)] ] -6- (1-Hydroxyethyl) -3-[[5- [1-hydroxy-3- (methyla Mino) propyl] -3-pyrrolidinyl] thio] -4-methyl-7-oxo-1-aza Bicyclo [3.2.0] hept-2-ene-2-carboxylic acid monohydrochloride ), ER35786 ((1R, 5S, 6S) -6- [1 (R) -hydroxymethyl] -2 -[2 (S)-[1 (R) -hydroxy-1- [pyrrolidin-3 (R) -yl] methyl] pi Loridin-4 (S) -ylsulfanyl] -1-methyl-1-carb-2-enem -3-carboxylic acid hydrochloride) and S4661 ((1R, 5S, 6S)- 2-[(3S, 5S) -5- (sulfamoylaminomethyl) pyrrolidin-3-yl] Thio-6-[(1R) -1-hydroxyethyl] -1-methylcarbapen-2-em Carboxyene selected from (-3-carboxylic acid). The composition described Stuff.   47. A compound of formula (I) as defined in claim 1 for use in the treatment of a bacterial infection. Or a pharmaceutically acceptable salt, solvate or hydrolyzed in vivo thereof ester.   48. In the manufacture of a medicament for the treatment of a bacterial infection, a compound of formula (I) or Is a pharmaceutically acceptable salt, solvate or ester thereof which is hydrolyzed in vivo. Use of files.   49. In combination with a carbapenem antibiotic, a therapeutically effective amount of metallo-β- Bacterial susceptibility in humans or animals, comprising administering a lactamase inhibitor How to treat dye.   50. A therapeutically effective amount of metallo in the manufacture of a medicament for the treatment of a bacterial infection -Use of a carbapenem antibiotic in combination with a [beta] -lactamase inhibitor.   51. Metallo-β-lactamase inhibitors can be used as carbapenem antibiotics and A pharmaceutical composition comprising a pharmaceutically acceptable carrier.