Abstract:
A method for the prophylaxis or treatment of infectious diseases caused by  helicobacter pyloir,  by administering a pharmacologically effective amount of a 1-methoylcarbapenem coumpund of formula (I) or a pharmacologically acceptable salt or ester thereof:                            
     R 1  represents a group of the following formula:                            
     R 2  is a hydrogen atom or a C 1 -C 6  alkyl group, and R 3  is a hydrogen atom or a C 1 -C 6  alkyl group.

Description:
This application is a continuation application of International Application PCT/JP97/01542 filed May 8, 1997. 
    
    
     BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     The present invention relates to an anti- helicobacter pylori  composition comprising 1-methylcarbapenem derivatives or pharmacologically acceptable salts or esters thereof as an active ingredient, use of the derivatives, salts or esters for the preparation of an anti- helicobacter pylori  medicament and a method which comprises administering a pharmacologically effective amount of the derivatives, salts or esters to warm-blooded animals for treatment and prevention of infectious diseases caused by  helicobacter pylori.    
     2. Background Information 
     According to recent studies, there are a number of reports on the phenomenon that  helicobacter pylori  is detected at a high ratio in patients suffering from chronic gastritis or digestive ulcers, and that such gastrointestinal disorders are cured by the eradication of  helicobacter pylori;  and on the phenomenon that the recurrence ratio of digestive ulcers shows a drastic decrease as a result of the eradication of this bacterium. It is therefore thought that infection with this bacterium relates to chronic and digestive ulcers and, furthermore, it even has a close relationship with gastric cancer or gastritis (G. E. Buck et al., J. Infect. Dis., 153, 664-669(1986), G. Geis et al., J. Clinical Microbiology, 930-932(1990), etc.). 
     At present, it is reported that bismuth compounds such as bismuth citrate, nitroimidazole compounds such as metronidazole and antibiotics such as tetracycline, amoxicillin and clarithromycin are effective against  helicobacter pylori.  None of these compounds has sufficient antibacterial activity and each has a chemical structure markedly different from that of the 1-methylcarbapenem derivatives which are an active ingredient to be employed in the present invention. 
     The 1-methylcarbapenem derivatives, which are an active ingredient of the present invention, are known compounds (for example, Japanese Patent Publication No. Hei 745499, Japanese Patent Application Kokai No. Hei 2-223587, Japanese Patent Application Kokai No. Hei 4-279588, Japanese Patent Application Kokai No. Hei 8-53453 etc.), but their anti- helicobacter pylori  activity is not known at all. 
     SUMMARY OF THE INVENTION 
     The present inventors have carried out an extensive investigation into the antibacterial activity of 1-methylcarbapenem derivatives. As a result, it has been found that specific 1-methylcarbapenem derivatives have excellent anti- helicobacter pylori  activity and are useful as an active ingredient in an anti- helicobacter pylori  composition (treatment or prevention of infectious diseases caused by  helicobacter pylori,  particularly, treatment). 
     The present invention provides an anti- helicobacter pylori  composition comprising 1-methylcarbapenem derivatives or pharmacologically acceptable salts or esters thereof as an active ingredient, use of the derivatives, salts or esters for the preparation of an anti- helicobacter pylori  medicament and a method comprising administering a pharmacologically effective amount of the derivatives, salts or esters to warm-blooded animals for treatment and prevention of infectious diseases caused by  helicobacter pylori.    
     1-Methylcarbapenem derivatives, an active ingredient of the present invention, have the following formula:                           
     wherein R 1  represents a group of the following formula:                           
     R 2  represents a hydrogen atom or a C 1 -C 6  alkyl group, and 
     R 3  represents a hydrogen atom or a C 1 -C 6  alkyl group. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     FIG. 1 is a graph depicting the effect of the treatment on mice. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     In the above formula (I), examples of the C 1 -C 6  alkyl group of R 2  or R 3  include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl t-butyl, pentyl and hexyl groups, preferably the C 1 -C 4  alkyl groups, more preferably the methyl or ethyl group and most preferably the methyl group. 
     R 1  is preferably the group of the formula (Ila). 
     The oxopyrrolidinyl part of the group of the formula (la) is preferably a 2-oxo-3-pyrrolidinyl or 2-oxo-4-pyrolidinyl group and most preferably the 2-oxo4-pyrrolidinyl group. 
     The thioxopyrrolidinyl part of the group of the formula (IId) is preferably a 2-thioxo-3-pyrrolidinyl or 2-thioxo-4-pyrrolidinyl group, and most preferably the 2-thioxo4-pyrrolidinyl group. 
     The pharmacologically acceptable salts of Compound (I) which are also an active ingredient of the present invention are salts of Compound (I) which exhibit antibacterial activity and are usable as a medicament when administered to a living body. Examples include inorganic salts such as lithium salts, sodium salts, potassium salts, calcium salts and magnesium salts; ammonium salts; and organic amine salts such as triethylamine salts, diisopropylamine salts and cyclohexylamine salts; preferably lithium salts, sodium salts and potassium salts; more preferably sodium salts and potassium salts; and most preferably sodium salts. 
     The pharmacologically acceptable esters of Compound (I) which are also an active ingredient of the present invention are esters of the compound (I) which exhibit antibacterial activity and are usable as a medicament when administered to a living body; and preferably esters which can be hydrolyzed in vivo and converted to the corresponding carboxylic acids. Specific examples include: 
     C 1 -C 4  alkyl esters (preferably, methyl and ethyl esters), 
     C 1 -C 4  alkoxycarbonyloxy-(C 1 -C 4  alkyl) esters [for example, methoxycarbonyloxymethyl esters, 1-(methoxycarbonyloxy)ethyl esters, ethoxycarbonyloxymethyl esters, 1-(ethoxycarbonyloxy)ethyl esters, propoxycarbonyloxymethyl esters, 1-(propoxycarbonyloxy)ethyl esters, isopropoxycarbonyloxymethyl esters, 1-(isopropoxycarbonyloxy)ethyl esters, butoxycarbonyloxymethyl esters, 1-(butoxycarbonyloxy)ethyl esters, isobutoxycarbonyloxymethyl esters, 1-(isobutoxycarbonyloxy)ethyl esters, t-butoxycarbonyloxymethyl esters, 1-(t-butoxycarbonyloxy)ethyl esters, 1-(t-butoxycarboyloxy)propyl esters and 1-(t-butoxycarbonyloxy)butyl esters, of which the methoxycarbonyloxymethyl esters, 1-(methoxycarbonyloxy)ethyl esters, ethoxycarbonyloxymethyl esters, 1-(ethoxycarbonyloxy) ethyl esters, isopropoxycarbonyloxymethyl esters, 1-(isopropoxycarbonyloxy)ethyl esters, t-butoxycarbonyloxymethyl esters or 1-(t-butoxycarbonyloxy)ethyl esters are preferred, the 1-(methoxycarbonyloxy)ethyl esters, 1-(ethoxycarbonyloxy)ethyl esters, 1-(isopropoxycarbonyloxy)ethyl esters, t-butoxycarbonyloxymethyl esters and 1-(t-butoxycarbonyloxy)ethyl esters being more preferred and the 1-(isopropoxycarbonyloxy)ethyl esters being most preferred], 
     C 5 -C 6  cycloalkyloxycarbonyloxy-(C 1 -C 4  alkyl) esters [for example, cyclopentyloxycarbonyloxymethyl esters, 1-(cyclopentyloxycarbonyloxy)ethyl esters, cyclohexyloxycarbonyloxymethyl esters, 1-(cyclohexyloxycarbonyloxy)ethyl esters, 1-(cyclohexyloxycarbonyloxy)propyl esters and 1-(cyclohexyloxycarbonyloxy)butyl esters, of which the cyclopentyloxycarbonyloxymethyl esters, 1-(cyclopentyloxycarbonyloxy)ethyl esters, cyclohexyloxycarbonyloxymethyl esters and 1-(cyclohexyloxycarbonyloxy)ethyl esters are preferred, the 1-(cyclopentyloxycarbonyloxy)ethyl esters and 1-(cyclohexyloxycarbonyloxy)ethyl esters being more preferred, and the 1-(cyclohexyloxycarbonyloxy)ethyl esters being most preferred; 
     C 2 -C 5  alkanoyloxy-(C 1 -C 4  alkyl) esters [for example, acetoxymethyl esters, 1-(acetoxy)ethyl esters, 1-(acetoxy)propyl esters, 1-(acetoxy)butyl esters, propionyloxymethyl esters, 1-(propionyloxy)ethyl esters, butyryloxymethyl esters, 1-(butyryloxy)ethyl esters, isobutyryloxymethyl esters, 1-(isobutyryloxy)ethyl esters, 1-(isobutyryloxy)propyl esters, 1-(isobutyryloxy)butyl esters, pivaloyloxymethyl esters, 1-(pivaloyloxy)ethyl esters, 1-(pivaloyloxy)propyl ester and 1-(pivaloyloxy)butyl esters, of which the acetoxymethyl esters, 1-(acetoxy)ethyl esters, propionyloxymethyl esters, 1-(propionyloxy)ethyl esters, butyryloxymethyl esters, 1-(butyryloxy)ethyl esters, isobutyryloxymethyl esters, 1-(isobutyryloxy)ethyl esters, pivaloyloxymethyl esters and 1-(pivaloyloxy)ethyl esters are preferred, the acetoxymethyl esters, 1-(acetoxy)ethyl esters, isobutyryloxymethyl esters, 1-(isobutyryloxy)ethyl esters, pivaloyloxymethyl esters and 1-(pivaloyloxy)ethyl esters being more preferred, and the pivaloyloxymethyl esters being most preferred]; 
     (C 5 -C 6  cycloalkylcarbonyloxy)- or (1-alkyl-C 5 -C 6  cycloalkylcarbonyloxy)-(C 1 -C 4  alkyl) esters [for example, cyclopentylcarbonyloxymethyl esters, 1-(cyclopentylcarbonyloxy)ethyl esters, 1-methylcyclopentylcarbonyloxymethyl esters, 1-(1-methylcyclopentylcarbonylxoy)ethyl esters, 1-ethylcyclopentylcarbonyl-oxymethyl esters, 1(1-ethylcyclopentylcarbonyloxy)ethyl esters, cyclohexylcarbonyloxymethyl esters, 1-(cyclohexylcarbonyloxy)ethyl esters, 1-(cyclohexylcarbonyloxy)propyl esters, 1-(cyclohexylcarbonyloxy)butyl esters, 1-methylcyclohexylcarbonyloxymethyl esters, 1-(1-methylcyclohexylcarbonyloxy)ethyl esters, 1-(1-methylcyclohexylcarbonyloxy)propyl esters, 1-(1-methylcyclohexylcarboyloxy)butyl esters, 1-ethylcyclohexylcarbonyloxymethyl esters, 1-(1-ethylcyclohexylcarbonyloxy)ethyl esters, 1(1-propylcyclohexylcarbonyloxymethyl esters and 1-butylcyclohexylcarbonyloxymethyl esters, of which the cyclopentylcarbonyloxymethyl esters, 1-(cyclopentylcarbonyloxy)ethyl esters, 1-methylcyclopentylcarbonyloxymethyl esters, 1-(1-methylcyclopentylcarbonyloxy)ethyl esters, 1-ethylcyclopentylcarbonyloxymethyl esters, cyclohexylcarbonyloxymethyl esters, 1-(cyclohexylcarbonyloxy)ethyl esters, 1-methylcyclohexylcarbonyloxymethyl esters, 1-(1-methylcyclohexylcarbonyloxy)ethyl esters and 1-ethylcyclohexylcarbonyloxymethyl esters are preferred, the cyclopentylcarbonyloxymethyl esters, 1-(cyclopentylcarbonyloxy)ethyl esters, 1-methylcyclopentylcarbonyloxymethyl esters, 1(1-methylcyclopentylcarbonyloxy)ethyl esters, cyclohexylcarbonyloxymethyl esters, 1-(cyclohexylcarbonyloxy)ethyl esters, 1-methylcyclohexylcarbonyloxymethyl esters and 1-(1 -methylcyclohexylcarbonyloxy)ethyl esters being more preferred, the cyclopentylcarbonyloxymethyl esters, 1-methylcyclopentylcarbonyloxymethyl esters, cyclohexylcarbonyloxymethyl esters and 1-methylcyclohexylcarbonyloxymethyl esters being much more preferred, and the 1-methylcyclohexylcarbonyloxymethyl esters being most preferred]; 
     phthalidyl esters; and 
     5-(C 1 -C 4  alkyl- or phenyl-)-2-oxo-1,3-dioxolen 4ylmethyl esters [for example, 5-methyl-2-oxo-1,3-dioxoleno-4-ylmethyl esters, 5-ethyl-2-oxo-1,3-dioxolen-4-ylmethyl esters, 5-propyl-2-oxo-1,3-dioxolen-4-ylmethyl esters, 5-butyl-2-oxo-1,3-dioxolen-4-ylmethyl esters and 5-phenyl-2-oxo-1,3-dioxolen-4-ylmethyl esters, of which the 5-methyl-2-oxo-1,3-dioxolen4-ylmethyl esters, 5-ethyl-2-oxo-1,3-dioxolen-4-ylmethyl esters and 5-phenyl-2-oxo-1,3-dioxolen4-ylmethyl esters are preferred, the 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl esters and 5-phenyl-2-oxo-1,3-dioxolen-4-ylmethyl esters being more preferred, and the 5-methyl-2-oxo-1,3-dioxolen4-ylmethyl esters being most preferred]. 
     Among these esters, the methoxycarbonyloxymethyl esters, 1-(methoxycarbonyloxy)ethyl esters, ethoxycarbonyloxymethyl esters, 1-(ethoxycarbonyloxy)ethyl esters, isopropoxycarbonyloxymethyl esters, 1-(isopropoxycarbonyloxy)ethyl esters, t-butoxycarbonyloxymethyl esters, 1-butoxycarbonyloxy)ethyl esters, cyclopentyloxycarbonyloxymethyl esters, 1-(cyclopentyloxycarbonyloxy)ethyl esters, cyclohexyloxycarbonyloxymethyl esters, 1-(cyclohexyloxycarbonyloxy)ethyl esters, acetoxymethyl esters, 1-(acetoxy)ethyl esters, propionyloxymethyl esters, 1-(propionyloxy)ethyl esters, butyryloxymethyl esters, 1-(butyryloxy)ethyl esters, isobutyryloxymethyl esters, 1-(isobutyryloxy)ethyl esters, pivaloyloxymethyl esters, 1-(pivaloyloxy)ethyl esters, cyclopentylcarbonyloxymethyl esters, 1-(cyclopentylcarbonyloxy)ethyl esters, 1-methylcyclopentylcarbonyloxymethyl esters, 1-(1-methylcyclopentylcarbonyloxy)ethyl esters, 1-ethylcyclopentylcarbonyloxymethyl esters, cyclohexylcarbonyloxymethyl esters, 1-(cyclohexylcarbonyloxy)ethyl esters, 1-methylcyclohexylcarbonyloxymethyl esters, 1-(1-methylcyclohexylcarbonyloxy)ethyl esters, 1-ethylcyclohexylcarbonyloxymethyl esters, phthalidyl esters, 5-methyl-2-oxo-1,3-dioxolen4-ylmethyl esters, 5-ethyl-2-oxo-1,3-dioxolen-4-ylmethyl esters and 5-phenyl-2-oxo-1,3-dioxolen-4-ylmethyl esters are preferred; 
     the 1-(methoxycarbonyloxy)ethyl esters, 1-(ethoxycarbonyloxy)ethyl esters, 1-(isopropoxycarbonyloxy)ethyl esters, t-butoxycarbonyloxymethyl esters, 1-(t-butoxycarbonyloxy)ethyl esters, 1-(cyclopentyloxycarbonyloxy)ethyl esters, 1-(cyclohexyloxycarbonyloxy)ethyl esters, acetoxymethyl esters, 1-(acetoxy)ethyl esters, isobutyryloxymethyl esters, 1-isobutyryloxy)ethyl esters, pivaloyloxymethyl esters, 1-(pivaloyloxy)ethyl esters, cyclopentylcarbonyloxymethyl esters, 1-(cyclopentylcarbonyloxy)ethyl esters, 1-methylcyclopentylcarbonyloxymethyl esters, 1-(1-methylcyclopentylcarbonyloxy)ethyl esters, cyclohexylcarbonyloxymethyl esters, 1-(cyclohexylcarbonyloxy)ethyl esters, 1-methylcyclohexylcarbonyloxymethyl esters, 1-(1-methylcyclohexylcarbonyloxy)ethyl esters, phthalidyl esters, 5-methyl-2-oxo-1,3-dioxolen4-ylmethyl esters and 5-phenyl-2-oxo-1,3-dioxolen-4-ylmethyl esters are more preferred; 
     the 1-(methoxycarbonyloxy)ethyl esters, 1-(ethoxycarbonyloxy)ethyl esters, 1-(isopropoxycarbonyloxy)ethyl esters, t-butoxycarbonyloxymethyl esters, 1-(t-butoxycarbonyloxy)ethyl esters, 1-(cyclopentyloxycarbonyloxy)ethyl esters, 1-(cyclohexyloxycarbonyloxy)ethyl esters, acetoxymethyl esters, 1-(acetoxy)ethyl esters, isobutyryloxymethyl esters, 1-(isobutyryloxy)ethyl esters, pivaloyloxymethyl esters, 1-(pivaloyloxy)ethyl esters, cyclopentylcarbonyloxymethyl esters, 1-methylcyclopentylcarbonyloxymethyl esters, cyclohexylcarbonyloxymethyl esters, 1-methylcyclohexylcarbonyloxymethyl esters, phthalidyl esters and 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl esters are still more preferred; 
     the 1-(isopropoxycarbonyloxy)ethyl esters, 1-(cyclohexyloxycarbonyloxy)ethyl esters, pivaloyloxymethyl esters, 1-methylcyclohexylcarboyloxymethyl esters and 5-methyl-2-oxo-1,3-dioxolen 4ylmethyl esters are particularly preferred; and 
     the 1-(isopropoxycarbonyloxy)ethyl esters, 1-(cyclohexyloxycarbonyloxy)ethyl esters and pivaloyloxymethyl esters are most preferred. 
     Compound (I) which is an active ingredient of the present invention contains asymmetric carbons in its molecule and therefore has various isomers with respect to them. The present application embraces various isomers of Compound (I) and mixtures of these isomers, of which the isomers having a (1R,5S,6S) configuration and an R configuration for the hydroxyl group at the α-position of the 6-substituent in the carbapenem skeleton, are preferred. The present application also embraces hydrated products of Compound (I) and its salts and esters. 
     Preferred examples of the compounds of formula (I) include: 
     (1) a compound wherein R 1  represents a group of formula (IIa) (in which R 2  represents a hydrogen atom or a C 1 -C 4  alkyl group), a group of formula (IIb), a group of formula (IIc) or a group of formula (IId) (in which R 3  represents a hydrogen atom or a methyl group), 
     (2) a compound wherein R 1  represents a group of formula (IIa) (in which R 2  represents a hydrogen atom or a methyl group), 
     (3) a compound wherein R 1  represents a 2-oxo-3-pyrrolidinyl, 1-methyl-2-oxo-3-pyrrolidinyl, 2-oxo-4-pyrrolidinyl or 1-methyl-2-oxo4-pyrrolidinyl group, 
     (4) a compound wherein R 1  represents a 2-oxo4-pyrrolidinyl or 1 -methyl-2-oxo-4-pyrrolidinyl group, 
     (5) a compound wherein R 1  represents a 2-oxo-4pyrrolidinyl group, 
     (6) a compound wherein the configuration in the carbapenem skeleton is a (1R,5S,6S) configuration, 
     (7) a compound wherein the configuration of the hydroxyl group at the α-position of the 6-substituent in the carbapenem skeleton is a R configuration, 
     (8) a compound whose pharmacologically acceptable salt is a lithium salt, sodium salt or potassium salt, 
     (9) a compound whose pharmacologically acceptable salt is a sodium salt or potassium salt, 
     (10) a compound whose pharmacologically acceptable salt is a sodium salt, 
     (11) a compound whose pharmacologically acceptable ester can be hydrolyzed in vivo and converted into the corresponding carboxylic acid, 
     (12) a compound whose pharmacologically acceptable ester is a 1-(methoxycarbonyloxy)ethyl ester, 1-(ethoxycarbonyloxy)ethyl ester, 1-(isopropoxycarbonyloxy)ethyl ester, t-butoxycarbonyloxymethyl ester, 1-(t-butoxycarbonyloxy)ethyl ester, 1-(cyclopentyloxycarbonyloxy)ethyl ester, 1-(cyclohexyloxycarbonyloxy)ethyl ester, acetoxymethyl ester, 1-(acetoxy)ethyl ester, isobutyryloxymethyl ester, 1-(isobutyryloxy)ethyl ester, pivaloyloxymethyl ester, 1-(pivaloyloxy)ethyl ester, cyclopentylcarbonyloxymethyl ester, 1-(cyclopentylcarbonyloxy)ethyl ester, 1-methylcyclopentylcarbonyloxymethyl ester, 1-(1-methylcyclopentylcarbonyloxy)ethyl ester, cyclohexylcarbonyloxymethyl ester, 1-(cyclohexylcarbonyloxy)ethyl ester, 1-methylcyclohexylcarbonyloxymethyl ester, 1-(1-methylcyclohexylcarbonyloxy)ethyl ester, phthalidyl ester, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl ester or 5-phenyl-2-oxo-1,3-dioxolen4-ylmethyl ester, 
     (13) a compound whose pharmacologically acceptable ester is a 1-(methoxycarbonyloxy)ethyl ester, 1-(ethoxycarbonyloxy)ethyl ester, 1-(isopropoxycarbonyloxy)ethyl ester, t-butoxycarbonyloxymethyl ester, 1-(t-butoxycarbonyloxy)ethyl ester, 1-(cyclopentyloxycarbonyloxy)ethyl ester, 1-(cyclohexyloxycarbonyloxy)ethyl ester, acetoxymethyl ester, 1-(acetoxy)ethyl ester, isobutyryloxymethyl ester, 1-(isobutyryloxy)ethyl ester, pivaloyloxymethyl ester, 1-(pivaloyloxy)ethyl ester, cyclopentylcarbonyloxymethyl ester, 1-methylcyclopentylcarbonyloxymethyl ester, cyclohexylcarbonyloxymethyl ester, 1-methylcyclohexylcarboyloxymethyl ester, phthalidyl ester or 5-methyl-2-oxo-1,3-dioxolen4-ylmethyl ester, 
     (14) a compound whose pharmacologically acceptable ester is a 1-(isopropoxycarbonyloxy)ethyl ester, 1-(cyclohexyloxycarbonyloxy)ethyl ester, pivaloyloxymethyl ester, 1-methylcyclohexylcarbonyloxymethyl ester or 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl ester, and 
     (15) a compound whose pharmacologically acceptable ester is a 1-(isopropoxycarbonyloxy)ethyl ester, 1-(cyclohexyloxycarbonyloxy)ethyl ester or pivaloyloxymethyl ester. 
     In each of the groups (1) to (5), (8) to (10) and (11) to (15), the larger the number is, the more preferred the compound is. 
     In addition, compounds obtained by selecting R 1  from the group (1) to (5), a configuration from (6) or (7), a salt from the group (8) to (10) and an ester from the group (11) to (15) and by using these in any combination are preferred. Examples of such compounds are as follows: 
     (16) a compound wherein R 1  represents a group of formula (Ila) (in which R 2  represents a hydrogen atom or a C 1 -C 4  alkyl group), group of formula (IIb), group of formula (IIc) or group of formula (IId) (in which R 3  represents a hydrogen atom or a methyl group), 
     the configuration in the carbapenem skeleton is a (1R,5S,6S) configuration, 
     the configuration of the hydroxyl group at the α-position of the 6-substituent in the carbapenem skeleton is a R configuration, 
     the pharmacologically acceptable salt is a lithium salt, sodium salt or potassium salt, and 
     the pharmacologically acceptable ester is one which can be hydrolyzed in vivo and converted into the corresponding carboxylic acid. 
     (17) a compound wherein R 1  represents a group of formula (IIa) (in which R 2  represents a hydrogen atom or a methyl group), 
     the configuration in the carbapenem skeleton is a (1R,5S,6S) configuration, 
     the configuration of the hydroxyl group at the α-position of the 6-substituent in the carbapenem skeleton is a R configuration, 
     the pharmacologically acceptable salt is a sodium salt or potassium salt, and 
     the pharmacologically acceptable ester is a 1-(methoxycarbonyloxy)ethyl ester, 1-(ethoxycarbonyloxy)ethyl ester, 1-(isopropoxycarbonyloxy)ethyl ester, t-butoxycarbonyloxymethyl ester, 1-(t-butoxycarbonyloxy)ethyl ester, 1-(cyclopentyloxycarbonyloxy)ethyl ester, 1-(cyclohexyloxycarbonyloxy)ethyl ester, acetoxymethyl ester, 1-(acetoxy)ethyl ester, isobutyryloxymethyl ester, 1-(isobutyryloxy)ethyl ester, pivaloyloxymethyl ester, 1-(pivaloyloxy)ethyl ester, cyclopentylcarbonyloxymethyl ester, 1-(cyclopentylcarbonyloxy)ethyl ester, 1-methylcyclopentylcarbonyloxymethyl ester, 1-(1-methylcyclopentylcarbonyloxy)ethyl ester, cyclohexylcarbonyloxymethyl ester, 1-(cyclohexylcarbonyloxy)ethyl ester, 1-methylcyclohexylcarbonyloxymethyl ester, 1-(1-methylcyclohexylcarbonyloxy)ethyl ester, phthalidyl ester, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl ester or 5-phenyl-2-oxo-1,3-dioxolen-4-ylmethyl ester, 
     (18) a compound wherein R 1  represents a 2-oxo-3-pyrrolidinyl group, 1-methyl-2-oxo-3-pyrrolidinyl group, 2-oxo-4-pyrrolidinyl group or 1-methyl-2-oxo-4-pyrrolidinyl group, 
     the configuration in the carbapenem skeleton is a (1R,5S,6S) configuration, 
     the configuration of the hydroxyl group at the α-position of the 6-substituent in the carbapenem skeleton is a R configuration, 
     the pharmacologically acceptable salt is a sodium salt or potassium salt, and 
     the pharmacologically acceptable ester is a 1-(methoxycarbonyloxy)ethyl ester, 1-(ethoxycarbonyloxy)ethyl ester, 1-(isopropoxycarbonyloxy)ethyl ester, t-butoxycarbonyloxymethyl ester, 1-(t-butoxycarbonyloxy)ethyl ester, 1-(cyclopentyloxycarbonyloxy)ethyl ester, 1-(cyclohexyloxycarbonyloxy)ethyl ester, acetoxymethyl ester, 1-acetoxy)ethyl ester, isobutyryloxymethyl ester, 1-(isobutyryloxy)ethyl ester, pivaloyloxymethyl ester, 1-(pivaloyloxy)ethyl ester, cyclopentylcarbonyloxymethyl ester, 1-methylcyclopentylcarbonyloxymethyl ester, cyclohexylcarbonyloxymethyl ester, 1-methylcyclohexylcarboyloxymethyl ester, phthalidyl ester or 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl ester, 
     (19) compounds wherein R 1  represents a 2-oxo-4-pyrrolidinyl group or 1-methyl-2-oxo-4-pyrrolidinyl group, 
     the configuration in the carbapenem skeleton is a (1R,5S,6S) configuration, 
     the configuration of the hydroxyl group at the a-position of the 6-substituent in the carbapenem skeleton is a R configuration, 
     the pharmacologically acceptable salt is a sodium salt or potassium salt, and the pharmacologically acceptable ester is a 1-isopropoxycarbonyloxy)ethyl ester, 1-(cyclohexyloxycarbonyloxy)ethyl ester, pivaloyloxymethyl ester, 1-methylcyclohexylcarbonyloxymethyl ester or 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl ester, and 
     (20) a compound wherein R 1  represents a 2-oxo-4-pyrrolidinyl group, 
     the configuration in the carbapenem skeleton is a (1R,5S,6S) configuration, 
     the configuration of the hydroxyl group at the a-position of the 6-substituent in the carbapenem skeleton is R a configuration, 
     the pharmacologically acceptable salt is a sodium salt, and 
     the pharmacologically acceptable ester is a 1-(isopropoxycarbonyloxy)ethyl ester, 1-(cyclohexyloxycarbonyloxy)ethyl ester or pivaloyloxymethyl ester. 
     Specific examples of the compounds represented by the formula (I) can be exemplified in Table 1.                           
     
       
         
               
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                 Compound No. 
                 R 
                 R 1 a 
               
               
                   
               
             
             
               
                  1 
                 H 
                 2-oxo-4-Pyrr 
               
               
                  2 
                 Na 
                 2-oxo-4-Pyrr 
               
               
                  3 
                 K 
                 2-oxo-4-Pyrr 
               
               
                  4 
                 MeOCO 2 CHMe 
                 2-oxo-4-Pyrr 
               
               
                  5 
                 EtOCO 2 CHMe 
                 2-oxo-4-Pyrr 
               
               
                  6 
                 Pr i OCO 2 CHMe 
                 2-oxo-4-Pyrr 
               
               
                  7 
                 Bu t OCO 2 CH 2   
                 2-oxo-4-Pyrr 
               
               
                  8 
                 Bu t OCO 2 CHMe 
                 2-oxo-4-Pyrr 
               
               
                  9 
                 Pn c OCO 2 CHMe 
                 2-oxo-4-Pyrr 
               
               
                 10 
                 Hx c OCO 2 CHMe 
                 2-oxo-4-Pyrr 
               
               
                 11 
                 AcOCH 2   
                 2-oxo-4-Pyrr 
               
               
                 12 
                 AcOCHMe 
                 2-oxo-4-Pyrr 
               
               
                 13 
                 Pr i CO 2 CH 2   
                 2-oxo-4-Pyrr 
               
               
                 14 
                 Bu t CO 2 CH 2   
                 2-oxo-4-Pyrr 
               
               
                 15 
                 Pn c CO 2 CH 2   
                 2-oxo-4-Pyrr 
               
               
                 16 
                 1-MePn c CO 2 CH 2   
                 2-oxo-4-Pyrr 
               
               
                 17 
                 Hx c CO 2 CH 2   
                 2-oxo-4-Pyrr 
               
               
                 18 
                 1-MeHxCOCH 2   
                 2-oxo-4-Pyrr 
               
               
                 19 
                 Phthz 
                 2-oxo-4-Pyrr 
               
               
                 20 
                 MODM 
                 2-oxo-4-Pyrr 
               
               
                 21 
                 H 
                 1-Me-2-oxo-4-Pyrr 
               
               
                 22 
                 Na 
                 1-Me-2-oxo-4-Pyrr 
               
               
                 23 
                 K 
                 1-Me-2-oxo-4-Pyrr 
               
               
                 24 
                 MeOCO 2 CHMe 
                 1-Me-2-oxo-4-Pyrr 
               
               
                 25 
                 EtOCO 2 CHMe 
                 1-Me-2-oxo-4-Pyrr 
               
               
                 26 
                 Pr i OCO 2 CHMe 
                 1-Me-2-oxo-4-Pyrr 
               
               
                 27 
                 Bu c OCO 2 CH 2   
                 1-Me-2-oxo-4-Pyrr 
               
               
                 28 
                 Bu t OCO 2 CHMe 
                 1-Me-2-oxo-4-Pyrr 
               
               
                 29 
                 Pn c OCO 2 CHMe 
                 1-Me-2-oxo-4-Pyrr 
               
               
                 30 
                 Hx c OCO 2 CHMe 
                 1-Me-2-oxo-4-Pyrr 
               
               
                 31 
                 AcOCH 2   
                 1-Me-2-oxo-4-Pyrr 
               
               
                 32 
                 AcOCHMe 
                 1-Me-2-oxo-4-Pyrr 
               
               
                 33 
                 Pr i OCO 2 CH 2   
                 1-Me-2-oxo-4-Pyrr 
               
               
                 34 
                 Bu t CO 2 CH 2   
                 1-Me-2-oxo-4-Pyrr 
               
               
                 35 
                 Pn c CO 2 CH 2   
                 1-Me-2-oxo-4-Pyrr 
               
               
                 36 
                 1-MePn c CO 2 CH 2   
                 1-Me-2-oxo-4-Pyrr 
               
               
                 37 
                 Hx c CO 2 CH 2   
                 1-Me-2-oxo-4-Pyrr 
               
               
                 38 
                 1-MeHx c CO 2 CH 2   
                 1-Me-2-oxo-4-Pyrr 
               
               
                 39 
                 Phthz 
                 1-Me-2-oxo-4-Pyrr 
               
               
                 40 
                 MODM 
                 1-Me-2-oxo-4-Pyrr 
               
               
                 41 
                 H 
                 2-oxo-3-Pyrr 
               
               
                 42 
                 Na 
                 2-oxo-3-Pyrr 
               
               
                 43 
                 K 
                 2-oxo-3-Pyrr 
               
               
                 44 
                 MeOCO 2 CHMe 
                 2-oxo-3-Pyrr 
               
               
                 45 
                 EtOCO 2 CHMe 
                 2-oxo-3-Pyrr 
               
               
                 46 
                 Pr i OCO 2 CHMe 
                 2-oxo-3-Pyrr 
               
               
                 47 
                 Bu t CO 2 CH 2   
                 2-oxo-3-Pyrr 
               
               
                 48 
                 Bu t CO 2 CHMe 
                 2-oxo-3-Pyrr 
               
               
                 49 
                 AcOCH 2   
                 2-oxo-3-Pyrr 
               
               
                 50 
                 AcOCHMe 
                 2-oxo-3-Pyrr 
               
               
                 51 
                 Pr i CO 2 CH 2   
                 2-oxo-3-Pyrr 
               
               
                 52 
                 Bu t CO 2 CH 2   
                 2-oxo-3-Pyrr 
               
               
                 53 
                 1-MePn c CO 2 CH 2   
                 2-oxo-3-Pyrr 
               
               
                 54 
                 1-MeHx c CO 2 CH 2   
                 2-oxo-3-Pyrr 
               
               
                 55 
                 Phthz 
                 2-oxo-3-Pyrr 
               
               
                 56 
                 MODM 
                 2-oxo-3-Pyrr 
               
               
                 57 
                 H 
                 1-Me-2-oxo-3-Pyrr 
               
               
                 58 
                 Na 
                 1-Me-2-oxo-3-Pyrr 
               
               
                 59 
                 K 
                 1-Me-2-oxo-3-Pyrr 
               
               
                 60 
                 MeOCO 2 CHMe 
                 1-Me-2-oxo-3-Pyrr 
               
               
                 61 
                 Pr i OCO 2 CHMe 
                 1-Me-2-oxo-3-Pyrr 
               
               
                 62 
                 Bu t OCO 2 CH 2   
                 1-Me-2-oxo-3-Pyrr 
               
               
                 63 
                 Bu t OCO 2 CHMe 
                 1-Me-2-oxo-3-Pyrr 
               
               
                 64 
                 AcOCH 2   
                 1-Me-2-oxo-3-Pyrr 
               
               
                 65 
                 AcOCHMe 
                 1-Me-2-oxo-3-Pyrr 
               
               
                 66 
                 Pr i CO 2 CH 2   
                 1-Me-2-oxo-3-Pyrr 
               
               
                 67 
                 Bu t CO 2 CH 2   
                 1-Me-2-oxo-3-Pyrr 
               
               
                 68 
                 1-MePn c CO 2 CH 2   
                 1-Me-2-oxo-3-Pyrr 
               
               
                 69 
                 1-MeHx c CO 2 CH 2   
                 1-Me-2-oxo-3-Pyrr 
               
               
                 70 
                 Phthz 
                 1-Me-2-oxo-3-Pyrr 
               
               
                 71 
                 MODM 
                 1-Me-2-oxo-3-Pyrr 
               
               
                 72 
                 H 
                 ImdzoPyrr 
               
               
                 73 
                 Na 
                 ImdzoPyrr 
               
               
                 74 
                 K 
                 ImdzoPyrr 
               
               
                 75 
                 Pr i OCO 2 CHMe 
                 ImdzoPyrr 
               
               
                 76 
                 Bu t CO 2 CH 2   
                 ImdzoPyrr 
               
               
                 77 
                 Hx c CO 2 CHMe 
                 ImdzoPyrr 
               
               
                 78 
                 H 
                 ThizAze 
               
               
                 79 
                 Na 
                 ThizAze 
               
               
                 80 
                 K 
                 ThizAze 
               
               
                 81 
                 Pr i OCO 2 CHMe 
                 ThizAze 
               
               
                 82 
                 Bu t CO 2 CH 2   
                 ThizAze 
               
               
                 83 
                 Hx c CO 2 CHMe 
                 ThizAze 
               
               
                 84 
                 H 
                 2-thioxo-4-Pyrr 
               
               
                 85 
                 Na 
                 2-thioxo-4-Pyrr 
               
               
                 86 
                 K 
                 2-thioxo-4-Pyrr 
               
               
                 87 
                 Pr i OCO 2 CHMe 
                 2-thioxo-4-Pyrr 
               
               
                 88 
                 Bu t CO 2 CH 2   
                 2-thioxo-4-Pyrr 
               
               
                 89 
                 Hx c CO 2 CHMe 
                 2-thioxo-4-Pyrr 
               
               
                 90 
                 H 
                 1-Me-2-thioxo-4-Pyrr 
               
               
                 91 
                 Na 
                 1-Me-2-thioxo-4-Pyrr 
               
               
                 92 
                 K 
                 1-Me-2-thioxo-4-Pyrr 
               
               
                 93 
                 Pr i OCO 2 CHMe 
                 1-Me-2-thioxo-4-Pyrr 
               
               
                 94 
                 Bu t CO 2 CH 2   
                 1-Me-2-thioxo-4-Pyrr 
               
               
                 95 
                 Hx c CO 2 CHMe 
                 1-Me-2-thioxo-4-Pyrr 
               
               
                   
               
             
          
         
       
     
     In the above Table, abbreviations represent the following groups, respectively. 
     Ac: acetyl 
     Bu t : t-butyl 
     Et: ethyl 
     Hx c : cyclohexyl 
     ImdzoPyrr: group of the formula (IIb) 
     Me: methyl 
     MODM: 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl 
     Phthz: phthalidyl 
     Pn c : cyclopentyl 
     Pn e : isopropyl 
     Pyrr: pyrrolidinyl 
     ThizAze: group of the formula (Ic) 
     In the above table, the following compounds are preferred: Compounds Nos. 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 20, 22, 23, 25, 26, 27, 28, 29, 30, 31, 32, 34, 35, 36, 37, 38, 40, 73, 76, 79, 82, 83, 85, 88, 91 and 94; 
     the following compounds are more preferrred: Compounds Nos. 2, 6, 10, 14, 18, 22, 26, 30, 34 and 38; and 
     the following compounds are much more preferred: 
     Compound No. 2: sodium 2-(2-oxo-4-pyrrolidinylthio)-6-(1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate, 
     Compound No. 14: pivaloyloxymethyl 2-(2-oxo-4-pyrrolidinylthio)-6-(1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate, 
     Compound No. 18: 1-methylcyclohexylcarbonyloxymethyl 2-(2-oxo4-pyrrolidinylthio)-6-(1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate, 
     Compound No. 22: sodium 2-(1-methyl-2-oxo-4pyrrolidinylthio)-6-(1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate, and 
     Compound No. 34: pivaloyloxymethyl 2-(1-methyl-2-oxo4-pyrrolidinylthio)-6-(1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate. 
     On the other hand, the following compounds are most preferred: 
     (1R,5 S,6S)-2-[(4R-2-oxo-4-pyrrolidinylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid, or the sodium salt or pivaloyloxymethyl ester thereof; 
     (1R,5 S,6S)-2-[(4S)-2-oxo-4-pyrrolidinylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid, or the sodium salt or pivaloyloxymethyl ester thereof; 
     (1R,5S,6S)-2-[(4R)-1-methyl-2-oxo-4-pyrrolidinylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl- 1-carbapen-2-em-3-carboxylic acid, or sodium salt or pivaloyloxymethyl ester thereof; and 
     (1R,5S,6S)-2-[(4S)-1-methyl-2--oxo4-pyrrolidinylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid, or sodium salt or pivaloyloxymethyl ester thereof. 
     Compounds (I), each of which is an active ingredient of the present invention, are known or can be prepared easily by a known method (for example Japanese Patent Application Kokai No. Hei 7-165759, Japanese Patent Application Kokai No. Hei 2-223587, Japanese Patent Application Kokai No. Hei 8-53453, Japanese Patent Application Kokai No. Hei 4-279588, etc.). 
     The 1-methylcarbapenem derivatives of formula (I), active ingredients of the present invention, have excellent anti-bacterial activity against various  helicobacter pylori  and lower toxicity, and so they are useful as an anti-bacterial agent for the treatment or prevention (particularly, treatment) of infectious diseases caused by  helicobacter pylori.    
     When the Compound (I) is used as an anti-bacterial agent, Compound (I) by itself or a mixture with a pharmacologically acceptable excipient, diluent, etc., can be administered orally in the form of tablets, capsules, granules, powders or syrups or parenterally in the form of injections. Of these, oral administration is recommended. 
     The above formulations can be prepared in a known manner by using additives. Examples of the additives include an excipient (for example sugar derivatives such as lactose, sucrose, dextrose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, α-starch, dextrin and carboxymethyl starch; cellulose derivatives such as crystalline cellulose, low-substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium and internally-crosslinked carboxymethyl cellulose sodium; gum arabic; dextran; pullulan; silicate derivatives such as soft silicic acid anhydride, synthetic aluminum silicate and magnesium aluminate metasilicate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; and sulfate derivatives such as calcium sulfate), a binder (for example the above-exemplified excipients, gelatin, polyvinyl pyrrolidone and Macrogol), a disintegrator (for example the above-exemplified excipients, chemically-modified starch or cellulose derivatives such as croscarmellose sodium, carboxymethyl starch sodium and crosslinked polyvinyl pyrrolidone), a lubricant (for example talc, stearic acid, metal salts of stearic acid such as calcium stearate and magnesium stearate; colloidal silica; waxes such as veegum and spermaceti; boric acid; glycol; carboxylic acids such as fumaric acid and adipic acid; sodium carboxylates such as sodium benzoate; sulfates such as sodium sulfate; leucine; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as silicic acid anhydride and silicic acid hydrate; and the same starch derivatives as those exemplified for the excipient), a stabilizer (for example paraoxybenzoates such as methyl paraben and propyl paraben; alcohols such as chlorobutanol benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenol derivatives such as phenol and cresol; thimerosal; acetic anhydride; and sorbic acid), a corrigent (for example, ordinarily-employed sweeteners, acidifiers and flavors), a diluent and a solution-forming agent for injections (for example, water, ethanol and glycerin). The dose of Compound (I) will vary depending upon the condition and age of the patient and the like. Orally, it is administered in an amount of 30 mg (preferably 50 mg) in a single dose as a lower limit and 5000 mg (preferably 300 mg) in a single dose as an upper limit, and intravenously, it is administered in an amount of 10 mg (preferably 30 mg) in a single dose as a lower limit and 3000 mg (preferably 200 mg) in a single dose as an upper limit. It is desirable to be administered one to six times per day depending upon the conditions of the patient, i.e., the person being treated. 
     The anti- helicobacter pylori  agent which contains Compound (I) of the present invention as an active ingredient may contain one or more other medicaments in addition. Any medicament that does not have adverse effects on Compound (I) of the present invention can be used. Examples include bismuth preparations (such as bismuth citrate and bismuth salicylate), nitroimidazole compounds (such as metronidazole), H 2  blocker type anti-ulcereratives (such as cimetidine, ranitidine hydrochloride, famotidine, roxatidine acetate hydrochloride and nizatidine), proton-pump inhibitor type anti-ulceratives (such as omeprazole, lansoprazole, rabeprazole, reminoprazole and saviprazole), mucous membrane protective factor enhancer type anti-ulceratives (such as plaunotol, teprenone and sofalcone), anti-bacterials (such as clarithromycin, azithromycin, erythromycin, roxithromycin and amoxicillin) and synthetic anti-bacterials (such as ofloxacin, levofloxacin, ciprofloxacin); preferably the bismuth preparations, nitroimidazole compounds, H 2  blocker type anti-ulceratives, proton-pump anti-ulceratives and mucous membrane protective factor enhancer type anti-ulceratives; more preferably, cimetidine, ranitidine hydrochloride, famotidine, roxatidine acetate hydrochloride, nizatidine, omeprazole, lansoprazole, rabeprazole, reminoprazole and saviprazole; and most preferably cimetidine, ranitidine hydrochloride, famotidine, omeprazole and lansoprazole. 
     The present invention will hereinafter be described more specifically by tests and preparation examples. It should, however, be understood that the present invention is not limited by these examples. 
     (Test 1) 
     In vitro activity against helicobacter pylon (MIC; μg/ml) 
       Helicobacter pylori  ( H. pylori ) from storage was smeared on a 7%-equine-defibrinated-blood-added brain heart infusion agar (BHIA) plate and cultured at 37° C. for 72 hours under microaerophilic and wet conditions. The colonies thus grown were picked and suspended in physiological saline to prepare a culture solution of 10 8  CFU/ml (viable microbe cell number per ml). The resulting culture solution was diluted to 10 to 50-fold with physiological saline, and one spot (about 10 μl) of the solution was inoculated on each of medicament-containing and medicament-free BHIA plates. Each of the plates was cultured at 37° C. for 72 hours under microaerophilic and wet conditions and the minimum inhibitory concentration (MIC: μg/ml) at which the growth of the colonies was inhibited was measured. The results are shown in Table 2. 
     
       
         
               
             
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 In vitro antibacterial activity (minimum 
               
               
                 inhibitory concentration, MIC: μg/ml) 
               
             
          
           
               
                 No. of 
                 MIC (μg/ml) 
               
             
          
           
               
                 
                   helicobacter 
                 
                 Compound 
                 Compound 
                 Compound 
                   
                   
               
               
                   pylori  strain 
                 No. 1 
                 No. 2 
                 No. 3 
                 AMPC 
                 CAM 
               
               
                   
               
               
                 9470 
                 ≦0.006 
                 ≦0.0006 
                 ≦0.006 
                 0.012 
                 0.006 
               
               
                 9472 
                 ≦0.006 
                 ≦0.006 
                 ≦0.006 
                 0.025 
                 0.006 
               
               
                 9474 
                 ≦0.006 
                 — 
                 — 
                 0.05 
                 0.025 
               
               
                 9824 
                 ≦0.006 
                 ≦0.006 
                 ≦0.006 
                 0.39 
                 1.5 
               
               
                 9828 
                 ≦0.006 
                 ≦0.006 
                 ≦0.006 
                 0.20 
                 6.25 
               
               
                   
               
             
          
         
       
     
     In the above Table 2, Compound 1 is sodium (1R,5S,6S)-2-[(4R)-2-oxo-4pyrrolidinylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate, Compound 2 is sodium (1R,5S,6S)-2-[(4R)-1-methyl-2-oxo-4-pyrrolidinylthio]-6[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate, Compound 3 is sodium (1R,5S,6S)-2-[(4S)-1-methyl-2-oxo-4-pyrrolidinylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate, AMPC stands for amoxicillin and CAM stands for clarithromycin. 
     (Test 2) 
     Therapeutic effects for nude mouse infected with helicobacter pylon 
     Bacteria ( helicobacter pylori  9470 strain) used for the test, which were cultured for 48 hours in a 2%-fetal-calf-serum-added brucella broth, were centrifuged. After removal of the supernatant, the residue was re-suspended in a {fraction (1/10)} amount of a brucella broth. The resulting suspended solution was orally administered to each of three to five nude mice in an amount of 1.5 ml per mouse. 10 days after the infection, administration of a medicament was started. A 0.5% tragacanth suspension of a medicament was orally administered for 4 days through an oral catheter at a dose of 0.3 ml/mouse, once a day. On the day after the final administration, the stomach was extirpated, homogenized and then diluted. The viable microbe cell number (CFU/stomach) was measured and the results are shown in FIG.  1 . 
     In FIG. 1, Medicament A is a control group, Medicaments B(1) and B(2) are CAM (clarithromycin: 1 mg/kg) and CAM (10 mg/kg), respectively, and Medicaments C(1) and C(2) are Compound 4, that is, pivaloyloxymethyl (1R,5S,6S)-2-[(4R)-2-oxo-4-pyrrolidinylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (1 mg/kg) and Compound 4 (10 mg/kg), respectively. The significant difference of Medicament B(2), Medicament C(1) or C(2) is p&lt;0.01 (vs the control group). 
     (Preparation Example 1) 
     
       
         
               
             
               
               
               
               
             
           
               
                   
               
               
                 Capsules 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Compound 4 
                 50.0 
                 mg 
               
               
                   
                 Lactose 
                 128.7 
               
               
                   
                 Corn starch 
                 70.0 
               
               
                   
                 Magnesium stearate 
                 1.3 
               
               
                   
                   
                 250 
                 mg 
               
               
                   
                   
               
             
          
         
       
     
     The above-described ingredients in powdery form were mixed, shifted through a 60-mesh sieve and used to fill a 250-mg No.3 gelatin capsule to give a capsule.