Aminooxypyrrolidinylthiocarbapenem compounds

Abstract: An antibacterial aminooxypyrrolidinylthiocarbapenem I, its production from the corresponding carbapenem V and thiol VI, its pharmaceutical formulation, and its use for combating bacteria are presented. The aminooxypyrrolidinylthiocarbapenem ( I ) and its intermediates ( V ) and ( VI ) have the following formulas: (wherein R is optionally substituted amino; R¹ is hydrogen or 1C to 5C alkyl; R² is hydrogen or a conventional hydroxy protective group; R³ is hydrogen or an imino protective group or imino substituent; R⁴ is 1C to 5C alkylene; and R⁵ is hydrogen or a conventional carboxy protective group; X is a leaving group; R⁶ is hydrogen or a thiol protective group; and wavy lines each shows a bond in R or S configuration and its salts).

Description: This invention relates to novel carbapenem antibacterials. More specifically, it relates to aminooxypyrrolidinylthiocarbapenems of formula I and its salts: wherein R is optionally substituted amino; R 1 is hydrogen or 1C to 5C alkyl; R 2 is hydrogen or a conventional hydroxy protective group; R 3 is hydrogen or an imino protective group or imino substituent; R 4 is 1C to 5C alkylene; and R 5 is hydrogen or a conventional carboxy protective group; and wavy lines each shows a bond in R or S configuration . Several carbapenem antibacterials having pyrrolidinylthio at position 2 are known {e.g., (5R,6S)-2-[1-(1-acetoimidoyl)pyrrolidin-3-ylthio]-6-[(1R)-1-hydroxy-ethyl]carba-2-penem-3-carboxylic acid (CS533), (1R,5S,6S)-2-[(3S,5S)-5-dimethylaminocarbonylpyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid (Meropenem), (1R,5S,6S)-2-[6,7-dihydro-5H-pyrazolo[1,2-a]-(1,2,4-triazolium-6-yl)thio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid (LJC-10627), (1R,5S,6S)-2-[(3S,5S)-5-methanesulfonylaminomethylpyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid (Japanese Patent Publication Kokai Showa-63-179876)}. However, new potent antibacterials are always demanded to cope with appearance of new resistant strains of bacteria. The present invention provides useful carbapenem antibacterials of Formula I having a pyrrolidinylthio group substituted by an unique aminooxyalkyl moiety at position 2. Compounds of Formula I are found to have excellent antibacterial activity in vitro against Gram-negative bacteria, physico dynamic characteristics, therapeutical properties in treating bacterial infections, as well as excellent chemical and metabolic properties in vivo. The followings explain some definitions for the compounds of this invention. In this specification, the substituent in the substituted amino R can be a 1C to 10C monovalent amino substituent selected from alkyl, acyl, alkoxy-carbonyl, optionally substituted carbamoyl, alkylsulfonyl, optionally substituted sulfamoyl; especially methyl, acetyl, carbomethoxy, N-methylcarbamoyl, methanesulfonyl, sulfamoyl or a 1C to 10C divalent amino substituent selected from alkylidene, cyclic diacyl; especially ethylid-ene or phthaloyl. R may have one or two of the said monovalent amino substituents or one of the said divalent amino substituents. The alkyl is a 1C to 10C straight or branched chain saturated hydrocarbon group (e.g., methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1,2-dimethylbutyl, hexyl, heptyl, octyl). The alkylene is a straight or branched 1C to 5C divalent hydrocarbon group (e.g., methylene, ethylene, propylene). The substituent R 3 is an 1C to 19C imino protective group including a 1C to 8C alkyl (e.g., trichloroethyl, methoxyethoxymethyl, tetrahydropyranyl), a 7C to 19C aralkyl (e.g., triphenylmethyl, methoxybenzyl), a 1C to 8C alkylthio, a 6C to 8C arylthio (e.g., nitrophenylthio), a 1C to 8C acyl [e.g., 1C to 8C alkanoyl (e.g., formyl, acetyl, chloroacetyl), a 2C to 8C alkoxycarbonyl (e.g., having methyl, ethyl, cyclopropylmethyl, cyclopropylethyl, isoproyl, butyl, isobutyl, hexyl, trichloroethyl, pyridylmethyl, or cyclohexyl in the alkoxy group), an 3C to 19C aralkoxycarbonyl (e.g., that having benzyl, diphenylmethyl, or nitrobenzyl in the aralkoxy group), a 7C to 12C aroyl (e.g., benzoyl, nitrobenzoyl)], a 3C to 9C trialkylsilyl, 1C to 5C amidino (e.g., amidino, dialkylamidino). or the like. The hydroxy protective group is an easily removable 1C to 19C ester forming group [carboxylic acyl, for example, lower alkanoyl (e.g., formyl, acetyl, propionyl, pivaloyl), aroyl, (e.g., benzoyl, toluoyl, xyloyl), a 2C to 10C alkoxycarbonyl (e.g., t-butoxycarbonyl, cyclopropoxymethoxycarbonyl), an 8C to 15C aralkoxycarbonyl (e.g., benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl)], an easily removable 2C to 8C ether forming group (e.g., tetrahydropyranyl, tetrahydrofuranyl, methoxymethyl, methoxyethoxymethyl), or a 3C to 10C hydrocarbylsilyl (e.g., trimethylsilyl, triethylsilyl, t-butyldimethylsilyl). The carboxy protective group can be one of those for synthetic purposes containing 1 to 19 carbon atoms known in this art as those introducable and removable without adverse effect on other parts of the molecule. Representative are ester forming groups, e.g., 1C to 8C alkyl (e.g., methyl, methoxymethyl, ethyl, ethoxymethyl, iodoethyl, propyl, isoproyl, butyl, isobutyl, ethoxyethyl, methylthioethyl, methanesulfonylethyl, trichloroethyl, t-butyl), 3C to 8C alkenyl (e.g., propenyl, allyl, prenyl, hexenyl, phenylpropenyl, dimethylhexenyl), 7C to 19C aralkyl (e.g., benzyl, methylbenzyl, dimethylbenzyl, methoxybenzyl, ethoxybenzyl, nitrobenzyl, aminobenzyl, diphenylmethyl, phenethyl, trityl, di--t-butylhydroxybenzyl, phthalidyl, phenacyl), 6C to 12C aryl (e.g., phenyl, tolyl, diisopropylphenyl, xylyl, trichlorophenyl, pentachlorophenyl, indanyl), 1C to 12C amino (e.g., forming an ester with acetone oxime, acetophenone oxime, acetaldoxime, N-hydroxysuccinimide, N-hydroxyphthalimide), 1-oxygenated-2C to 15C alkyl {e.g., straight, branched, cyclic, or partially cyclic alkanoyloxyalkyl (e.g., acetoxymethyl, acetoxyethyl, propionyloxymethyl, pivaloyloxymethyl, pivaloyloxyethyl, cyclohexaneacetoxyethyl, cyclohexanecarbonyloxycyclohexylmethyl), 3C to 15C alkoxycarbonyloxyalkyl (e.g., ethoxycarbonyloxyethyl, isopropoxycarbonyloxyethyl, isopropoxycarbonyloxypropyl, t-butoxycarbonyloxyethyl, isopentyloxycarbonyloxypropyl, cyclohexyloxycarbonyloxyethyl, cyclohexylmethoxycarbonyloxyethyl, bornyloxycarbonyloxyisopropyl), 2C to 8C alkoxyalkyl (e.g., methoxymethyl, methoxyethyl), 4C to 8C 2-oxacycloalkyl (e.g., tetrahydropyranyl, tetrahydrofuranyl)}, 8C to 12C aralkyl (e.g., phenacyl, phthalidyl), 6C to 12C aryl (e.g., phenyl, xylyl, indanyl), 2C to 12C alkenyl (e.g., allyl, prenyl, 2-oxo-1,3-dioxol-4-ylmethyl), or the like. The salt at R 5 is preferably a light metal forming a pharmaceutically acceptable ion conventional in the penicillin and cephalosporin fields and belonging to group I to III and period 2 to 4 of the Periodical Table, for example, an alkali metal (e.g., sodium, potassium, lithium), an alkaline earth metal (e.g., magnesium, calcium), aluminum, or the like. The ammonium salt at R 5 is preferably a salt with 1C to 12C alkylamine (e.g., trimethylamine, triethylamine, methylmorpholine) or a 4C to 9C aromatic base (e.g., pyridine, collidine, picoline, quinoline). The acid for the acid addition salt at R or R 3 is a pharmaceutically acceptable mineral acid (e.g., nitric acid, hydrochloric acid, sulfuric acid), or 1C to 5C organic acid (e.g., citric acid, succinic acid). These groups can further be substituted. Compounds of formula I are all useful for the purpose of this invention. Especially useful are the followings and their alkali metal salts in which the stereochemistry in the pyrrolidine ring is (2S,4R)- or (2S, 4S)-: i.e., R is amino, R 1 is methyl, R 2 and R 3 are hydrogens, R 4 is methylene, and R 5 is hydrogen; R is acetylamino, R 1 is methyl, R 2 and R 3 are hydrogens, R 4 is methylene, and R 5 is hydrogen; R is carbomethoxyamino, R 1 is methyl, R 2 and R 3 are hydrogens, R 4 is methylene, and R 5 is hydrogen; R is methylcarbamoylamino, R 1 is methyl, R 2 and R 3 are hydrogens, R 4 is methylene, and R 5 is hydrogen; R is methanesulfonylamino, R 1 is methyl, R 2 and R 3 are hydrogens, R 4 is methylene, and R 5 is hydrogen; R is sulfamoylamino, R 1 is methyl, R 2 and R 3 are hydrogens, R 4 is methylene, and R 5 is hydrogen; R is methylamino, R 1 is methyl, R 2 and R 3 are hydrogens, R 4 is methylene, and R 5 is hydrogen; and R is ethylideneamino, R 1 is methyl, R 2 and R 3 are hydrogens, R 4 is methylene, and R 5 is hydrogen. This invention also provides a method for producing Compounds of formula I by condensing a carbapenem of formula V or its reactive derivative with a novel thiol of formula VI (R 6 = H) or its reactive derivative followed by optional deprotection or modification. The carbapenem of formula V and the novel thiol of formula VI have the following formulas: (wherein R, R 1 , R 2 , R 3 , R 4 , and R 5 are as defined above, X is a leaving group, and R 6 is hydrogen or a thiol protective group) The leaving group X in the carbapenem of formula V is conventional in the art and can be a 1C to 8C alkanesulfonyloxy (e.g., methanesulfonyloxy, trifluorosulfonyloxy), a 6C to 10C arylsulfonyloxy (e.g., phenylsulfonyloxy, bromobenzenesulfonyloxy, toluenesulfonyloxy), phosphoryloxy (e.g., diphenylphosphoryloxy), or a 1C to 8C sulfinyl (e.g., ethylsulfinyl, phenylsulfinyl). The starting carbopenem of formula V or its production is known. This invention further provides a novel pyrrolidinylthiol of formula VI, a useful intermediate for producing useful carbapenems. The thiol of formula VI is preparable from D- or L-hydroxyproline by combining the following steps in an order suitable for the conventional reactions: 1) Protecting the ring nitrogen (e.g., t-butoxycarbonyl, p-nitrobenzyloxycarbonyl with the corresponding chloride or anhydride and an organic base), 2) Activating the hydroxy for substitution to thiol (e.g., esterification with alkane or arylsulfonic acid chloride to form a leaving group), 3) Substituting the activated hydroxy with a sulfur function (e.g., triphenylmethylthiol with sodium salt), 4) Reducing the carboxy to methylol (e.g., with alkali metal borohydride), if required after activation (e.g., esterification with lower alkanol), 5) Introducing an amino group to the methylol (e.g., with N-hydroxyphthalimide), if required followed by deprotection (e.g., with hydrazine) or modification at amino as R to form the desired R 4 OR group, and 6) Deprotecting at the ring R, R 3 , or thiol, if required. Preferable R 6 is 1C to 10C alkanoyl (e.g., acetyl, isobutyryl). 7C to 10C aroyl (e.g., benzoyl, toluoyl). or 7C to 19C aralkyl (e.g., trityl, benzhydryl). The carbapenem of formula V and thiol of formula VI are condensed in a conventional manner in an aprotic polar solvent (e.g., acetonitrile) in the presence of a tertiary amine (e.g., diisopropylamine) at a low temperature, for example, -50 to +30°C (preferably -40 to 10°C) for 10 minutes to 10 hours (preferably 30 minutes to 5 hours). The product is subjected to deprotection, modification at the ring nitrogen, etc. to obtain the desired Compounds of formula I. The deprotection can be done in a conventional manner for producing carbapenem compounds. For example, a p-nitrobenzyl ester as R 5 is removed in a mixture of tetrahydrofuran and 2-(morpholin-4-yl)ethanesulfonic acid buffer solution by catalytic hydrogenation using palladium on charcoal. Further, some of the carboxy protective ester groups for R 5 (e.g. allyl, isoprenyl, p-methoxybenzyl, diphenylmethyl) and amino protective carbonate acyl groups in R or imino protective carbonic acyl groups for R 3 (e.g., t-butoxycarbonyl, allyloxycarbonyl, p-methoxybenzyloxycarbonyl) can be removed using 1 to 20 (preferably 2 to 15) equivalents of a Lewis acid (e.g., aluminum chloride, stannic chloride, titanium chloride) or a carboxylic acid (e.g., trifluoroacetic acid) in an aprotic solvent (e.g., dichloromethane, anisole, nitromethane) for 1 to 10 (preferably 1 to 5 hours) at -40 to 10 (preferably -30 to 0)°C. A trialkylsilyl hydroxy protective group at R 1 (e.g., trimethylsilyl, triethylsilyl, t-butyldimethylsilyl) can be removed with an aqueous acid (e.g., hydrochloric acid or the like mineral acid). A modification of the ring imino, amidinio introduction, is as follows: Ethylformimidate hydrochloride is added in several portions to a solution of a Compound of formula I in a phosphate buffer of about pH 7 under ice cooling while keeping the pH at 8.5 with 1N-sodium hydroxide. The work up of the reaction mixture is done in a conventional manner in the art to give the free acid, for example, removing unreacted reagent, purifing by crystallization, adsorption and elution, chromatography, lyophilization, etc. Compounds of formula I show potent antibacterial activity in vitro and good physico dynamic properties (e.g., urinary recovery, maximum blood level in mice, and stability to human renal dehydropeptidase 1) as compared with some known carbapenems. For example, Compounds of formula I in which R is methanesulfonylamino (M) or sulfamido (H) show the following percentage improvements over some known carbapenems: vs. Imipenem: twice the antibacterial activity in vitro or more against Gram-negative bacteria (e.g., Escherichia coli H, Escherichia coli SR 5028, Klebsiella pneumoniae SR1, Proteus mirabilis PR4, Morgania morganii SR9, Enterobacter cloacae SR233) (M, H), urinary recovery in mice (M:23%, H:44%), and stability against human renal dehydropeptidase-1 (M:53%, H:39%). vs. Meropenem: urinary recovery (M:151%, H:192%), maximum blood level (M:62%, H:92%), protection of mice from Streptococcus aureus Smith infection (M:370%, H:1300%), and stability to human renal dehydropeptidase-1 (M:3%, H:13%). vs. CS 533: twice the antibacterial activity in vitro or more against Gram-negative bacteria (e.g., Escherichia coli H, Escherichia coli SR 5028, Klebsiella pneumoniae SR1, Proteus mirabilis PR4, Morgania morganii SR9) (M, H), maximum blood level (M:27%, H:51%), urinary recovery in mice (M:71%, H:99%), and stability to human renal dehydropeptidase-1 (M:63%, H:48%). vs. LJ 10627: twice the antibacterial activity in vitro or more against Gram-negative bacteria (e.g., Proteus mirabilis PR4, Proteus vulgaris CN-329, Proteus vulgaris SR3 , Margania morganii SR9, Serratia marsescens A13880) (M, H). vs. a compound in Japanese Patent Publication Kokai 179876/1988: about twice the activity in vitro against Staphylococcus aureus SR 77 and Morgania morganii SR 9 (M) . Thus, Compounds of formula I are useful as medicines, veterinary drugs, disinfectants, antiperishables, etc., and this invention provides an antibacterial agent containing the compound as an effective component and a method for disinfection by contacting the compound with bacteria. Compound of formula I in which R 5 is an alkali metal is suitable for parenteral administration (e.g., intravenous injection, intramuscular injection, drip) and presented in the form of an injection, vials, etc., if required accompanied by a stabilizing and solubilizing agent. The free acid can form an aqueous solution by neutralization before administration. The esters can be used for oral administration as tablets, capsules, granules, powders, etc., for injection as suspensions, oily injections, etc., and for external and topical use as a suppository, eye solution, ointment, emulsion, spray, etc. These preparations can be produced using conventional additives in a conventional manner. An effective amount of compound of formula I or its salt is given to an infected subject by way of, e.g., oral or parenteral route, although the latter is more preferable. For parenteral administration, the compound is formulated to afford an aqueous solution or suspension (suitable for e.g., subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection). For oral administration, Compound of formula I as an acid or ester is mixed with a conventional formulation carrier, diluent, or additives and encapsulated or tabletted. It may be formulated to give a powder or granule in a conventional manner. Preferably the daily dose is about 100 mg to 6 g (e.g., 250 mg to 3 g) for injection and about 100 mg to 6 g (e.g., 250 mg to 4 g) for oral use. The following Examples and Experiment are given to illustrate this invention. These examples, however, are not intended to limit the scope of this invention. The abbreviations are as follows: Boc = t-butoxycarbonyl. Et = ethyl. Ft = phthalyl. Me = methyl. Pnz = p-nitrobenzyloxycarbonyl. Pmz = p-methoxybenzyloxycarbonyl. Tr = trityl. THF = tetrahydrofuran. Example 1. Synthesis of 3-substituent A. Preparation of protected thioaminooxymethylpyrrolidine 1) (2S,4R)-4-hydroxy-2-methoxycarbonyl-1-p-nitrobenzyloxycarbonylpyrrolidine (esterification) Thionyl chloride (18.7 ml) and, after 5 minutes stirring, N-p-nitrobenzyloxycarbonyl-L-hydroxyproline (1: 72.4 g) are added dropwise to a mixture of methanol (94.5 ml) and dichloromethane (945 ml) under ice cooling and the mixture is stirred overnight at room temperature. The reaction mixture is concentrated in vacuo to give crude (2S,4R)-4-hydroxy-2-methoxycarbonyl-1-p-nitrobenzyloxycarbonylpyrrolidine (86.5 g) as pale yellow oil. This product can be used in the next step without further purification. IR ν (CHCl 3 ) cm -1 : 3450, 1742, 1703, 1605. 1 HNMR δ (CDCl 3 ) ppm: 1.77(1H, s), 2.05 to 2.45(2H, m), 3.55 to 3.8(2H, m), 3.66, 3.76(3H, 2s), 4.49 to 4.62(2H, m), 5.06 to 5.35(2H, m), 7.43 to 7.56(2H, m), 8.22(2H, d, J=8.2Hz). 2) (2S,4R)-4-methanesulfonyloxy-2-methoxycarbonyl-1-p-nitrobenzyloxycarbonylpyrrolidine (2) (hydroxy activation) Triethylamine (52 ml) and then methanesulfonyl chloride (21.6 ml) are added to a solution of crude (2S,4R)-4-hydroxy-2-methoxycarbonyl-1-p-nitrobenzyloxycarbonylpyrrolidine (86.1 g) in dichloromethane (1 liter) under ice cooling and the mixture is stirred for 25 minutes. The reaction mixture is acidified with diluted hydrochloric acid and stirred. The organic layer is taken, washed with aqueous sodium hydrogen carbonate and water, dried over sodium sulfate, and concentrated in vacuo to give (2S,4R)-4-methanesulfonyloxy-2-methoxycarbonyl-1-p-nitrobenzyloxycarbonylpyrrolidine (2: 90.0 g) as an organge oil. This product can be used in the next step without further purification. IR ν (CHCl 3 ) cm -1 : 1741, 1703, 1602. 1 HNMR δ (CDCl 3 ) ppm: 2.22 to 2.82(2H, m), 3.07(3H, s), 3.67, 3.78(3H, 2s), 3.75 to 4.03(2H, m), 4.55(1H, t, J=7.8Hz), 5.08 to 5.39(3H, m), 7.43 to 7.58(2H, m), 8.23(2H, d, J=8.6Hz). 3) (2S,4S)-4-triphenylmethylthio-2-methoxycarbonyl-1-p-nitrobenzyloxycarbonylpyrrolidine (3) (thiolation) Triphenylmethylmercaptan (10.9 g) is added in small portions to a suspension of sodium hydride (1.26 g) (60% dispersion in oil) in dimethylformamide (50 ml) under ice cooling and stirred for 5 minutes at room temperature. A solution of crude (2S,4R)-4-methanesulfonyloxy-2-methoxycarbonyl-1-p-nitrobenzyloxycarbonylpyrrolidine (2: 10.6 g) in dimethylformamide (80 ml) is added to this mixture and the whole is stirred in an oil bath at 50°C overnight. The reaction mixture is diluted with ethyl acetate and mixed with ice water containing 1N-hydrochloric acid (35 ml). The organic layer is taken, washed with water and satd. brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by silica gel chromatography (toluene-ethyl acetate) to give (2S,4S)-4-triphenylmethylthio-2-methoxycarbonyl-1-p-nitrobenzyloxycarbonylpyrrolidine (3 : 9.12 g) an orange foam (Yield: 52 % from hydroxyproline) and the starting compound (2: 3.11g: Yield: 29%). IR ν (CHCl 3 ) cm -1 : 1745, 1702, 1602. 1 HNMR δ (CDCl 3 ) ppm: 1.64 to 2.36(2H, m), 2.68 to 3.32(2H, m), 3.32 to 3.55(1H, m), 3.61, 3.65, 3.72(3H, 3s), 4.01 to 4.27(1H, m), 4.95 to 5.32(2H, m), 7.15 to 7.53(17H, m), 8.14 to 8.27(2H, m). 4) ( 2S,4S) - 4-triphenylmethylthio-2-hydroxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine (Reduction of carbomethoxy) A solution of sodium borchydride (371 mg) in ethanol (15 ml) and a solution of lithium chloride (554 mg) in tetra-hydrofuran (15 ml) are added to a solution of (2S,4S)-4-triphenylmethylthio-2-nethoxycarbonyl-1-p-nitrobenzyloxycarbonylpyrolidine (3: 3.63 g) in tetra-hydrofuran (36 ml) under ice cooling and the mixture is warmed to room temperature and stirred for 110 minutes. The reaction mixture is diluted with ethyl acetate under ice cooling, and neutralized with 1N-hydrochloric acid (10 ml) to decompose the remaining reagent. The organic layer is taken, washed with water and saturated brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by silica gel chromatography to give (2S,4S)-4-triphenylmethylthio-2-hydroxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine (4: 3.02 g) as colorless foam. Yield: 88%. IR ν (CHCl 3 ) cm -1 : 3400, 1679, 1603. 1 HNMR δ (CDCl 3 ) ppm : 1.3 to 2.13(2H, m), 1.6(1H, brs), 2.65 to 4.3(6H, m), 5.03 to 5.2(2H, m), 7.07 to 7.55(17H, m), 8.15 to 8.3(2H, m). 5) (2S,4S)-4-triphenylmethylthio-2-phthalimidoxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine (5) (introduction of imidooxy) Triphenylphosphine (315 mg), azodicarboxylic acid diethyl ester (189µl) and, after stirring for 5 minutes, N-hydroxyphthalimide (196 mg), are added to a solution of (2S,4S)-4-triphenylmethylthio-2-hydroxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine (4: 555 mg) in tetrahydrofuran (6 ml) under ice cooling, and the mixture is stirred for 45 minutes. The reaction mixture is concentrated in vacuo. The residue is purified by silica gel column chromatography to give (2S,4S)-4-triphenylmethylthio-2-phthalimidoyloxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine (5: 686 mg) as a pale yellow foam. Yield: 98 %. IR ν (CHCl 3 ) cm -1 : 1783, 1725, 1693, 1602. 1 HNMR δ (CDCl 3 ) ppm: 1.8 to 2.5(2H, m), 2.5 to 3.0(2H, m), 3.15 to 3.54(1H, m), 3.94(1H, brs), 4.08 to 4.5(2H, m), 4.98 to 5.25(2H, m), 7.1 to 7.6(17H, m), 7.65 to 7.95 (4H, m), 8.0 to 8.3(2H, m). 6) (2S,4S)-4-triphenylmethylthio-2-aminooxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine (6) (removing phthalimido) Methylhydrazine (42 µl) is added to a solution of (2S,4S)-4-triphenylmethylthio-2-phthalimidoyloxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine (5: 501 mg) in dichloromethane (5 ml) at -40°C, and the mixture is stirred for 5 minutes and then under ice cooling for further 30 minutes to give a solution of (2S,4S)-4-triphenylmethylthio-2-aminooxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine (6). B. Introduction of amino substituent (2S,4S)-4-triphenylmethylthio-2-acetylaminooxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine (7a) (acetylation) Pyridine (93µl) and acetyl chloride (66µl) are added to a solution of (2S,4S)-4-triphenylmethylthio-2-aminooxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine (6) preparable as above A (6) in dichloromethane and the mixture is stirred for 25 minutes. 1N-hydrochloric acid (1 ml) and ethyl acetate are added to the reaction mixture. The organic layer is taken, washed with water, aqueous sodium hydrogen carbonate, and brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by silica gel chromatography to give (2S,4S)-4-triphenylmethylthio-2-acetylaminooxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine (7: 385 mg) as a pale yellow foam. Yield : 88 %. In a manner similar to B above, the amino substituent is introduced to aminooxypyrrolidine (6) produced in A(6) above under the conditions given in Table 1 to give protected mercaptides. The producing conditions for compounds 7a (prepared by B) to 7g are listed on Table 1. Reaction conditions for introducing amino substituent Reagent equivalents Solv. Base equivalents Temp °C Time min. Crop % a MeCOCl 1.3 CH 2 Cl 2 Py 1.6 0 25 88 b ClCO 2 Me 1.3 CH 2 Cl 2 Py 1.6 0 20 98 c MeNCO 4.6 CH 2 Cl 2 rt 105 100 d ClSO 2 Me 1.55 CH 2 Cl 2 Py 2.4 0 100 94 e' ClSO 2 NHCO 2 PMB 1.1 CH 2 Cl 2 Et 3 N 1.2 0 30 86 f' MZ-SDP 1.2 C 6 H 6 refl 100 60 g MeCHO 5.0 CH 2 Cl 2 0 30 93 Physical constants of protected mercaptides (7a to 7g) Compound 7a R = acetylamino IR ν (CHCl 3 ) cm -1 : 3260, 1680, 1600. 1 HNMR δ (CDCl 3 ) ppm: 1.3 to 2.37(2H, m), 1.87(3H, brs), 2.7 to 2.9(2H, m), 2.98 to 3.22(1H, m), 3.45 to 4.27(3H, m), 5.10, 5.17(2H, 2s), 7.07 to 7.54 (17H, m), 8.17 to 8.30(2H, m). Compound 7b R = carbomethoxyamino IR ν (CHCl 3 cm -1 : 3360, 1720, 1685, 1600. 1 HNMR δ (CDCl 3 ) ppm: 1.38 to 2.38(2H, m), 2.7 to 2.9(2H, m), 2.93 to 3.23(1H, m), 3.47 to 4.23(3H, m), 3.73(3H, s), 5.10, 5.17(2H, 2s), 7.1 to 7.5(17H, m), 8.13 to 8.35(2H, m). Compound 7c R = methylcarbamoylamino IR ν (CHCl 3 ) cm -1 : 3445, 3310, 1685, 1602. 1 HNMR δ (CDCl 3 ) ppm: 1.3 to 2.3(2H, m), 2.7 to 2.92(2H, m), 2.8(3H, brs), 3.05 to 3.58(1H, m), 3.5 to 4.2(3H, m), 5.0 to 5.25(2H, m), 6.12 (1H, brs), 7.1 to 7.52(17H, m), 8.15 to 8.3(2H, m). Compound 7d R = mesylamino IR ν (CHCl 3 ) cm -1 : 3260, 1687, 1602. 1 HNMR δ (CDCl 3 ) ppm: 1.2 to 2.35(2H, m), 2.65 to 2.9(2H, m), 2.96(3H, s), 2.95 to 3.6(1H, m), 3.73 to 4.35(3H, m). 5.08, 5.16(2H, 2s), 7.05 to 7.55(17H, m), 7 .86, 7.95(1H, 2s), 8.1 to 8.3(2H, m). Compound 7e' R = N-sulfamoyl-N-Pmz-amino IR ν (CHCl 3 ) cm -1 : 3370, 3245, 1727, 1687, 1601. 1 HNMR δ (CDCl 3 ) ppm: 1.35 to 2.35(2H, m), 2.65 to 3.6(3H, m), 3.76(3H, s), 3.8 to 4.25(3H, m), 4.95 to 5.2(3H, m), 6.75 to 6.9(2H, m), 7.08 to 7.55(19H , m), 7.6 to 8.4(3H, m). Compound 7f' R = Pmz-amino IR ν (CHCl 3 ) cm -1 : 3375, 1740, 1695, 1607. 1 HNMR δ (CDCl 3 ) ppm: 1.35 to 2.33(2H, m), 2.65 to 3.6(3H, m), 3.79(3H, s), 3.65 to 4.2(3H, m), 4.95 to 5.25(4H, m), 6.87(2H, d, J=9Hz), 7.07 to 7.55(19H, m), 8.1 to 8.3(3H, m). Compound 7g R = ethylideneamino IR ν (CHCl 3 ) cm -1 : 1692, 1600. 1 HNMR δ (CDCl 3 ) ppm: 1.65 to 2.3(2H, m), 1.75 to 1.85(3H, m), 2.6 to 3.62(3H, m), 3.78 to 4.35(3H, m), 5.0 to 5.25(2H, m), 6.71(0.5H, q, J=5.6Hz), 7.1 to 7.6 (17.5H, m), 8.1 to 8.3(2H, m). C. Modification of protected amino 1) (2S,4S)-4-triphenylmethylthio-2-sulfamoylaminooxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine (7e) (deprotection at aminooxy) Anisole (10 ml) and trifluoroacetic acid (10 ml) are added to a solution of (2S,4S)-4-triphenylmethylthio-2-N-p-methoxybenzyloxycarbonylsulfamoylaminooxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine (7e': 9.2 g) in dichloromethane (100 ml) under ice cooling, and the mixture is stirred for 1 hour and concentrated in vacuo. The residue is purified by silica gel chromatography to give (2S,4S)-4-triphenylmethylthio-2-sulfamoylaminooxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine (7e: 5.74 g) as a yellow foam. Yield: 78 %. Compound 7e R = sulfamoylamino IR ν (CHCl 3 ) cm -1 : 3440, 3355, 3245, 1692, 1607. 1 HNMR δ (CDCl 3 ) ppm: 1.3 to 2.4(2H, m), 2.7 to 3.6(3H, m), 3.75 to 4.3 (3H, m), 4.9 to 5.25(3H, m), 7.08 to 7.6(17H, m), 7.6 to 7.75(1H, m), 8.1 to 8.3(2H, m). 2) (2S,4S)-4-triphenylmethylthio-2-N-p-methoxybenzyloxycarbonyl-N-methylaminooxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine (7f") (methylation at aminooxy) A solution of (2S,4S)-4-triphenylmethylthio-2-N-p-methoxybenzyloxycarbonylaminooxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine (7f': 965 mg) in dimethylformamide (2 ml) and, after stirring for 15 minutes, methyl iodide (164 µl), are added dropwise to a suspension of sodium hydride (57.9 mg: 60% dispersion in oil) in dimethylformamide (8ml) under ice cooling, and the mixture is stirred for 30 minutes. The reaction mixture is diluted with ethyl acetate, washed with water, dried over sodium sulfate, and concentrated in vacuo to give crude (2S,4S)-4-triphenylmethylthio-2-N-p-methoxybenzyloxycarbonyl-N-methylaminooxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine (7f": 821 mg). This product can be used in the next step without further purification. Compound 7f" R = N-methyl-N-Pmz-amino 1 HNMR δ (CCCl 3 ) ppm: 1.7 to 2.3(2H, m), 2.6 to 3.65(3H, m), 3.08(3H, s), 3.7 to 4.2(3H, m), 3.76, 3.78(3H, 2s), 4.95 to 5.25(4H, m), 6.8 to 7.0(2H, m) 7.1 to 7.6(19H, m), 8.05 to 8.35(2H, m). 3) (2S,4S)-4-triphenylmethylthio-2-N-methylaminooxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine (7f) (deprotection at aminooxy) Anisole (1 ml) and trifluoroacetic acid (1 ml) are added to a solution of crude (2S,4S)-4-triphenylmethylthio-2-N-p-methoxybenzyloxycarbonyl-N-methylaminooxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine (7f": 821 mg) in dichloromethane (8.2 ml) under ice cooling and the mixture is stirred for 20 minutes and concentrated in vacuo. The residue is purified by silica gel chromatography to give (2S,4S)-4-triphenylmethylthio-2-N-methylaminethyl-1-p-nitrobenzyloxycarbonylpyrrolidine (7f) trifluoroacetate (843 mg). Yield: 94 %. Compound 7f R = methylamino IR ν (CHCl 3 ) cm -1 : 3400, 1685, 1605. 1 HNMR δ (CDCl 3 ) ppm: 1.47 to 2.42(2H, m), 2.65 to 3.52(3H, m), 2.84(3H, s), 4.02 to 4.45(3H, m), 5.09, 5.15(2H, 2s), 7.1 to 7.6(17H, m), 8.05 to 8.5(2H, m). D. Deprotection at thiol (2S,4S)-4-mercapto-2-acetylaminooxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine (8a) (detritylation) Pyridine (149 ml) and then a solution of silver nitrate (289 mg) in a mixture of water (1.5 ml) and methanol (15 ml) are added dropwise to a solution of (2S,4S)-4-tritylthio-2-acetylaminooxymethyl-1-p-nitrobenzyl oxycarbonylpyrrolidine (7a: 452 mg) in methanol (9 ml) under ice cooling and the mixture is stirred for 25 minutes. Separated silver salt is collected by filtration, washed with methanol, ether, and petroleum ether, and dried. Hydrogen sulfide gas is introduced to a suspension of this crude silver salt in a mixture of dichloromethane (3.5 ml) and methanol (3.5 ml) for 5 minutes. The resulting silver sulfide is filtered off and washed with a mixture of methanol and dichloromethane. The filtrate is concentrated in vacuo. The residue is purified by silica gel chromatography to give (2S,4S)-4-mercapto-2-acetylaminooxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine (8a: 198 mg) as a pale yellow foam. Yield: 73 %. Under the reaction conditions listed in Table 2, the protected mercaptides (7a to 7g) is deprotected to give mercaptopyrrolidine (8a to 8 g) in a manner similar to the above. Removing of mercapto protective group amino substituent in R Solvent pyridine equiv. AgNO 3 equiv. Crop (%) a acetyl MeOH 2.5 2.3 73 b methoxycarbonyl MeOH 2.5 2.3 64 c methylcarbamoyl MeOH 2.5 2.3 73 d mesyl MeOH-THF 2.5 2.3 68 e sulfamoyl MeOH-THF 2.5 2.3 62 f methyl MeOH 3.5 2.3 50 g ethylidene MeOH-THF 2.5 2.3 72 Physical constants of mercaptopyrrolidines (8a to 8 g) Compound 8a R = acetylamino IR ν (CHCl 3 ) cm -1 : 3350, 1687, 1603. 1 HNMR δ (CDCl 3 -CD 3 OD) ppm: 1.65 to 2.15(1H, m), 1.89(3H, s), 2.52 to 2.72(1H, m), 3.1 to 3.45(2H, m), 3.95 to 4.3(4H, m), 5.23(2H, m), 7.53(2H, d, J=8.8Hz), 8.24(2H, d, J=8.8Hz). Compound 8b R = carbomethoxyamino IR ν (CHCl 3 ) cm -1 : 3360, 1742, 1690, 1601. 1 HNMR δ (CDCl 3 ) ppm: 1.5 to 1.82(2H, m), 1.78(1H, d, J=6.6Hz), 2.5 to 2.7(1H, m), 3.06 to 3.44(2H. m), 3.76(3H, s), 3.88 to 4.4(4H, m), 5.23 (2H, s) 7.52(2H, d, J=8.8Hz), 8.23(2H, d, J=8.8Hz). Compound 8c R = methylcarbamoylamino IR ν (CHCl 3 ) cm -1 : 3440, 3325, 1683, 1602. 1 HNMR δ (CDCl 3 ) ppm: 1.4 to 1.9(2H, m), 1.78(1H, d, J=6.4Hz), 2.51 to 2.69(1H , m), 2.83(3H, d, J=4.8Hz). 3.1 to 3.47(2H, m), 3.88 to 4.4(4H, m), 5.23(2H, s), 7.52(2H, d, J=8.8Hz), 8.23(2H, d, J=8.8Hz). Compound 8d R = mesylamino IR ν (CHCl 3 ) cm -1 : 3270, 1692, 1600. 1 HNMR δ (CDCl 3 ) ppm: 1.45 to 1.65(1H, m), 1.79(1H, d, J=6.2Hz), 2.5 to 2.7(1H, m), 3.01(3H, s), 3.03 to 3.5(2H, m), 3.97 to 4.5(4H, m), 5.22 (2H, s), 7.52(2H, d, J=8.8Hz), 7.92(1H, s), 8.23(2H, d, J=8.8Hz). Compound 8e R = sulfamoylamino IR ν (CHCl 3 ) cm -1 : 3375, 3320, 3220, 1679, 1595. 1 HNMR δ (CDCl 3 ) ppm: 1.45 to 1.75(1H, m), 1.81(1H, d, J=6.4Hz), 2.5 to 2.7(1H, m). 3.1 to 3.5(2H, m), 4.0 to 4.45(4H, m), 5.21(2H, s), 5.29(2H, s), 7.52(2H, d, J=8.6Hz), 7.77(1H, s), 8.22(2H, d, J=8.6Hz). Compound 8f R = methylamino IR ν (CHCl 3 ) cm -1 : 3470, 1695, 1603. 1 HNMR δ (CDCl 3 ) ppm: 1.7 to 1.97(1H, m), 1.75(1H, d, J=6.6Hz), 2.46 to 2.7(1H, m), 2.69(3H, s), 3.07 to 3.4(2H, m), 3.7 to 4.25(4H, m), 5.22 (2H, s), 7.53(2H, d, J=8.8Hz), 8.22(2H, d, J=8.8Hz). Compound 8g R = ethylideneamino IR ν (CHCl 3 ) cm -1 : 3370, 1698, 1602. 1 HNMR δ (CDCl 3 ) ppm: 1.65 to 2.05(2H, m), 1.84(3H, d, J=5.8Hz), 2.45 to 2.65 (1H, m), 3.0 to 3.4(2H, m), 3.97 to 4.5(4H, m), 5.23(2H, s), 6.75 (0.5H, q, J=5.8Hz), 7.42(0.5H, q, J=5.8Hz), 7.53(2H, d, J=9.0Hz), 8.22 (2H, d, J=9.0Hz). E. Preparation of stereoisomeric aminooxymethylpyrrolidine 1) (2R,4S)-1-t-butoxycarbonyl-4-tritylthiopyrrolidine-2-methanol (2) (thiation) A solution of tritylmercaptane (1.41 g: 5.09 mol) and sodium hydride (178 mg: 4.41 mol) in tetrahydrofuran (8.8 ml) is added dropwise to a solution of (2R,4R)-1-t-butoxycarbonyl-4-mesyloxypyrrolidine-2-methanol (1: 1.00 g: 3.34 mol) in tetrahydrofuran (3.4 ml) at room temperature and the mixture is stirred at room temperature for 100 minutes. The reaction mixture is diluted with ethyl acetate (30 ml) and ice water (30 ml). The organic layer is taken, washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel chromatography to give (2R,4S)-1-t-butoxycarbonyl-4-tritylthiopyrrolidine-2-methanol (2: 1.42 g). Yield : 88 %. IR ν (KBr) cm -1 : 3430, 1690. 1 HNMR δ (CDCl 3 ) ppm: 1.2 to 1.5(m, 1H), 1.43(d, J=1.6Hz, 9H), 1.6 to 1.9 (m, 1H), 2.7 to 3.5(m, 5H), 3.8 to 4.0(m, 1H), 7.1 to 7.6(m, 15H). 2) (2R,4S)-1-t-butoxycarbonyl-2-phtalimidooxymethyl-4-tritylthiopyrrolidine (3) (introduction of imidooxy) Triphenylphosphin (892 mg: 3.40 mol), N-hydroxyphthalimide (705 mg 4.32 mol) and azodicarboxylic acid diethyl ester (0.59 ml: 3.74 mol) are added to a solution of (2R,4S)-1-t-butoxycarbonyl-4-tritylthiopyrro lidine-2-methanol (2: 1.37 g: 2.88 mol) in tetrahydrofuran (8.6 ml) under ice cooling and the mixture is stirred under ice cooling for 90 minutes. The reaction mixture is diluted with ethyl acetate (30 ml) and ice water (30 ml). The organic layer is taken, washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel chromatography to give (2R,4S)-1-t-butoxycarbonyl-2-phtalimidooxymethyl-4-tritylthiopyrrolidine (3: 1.73 g). Yield : 97 %. IR ν (KBr) cm -1 : 3420, 1790, 1735, 1694. 1 HNMR δ (CDCl 3 ) ppm: 1.35(s, 9H), 1.8 to 2.4(m, 2H), 2.7 to 3.2(m, 2H), 3.8 to 4.3(m, 2H), 7.1 to 7.6(m, 15H), 7.6 to 7.9(m, 4H). 3) (2R,4S)-1-t-butoxycarbonyl-2-sulfamidooxymethyl-4-tritylthiopyrrolidine (4) (modification at aminooxy) Methylhydrazine 187 µl (3.54 mol) at -30°C is added dropwise to a solution of (2R,4S)-1-t-butoxycarbonyl-2-phtalimidooxymethyl-4-tritylthiopyrrolidine (3: 2.00 g: 3.22 mol) in dichloromethane (25.8 ml) in nitrogen, and the mixture is stirred at the same temperature for 35 minutes and under ice cooling for 25 minutes. The reaction mixture is diluted with dichloromethane (25 ml) and the separating crystals are removed by filtration. The filtrate is washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. A solution of triethylamine (895 µl: 6.44 mol) and sulfamoyl chlorida (4.83 mol) in dichloromethane is added to a solution of the residue in dichloromethane (25.0 ml) at -40°C and the mixture is stirred at -40°C for 40 minutes, and then diluted with water (30 ml). The organic layer is taken, washed with aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel chromatography to give (2R,4S)-1-t-butoxycarbonyl-2-sulfamidooxymethyl-4-tritylthiopyrrolidine (4: 1.45 g). Yield : 81 %. IR ν (KBr) cm -1 : 3400, 3240, 1670. 1 HNMR δ (CDCl 3 ) ppm: 1.1 to 1.4(m, 1H), 1.41(s, 9H), 1.6 to 1.9(m, 1H), 2.7 to 3.2(m, 3 H), 3.2 to 3.9(m, 2H), 3.9 to 4.3(m, 1H), 4.6 to 5.1(m, 2H), 7.1 to 7.6(m, 15H), 7.8 to 8.0(m, 1H). 4) (2R,4S)-1-t-butoxycarbonyl-2-sulfamidooxymethyl-4-mercaptopyrrolidine (5) (Deprotection at thiol) A solution of pyridine (0.49 ml: 6.03 mol), silver nitrate (945 mg, 5.57 mol) in water (4.7 ml) - methanol (47.0 ml) is added to a solution of (2R,4S)-1-t-butoxycarbonyl-2-sulfamidooxymethyl-4-tritylthiopyrrolidine (4: 1.35 g: 2.42 mol) in a mixture of methanol (24.3 ml) and tetrahydrofuran (2.7 ml) under ice cooling, and the mixture is stirred at the same temperature for 40 minutes, and concentrated under reduced pressure. The residue is washed with toluene and again concentrated under reduced pressure. Hydrogen sulfide is bubbled through a solution of the residue in dichloromethane (24.2 ml) - methanol (7.3 ml) under ice cooling for 5 minutes. The reaction mixture is diluted with dichlorometh ane (30 ml), filtered to remove the black precipitate, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel chromatography to give (2R,4S)-1-t-butoxycarbonyl-2-sulfamidooxymethyl-4-mercaptopyrrolidine (5: 502 mg). Yield : 64 %. IR ν (CHCl 3 ) cm -1 : 3440, 3350, 3280, 1682. 1 HNMR δ (CDCl 3 ) ppm: 1.47(s, 9H), 1.6 to 1.8(m, 3H), 1.8 to 2.2(m, 1H), 3.2 to 3.5(m, 2H), 3.6 to 4.1(m, 3H), 4.2 to 4.5(m, 1H), 5.10(s, 2H), 7.8 to 8.0 (m, 1H). Example 2. Condensation 1) (1R,5S,6S)-2-[(3S,5S)-{5-acetylaminooxymethyl-1-p-nitrobenzyloxycarbonyl}pyrrolidin-3-ylthio]-6-[(1R)-1-hydroxymethyl]-1-methyl-1-carba -2-penem-3-carboxylic acid p-nitrobenzyl ester (IIa) Diisopropylethylamine (89 µl) and trifluoromethanesulfonic acid anhydride (71 µl) are added to a solution of (1R,5S,6S)-2-oxo-6-[(1R)-1 hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid p-nitrobenzyl ester (154 mg) in acetonitrile (3 ml) at -40°C and the mixture is stirred for 15 minutes to give a solution of (1R,5S,6S)-2-trifluoromethanesulfonyloxy-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid p-nitrobenzyl ester (III). A solution of diisopropylethylamine (89 µl) and 4-mercapto-2-acetylamine oxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine (8a: 190 mg) in acetonitrile (1.5 ml) is added dropwise to this solution of (III) at -40°C and the mixture is stirred at the same temperature for 2 hours and under ice cooling for 30 minutes and diluted with ethyl acetate. The reaction mixture is washed with water and saturated brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by silica gel chromatography to give (1R,5S,6S)-2-[(3S,5S)-5-acetylaminooxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid p-nitrobenzyl ester (IIa: 270 mg) as a pale yellow powder. Yield: 89 %. Under the conditions listed in Table 3, trifluoromethanesulfonate (III) is condensed with mercaptopyrrolidine (8a to 8g) by a manner similar to the one for the corresponding carbapenems (IIa to IIg). Reaction conditions of condensation Product carbapenem II amino substituent in R Starting thiol equivalents Time (min.) at -40°C and 0°C Crop (%) a acetyl 8 a (1.2) 120 30 89 b carbomethoxy 8 b (1.2) 30 30 78 c methylcarbamoyl 8 c (1.2) 45 40 83 d mesyl 8 d (1.2) 65 -- 82 e sulfamoyl 8 e (1.2) 70 35 72 f methyl 8 f (1.2) 30 30 63 g ethylidene 8 g (1.2) 25 65 74 Physical constants of protected carbapenems (II) Compound IIa R = acetylamino IR ν (CHCl 3 ) cm -1 : 3365, 1765, 1690, 1602. 1 HNMR δ (CDCl 3 ) ppm: 1.28(3H, d, J=7.2Hz), 1.37(3H, d, J=6.2Hz), 1.4 to 2.2(3H, m), 1.91(3H, s), 2.52 to 2.7(1H, m), 3.28(1H, dd. J 1 =6.2Hz, J 2 = 2.6Hz), 3.22 to 3.45(2H, m), 3.55 to 4.48(7H, m), 5.23, 5.50(2H, ABq. J= 13.7Hz), 5.24(2H, s), 7.52(2H, d, J=8.8Hz), 7.65(2H, d, J=8.8Hz), 8.22 (2H, d, J=8.8Hz), 8.23(2H, d, J=8.8Hz). Compound IIb R = carbomethoxyamino IR ν (CHCl 3 ) cm -1 : 3375, 1765, 1695, 1602. 1 HNMR δ (CDCl 3 ) ppm: 1.28(3H, d, J=7.2Hz), 1.37(3H, d, J=6.2Hz), 1.64 (2H, brs), 1.7 to 1.9(1H, m), 2.48 to 2.72(1H, m), 3.28(1H, dd, J 1 =6.2 Hz, J 2 =2.6Hz), 3.22 to 3.43(2H, m), 3.58 to 3.82(1H, m), 3.76(3H, s), 3.9 to 4.45(6H, m), 5.23, 5.50(2H, ABq, J=13.7Hz), 5.23(2H, s), 7.52 (2H, d, J=8.8Hz), 7.65(2H, d, J=8.8Hz), 8.23(2H, d, J=8.8Hz), 8.24(2H, d, J=8.8Hz). Compound IIc R = methylcarbamoylamino IR ν (CHCl 3 ) cm -1 : 3440, 3380, 3330, 1767, 1685, 1601. 1 HNMR δ (CDCl 3 ) ppm: 1.26(3H, d, J=7.4Hz), 1.37(3H, d, J=6.2Hz), 1.73 (3H, brs), 2.42 to 2.75(1H, m), 2.83(3H, d, J=4.8Hz), 3.2 to 3.45(2H, m), 3.28(1H, dd, J 1 =6.2Hz, J 2 =2.6Hz). 3.58 to 4.47(7H, m), 5.22, 5.51 (2H, ABq, J=13.0Hz), 5.23(2H, s), 7.52(2H, d, J=8.8Hz), 7.65(2H, d, J= 8.8Hz), 8.22(2H, d, J=8.8Hz), 8.23(4H, d, J=8.8Hz). Compound IId R = mesylamino IR ν (CHCl 3 ) cm -1 : 3410, 3280, 3190, 1768, 1698, 1602. 1 HNMR δ (CDCl 3 ) ppm: 1.29(3H, d, J=7.2Hz), 1.37(3H, d, J=6.8Hz), 1.73 to 2.13 (1H, m), 1.98(2H, s), 2.54 to 2.78(1H, m), 3.03(3H, s), 3.29(1H, dd, J 1 =6.8Hz. J 2 =2.6Hz), 3.2 to 3.5(2H, m), 3.62 to 4.5(7H, m), 5.22(2H, s), 5.22, 5.50(2H, ABq, J=13.6Hz), 7.43 to 7.66(2H, m), 7.65(2H, d, J= 8.8Hz), 8.22(2H, d, J=8.8Hz), 8.24(2H, d, J=8.8Hz). Compound IIe R = sulfamoylamino IR ν (KBr) cm -1 : 3390, 3235, 3105, 3080, 1762, 1696, 1602. 1 HNMR δ (CDCl 3 -CD 3 OD) ppm: 1.27(3H, d, J=7.2Hz), 1.34(3H, d, J=6.2Hz), 1.77 to 2.2(1H, m), 2.35 to 2.78(1H, m), 3.27(1H, dd, J 1 =6.2Hz, J 2 =2.6 Hz), 3.3 to 3.46(2H, m), 3.63 to 3.82(1H, m), 3.97 to 4.4(6H, m), 5.22 (2H, s), 5.24, 5.48(2H, ABq, J=13.7Hz), 7.47 to 7.62(2H, m), 7.66(2H, d, J=8.8Hz), 8.22(2H, d, J=8.8Hz), 8.23(2H, d, J=8.8Hz). Compound IIf R = methylamino IR ν (CHCl 3 ) cm -1 : 3390, 1767, 1697, 1602. 1 HNMR δ (CDCl 3 ) ppm: 1.28(3H, d, J=7.8Hz), 1.37(3H, d, J=6.8Hz), 1.75 to 2.15 (1H, m), 2.38 to 2.7(1H, m), 2.68(3H, s), 3.15 to 3.53(2H, m), 3.27(1H, dd, J 1 =6.8Hz, J 2 =2.6Hz), 3.5 to 4.35(7H, m), 5.23(2H, s), 5.23, 5.51(2H, ABq, J= 13.2Hz), 7.53(2H, d, J=8.8Hz), 7.65(2H, d, J=8.8Hz), 8.22(4H, d, J=8.8Hz). Compound IIg R = ethylideneamino IR ν (CHCl 3 ) cm -1 : 3370, 1768, 1700, 1603. 1 HNMR δ (CDCl 3 ) ppm: 1.28(3H, d, J=7.0Hz), 1.37(3H, d, J=6.4Hz), 1.65(1H, brs), 1.82(3/2H, d, J=5.6Hz), 1.83(3/2H, d, J=5.6Hz), 1.9 to 2.2(1/2H, m), 2.4 to 2.65(1/2H, m), 3.15 to 3.75(4H, m), 3.9 to 4.4(7H, m), 5.25(2H, s), 5.24, 5.52(2H, ABq, J=14Hz), 6.75(1/2H, q, J=5.6Hz), 7.40(1/2H, q, J=5.6Hz), 7.54(2H, d, J=8.8Hz), 7.66(2H, d, J=8.8Hz), 8.23(2H, d, J=8.8Hz). 2) (1R,5S,6S)-2-[(3S,5R)-1-t-butoxycarbonyl-5-sulfamidooxymethylpyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carba-2-penem-3 -carboxylic acid diphenylmethyl ester A solution of diisopropylethylamine (0.30 ml: 1.73 mMol.) in acetonitrile (2.1 ml) is adder dropwise to a solution of (1R,5S,6S)-2-diphenoxyphosphonyloxy-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carba-2-penem-3-car boxylic acid diphenylmethyl ester (832 mg: 1.33 mMol.) and (2R,4S)-1-t-butoxycarbonyl-2-sulfamidooxymethyl-4-mercaptopyrrolidine (522 mg: 1.59 mMol.) in acetonitrile (4.2 ml) in nitrogen under ice cooling, and the mixture is stirred at the same temperature for 3 hours. The mixture is diluted with ethyl acetate (30 ml) and ice water (30 ml). The organic layer is taken, washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel chromatography to give (1R,5S,6S)-2-[(3S,5R)-1-t-butoxycarbonyl-5-sulfamidooxymethylpyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid diphenylmethyl ester (843 mg). Yield : 90 %. IR ν (KBr) cm -1 : 3390, 3240, 1765. 1 HNMR δ (CDCl 3 ) ppm: 1.26(d, J=7.2Hz, 3H), 1.42(s, 9H), 3.1 to 3.5(m, 2H), 3.52∼4.4(m, 5H), 5.22 to 5.4(m, 1H), 5.6 to 5.8(m, 1H), 6.93(s, 1H), 7.1 to 7.7(m, 10H), 7.7 to 7.9(m, 1H). UV λ max: 321nm. Example 3. Deprotection 1) Deprotections to afford (3S,5S)-mercaptopyrrolidine isomers 10% palladium/carbon (1 weight) is added to a solution of (1R,5S,6S) -2-[(3S,5S)-R substituted aminooxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid p-nitrobenzyl ester (IIa: 1 part) in a mixture of tetrahydrofuran (15 volume) and 0.05M 2-(morpholin-4-yl)ethanesulfonic acid buffer (pH 6.86: 30 volume) and the mixture is shaken at room temperature under a hydrogen atmosphere for 2 to 3 hours. The reaction mixture is filtered to remove the catalyst and the filtrate is washed with dichloromethane and ether and passed through a column of styrene-divinyl benzene copolymer resin absorbent. The absorbed material is eluted with aqueous 10 % methanol. The eluate is lyophilized to give (1R,5S, 6S)-2-[(3S,5S)-5-R substituted aminooxymethylpyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid (Ia). Yield: 20 to 56 %. In a similar manner, protected 2-[(3S,5S)-5-R substituted aminooxymethylpyrrolidin-3-ylthio]-carbapenems (IIa to IIg) are deprotected under the same condition as above to give the corresponding carbapenems (Ia to Ig). Physical constants of carbapenem (I) Compound Ia R = acetylamino IR ν (KBr) cm -1 : 3410, 1748, 1672, 1583. UV λ max ε (H 2 O) nm: 297 (9700). 1 HNMR δ (D 2 O) ppm: 1.21(3H, d, J=7.4Hz), 1.28(3H, d, J=6.4Hz), 1.68 to 1.84(1H, m), 1.94(3H, s), 2.62 to 2.8(1H, m), 3.29 to 3.47(2H, m), 3.46(1H, dd, J 1 =6.4Hz, J 2 =2.6Hz), 3.66 to 3.77(1H, m), 3.96 to 4.14(2H, m), 4.16 to 4.32(4H, m). This compound shows potent prevention of infection in mice caused by e.g., Staphylococcus aureus Smith (0.099 mg/kg) and Pseudomonas aeruginosa SR24 (0.58 mg/kg). Compound Ib R = carbomethoxyamino IR ν (KBr) cm -1 : 3420, 1748, 1588. UV λ max ε (H 2 O) nm: 297 (9600). 1 HNMR δ (D 2 O) ppm: 1.21(3H, d, J=7.2Hz), 1.28(3H, d, J=6.2Hz), 1.65 to 1.85(1H, m), 2.62 to 2.81(1H, m), 3.28 to 3.55(2H, m), 3.46(1H, dd, J 1 =6.2Hz, J 2 =2.6Hz), 3.65 to 3.77(1H, m), 3.76(3H, s), 3.97 to 4.15(2H, m), 4.1 to 4.3(4H, m). This compound shows potent prevention of infection in mice caused by e.g., Staphylococcus aureus Smith (0.11 mg/kg) and Pseudomonas aeruginosa SR24 (0.57 mg/kg). Compound Ic R = methylcarbamoylamino IR ν (KBr) cm -1 : 3380, 1755, 1663, 1587, 1545. UV λ max ε (H 2 O) nm: 297 (9600). 1 HNMR δ (D 2 O) ppm: 1.21(3H, d, J=7.2Hz), 1.28(3H, d, J=6.0Hz), 1.64 to 1.78(1H, m), 2.61 to 2.8(1H, m), 2.76(3H, s), 3.29 to 3.45(2H, m), 3.46(1H, dd, J 1 =6.0Hz, J 2 =2.6Hz), 3.59 to 3.72(1H, m), 3.93 to 4.31(6H, m). This compound shows potent prevention of infection in mice caused by e.g., Staphylococcus aureus Smith (0.057 mg/kg) and Pseudomonas aeruginosa SR24 (0.40 mg/kg). Compound Id R = methanesulfonylamino IR ν (KBr) cm -1 : 3410, 1750, 1585. UV λ max ε (H 2 O) nm: 297 (9600). 1 HNMR δ (D 2 O) ppm: 1.21(3H, d, J=7.4Hz), 1.28(3H, d, J=6.2Hz), 1.62 to 1.82(1H, m), 2.63 to 2.78(1H, ml, 3.18(3H, s), 3.27 to 3.44(2H, m), 3.46(1H, dd, J 1 =6.2Hz, J 2 =2.8Hz), 3.56 to 3.69(1H, m), 3.91 to 4.15(2H, m), 4.13 to 4.34(4H, m). Elemental Analysis (C 15 H 25 N 3 O 7 S 2 ·0.54H 2 O) Calcd.: C, 43.16; H, 6.15; N, 9.44; S, 14.40. Found : C, 42.95; H, 6.05; N, 9.73; S, 14.12. This compound shows potent antibacterial activity in vitro against e.g., Escherichia coli SR5028 (0.05µg/ml) and Pseudomonas aeruginosa PA01-Jdg (0.01µg/ml): and a high urinay recovery in mice (38.6 %). Compound Ie R = sulfamoylamino IR ν (KBr) cm -1 : 3300, 3210, 1749, 1588. UV λ max ε (H 2 O) nm: 297 (9400). 1 HNMR δ (D 2 O) ppm: 1.21(3H, d, J=7.4Hz), 1.28(3H, d, J=6.2Hz), 1.6 to 1.78(1H, m), 2.58 to 2.77(1H, m), 3.25 to 3.46(2H, m), 3.45(1H, dd, J 1 =6.2Hz, J 2 =2.6Hz), 3.53 to 3.65(1H, m), 3.89 to 4.1(2H, m), 4.13 to 4.35(4H, m). Elemental Analysis (C 15 H 24 N 4 O 7 S 2 ·0.5H 2 O) Calcd.: C, 40.43; H, 5.66; N, 12.58; S, 14.39. Found : C, 40.23; H, 5.88; N, 12.58; S, 14.30. This compound shows potent antibacterial activity in vitro against e.g., Escherichia coli SR5028 (0.05µg/ml) and Pseudomonas aeruginosa A25619 (0.1µg g/ml) and SR1012 (0.4µg/ml); potent prevention of infection in mice caused by e.g., Staphylococcus aureus Smith (0.038 mg/kg) and Pseudomonas aeruginosa SR24 (0.20 mg/kg); and a high urinay recovery in mice (45 %). Compound If R = methylamino IR ν (KBr) cm -1 : 3400, 3260, 1751, 1592. UV λ max ε (H 2 O) nm: 297( 9000). 1 HNMR δ (D 2 O) ppm: 1.21(3H, d, J=7.4Hz), 1.28(3H, d, J=6.2Hz), 1.64 to 1.83(1H, m), 2.67(3H, s), 2.6 to 2.8(1H, m), 3.29 to 3.45(2H, m), 3.46(1H, dd, J 1 =6.2Hz, J 2 =2.6Hz), 3.58 to 3.72(1H, m), 3.9 to 4.08(4H, m), 4.17 to 4.33(2H, m). This compound shows potent antibacterial activity in vitro against e.g., Escherichia coli H (0.05µg/ml) and a high urinay recovery in mice (52.1 %). Compound Ig R = ethylideneamino (E : Z = 1 : 1) IR ν (KBr) cm -1 : 3420, 1757, 1590. UV λ max ε (H 2 O) nm: 297(9300). 1 HNMR δ (D 2 O) ppm: 1.22(3H, d, J=7.2Hz), 1.28(3H, d, J=6.2Hz), 1.7 to 1.9(1H, m), 1.86, 1.89(3H, 2d, J 1 =6.0Hz, J 2 =5.6Hz), 2.62 to 2.82(1H, m), 3.26 to 3.47(2H, m), 3.44 to 3.52(1H, m), 3.57 to 3.75(1H, m), 3.92 to 4.17(2H, m), 4.15 to 4.48(4H, m), 7.0, 7.62(1H, 2q, J 1 =5.6Hz, J 2 =6.0Hz). This compound shows potent antibacterial activity in vitro against e.g., Pseudomonas aeruginosa PA01-Jdg (0.02µg/ml); high maximum blood level in mice (27.7 µg/ml) and a high urinay recovery in mice (39.4 %). 2) Deprotection to afford (3S,5R)-mercaptopyrrolidine isomer A solution of aluminum chloride (1.22 g: 9.12 mMol.) in a mixture of dichloromethane (9.1 ml) - anisole (9.1 ml) - nitromethane (9.1 ml) is added dropwise to a solution of (1R,5S,6S)-2-[(3S,5R)-1-t-butoxycarbonyl -5-sulfamidooxymethylpyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid diphenylmethyl ester (800 mg: 1.14mMol.) in dichloromethane (4.6 ml) at -35°C and the mixture is stirred at the same temparature for 3 hours. The reaction mixture is diluted with a solution of sodium acetate (2.25 g) in water (23 ml). The aqueous layer is taken, washed with dichloromethane and purified by column chromatography over styrene-divinylbenzene copolymer to give (1R, 5S,6S)-2-[(3S,5R)-5-sulfamidooxymethylpyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid (364 mg). Yield : 73 %. IR ν (KBr) cm -1 : 3400, 1750. 1 HNMR δ (D 2 O) ppm: 1.18(d, J=7.0Hz, 3H), 1.24(d, J=6.4Hz, 3H), 2.12 to 2.4(m, 2H), 3.22 to 3.5(m, 3H), 3.68(dd, J=5.4Hz, J=12.4Hz, 1H), 4.0 to 4.4(m, 6H). UV λ max : 296nm. This compound shows potent antibacterial activity in vitro against e.g., Margania morganii SR9 (0.2µg/ml) and Pseudomonas aeruginosa A25619 (0.1µg/ml), and Pseudomonas aeruginosa SR1012 (0.4 µg/ml). Example 4. Modification at the pyrrolidine nitrogen (1R,5S,6S)-2-[(3S,5S)-1-iminomethyl-5-methanesulfonylaminooxymethylpyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carba-2-penem-3 -carboxylic acid (Ih) 1N-sodium hydroxide and ethylformimidate hydrochloride (270 mg) are added to a solution of (1R,5S,6S)-2-[(3S,5S)-5-methanesulfonylaminooxymethylpyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid (Id: 62 mg) in a phosphate buffer (15 ml) of pH 7.1 under ice cooling in several portions while keeping the reaction medium at pH 8.5, and the mixture is stirred at the same temperature for 25 minutes. The reaction mixture is adjusted to pH 7.0 with 1N-hydrochloric acid, purified by chromatography on styrene-divinylbenzene copolymer, and lyophilized to give (1R,5S,6S)-2-[(3S,5S)-5-methanesulfonylaminooxymethylpyrrolidin-3-yl-thiol]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid (Ih: 49 mg) as colorless foam. Yield: 63 %. Compound Ih R 3 = iminomethyl, R = amino IR ν (KBr) cm -1 : 3360, 1748, 1701, 1630, 1582. UV λ max ε (H 2 O) nm: 297 (8700). 1 HNMR δ (D 2 O) ppm: 1.21(3H, d, J=7.4Hz), 1.29(3H, d, J=6.2Hz), 1.8 to 2.03 (1H, m), 2.6 to 2.85(1H, m), 3.14(3H, s), 3.3 to 3.6(2H, m), 3.46 (1H, dd, J 1 =6,2Hz, J 2 =2.8Hz), 3.88 to 4.52(7H, m), 8.08(1H, s). Example 5. Stereoisomers at position 5 of pyrrolidinylthio In a manner similar to those of Examples 1 to 4, the stereoisomers (1R,5S,6S) -2-[(3R,5S)-5-acetamidooxymethylpyrrolidin-3-yl-thiol]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid, (1R,5S,6S)-2-[(3R,5R)-5-methylcarbamoylaminooxymethylpyrrolidin-3-ylthiol]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid, (1R,5S,6S)-2-[(3R,5S)-5-sulfamoylaminooxymethylpyrrolidin-3-yl-thio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid, (1R,5S,6S)-2-[(3R,5R) -5-sulfamoylaminooxymethylpyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid, (1R,5S,6S)-2-[(3R, 5S)-5-methanesulfonylaminooxymethylpyrrolidin-3-yl-thio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid, and (1R,5S,6S)-2-[(3R,5R)-5-methanesulfonylaminooxymethylpyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid are prepared from the stereoisomers at position 4 of (D or L)-hydroxyproline. Formulation Example 1. (injection) The sodium salt of (1R,5S,6S)-2-[(3S,5S)-5-methanesulfonylaminooxymethylpyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid (1 g) in a 5 ml vial may be dissolved in sterillized water for injection (1 ml) before use and given by intravenus injection thrice a day to an adult patient suffering from pyelitis. Formulation Example 2. (infusion) An aqueous solution of sodium (1R,5S,6S)-2-[(3S,5S)-5-sulfamidooxymethylpyrrolidin-3-ylthio]-6-[(1R-1-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylate (1 g) may be adjusted to pH 7.5 with sodium hydrogen carbonate and is placed in a 150 ml bottle and lyophilized. The lyophilizate is dissolved in sterillized water for injection (100 ml) and may be dripped intravenously to an adult patient immediately after or during a surgical operation for preventing post operative bacterial infection. Formulation Example 3. (suspension) Microcrystalline (1R,5S,6S)-2-[(3S,5R)-5-sulfamidooxymethylpyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid (2 g) in a 5 ml vial is suspended in sterilized water (3 ml) for injection, and may be given intramuscularly twice a day to an adult patient suffering from suppurative inflammation. Experiment. Stability against human renal dehydropeptidase-1 A solution (1 µl) of test carbapenem compound (50µg) in 50 mM-tris-hydrochloric acid buffer (pH 7.5: 1 ml) is added to a solution of human renal dehydropeptidase-1 in 50mM tris-hydrochloric acid buffer (pH 7.5: 0.33 unit/ml: 10 µl), and the mixture is stirred at 37°C for 60 minutes. The reaction is quenched with methanol (10 µl) and diluted with 0.1M phosphate buffer (pH 7.0: 80 µl). The remaining anti-bacterial potency of this solution is measured. Among compounds of formula I, Id (R = methanesulfonylamino) showed 71 % and Ie (R = sulfamoylamino) showed 78 % activity. In contrast, known compounds, (5R,6S)-2-formimidoylaminoethylthio-6-[(1R)-1-hydroxyethyl]-1-carba-2-penem-3-carboxylic acid (imipenem), (5R,6S)-2-[1-(1-acetoimidoyl)pyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]carba-2-penem-3-carboxylic acid (CS533) and (1R,5S,6S)-2-[(3S,5S)-5-dimethylaminocarbonylpyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid (Meropenem) showed values of 51%, 48%, and 69%, respectively.

Claims: An aminooxypyrrolidinylthiocarbapenem compound of formula I and its pharmaceutically acceptable salts: (wherein R is optionally substituted amino wherein, the substituent can be a 1C to 10C monovalent amino substituent selected from alkyl, acyl, alkoxy-carbonyl, optionally substituted carbamoyl, alkylsulfonyl, optionally substituted sulfamoyl; or a 1C to 10C divalent amino substituent selected from alkylidene, cyclic diacyl; and wherein R may have one or two of the said monovalent amino substituents or one of the said divalent amino substituents; R 1 is hydrogen or 1C to 5C alkyl; R 2 is hydrogen or a conventional hydroxy protective group; R 3 is hydrogen or an imino protective group or imino substituent; R 4 is 1C to 5C alkylene; and R 5 is hydrogen or a conventional carboxy protective group; and wavy lines each shows a bond in R or S configuration). A compound claimed in Claim 1 wherein the divalent amino substituent is ethylidene or phthaloyl. A compound claimed in Claim 1 wherein the stereochemistry in the pyrrolidine ring is either in (2S,4R) or (2S,4S)-configuration. A compound claimed in Claim 1 wherein R 1 is methyl. A compound claimed in Claim 1 wherein R 4 is methylene. A compound claimed in Claim 1 wherein R 2 is hydrogen or tri-1C to 4C alkylsilyl. A compound claimed in Claim 1 wherein R 3 is hydrogen. A compound claimed in Claim 1 wherein R 5 is hydrogen or alkali metal. A compound claimed in Claim 1 wherein R is methanesulfonylamino, or sulfamoylamino. A compound claimed in Claim 1 wherein R is amino, R 1 is methyl, R 2 and R 3 are hydrogens, R 4 is methylene, and R 5 is hydrogen; R is acetylamino, R 1 is methyl, R 2 and R 3 are hydrogens, R 4 is methylene, and R 5 is hydrogen; R is carbomethoxyamino, R 1 is methyl, R 2 and R 3 are hydrogens, R 4 is methylene, and R 5 is hydrogen; R is methylcarbamoylamino, R 1 is methyl, R 2 and R 3 are hydrogens, R 4 is methylene, and R 5 is hydrogen; R is methanesulfonylamino, R 1 is methyl, R 2 and R 3 are hydrogens, R 4 is methylene, and R 5 is hydrogen; R is sulfamoylamino, R 1 is methyl, R 2 and R 3 are hydrogens, R 4 is methylene, and R 5 is hydrogen; R is methylamino, R 1 is methyl, R 2 and R 3 are hydrogens, R 4 is methylene, and R 5 is hydrogen; or R is ethylideneamino, R 1 is methyl, R 2 and R 3 are hydrogens, R 4 is methylene, and R 5 is hydrogen; or its alkali metal salt, provided that its stereochemistry at the pyrrolidine ring is (2S,4R)- or (2S,4S)-. A process for preparing a compound claimed in Claim 1 which comprises treating a carbapenem of formula V or its reactive derivative with a thiol of formula VI (R 5 is hydrogen) or its reactive derivative: (wherein R, R 1 , R 2 , R 3 , R 4 , and R 5 are as defined in Claim 1, R 5 is hydrogen or a thiol protective group, and X is a leaving group) and, if required, followed by removing of a protective group at R, R 1 , R 2 , R 3 , and/or R 5 . The thiol of formula VI: (wherein R, R 3 and R 4 are as defined in Claim 1 and R 6 is hydrogen or a thiol protecting group). A pharmaceutical formulation containing a compound claimed in any one of claims 1 to 9 as an active ingredient. A pharmaceutical formulation according to Claim 12 which is useful as an antibacterial agent. A method for the preparation of a pharmaceutical composition according to claims 12 or 13 comprising combining a compound prepared according to any one of claims 1 to 9 with a pharmaceutically acceptable carrier.

Inventors: KII MAKOTO, SENDO YUJI, KII, MAKOTO, SENDO, YUJI
Applicants: SHIONOGI & CO, SHIONOGI SEIYAKU KABUSHIKI KAISHA
Application year: 1992
Main classification: C07D477
IPC codes: C07D477, A61K31, A61P31, C07D207