HK1027805A - Carbapenem compound use thereof and intermediate compound therefor - Google Patents

Description

Carbapenem compound, use thereof and intermediate compound thereof

Technical Field

The present invention relates to a novel penem (Carbapenem) compound or a pharmaceutically acceptable salt thereof which is useful as a prophylactic and therapeutic agent for bacterial infections, and more particularly, to a novel penem compound or a pharmaceutically acceptable salt thereof having sufficient antibacterial properties and oral absorbability, an oral antibacterial agent containing the compound as an active ingredient, and an intermediate compound or a salt thereof for producing the penem compound.

Background

Many compounds having a penem skeleton have been found to be useful as remedies for infectious diseases, and among them, several penem compounds having excellent antibacterial activity have been put to practical use or are under practical development. For example, carbapenem compounds of formula A.Has been put into practical use and supplied to the clinicalBed application. The carbapenem compound has a broad antibacterial spectrum and a strong antibacterial activity, and overcomes the instability to renal dehydropeptidase which is considered to be a disadvantage of carbapenem compounds of the prior art, and has an excellent feature that it can be administered alone without using a stabilizer.

However, these carbapenem compounds have poor absorption through the digestive tract, and can be administered clinically as injections. Oral drugs are easy and simple to administer compared with injections, and are extremely useful clinically. Therefore, the development of carbapenem compounds for oral administration having potent antibacterial activity, broad antibacterial spectrum and excellent absorbability through the digestive tract has been strongly desired.

The object of the present invention is to provide a carbapenem compound having excellent antibacterial activity and absorbability through the digestive tract.

Another object of the present invention is to provide a use of the carbapenem compound.

Still another object of the present invention is to provide an intermediate suitable for the production of the carbapenem compound.

DISCLOSURE OF THE INVENTION

The present inventors have made extensive studies in order to achieve the above object, and as a result, have found that a novel carbapenem compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof is excellent in absorbability through the digestive tract, and that these compounds have a very strong antibacterial property and are extremely useful as an antibacterial agent for oral administration, and further found a novel intermediate compound useful for the production of the compound, and finally completed the present invention.

That is, the present invention relates to

(1) A carbapenem compound (I) represented by the general formula (I) or a pharmaceutically acceptable salt thereofIn the formula, R¹And R²May be the same or different and are each a modifying group hydrolyzable in the living body, R³And R⁴Which may be the same or different, are each lower alkyl, or R³、R⁴Taken together with the nitrogen atom to which they are attached represent a cyclic amino group;

(2) the carbapenem compound of (1) above, wherein R is¹And R²May be the same or different and are each a modifying group hydrolyzable in the living body, R³And R⁴May be the same or different and are each lower alkyl;

(3) the carbapenem compound of (1) above, wherein R is²Is 5-methyl-1, 3-dioxolan-2-on-4-ylmethyl, R³And R⁴Are both methyl;

(4) the carbapenem compound of (1) above, wherein R is¹Is pivaloyloxymethyl, R²Is 5-methyl-1, 3-dioxolan-2-one-4-ylmethyl;

(5) the carbapenem compound of (1) above, wherein R is¹And R²Are each pivaloyloxymethyl;

(6) the carbapenem compound of (1) above or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:

pivaloyloxymethyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate,

pivaloyloxymethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-pivaloyloxymethyl) pyrrolidin-3-ylthio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate,

pivaloyloxymethyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-on-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate hydrochloride,

pivaloyloxymethyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-diethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate,

pivaloyloxymethyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-methylethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate,

pivaloyloxymethyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5- (1-pyrrolidinocarbonyl) -1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate,

pivaloyloxymethyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5- (1-piperidinylcarbonyl) -1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate, and

pivaloyloxymethyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5- (1-azetidinylcarbonyl) -1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate;

(7) an antibacterial agent comprising as an active ingredient a carbapenem compound of the general formula (I) described in (1) above or a pharmaceutically acceptable salt thereof;

(8) the antibacterial agent according to the above (7), which is for oral administration;

(9) a carbapenem compound represented by the formula (II)In the formula, R²Is a modifying group which is hydrolyzable in vivo, R³And R⁴Can be the sameOr, which may be different, are each lower alkyl, or R³、R⁴Together with the nitrogen atom to which they are attached represent a cyclic amino group, R⁵Is a hydrogen atom or a carboxyl protecting group; and

(10) the carbapenem compound of (9) above or a salt thereof, which is selected from the group consisting of:

p-nitrobenzyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate, and

sodium (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate.

Various definitions used in the present specification are explained below.

R¹And R²The "modified group hydrolyzable in vivo", which is preferred, is hydrolyzable in the intestinal tract or blood, and examples thereof include optionally substituted aryl (e.g., phenyl, tolyl, xylyl, 2, 3-indanyl, etc.), 1-alkanoyloxyalkyl, 1-alkoxycarbonyloxyalkyl, 2-benzo [ c ] oxy]Furanone group, 5-methyl-1, 3-dioxolan-2-on-4-ylmethyl group, and the like. Of these, preferred are 1-alkanoyloxyalkyl, 1-alkoxycarbonyloxyalkyl and 5-methyl-1, 3-dioxolan-2-on-4-ylmethyl.

The "aryl group which may have a substituent(s)" is preferably an unsubstituted aryl group or an aryl group substituted with 1 to 3 substituent(s), and the substituent(s) may be the same or different. Specific examples of the substituent include alkyl groups having 1 to 4 carbon atoms such as methyl group and ethyl group.

The number of carbon atoms of the alkanoyl moiety in the "1-alkanoyloxyalkyl" is preferably 2 to 10, more preferably 2 to 7, and may be any of straight chain, branched chain and cyclic, and the number of carbon atoms of the alkyl moiety is preferably 1 to 3, more preferably 1 or 2.

Examples of the "1-alkanoyloxyalkyl group" include acetoxymethyl, propionyloxymethyl, n-butyryloxymethyl, isobutyryloxymethyl, pivaloyloxymethyl, n-valeryloxymethyl, 2-methylbutyryloxymethyl, isovaleryloxymethyl, n-hexanoyloxymethyl, 3-methylpentanyloxymethyl, neohexanoyloxymethyl, 2-methylhexanoyloxymethyl, 2, 2-dimethylvaleryloxymethyl, neoheptanoyloxymethyl, cyclohexanecarbonyloxymethyl, cyclohexylacetoxymethyl, 1-acetoxyethyl, 1-propionyloxyethyl, 1-n-butyryloxyethyl, 1-isobutyryloxyethyl, 1-n-valeryloxyethyl, 1-pivaloyloxyethyl, 1-isovaleryloxyethyl, 1-n-hexanoyloxyethyl, 1-cyclohexanecarbonyloxyethyl and the like.

The "1-alkoxycarbonyloxyalkyl" has preferably 1 to 10, more preferably 1 to 7 carbon atoms in the alkoxy moiety, and may be any of straight chain, branched chain and cyclic, and has preferably 1 to 3, more preferably 1 or 2 carbon atoms in the alkyl moiety.

Examples of the "1-alkoxycarbonyloxyalkyl group" include 1-methoxycarbonyloxyethyl group, 1-ethoxycarbonyloxyethyl group, 1-n-propoxycarbonyloxyethyl group, 1-isopropoxycarbonyloxyethyl group, 1-n-butoxycarbonyloxyethyl group, 1-sec-butoxycarbonyloxyethyl group, 1-tert-butoxycarbonyloxyethyl group, 1-pentyloxycarbonyloxyethyl group and 1-cyclohexyloxycarbonyloxyethyl group.

R³And R⁴The "lower alkyl group" in (1) refers to a linear or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl and neohexyl groups. Among them, preferred are methyl, ethyl, propyl and butyl.

R³、R⁴The "cyclic amino group" formed together with the nitrogen atom to which they are attached means a 4 to 6-membered cyclic amino group, and examples of the cyclic amino group include azetidinyl, pyrrolidinyl, piperidinyl and the like.

As R⁵Examples of the "protecting group for a carboxyl group" in (1) include tert-butyl group, tert-pentyl group, benzyl group, p-nitrobenzyl group, p-methoxybenzyl group, benzhydryl group, p-nitrophenyl group, methoxymethyl group, ethoxymethyl group, benzyloxymethyl group, methylthiomethyl group, trityl group, 2, 2, 2-trichloroethyl group, trimethylsilyl group, diphenylmethoxybenzenesulfonylmethyl group, dimethylaminoethyl group and the like. Among them, preferred are p-nitrobenzyl, p-methoxybenzyl and benzhydryl.

Carbapenem compound (I) and carbapenem compound (II) may form a pharmaceutically acceptable salt.

The carbapenem compound (I) and carbapenem compound (II) can form an acid addition salt because of having a basic group, and the acid used for forming such an acid addition salt is not particularly limited as long as it is a pharmaceutically acceptable acid. Examples of such acids include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid, and organic acids such as oxalic acid, fumaric acid, maleic acid, citric acid, tartaric acid and methanesulfonic acid.

Carbapenem compound (II) having carboxyl group (R)⁵Is a hydrogen atom) may form a salt at its carboxyl group. Examples of the salt at the carboxyl group include alkali metal salts (e.g., sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g., calcium salt, magnesium salt, etc.), organic base salts (e.g., triethylamine salt, dicyclohexylamine salt, pyridine salt, etc.), and the like.

Preferred specific examples of carbapenem compound (I) and carbapenem compound (II) of the present invention are as follows.

Pivaloyloxymethyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate, (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) - 1-Pivaloyloxyethyl 1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate, (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate, (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, n-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-on-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylic acid 1-isopropoxycarbonyloxyethyl ester, (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-on-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2- 1-ethoxycarbonyloxyethyl alkene-3-carboxylate, (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapenem-2-em-3-carboxylate 1-cyclohexyloxycarbonyloxyethyl ester, (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-Dioxolan-2-on-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylic acid (5-methyl-1, 3-dioxolan-2-on-4-yl) methyl ester, (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-on-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em -p-nitrobenzyl 3-carboxylate, (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-on-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate benzhydryl ester, (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-on-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapenem-2-em-3-carboxylic acid p-methoxybenzyl ester, (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapenem-2-em-3-carboxylic acid, (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-pivaloyloxymethyl) pyrrolidin-3-c-ylic acid Pivaloyloxymethyl (1R) -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate, (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-pivaloyloxymethyl) pyrrolidin-3-ylthio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate 1-pivaloyloxyethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-pivaloyloxymethyl) pyrrolidin-3-ylthio ] -6- [ (1R, 5S, 6S) R) -1-hydroxyethyl ] -1-methylcarbapenem-2-em-3-carboxylic acid 1-acetoxyethyl ester, (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-pivaloyloxymethyl) pyrrolidin-3-ylthio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapenem-2-em-3-carboxylic acid 1-isopropoxycarbonyloxyethyl ester (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-pivaloyloxymethyl) pyrrolidin-3-ylthio ] -6- [ (1R) -1-hydroxylcarboxymethyl) pyrrolidin-3-ylthio ] -6 Ethyl ] -1-methylcarbapenem-2-em-3-carboxylic acid 1-ethoxycarbonyloxyethyl ester, (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-pivaloyloxymethyl) pyrrolidin-3-ylthio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapenem-2-em-3-carboxylic acid 1-cyclohexyloxycarbonyloxyethyl ester, (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-pivaloyloxymethyl) pyrrolidin-3-ylthio ] -6- [ (1R) -1-hydroxyethyl ] -1-2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-pivaloyloxymethyl) pyrrolidin-3-ylthio ] -6 -methylcarbapenem-2-em-3-carboxylic acid (5-methyl-1, 3-dioxolan-2-on-4-yl) methyl ester, (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-pivaloyloxymethyl) pyrrolidin-3-ylthio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapenem-2-em-3-carboxylic acid p-nitrobenzyl ester, (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-pivaloyloxymethyl) pyrrolidin-3-ylthio ] -6- [ (1R) -1 Diphenylmethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-pivaloyloxymethyl) pyrrolidin-3-ylthio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapenem-2-em-3-carboxylate p-methoxybenzyl ester, (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-pivaloyloxymethyl) pyrrolidin-3-ylthio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapenem-yl) pyrrocyanide 2-ene-3-carboxylic acid, 2-methyl-ethyl-phenyl;

pivaloyloxymethyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-on-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate hydrochloride,

pivaloyloxymethyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-diethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate,

pivaloyloxymethyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-methylethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate,

pivaloyloxymethyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5- (1-pyrrolidinocarbonyl) -1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate,

pivaloyloxymethyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5- (1-piperidinylcarbonyl) -1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate, and

pivaloyloxymethyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5- (1-azetidinylcarbonyl) -1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate, and the like.

Carbapenem compound (I) or a pharmaceutically acceptable salt thereof and carbapenem compound (II) or a pharmaceutically acceptable salt thereof can be produced by any of the following production methods 1 to 4.

Preparation method 1In the formula, R¹、R²、R³And R⁴X represents a leaving group such as a halogen atom (e.g., chlorine, bromine or iodine), an alkanesulfonyloxy group (e.g., methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy or butanesulfonyloxy), or an arylsulfonyloxy group (e.g., benzenesulfonyloxy or toluenesulfonyloxy).

Compound (I) can be prepared by reacting compound (IIa) [ R in formula (II) ]⁵A compound which is a hydrogen atom is dissolved in a solvent which does not inhibit the reaction (e.g., dioxane, acetonitrile, tetrahydrofuran, chloroform, dichloromethane, vinyl chloride, benzene, ethyl acetate, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, or the like, or a mixture thereof), and reacted with about 1 to 5 times by mol, preferably about 1 to 2 times by mol, of the compound (III) in the presence of a base.

The base to be used is not particularly limited, but preferably includes inorganic bases such as sodium hydrogencarbonate and potassium carbonate, and organic bases such as triethylamine and diisopropylethylamine.

The reaction temperature is not particularly limited, but is preferably relatively low in order to suppress side reactions, and is usually from-30 ℃ to 40 ℃, preferably from-20 ℃ to 0 ℃. The reaction time varies mainly depending on the reaction temperature, the kind of the reaction reagent, etc., but is usually from 30 minutes to 10 hours or more.

If necessary, the compound (IIa) may be derivatized to form a reactive derivative thereof (e.g., an alkali metal salt such as a sodium salt or a potassium salt, an alkaline earth metal salt such as a calcium salt, a triethylamine salt, a dicyclohexylamine salt, a pyridine salt, etc.), and then reacted with the compound (III).

Preparation method 2In the formula, R¹、R²、R³、R⁴And X are as defined above.

The compound (I) can be obtained by dissolving the compound (IV) in a solvent (for example, dioxane, acetonitrile, tetrahydrofuran, chloroform, dichloromethane, vinyl chloride, benzene, ethyl acetate, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, or the like, or a mixture thereof) which does not inhibit the reaction, and reacting the compound (IV) with the compound (V) in an amount of about 1 to 5 times by mol, preferably about 1 to 2 times by mol. Further, compound (IV) can also be obtained by reacting compound (III) with a carboxylic acid as described in Japanese patent application laid-open No. 60-233076 and the like, in the same manner as in production Process 1.

The reaction may also be carried out in the presence of a base. The base to be used is not particularly limited, but preferably includes an inorganic base such as sodium hydrogencarbonate and potassium carbonate, and an organic base such as triethylamine and diisopropylethylamine.

The reaction temperature is not particularly limited, but is preferably relatively low in order to suppress side reactions, and is usually from-30 ℃ to 40 ℃, preferably from-20 ℃ to 0 ℃. The reaction time varies mainly depending on the reaction temperature, the kind of the reaction reagent, etc., but is usually from 30 minutes to 10 hours or more.

Preparation method 3In the formula, R²、R³、R⁴And R⁵As defined above, R⁶It represents an alkanesulfonyl group such as a methanesulfonyl group, an ethanesulfonyl group, a propanesulfonyl group or a butanesulfonyl group, an arylsulfonyl group such as a benzenesulfonyl group or a toluenesulfonyl group, a dialkylphosphoryl group such as a dimethylphosphoryl group, a diethylphosphoryl group, a diisopropylphosphoryl group or a dibutylphosphoryl group, or a diarylphosphoryl group such as a diphenylphosphoryl group or a ditolylphosphoryl group.

The compound (II) can be obtained by dissolving the compound (VI) described in JP-A-8-12676 or the like in a solvent which does not inhibit the reaction (e.g., dioxane, acetonitrile, tetrahydrofuran, chloroform, dichloromethane, vinyl chloride, benzene, ethyl acetate, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, or the like, or a mixture thereof), and reacting the compound (VI) with the mercapto compound (VII) in an amount of about 1 to 5 times by mole, preferably about 1 to 3 times by mole in the presence of a base.

The base to be used is not particularly limited, but preferably includes an inorganic base such as sodium hydrogencarbonate and potassium carbonate, and an organic base such as triethylamine and diisopropylethylamine.

The reaction temperature is not particularly limited, but is preferably relatively low in order to suppress side reactions, and is usually from-30 ℃ to 40 ℃, preferably from-20 ℃ to 0 ℃. The reaction time varies mainly depending on the reaction temperature, the kind of the reaction reagent, etc., but is usually from 30 minutes to 10 hours or more.

The compound (VII) as a starting material in the synthesis of the compound (II) can be obtained as follows.

Process for producing Compound (VII)In the formula, R²、R³、R⁴And X is as defined above, R⁷Is a protecting group for mercapto, R⁸Is a protecting group for amino.

The synthesis of compound (VII) can be carried out as follows: the compound (X) resulting from the removal of the amino-protecting group R8 of the compound (IX) described in Japanese patent application laid-open No. Sho 60-233076 and the like by a method known per se is reacted with the compound (V) to give the compound (XI) in the same manner as in production Process 2, and then the thiol-protecting group is removed by a method known per se. As the protecting groups for a mercapto group and an amino group, those used in the art can be generally used.

Preparation method 4In the formula, R²、R³、R⁴、R⁵And X are as defined above.

Compound (II) can be obtained by reacting compound (VIII) described in Japanese patent laid-open publication No. Sho 60-233076 and the like with compound (V) in the same manner as in preparation Process 2.

The carbapenem compound (II) thus obtained can be converted into a carbapenem compound by removing the carboxyl-protecting group according to a conventional methodTo R⁵A carboxylic acid derivative which is a hydrogen atom. The method for removing the protecting group varies depending on the kind thereof, but it can be generally removed by a method known in the art.

Carbapenem compound (I) and carbapenem compound (II) can be purified, if necessary, by a conventional method such as recrystallization, fractional thin-layer chromatography, column chromatography, etc. And if necessary, purified to form a salt thereof.

Carbapenem compound (I) or carbapenem compound (II) can be converted into a pharmaceutically acceptable salt thereof by a method known per se.

Preferred stereoarrangements of the object compounds (I) and (II) of the present invention are the following compounds (Ia) and (IIb):in the formula, R¹、R²、R³And R⁴The definitions of (A) and (B) are respectively the same as above,in the formula, R²、R³、R⁴And R⁵The definitions of (A) and (B) are as defined above.

Carbapenem compound (I) or a pharmaceutically acceptable salt thereof can be rapidly absorbed into the blood by oral administration, and as a metabolite thereof, R in the general formula (I) is changed to R¹And R²A carbapenem compound which is a hydrogen atom or a pharmaceutically acceptable salt thereof, and exhibits a high blood concentration.

In addition, the carbapenem compound (I) is prepared into pharmaceutically acceptable salts, so that the solubility in the digestive tract is remarkably improved, the absorption effect is further improved, and the absorbability is further improved.

Therefore, an agent for preventing and treating infectious diseases, which comprises carbapenem compound (I) or a pharmaceutically acceptable salt thereof, has excellent effects as described below when administered orally, and can be administered usually as an oral agent.

Each of the prophylactic and therapeutic agents for infectious diseases can be prepared by diluting with a pharmaceutical excipient according to a known method. As the excipient, for example, starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc. can be used.

Further, it is preferable to further add an organic acid to each of the agents for preventing and treating infectious diseases. This improves the solubility of carbapenem compound (I) or a pharmaceutically acceptable salt thereof in the digestive tract, and facilitates absorption into the blood.

The organic acid is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include organic carboxylic acids such as maleic acid, fumaric acid, tartaric acid, citric acid, succinic acid, malic acid, oxalic acid, mandelic acid, malonic acid, and benzoic acid. The amount of the organic acid is usually 0.01 to 20 mol, preferably 0.02 to 2 mol, based on 1 mol of the carbapenem compound (I) or a pharmaceutically acceptable salt thereof.

In each of the agents for preventing and treating infectious diseases, other additives may be further compounded as necessary, and preferable examples of the additives include binders (e.g., starch, gum arabic, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, etc.), lubricants (e.g., magnesium stearate, talc, etc.), and disintegrating agents (e.g., calcium carboxymethyl cellulose, talc, etc.). After mixing the respective components, the mixture can be formulated into a dosage form suitable for oral administration, such as a capsule, a tablet, a fine granule, a dry syrup, etc., by a method known per se, to prepare an agent for preventing and treating infectious diseases for oral administration.

The amount of carbapenem compound (I) or a pharmaceutically acceptable salt thereof to be administered varies depending on the subject, symptoms and other factors, but when it is administered to a suppurative disease such as an adult, it is administered 1 to 4 times per day, for example, and the amount of 1 to 40mg/kg of body weight is about 1 to 4 times per day.

The carbapenem compound (I) or a pharmaceutically acceptable salt thereof may be used in combination with other antibacterial active substances, for example, antibacterial agents (e.g., penicillins, aminoglycosides, and cephalosporins) or therapeutic agents for systemic symptoms caused by bacterial infection (e.g., antipyretics, analgesics, and anti-inflammatory agents).

The physical properties and preparation of the compounds of the present invention are specifically illustrated by the following examples, but the present invention is not limited thereto.

Example 1

P-nitrobenzyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate

867mg of (2S, 4S) -2-N, N-dimethylaminocarbonyl-4-mercapto-1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methylpyrrolidine was dissolved in 11ml of acetonitrile, and (1R, 5S, 6S) -2-diphenylphosphino-6- [ (1R) -1-hydroxyethyl group was added dropwise to the solution at-40 to-30 ℃ under a nitrogen stream]1.5g of p-nitrobenzyl 1-methylcarbapenem-2-ene-3-carboxylate and 1.05ml of diisopropylethylamine in 15ml of acetonitrile. After stirring at the same temperature for 1 hour, 200ml of ethyl acetate was added, and the mixture was washed with 100ml of saturated saline solution and dried with thenardite. Ethyl acetate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give 1.0g of the title compound.¹H-NMR(DMSO-d₆)δppm：1.06(d，J＝7.5Hz，3H)，1.16(d，J＝6.5Hz，3H)，1.30～1.80(m，1H)，2.02(s，3H)，2.50～4.30(m，9H)，2.82(s，3H)，3.01(s，3H)，3.57(s，2H)，5.01(d，J＝5.0Hz，1H)，5.25，5.50(ABq，J＝13.5Hz，2H)，7.67，8.22(ABq，J＝8.5Hz，4H).

Example 2

Sodium (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate

The reaction product of (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R, 6S) -l-methyl-pyrrolidin-1-yl-methyl-pyrrolidin-3-ylthio ] -amide) 730mg of p-nitrobenzyl (1-hydroxyethyl) -1-methylcarbapenem-2-ene-3-carboxylate was dissolved in a mixture of 22ml of tetrahydrofuran and 33ml of 0.1M phosphate buffer (pH7.0), and 550mg of 10% palladium-charcoal was added thereto, followed by hydrogenation at room temperature for 2.5 hours. The reaction mixture was filtered through celite, and the obtained filtrate was washed with diethyl ether and concentrated under reduced pressure to about 5 ml. The resulting solution was subjected to chromatography using Dia Ion HP-21 (manufactured by Mitsubishi chemical industries, Ltd.), concentrated under reduced pressure and freeze-dried to obtain the title compound (300 mg). IR (liquid Paraffin, cm)^-1)：3385、1815、1750、1600。¹H-NMR(DMSO-d₆)δppm：1.05(d，J＝7.5Hz，3H)，1.15(d，J＝6.5Hz，3H)，1.20～1.70(m，1H)，2.03(s，3H)，2.50～4.20(m，9H)，2.81(s，3H)，3.01(s，3H)，3.60(s，2H)，4.40～5.50(br，1H).

Example 3

Pivaloyloxymethyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate

500mg of sodium (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate was dissolved in 2.5ml of N, N-dimethylformamide and cooled to-5 ℃. 350mg of pivaloyloxymethyl iodide was added thereto, and after stirring at the same temperature for 1 hour, 100ml of ethyl acetate was added, and the mixture was washed with 100ml of 5% saline solution and dried with thenardite. Ethyl acetate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (370 mg). IR (liquid Paraffin, cm)^-1)：3400、1820、1755、1640。¹H-NMR(DMSO-d₆)δppm：1.00～1.30(m，15H)，1.30～1.80(m，1H)，2.03(s，3H)，2.50～4.30(m，9H)，2.82(s，3H)，3.01(s，3H)，3.55(s，2H)，5.00(d，J＝5.0Hz，1H)，5.70，5.87(ABq，J＝5.5Hz，2H).

Example 4

Pivaloyloxymethyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate

(1) 580mg of sodium (1R, 5S, 6S) -2- [ (3S, 5S) -5-N, N-dimethylaminocarbonylpyrrolidin-4-ylthio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapenem-2-em-3-carboxylate was suspended in 2.9ml of N, N-dimethylformamide and cooled to-5 ℃. Pivaloyloxymethyl iodide (520 mg) was added thereto, and after stirring at the same temperature for 1 hour, ethyl acetate (150 ml) was added, and the mixture was washed with 5% saline (150 ml) and dried over anhydrous sodium sulfate. Ethyl acetate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give pivaloyloxymethyl (1R, 5S, 6S) -2- [ (3S, 5S) -5-N, N-dimethylaminocarbonylpyrrolidin-4-ylthio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate (350 mg).¹H-NMR(DMSO-d₆)δppm：1.02～1.30(m，15H)，1.30～1.80(m，1H)，2.50～4.40(m，10H)，2.87(s，3H)，2.99(s，3H)，4.90～5.10(m，1H)，5.70，5.85(ABq，J＝6.0Hz，2H).

(2) 330mg of the compound obtained in example 4(1) was dissolved in 1.7ml of N, N-dimethylformamide and cooled to 5 ℃. 190mg of (5-methyl-1, 3-dioxolan-2-on-4-yl) methyl bromide and 0.11ml of triethylamine were added thereto, and after stirring at the same temperature for 1.5 hours, 150ml of ethyl acetate was added thereto, the mixture was washed with 100ml of 5% saline, and the aqueous layer was extracted 2 times with 150ml of ethyl acetate. The ethyl acetate layers were combined, dried over thenardite, and the ethyl acetate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound 230 mg.

IR and¹the H-NMR data agree with those of example 3.

Example 5

Pivaloyloxymethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-pivaloyloxymethyl) pyrrolidin-3-ylthio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate

Pivaloyloxymethyl (1R, 5S, 6S) -2- [ (3S, 5S) -5-N, N-dimethylaminocarbonylpyrrolidin-4-ylthio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate (400 mg) obtained in example 4(1) was reacted with pivaloyloxymethyl iodide (290 mg) according to the method of example 4(2) to obtain 190mg of the title compound.¹H-NMR(DMSO-d₆)δppm：1.02～1.30(m，24H)，1.30～1.80(m，1H)，2.50～4.40(m，10H)，2.87(s，3H)，2.99(s，3H)，4.90～5.10(m，1H)，5.70，5.85(ABq，J＝6.0Hz，2H).

Example 6

Pivaloyloxymethyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-on-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate hydrochloride

Pivaloyloxymethyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-on-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate (1.49 g) obtained in example 3 was dissolved in ethyl acetate 30ml and cooled to 5 ℃. 0.35ml of a solution of hydrogen chloride dissolved in 2-propanol at 8.68N was added, and the mixture was stirred at the same temperature for 15 minutes. The precipitated crystals were collected by filtration and washed with ethyl acetate and then with diethyl ether to obtain 1.2g of the title compound. IR (liquid Paraffin, cm)^-1)：3355、1825、1770、1740、1660。¹H-NMR(D₂O)δppm：1.10～1.40(m，6H)，1.19(s，9H)，1.70～2.10(m，1H)，2.19(s，3H)，2.80～3.20(m，1H)，2.99(s，3H)，3.09(s，3H)，3.30～3.70(m，2H)，3.80～4.10(m，2H)，4.10～4.50(m，5H)，4.80～5.00(m，1H)，5.86，5.96(ABq，J＝6.0Hz，2H).

The compounds of examples 7 to 11 were synthesized and examined for physical properties in the same manner as described in any of examples 1 to 5.

Example 7

(1R，Pivaloyloxymethyl 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-diethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-on-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate¹H-NMR(DMSO-d₆)δppm：1.10～1.30(m，21H)，1.30～1.80(m，1H)，2.03(s，3H)，2.50～4.30(m，13H)，3.56(s，2H)，5.10(d，J＝5.0Hz，1H)，5.66，5.85(ABq，J＝5.5Hz，2H).

Example 8

Pivaloyloxymethyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-methylethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate¹H-NMR(DMSO-d₆)δppm：1.10～1.30(m，18H)，1.30～1.80(m，1H)，2.05(s，3H)，2.50～4.30(m，11H)，2.93，3.03(s，s，3H)，3.58(s，2H)，5.05(d，J＝5.0Hz，1H)，5.68，5.87(ABq，J＝5.5Hz，2H).

Example 9

Pivaloyloxymethyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5- (1-pyrrolidinocarbonyl) -1- (5-methyl-1, 3-dioxolan-2-on-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate¹H-NMR(DMSO-d₆)δppm：1.00～1.30(m，15H)，1.30～1.80(m，1H)，1.80～2.10(m，4H)，2.05(s，3H)，2.50～4.30(m，13H)，3.58(s，2H)，5.07(d，J＝5.0Hz，1H)，5.67，5.83(ABq，J＝5.5Hz，2H).

Example 10

Pivaloyloxymethyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5- (1-piperidinylcarbonyl) -1- (5-methyl-1, 3-dioxolan-2-on-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate¹H-NMR(DMSO-d₆)δppm：1.00～1.30(m，15H)，1.30～1.80(m，7H)，2.03(s，3H)，2.50～4.30(m，13H)，3.57(s，2H)，5.10(d，J＝5.0Hz，1H)5.66，5.83(ABq，J＝5.5Hz，2H).

Example 11

Pivaloyloxymethyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5- (1-azetidinylcarbonyl) -1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate¹H-NMR(DMSO-d₆)δppm：1.00～1.30(m，15H)，1.30～1.80(m，1H)，2.05(s，3H)，2.50～4.50(m，15H)，3.57(s，2H)，5.05(d，J＝5.0Hz，1H)，5.68，5.85(ABq，J＝5.5Hz，2H).

The following compounds were obtained by the method described in any of examples 1 to 5.

(1) (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylic acid 1-pivaloyloxyethyl

(2) 1-Acetoxyethyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate

(3) 1-Isopropoxycarbonyloxyethyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate

(4) (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylic acid 1-ethoxycarbonyloxyethyl ester

(5) (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylic acid 1-cyclohexyloxycarbonyloxyethyl ester

(6) (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate

(7) Diphenylmethyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate

(8) P-methoxybenzyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate

(9) (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-pivaloyloxymethyl) pyrrolidin-3-ylthio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylic acid 1-pivaloyloxyethyl ester

(10) (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-pivaloyloxymethyl) pyrrolidin-3-ylthio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylic acid 1-acetoxyethyl ester

(11) (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-pivaloyloxymethyl) pyrrolidin-3-ylthio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylic acid 1-isopropoxycarbonyloxyethyl ester

(12) (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-pivaloyloxymethyl) pyrrolidin-3-ylthio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylic acid 1-ethoxycarbonyloxyethyl ester

(13) (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-pivaloyloxymethyl) pyrrolidin-3-ylthio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylic acid 1-cyclohexyloxycarbonyloxyethyl ester

(14) (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-pivaloyloxymethyl) pyrrolidin-3-ylthio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylic acid (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ester

(15) P-nitrobenzyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-pivaloyloxymethyl) pyrrolidin-3-ylthio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate

(16) Diphenylmethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-pivaloyloxymethyl) pyrrolidin-3-ylthio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate

(17) P-methoxybenzyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-pivaloyloxymethyl) pyrrolidin-3-ylthio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate

(18) (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-pivaloyloxymethyl) pyrrolidin-3-ylthio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylic acid

Then, in order to demonstrate the excellent properties of the compound of the present invention, oral absorption experiments were performed as follows.

EXAMPLE 1 (oral absorption experiment)

The recovery rate in urine was determined by orally administering 20mg/kg of the compound of the present invention (the compound of example 6) to dogs (3 dogs in a group), and measuring the concentration of the carbapenem compound (A) in urine by the disk method using Escherichia coli (Escherichia coli NIHJ) and agar nutrient medium (Difco) as test bacteria for 0 to 3, 3 to 6, and 6 to 24 hours. The results are shown in Table 1.

TABLE 1

Test compounds	Recovery in urine (%)
					0 to 3 hours	3-6 hours	6 to 24 hours	0 to 24 hours
	Example 6	10.3	2.4	0.3					13.0

EXAMPLE 2 (oral absorption experiment)

The recovery rate in urine was determined by orally administering 20mg/kg of the compound of the present invention (the compound of example 6) to dogs (3 dogs in a group), and measuring the plasma concentration of the hydrolyzed carbapenem compound (A) by the paper disc method using Escherichia coli (Escherichia coli NIHJ) and agar nutrient medium (Difco) as test bacteria for 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0 and 6.0 hours.

The results are shown in tables 2 and 3.

TABLE 2

Test compounds	Plasma concentration (μ g/ml)
					0.25 hour	0.5 hour	1.0 hour	1.5 hours
	Example 6	5.06	6.56	7.60					7.67

TABLE 3

Test compounds	Plasma concentration (μ g/ml)
					2.0 hour	3.0 hours	4.0 hours	6.0 hours
	Example 6	5.92	3.68	1.92					0.43

The carbapenem compound (I) or a pharmaceutically acceptable salt thereof of the present invention is excellent in absorbability in the digestive tract upon oral administration, exhibits satisfactory antibacterial activity against a wide range of bacterial species, and is extremely useful as a prophylactic/therapeutic agent for infectious diseases (particularly bacterial infectious diseases). Each of these prophylactic and therapeutic agents for infectious diseases is useful as a prophylactic and therapeutic agent for diseases (e.g., suppurative diseases, respiratory infection, biliary tract infection, urinary tract infection, etc.) caused by bacteria in warm-blooded animals (dogs, cats, cows, horses, rats, mice, etc.) including humans.

The present application is based on japanese patent application hei 9-year patent application No. 25671 and hei 9-year patent application No. 248903, the contents of which are all incorporated in the present specification.

Claims (10)

1. A penem (Carbapenem) compound represented by the general formula (T) or a pharmaceutically acceptable salt thereofIn the formula, R¹And R²May be the same or different and are each a modifying group hydrolyzable in the living body, R³And R⁴Which may be the same or different, are each lower alkyl, or R³、R⁴Taken together with the nitrogen atom to which they are attached represent a cyclic amino group.

2. The carbapenem compound of claim 1, wherein R is¹And R²May be the same or different and are each a modifying group hydrolyzable in the living body, R³And R⁴Which may be the same or different, are each lower alkyl groups.

3. The carbapenem compound of claim 1, wherein R is²Is 5-methyl-1, 3-dioxolan-2-on-4-ylmethyl, R³And R⁴Are all methyl.

4. The carbapenem compound of claim 1, wherein R is¹Is pivaloyloxymethyl, R²Is 5-methyl-1, 3-dioxolan-2-one-4-ylmethyl.

5. The carbapenem compound of claim 1, wherein R is¹And R²Are pivaloyloxymethyl.

6. The carbapenem compound of claim 1, wherein the carbapenem compound is selected from the group consisting of:

pivaloyloxymethyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate,

pivaloyloxymethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1 pivaloyloxymethyl) pyrrolidin-3-ylthio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate,

pivaloyloxymethyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-on-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (IR) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate hydrochloride,

pivaloyloxymethyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-diethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate,

pivaloyloxymethyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-methylethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate,

pivaloyloxymethyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5- (1-pyrrolidinocarbonyl) -1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate,

pivaloyloxymethyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5- (1-piperidinylcarbonyl) -1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate, and

pivaloyloxymethyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5- (1-azetidinylcarbonyl) -1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate.

7. An antibacterial agent comprising as an active ingredient a carbapenem compound of the general formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof.

8. The antibacterial agent according to claim 7, which is for oral administration.

9. A carbapenem compound represented by the formula (II)In the formula, R²Is a modifying group which is hydrolyzable in vivo, R³And R⁴Which may be the same or different, are each lower alkyl, or R³、R⁴And the nitrogen to which they are attachedThe atoms taken together represent a cyclic amino group, R⁵Is a protecting group for a hydrogen atom or a carboxyl group.

10. The carbapenem compound of claim 9, wherein the carbapenem compound is selected from the group consisting of:

p-nitrobenzyl (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate, and

sodium (1R, 5S, 6S) -2- { (3S, 5S) - [ 5-N, N-dimethylaminocarbonyl-1- (5-methyl-1, 3-dioxolan-2-one-4-yl) methyl ] pyrrolidin-3-ylthio } -6- [ (1R) -1-hydroxyethyl ] -1-methylcarbapen-2-em-3-carboxylate.