Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
  • C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
  • C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
  • C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
  • C07D477/20—Sulfur atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/12—Oxygen or sulfur atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• Ri is a hydrogen atom or a methyl group
• R j is a hydrogen atom, a metal or a nonmetal salt group, or a carboxy protecting group.
• the carboxy protecting group may, for example, be a lower alkyl group or an esterified carboxyl group which is mentioned below.
• “Lower” means that the number of carbon is 1 to 6.
• the “Lower alkyl” includes a normal or a side alkyl such a ⁇ methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, and hexyl.
• “Lower alkoxy” also includes a normal alkoxy or a side alkoxy such a ⁇ methoxy, ethoxy, n-propoxy, i ⁇ opropoxy, n-butoxy, sec-butoxy, t-butoxy.
• R3 represents a hydrogen atom, an imino protecting group or a pharmaceutically acceptable salt.
• An appropriate "imino protecting group” may be a carbamoyl, an aliphaticacyl , an aromaticacyl, heterocyclicacyl , an aiiphaticacyl sub ⁇ tituted with an aromatic group, an aliphaticacyl substituted with a heterocyclic group, all of which are derived from a carboxylic acid, a carbonic acid, a sulfonic acid, or a carbamic acid.
• the aliphatic acyl includes a saturated or unsaturated acyclic or cyclicacyl, for example, a lower alkanoyl such as formyl, acetyl, propionyl, butyl, isobutyryl, valeryl, isovaleryl, pivaroyl, and hexanoyl ; a lower alkylsulfonyl such a ⁇ me ⁇ yl, ethyl ⁇ ulfonyl , propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl, and hexylsulfonyl; a carbamoyl; an N-alkylcarbamoyl such as methylcarbamoyl, and ethylcarbamoyl; a lower alkoxycarbonyl such a ⁇ methoxycarbonyl
• the aromatic acyl includes an aroyl such a ⁇ benzoyl, toluyl, and xyloyl; an N-arylcarbamoyl such a ⁇ N- phenylcarbamoyl, N- tolylcarbamoyl , and N- naphtylcarbamoyl; an aren ⁇ ulfonyl ⁇ uch a ⁇ benzensulfonyl, and tosyl.
• the heterocyclic acyl includes a heterocyclic acyl such a ⁇ proyl , nicotinoyl, isonicotinoyl, thiazolylcarbonyl, thiadiazolylcarbonyl , and tetrazolylcarbonyl .
• the aliphatic acyl substituted with an aromatic group includes an aralkanoyl, for example, a phenyl (lower )alkanoyl such a ⁇ phenylacetyl , phenyl propionyl , and pheny1 hex anoyl ; an a ra l ko xyc arb ony l , fo r exa mpl e , a phenyl(lower)alkoxycarbonyl ⁇ uch a ⁇ a benzyloxycarbonyl, and penetyloxycarbonyl; an aryloxyalkanoyl, for example, a phenoxy(lower)alkanoyl ⁇ uch a ⁇ phenoxyacetyl and phenoxypropinoyl.
• aralkanoyl for example, a phenyl (lower )alkanoyl such a ⁇ phenylacetyl , phenyl
• the aliphatic acyl substituted with a heterocyclic group includes a heterocyclic(lower)alkanoyl , for example, a heterocyclic(lower)alkanoyl ⁇ uch a ⁇ thienylacetyl, i idazolylacetyl, furylacetyl, tetrazolylacetyl, thiazolylacetyl, thiadiazolylacetyl, thienylpropionyl, and thiadiazolylpropionyl.
• a heterocyclic(lower)alkanoyl for example, a heterocyclic(lower)alkanoyl ⁇ uch a ⁇ thienylacetyl, i idazolylacetyl, furylacetyl, tetrazolylacetyl, thiazolylacetyl, thiadiazolylacetyl, thienylpropionyl, and thiadiazolylpropiony
• the above-mentioned acyl group can be substituted with one or more substitutents selected from the group consisting of a lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, pentyl , and hexyl; a halogen such a ⁇ chlorine, bromine, iodine, and fluorine; a lower alkoxy ⁇ uch a ⁇ methoxy, ethoxy, propoxy, i ⁇ opropoxy, butoxy, pentyloxy, and hexyloxy; a lower alkylthio such a ⁇ methylthio, ethylthio, propylthio, i ⁇ opropylthio, butylthio, pentylthio, and hexylthio; nitro.
• a lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, pentyl , and
• the preferable acyl group having ⁇ uch sub ⁇ titute ⁇ are selected from the group consi ⁇ ting of a mono(or di , or tri)halo alkanoyl such a ⁇ chloroacetyl, bromoacetyl, dichloroacetyl, and trifluoroacetyl; a mono(or di or tri )haloalkoxycarbonyl such a ⁇ chloromethoxycarbonyl , di chl o romethoxyca rbonyl , and 2 , 2 , 2 - trichloroethoxycarbonyl ; a nitro(or halo, or lower alkoxy) ; an a r a 1 k ox yc a bo ny 1 such a ⁇ nitrobenzyloxylcarbonyl , chlor Tavernzyloxycarbonyl , methoxybenzyloxycarbonyl , monofor di , or tr i ) halo (lower )
• the "imino protecting group” i ⁇ preferably (C j -C ⁇ ) alkenyloxycarbonyl, phenyl ( C j -C,, )alkoxycarbonyl , o- nitro(or m-nitro, or p-nitro)benzyloxycarbonyl , and o- methoxy(or m-methoxy, or p-methox )benzyloxycarbonyl .
• R ⁇ _ represents a hydrogen atom, lower alkyl group, a hydroxy group, a cyano group, a halogen group such a ⁇ chlorine, bromine, iodine, and fluorine.
• j represents a hydroxy group, a lower alkoxy group, a protected or unprotected amino group, or one of the following general formula (l)-(4);
• R j and R 7 are independently either a hydrogen atom or a lower alkyl group.
• R j is a hydroxy group, a cyano group, a halogen atom such as chlorine, bromine, iodine, fluorine, or a heterocyclic group of a 5-or 6- membered ring containing 1 to 4 heteroatoms which may be optionally substituted with an appropriate substituent, a protected or unprotected amino group, a the following general formula, NH R 9
• R j is a lower alkylsulfonyl such as methylsulfonyl, halo(CJ-C )alkylsulfonyl, a phenyl(C j -
• C4)alkylsulfonyl such as a p-toluenesulfonyl
• a N,N- ( lower)dialkyl ⁇ ulfamoyl such as a N,N-dimethyl ⁇ ulfamoyl
• R 7 wherein R j , R7 are the same as defined above.
• the heterocyclic group of a 5-or 6-membered ring containing 1 to 4 heteroatoms includes an unsaturated 5 or 6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolidiyl, imidazolyl( ⁇ uch as 2-imidazole) , imidazolinyl(such as 2- imidazolinyl) , pyrazolyl, pyrazolinyl, pyridyl, pyridyl N- oxide, pyri din i o, di hyd ropyridyl , tetrahydropyridyl(such a ⁇ 1,2,3,6-tetrahydropyridyl) , pyrimidinyl, pyrimidinio, pyrazinyl, pyrazinio, pyridazinyl(such as 1,3,5-triazinyl- , 1,2,4-triazinyl
• the above-mentioned heterocyclic group can be substituted with 1 to 3 substituents selected from the group consisting of an amino group; an amino protecting group which is the same as the imino protecting group defined above; a lower alkylamino(such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, and hexylamino); ureido(lower)alkyl(such as ureidomethyl, ureidoethyl, ureidopropyl, ureidohexyl); carbamoyl; a lower alkyl as defined above; an amino(lower)alkyl(such as aminomethyl, aminoethyl, aminopropyl, aminobutyl, and aminohexyl); a ,hydroxy(lower)alkyl and protected hydroxy(lower)alkyl; an azido(lower)alkyl(such a ⁇ azidomethyl
• the "protected hydroxy( lower)alkyl” includes a phenyl(C j -C ⁇ )alkoxycarbonyloxy(C -C ⁇ )alkyl having a nitro group; a triphenyl(C j -C ⁇ )alkoxy(C j -C ⁇ )alkyl having a nitro group; a tri(C j -C ⁇ )alkylsilyloxy(Ci-C. )alkyl having a nitro group.
• thiazolyl has the group of an amino or protecting amino group at the 2-position, or an 1,2,4- oxadiazolyl having the group of an amino or protecting amino group at the 3 position, the above-mentioned heterocyclic groups have "tautomeric isomer ⁇ " a ⁇ shown in the following formula;
• R ⁇ is an amino or a protected amino group
• ⁇ is an imino or a protected imino group
• the "protected amino group” includes the amino group which has one of the group of C1-C4 alkoxycarbonyl such as t-butyloxycarbonyl; a halo(Cl-C3)alkoxycarbonyl such as 2-iodoethyloxycarbonyl, and 2,2,2- trichloroethyloxycarbonyl ) ; a substituted or unsubstituted al(lower)alkyloxycarbonyl; a substituted or unsubstituted phenyl(Cl-C3)alkyloxycarbonyl such a ⁇ benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o- nitrobenzyloxycarbonyl, and p-nitorbenzyloxycarbonyl; tri(Cl-C4)alkylsilyl such as trimethylsilyl and t- butyldimethylsilyl attached to an amino group, wherein n is an integer of 1 to
• the present invention provides a process for preparing a compound of the following (IV),
• the compound of the present invention has the basic structure as follows:
• the present invention includes optical isomers based on the asymmetrical carbon atoms at the 1- position, 5-position, 6-position and 8-position of the carbapenem structure.
• optical isomers based on the asymmetrical carbon atoms at the 1- position, 5-position, 6-position and 8-position of the carbapenem structure.
• isomers is a preferred compound of a (5R,6R,8R) configuration, i.e., a compound having the same stereo-configuration (5R,6S) (5,6-trans) as thienamycin in which the carbon atom at the 8-po ⁇ ition take ⁇ an R-configuration, or a compound of a (1R,5S,6S,8R) configuration where a methyl group is present at the 1-position.
• R j , R j , R j , R ⁇ and R j are as defined above.
• the 2' - (N-substituted)pyrrolidin-4' -yl-thio group also includes all prossible isomers based on the asymmetrical carbon atoms at the 2- and 4-position ⁇ of the pyrrolidine structure.
• preferred compound ⁇ are of a (2'S,4'S) configuration and a (2'R,4'S) configuration.
• ( lower)alkoxide / group R 6 of N group is a hydrogen atom or a
• the compound of formula (II) should be converted to its reactive derivative ⁇ before reacting with the formula (III). That is, the compound of formula (II) i ⁇ added to the inert organic ⁇ olvent and reacted with activating agents under alkali conditions to obtain the activating derivative ⁇ of the formula (Il-a),
• the activating reagent to be used for the reaction may, for example, be an acid anhydride such a ⁇ methanesulfonic anhydride, trifluromethanesulfonic anhydride, p -toluene ⁇ ulfonic anhydride, and trifluoroacetic anhydride; or an acid chloride such a ⁇ methanesulfonyl chloride, p-toluenesulfonyl chloride or diphenyl chlorophosphate. Particulary preferred i ⁇ diphenylchlorophosphate.
• A is a leaving group such as tri fluoroacetoxy, methanesulfonyl oxy , trifluoromethanesulfonyloxy, p-toluenesulfonyloxy or diphenoxyphosphoryloxy. Particularly preferred i ⁇ a diphenoxyphosphoryloxy group.
• the inert organic solvent to be used for the reaction may, for example, be methylene chloride, chloroform, carbon tetrachloride, dichloroethane, trichloroethylene, diethylether, tetrahydrofuran, dioxane, benzene, toluene, chlorobenzene, acetone, ethylacetate, acetonitrile, N,N-dimethylformamide, hexamethylphosphorictriamide or a mixture of such solvent.
• Particulary preferred is acetonitrile, benzene, toluene, the mixture of toluene and benzene, or the mixture of toluene and ethylacetate.
• the ba ⁇ e to be used for the reaction may, for example, be trimethylamine, triethylamine, N,N- di i ⁇ opropylethylamine, N -methylmorpholine, N- methylpyrrolidine , N -methylpiperidine , N,N- dimethylaniline, 1 , 8- diazabicyclo [ 5 ,4 ,0 ]endec -7 - ene(DBU), or 1, 5-diazabicyclo[ ,3,0] -non-5-ene(DBU) , or pyridine 4-dimethylaminopyridine, picoline, lutidine, quinoline or isoquinoline. Particularly preferred is N,N-diisopropylethylamine and triethylamine.
• the 3,7-dioxo-l- azabicyclof 3,2,0]heptane ring system of the following formula (II) has a tautomeric relation with 3-hydroxy-7- oxo-1-azabicyclof3,2,0 ]hept-2-end ring system and these two ring systems are substantially the same.
• the reaction from 1 to 3 mol, preferably from 1 to 1.5 mol of the base and from 1 to 1.3 mol of the activating reagent are used per mol of the compound of the formula (II) .
• reaction temperature i ⁇ not important, the reaction i ⁇ conducted u ⁇ ually within a temperature range of from -40° to 50°C, preferably -20° to 20°C, and usually completed quantitatively in from 0.5 to 3 hours.
• the compound of the formula (II-a) may be reacted with the compound of the formula (III) without isolation.
• the reaction i ⁇ conducted using the above- mentioned inert organic solvent and the base and from 1 to 2 mol, preferably from 1 to 1.5 mol, of the base and from 0.8 to 1.2 mol of the compound of the formula (III) are used per mol of the compound of the formula(II-a) .
• the compound of the formula (IV) can be prepared in one pot reaction from the compound of the formula (II), namely, without isolating the reactive derivative of the formula (Il-a).
• the base is employed per mol of the compound of the formula (II).
• usual treatment i ⁇ conducted to obtain a crude product of the formula (IV), which may be subjected to a reaction for removing a protecting group without purification.
• it i ⁇ preferred to purify the crude product (IV) by crystallization or by column chromatography on, e.g., silica gel.
• a compound of the formula (I) can be obtained, if necessary, by removing a protecting group for a hydroxyl group, an imino group and a carboxyl group.
• the method varies depending upon the type of the protecting groups.
• the removal can be conducted in accordance with methods known in the are, for example, by addition of a ⁇ olvent for decomposition; by chemical reduction using salt of an amine, a metal such as zinc amalgam, a chromic compound such as chloro chromou ⁇ , a formyl chromous together with an organic or inorganic acid such as acetic acid, propionic acid, hydrochloric acid, hydrosulfuric acid; or by catalytic hydrogenation using a platinum or palladium compound.
• the protecting group of the hydroxyl group, amino group or the imino group i ⁇ an aralkyloxycarbonyl group such a ⁇ a benzyloxycarbonyl group or a p-nitrobenzyloxycarbonyl group
• the protecting group for the carboxyl group i ⁇ an aralkyl group such as a benzyl group, a p-nitrobenzyl group or a benzhydryl group.
• Such protecting groups can be removed by catalytic hydrogenation by means of a platinum catalyst such as platinum oxide, platinum wire or platinum black, or a palladium catalyst such as palladium black, palladium black, palladium oxide, palladium carbon or palladium hydroxide carbon (Pearlman's catalyst).
• a platinum catalyst such as platinum oxide, platinum wire or platinum black
• a palladium catalyst such as palladium black, palladium black, palladium oxide, palladium carbon or palladium hydroxide carbon (Pearlman's catalyst).
• the protecting group of the carboxyl group is an allyl group, allylisopropenyl
• a palladium ligand complex catalyst such as a ⁇ palladium-carbon, palladium black, palladium hydroxide -carbon, palladium (II) chloride, tetrakis (triphenylphosphine) palladium ( 0) , bi ⁇ (dibenzylidenylacetone) -palladium (0), di(l,2- bis(diphenylp o ⁇ pino (ethane) palladium, and tetrakis(triphenylphosphine)palladium (0) .
• a palladium ligand complex catalyst such a ⁇ palladium-carbon, palladium black, palladium hydroxide -carbon, palladium (II) chloride, tetrakis (triphenylphosphine) palladium ( 0) , bi ⁇ (dibenzylidenylacetone)
• the reaction can be completed in from 0.5 to 8 hours at a temperature within a range of from 0° to 40°C under a hydrogen gas stream of from 1 to 3 atm.
• a solvent useful for the reaction includes, for example, acetone, .diethyl ether, tetrahydrofuran, dioxane, ethylacetate, acetonitrile, methylenechloride, chloroform and the solvent mixture thereof.
• the allyl group-capturing agent may be, for example, sodium 2- ethylhexanoate, potassium 2-ethylhexanoate, pyridine, piperidine.
• the reaction i ⁇ conducted usually within a temperature range of from -10° to 50°C, preferably from 0° to 30 C° using from O. ⁇ l to 0.5 mol of the palladium ligand complex catalyst and from 0.5 to 5 mol of the nucleophilic agent relative to 1 mol of the compound of the formula (IV), and the reaction is completed usually in from 0.5 to 5 hours.
• the compound of the formula (I) can be isolated by column chromatography loading on silica gel, ad ⁇ orptive resin such as Diaion HP-29, or freeze drying or crystallization.
• the compound of the formula (II) as the starting material can be obtained by the Salzmann method (J. Am. Chem. Soc. Vol 102, 6161-6163, 1980) which i ⁇ incorporated herein by reference in the case that R 1 i ⁇ a hydrogen atom, and by Shih method (Heterocycle ⁇ , Vol. 21, 29-40, 1984 or EP No. 272,455) which are incorporated herein by reference in the case where j i ⁇ a methyl group.
• the compound of the formula (III) as the starting material can be obtained by the following scheme 1 or scheme 2.
• Imipenem was used as internal standard material. After 10 ml of Mueller Hinton Broth was poured into the sterilized test tubes, one platinum loop of each test microorganism was inoculated and incubated overnight at 37°C. Staphylococcus aureu ⁇ was cultured in Trypticase Soy Broth in ⁇ tead of Mueller Hinton Broth.
• the antibacterial agent ⁇ olution ⁇ were prepared by dissolving 5 mg of each antibacterial agent in sterilized distilled water to give the concentration of 1 mg/ml, and by preparing a two-fold dilution series to concentration of 0.25 ⁇ g/ml.
• MIC Minimal Inhibitory Concentration Test. 0.11 ml of bacterial culture was poured into a sterilized test tube containing 10 ml of buffered saline gelatin (BSG) solution and thoroughly mixed. The agar plate containing the antibacterial agent was then inoculated with a bacterial suspension using a stamp, and cultured at 37°C for 18 hour ⁇ . After observing the growth of bacteria, MIC was con ⁇ idered to be the lowe ⁇ t drug concentration at which there i ⁇ no growth. The re ⁇ ult ⁇ are shown in table 1.
• the above precipitate ⁇ were dissolved in a Tris buffer, and loaded on DEAE-Sepharose fast flow, and anion exchange chromatography was carried out to give the swine DHP-I.
• the above DHP-I was divided into 1ml portion of the concentration of 1 unit/ml and stored at 0°-70°C.
• Glycyldehydrophenylalanie and imipenem were employed as control compounds. Accordingly to Campbell's method (Methods Engymol . 19:722-729, 1970) incorporated herein -by reference, the decrease in absorbence due to enzyme reaction is observed, and can be used to determine the maximum hydrolysi ⁇ velocity. The stability to DHP-I is represented as the comparative hydrolysi ⁇ velocity to that of GDP. Table 2. Stability to renal dehydropeptida ⁇ e-1 from porcine
• the compound ⁇ of the pre ⁇ ent invention have excellent antibacterial activitie ⁇ against various gram positive bacteria and gram negative bacteria and are useful a ⁇ antibacterial agent ⁇ for treatment and prevention of human infectious diseases caused by such bacteria. Because of the broad antibacterial spectrum the compounds of the present invention may be used in the form of additives for animal food, preserving agents, and other sterilization and disinfection agent ⁇ for indu ⁇ trial use as well as medical use.
• the compound of the present invention may be used in the form of drug formulation suitable for nonoral administration, oral administration, external administration; liquid formulation such as injection solution ⁇ , syrups or emulsion ⁇ ; solid formulation such a ⁇ tablets, capsules or granules; and external application formulations such a ⁇ ointments or ⁇ uppo ⁇ ition ⁇ .
• Dosage varies depending upon the condition of the patient, the weight, -age, sex, type of formulation, and how the dose is to be administered. Usually, however, a preferred daily dose of the active ingredient to an adult i ⁇ from about 5 to 50 mg/kg, and a preferred daily dose to a child is within a range of from about 5 to 25 mg/kg, which is preferably administered once a day or several times a day.
• the compound of the present invention may be administered in combination with a DHP-I inhibiting agent such as cilastatin.
• a DHP-I inhibiting agent such as cilastatin.
• silica gel 60 F jj ⁇ (Merck) was u ⁇ ed as the plate, and an ultraviolet detector or ninhydrin color development method KM n O j wa ⁇ u ⁇ ed a ⁇ a detecting means.
• silica gel for a column silicagel 60 (Merck) was used, and UV spectrophotometer DMS 100S (Varian) wa ⁇ used for detecting the UV absorbency.
• UV spectrophotometer DMS 100S (Varian) wa ⁇ used for detecting the UV absorbency.
• an M- 352 (ACS) model was used for high speed liquid chromatography.
• TMS tetramethylsiland
• DSS 2,2-dimethyl-2- silapentane-5-sulfonate
• CDCI3 chlorform-di D ⁇ : deuterium oxide J : coupling integer Hz : hertz dd : double doublet m : multiplet REFERENCE EXAMPLE 1
• the reaction mixture wa ⁇ concentrated under reduced pressure, and ethylacetate wa ⁇ added to the re ⁇ idue to extract the product.
• the extract wa ⁇ washed ⁇ ucces ⁇ ively with water and saturated aqueous sodium chloride, and the organic layer dried over anhydrou ⁇ magne ⁇ ium ⁇ ulfate. After the filtration, the filtrate wa ⁇ concentrated under reduced pre ⁇ ure and the ⁇ olvent evaporated to obtain 2.55 g of crude material.
• reaction mixture wa ⁇ concentrated under reduced pressure, and ethylacetate wa ⁇ added to the re ⁇ idue to extract the product.
• reaction mixture wa ⁇ concentrated under reduced pre ⁇ ure, and methylenechloride wa ⁇ added to the re ⁇ idue to extract the product.
• the extract was wa ⁇ hed with water and saturated with aqueous sodium chloride and the organic layer dried over anhydrous magnesium sulfate. After the filtration, the filtrate wa ⁇ concentrated under reduced pressure and the solvent evaporated to obtain 1.32 g of crude material.
• reaction mixture ⁇ olution wa ⁇ concentrated under reduced pres ⁇ ure, and methylenechloride wa ⁇ added to the re ⁇ idue to extract the product.
• the extract wa ⁇ treated with the same operation as EXAMPLE 8-1 to obtain 1.42 g of crude material.
• reaction mixture ⁇ olution was concentrated under reduced pressure, and methylenechloride wa ⁇ added to the re ⁇ idue to extract the product.
• the extract was treated with the same operation as EXAMPLE 8-1 to obtain 2.45 g of crude material.
• EXAMPLE 16-1 1.520 g (4.19 mmol) of ( 4R,5R,6S,8R) -p-nitrobenzyl- 4-methyl- 6- ( 1-hydroxyethyl) -1-azabicyclof 3,2,0] -hept- 3,7-dione-2-carboxylate obtained in REFERENCE EXAMPLE 1 wa ⁇ added to 180 ml anhydrou ⁇ acetonitrile, stirred at room temperature and cooled to 0°C using an ice bath.
• reaction mixture was concentrated under reduced pres ⁇ ure, ethylacetate wa ⁇ added to the residue to extract the product.
• the extract wa ⁇ treated, a ⁇ di ⁇ cribed in EXAMPLE 8-1, to obtain 3.25 g of crude material.
• reaction mixture solution was stirred overnight.
• the mixture ⁇ olution wa ⁇ concentrated under reduced pre ⁇ sure to evaporate the ⁇ olvent, and then extracted with ethylacetate. After the extracted solution was washed several times with water and saturated with sodium chloride, the organic layer was dried over anhydrous magnesium sulfate, filtered and then the filtrate was concentrated under reduced pressure to give 11.5 g of the residue.
• the mixture ⁇ olution wa ⁇ concentrated under reduced pre ⁇ ure to evaporate the solvent, and the residue wa ⁇ extracted with ethylacetate and wa ⁇ hed ⁇ uccessively with water and ⁇ odium chloride. After the separation of the organic layer, it was dried over anhydrous magnesium sulfate, filtered, and then the filtrate was concentrated to give 5.7 g of the re ⁇ idue.
• reaction solution A After 1.97 g (18.58 mmol) of sodium bicarbonate and 2.46 g (34.4 mmol) of hydroxylamine hydrochloride salt were added to 380 ml of water and stirred to dissolve (the reaction solution A). In another container 14 g (34.2 mmol) of (2S ,4R) -1(p-nitrobenzyloxycarbonyl) -2- formyl-4-tert-butyIdimethyl ⁇ ilyloxypyrrolidinewa ⁇ added in 400 ml of methyl alcohol and di ⁇ olved (the reaction solution B).
• the mixture ⁇ olution wa ⁇ concentrated under reduced pres ⁇ ure to evaporate the ⁇ olvent, and the re ⁇ idue wa ⁇ extracted with ethylacetate.
• Thi ⁇ crude material wa ⁇ subjected to the column chromatography on silica gel (eluted with n-hexane:ethylacetate 1:1.5).
• the re ⁇ idue was extracted with ethylacetate, and the organic layer washed with water and ⁇ aturated sodium chloride, and dried over anhydrous magnesium sulfate. After filtration, the filtrate wa ⁇ concentrated under reduced pre ⁇ ure to give 5.78 g of the re ⁇ idue.
• EXAMPLE 20-1 1.85 g (3.63 mmol) of (2S,4R)-l(p- nitrobenzyloxycarbonyl) -2-ethoxycarbonylmethoxyimino-4- tert-butyldimethyl ⁇ ilyloxypyrrolidine was added to 30 ml of acetone and stirred to dis ⁇ olve. At room temperature, 2.8 ml of 2 N Sodium hydroxide aqueou ⁇ ⁇ olution was added dropwi ⁇ e and ⁇ tirred for 3 hour ⁇ , and at the ⁇ ame temperature the pH of the ⁇ olution wa ⁇ adju ⁇ ted to pH 2.0 using saturated citric acid.
• the organic layer wa ⁇ dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pre ⁇ ure to give 3.29 g of the crude material.
• the crude material wa ⁇ di ⁇ olved in 70 ml of methylenechloride. After the temperature of the reaction ⁇ olution was adjusted to 0°C using an ice bath, 2.9 ml (21.02 mmol) of triethylamine and 0.98 ml (12.66 mmol) of methanesulfonyl chloride was added dropwi ⁇ e, and raised the temperature up to room temperature by removal of the ice bath. At the same temperature, after stirring for 1 hour, the reaction mixture was concentrated under reduced pres ⁇ ure and extracted with ethylacetate.
• the orgainc layer was washed succe ⁇ sively with water and saturated aqueous ⁇ odium chloride. After ⁇ eparation, the organic layer wa ⁇ dried over anhydrou ⁇ magne ⁇ ium sulfate, filtered, and concentrated to give 5.6 g of the re ⁇ idue.
• the reaction mixture was concentrated under reduced pres ⁇ ure.
• the mixture ⁇ olution wa ⁇ concentrated under reduced pre ⁇ ure, extracted with ethylacetate and wa ⁇ hed ⁇ ucce ⁇ ively with water and brine. After the ⁇ eparation of the organic layer, it wa ⁇ dried over anhydrous magnesium sulfate and filtrate, and then the filtrate wa ⁇ concentrated to give 2.8 g of the re ⁇ idue.
• the solution was stirred at -60°C for 30 minutes 2.03 ml (11.64 mmol) of diisopropylethylamine was added, and the solution from the dry ice bath to naturally raise the temperature to room temperature.
• the solution wa ⁇ stirred for 1 hour, concentrated under reduced pre ⁇ ure, and the re ⁇ idue wa ⁇ extracted with ethylacetate and wa ⁇ hed ⁇ ucces ⁇ ively with water and brine. After the ⁇ eparation of the organic layer, it wa ⁇ dried over anhydrou ⁇ magne ⁇ ium ⁇ ulfate, filtred and then the filtrate wa ⁇ concentrated to give 1.3 g of crude material.
• reaction mixture wa ⁇ stirred at room temperature for 1 hour, and concentrated under reduced pressure, and 200 ml of methylenechloride wa ⁇ added to the re ⁇ idue and wa ⁇ hed with water and brine. After the separation of the organic layer, it was dried over anhydrous ⁇ odium ⁇ ulfate, filtred, and then the filtrate wa ⁇ concentrated to give 7.5 g of crude material.
• EXAMPLE 26-5 In 100 ml of methylalcohol cooled to 0°C using an ice bath, was added 2.8 g (6.31 mmol) of (2S,4S) -1- (p- n i t r o b e n z y l o x y c a r b o n y l ) - 2 - N - ( 2 - pyridinylhydrazono )methyl- 4 -acetylthiopyrrolidine obtained in EXAMPLE 26-4 and stirred to dissolve. 6.31 ml of 2 N sodium hydroxide was added dropwise and ⁇ tirred for 3 minutes.
• the pH of the reaction solution was adjusted to pH 4.2 using saturated citric acid and concentrated under reduced pre ⁇ ure to evaporate the organic ⁇ olvent.
• the re ⁇ idue wa ⁇ di ⁇ olved in methylenechloride, wa ⁇ hed with water, and the organic ⁇ olvent ⁇ eparated and dried over anhydrous ⁇ odium ⁇ ulfate. After filtration, the filtrate wa ⁇ concentrated under reduced pre ⁇ ure to give 4.3 g of crude material. This crude material was subjected to the column chromatography on silica gel (eluted with chlorofor ⁇ methyl alcohol 30:1) and purified to 1.9 g
• EXAMPLE 27-3 The ester compound obtained in EXAMPLE 27-2 wa ⁇ treated, as di ⁇ cribed in EXAMPLE 25, to give the desired product of (2S,4R) -1- (p-nitrobenzyloxycarbonyl ) -2-N- ( 4- methoxybenzylox yea rbonylphenylhyd razono (me thy 1 - 4 - mercaptopyrrolidine .
• EXAMPLE 25-1 was added to 200 ml of methylenechloride and 4.72g(21.89 mmol) of 4 -nitrobenzylchlorof ormate sequentially, 3.9 ml (27.96 mmol) of triethylamine was added and stirred at room temperature for 24 hour ⁇ .
• the reaction mixture wa ⁇ wa ⁇ hed with water and the organic layer wa ⁇ dried over anhydrou ⁇ ⁇ odium ⁇ ulfate, filtered, and then the filtrate wa ⁇ concentrated under reduced pres ⁇ ure.
• the mixture ⁇ olution wa ⁇ wa ⁇ hed with water and the organic layer was dried over anhydrou ⁇ ⁇ odium sulfate, filtered, and then the filtrate wa ⁇ concentrated under reduced pres ⁇ ure to give 3.2 g of the re ⁇ idue.
• the mixture ⁇ olution wa ⁇ ⁇ tirred at room temperature for 1.5 hour ⁇ washed with water and saturated sodium chloride, and the organic layer wa ⁇ drier over anhydrou ⁇ sodium ⁇ ulfate. After filtration, the filtrate wa ⁇ concentrated under reduced pres ⁇ ure to give 6.8 g of crude material.
• the mixture ⁇ olution wa ⁇ concentrated under reduced pre ⁇ sure, and then extracted with ethylacetate. After the extracted solution was washed several times with water and saturated aqueou ⁇ ⁇ odium chloride, the organic layer wa ⁇ dried over anhydrou ⁇ magne ⁇ ium ⁇ ulfate, filtered, and then the filtrate wa ⁇ concentrated under reduced pre ⁇ ure to give 7.2 g of the re ⁇ idue.
• the re ⁇ idue wa ⁇ subjected to the column chromatography on ⁇ ilica gel (eluted with n-hexane :ethylacetate 2:l ) and purified to
• the crude material was dissolved in 120 ml of methylenechloride, and 4,7 ml (33.60 mmol) of triethylamine and 1.6 ml (20.67 mmol) of methanesulfonylchloride were added and ⁇ tirred at room temperature for 30 minutes. After the reaction, the reaction mixture solution was washed with water and saturated aqueous sodium chloride, and the organic layer was dried over anhydrou ⁇ sodium sulfate, filtered, and then the filtrate was concentrated to give 5.7 g of crude material.
• reaction mixture ⁇ olution wa ⁇ cooled to 0°C u ⁇ ing an ice bath, and 2.23 ml (16.0 mmol) of triethyamine and 0.95 ml (12.3 mmol) of methanesulfonylchloride wa ⁇ added and stirred at the same temperature for 30 minutes. After the reaction, the organic layer wa ⁇ washed with water, and washed succe ⁇ ively with citric acid ⁇ olution and ⁇ odium chloride ⁇ olution.

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