JP2002029972A - Antimicrobial agent containing carbapenem ester compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an antimicrobial agent containing a carbapenem compound as the active ingredient, having excellent antimicrobial activity and oral absorbability. SOLUTION: This antimicrobial agent is obtained by including a carbapenem ester compound having general formula (1) [wherein R2 is a 1-20C alkyl, a 3-7C cycloalkyl or a (3-7C cycloalkyl)-(1-6C alkyl); and R3 is H or a 1-4C alkyl] or a pharmacologically permissible derivative thereof as the active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical composition for preventing or treating bacterial infections, comprising a carbapenem ester compound having excellent antibacterial activity or a pharmaceutically acceptable derivative thereof as an active ingredient, and a bacterial infection. The invention relates to their use for the manufacture of a medicament for the prevention or treatment of diseases, and to a method for preventing or treating bacterial infections by administering a pharmacologically effective amount thereof to a warm-blooded animal.

[0002]

2. Description of the Related Art Thienamycin derivatives, which are carbapenem antibiotics, have excellent antibacterial activity, but have low chemical and biological stability, so that they are dehydropeptidases, enzymes present in the human body. It is easily degraded by I and loses its activity, and its urine recovery is low. Furthermore, some experimental animal species may be toxic to the kidneys. Therefore, thipenamicin derivative imipenem was developed as a combination with dehydropeptidase-I inhibitor cilastatin, and panipenem was developed with betamipron, an organic anion transport inhibitor. Thereafter, it was found that the chemical stability and stability against dehydropeptidase-I were improved by introducing a methyl group at the 1-position of the carbapenem skeleton, and a carbapenem derivative usable as a single agent such as meropenem was also developed. Was done. However, these are all injections and have not been developed as oral preparations or suppositories. Therefore, development of a carbapenem derivative that, when administered to a living body, is efficiently absorbed and then hydrolyzed to exhibit antibacterial activity has been desired. JP-A-2-49783, JP-A-7-497
165759, JP-A-2-223587,
JP-A-4-279588, JP-A-8-53453
Issue, The Journal of Antibiotics 50 (5), 429-439
(1997), the carboxyl group at the 3-position of the carbapenem skeleton is an acyloxyalkyl group, an alkoxycarbonyloxyalkyl group or a 5-methyl-2-oxo-
Specifically disclosed are carbapenem ester derivatives protected with an in vivo hydrolyzed ester residue such as a 1,3-dioxolen-4-ylmethyl group.

[0003] Although simple ester residues such as an alkyl group are exemplified as ester residues hydrolyzed in the living body, they are specifically used for use as an effective antibacterial agent for oral administration. There are no examples of synthesis and examination of absorbability.

[0004]

DISCLOSURE OF THE INVENTION The present inventors have studied various carbapenem derivatives having an ester residue which have not been specifically disclosed. As a result, the carbapenem ester compound represented by the general formula (I) of the present invention having an ester residue such as alkyl is more stable and lower in production cost than the ester derivatives known specifically so far, and can be used in the digestive tract. Was found to be excellent in absorbency. Furthermore, the compound (I) of the present invention has low toxicity and has been found to be effective as an antibacterial agent for treating or preventing (especially treating) bacterial infections, thereby completing the present invention.

[0005]

The present invention provides a compound represented by the general formula (I):

[0006]

Embedded image [Wherein, R ¹ represents the following general formula (IIa)

[0007]

Embedded image (Wherein R ³ represents a hydrogen atom or a C1-C4 alkyl group), and R ² represents a C1-C20 alkyl group, a C3-C7 cycloalkyl group or a C3-C
7 represents a 7 cycloalkyl-C1-C6 alkyl group. A pharmaceutical composition for preventing or treating bacterial infections, comprising a carbapenem ester compound having the formula (I) or a pharmacologically acceptable derivative thereof as an active ingredient, and a medicament for preventing or treating bacterial infections. A method for the prevention or treatment of bacterial infections by administering their use, a pharmacologically effective amount thereof to a warm-blooded animal.

In the group represented by the formula (IIa) for R ¹ , the “C 1 -C 4 alkyl group” for R ³ is a linear or branched alkyl group having 1 to 4 carbon atoms, for example, methyl , Ethyl, n-propyl, isopropyl, n-butyl or t-butyl group, preferably a methyl or ethyl group, more preferably a methyl group.

R ³ is preferably a hydrogen atom or a methyl group, most preferably a hydrogen atom.

In the group represented by the formula (IIa) for R ¹ , the 2-oxopyrrolidinyl group is preferably substituted at the 4-position.

The group represented by formula (IIa) for R ¹ is preferably a 2-oxo-4-pyrrolidinyl or 1-methyl-2-oxo-4-pyrrolidinyl group, most preferably a 2-oxo-pyrrolidinyl group. 4-pyrrolidinyl group.

The "C1-C20 alkyl group" for R ² is a linear or branched alkyl group having 1 to 20 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- Butyl, 3-methylbutyl, pentyl, 2-pentyl, 3-pentyl, 3-methylpentyl, hexyl, 2-methylpentyl, heptyl, 2-heptyl, 3-heptyl, 4-heptyl, octyl, nonyl, decyl, undecyl, Dodecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl,
Examples thereof include octadecyl and nonadecyl groups, and preferably C1-C10 such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, 3-pentyl, 3-methylbutyl, hexyl, heptyl, octyl or nonyl groups. Alkyl group, more preferably a C2-C6 alkyl group such as ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, 3-pentyl, 3-methylbutyl or hexyl group, most preferably ethyl, propyl, Butyl, isobutyl, 3-
It is a methylbutyl or pentyl group.

"C3-C7 cycloalkyl group" for R ²
Is a saturated cyclic alkyl group having 3 to 7 carbon atoms,
For example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group can be mentioned, preferably a C4-C6 cycloalkyl group such as a cyclobutyl, cyclopentyl or cyclohexyl group, and most preferably a cyclohexyl group.

R ² "C3-C7 cycloalkyl-C1
The "-C6 alkyl group" is an alkyl group having 1 to 6 carbon atoms substituted by a saturated cyclic alkyl having 3 to 7 carbon atoms, such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, Heptylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, cyclohexylpropyl, cyclohexylbutyl, cyclohexylpentyl,
Cyclohexylhexyl, cycloheptylmethyl, cycloheptylethyl and the like can be mentioned.
A 3-C6 cycloalkyl-C1-C3 alkyl group, more preferably a C3-C6 cycloalkyl-methyl group, particularly preferably a cyclopentylmethyl or cyclohexylmethyl group, most preferably a cyclohexylmethyl group. is there.

Compound (I) has a hydroxyl group (OH group) in the molecule.
And an amide nitrogen residue (CONH group), so that either or both of these groups can lead to a “pharmacologically acceptable derivative”. The “pharmacologically acceptable derivative” of the compound (I) is a compound which is decomposed by hydrolysis or the like when administered to a living body, and the compound (I) or the ester portion of the compound (I) is hydrolyzed. It is a derivative capable of producing the resulting carboxylic acid compound.

The group forming such a derivative includes:
For example, a C1-C10 alkanoyl group, a C1-C10 alkoxy-carbonyl group, a C6-C10 aryl-carbonyl group, a 5- (C1-C4 alkyl) -2-oxo-
A 1,3-dioxolen-4-ylmethyl group can be mentioned, and a C1-C10 alkanoyl group is preferred.

The "C1-C10 alkanoyl group" is an alkanoyl group having 1 to 10 carbon atoms and includes, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, octanoyl, nonanoyl, decanoyl and the like. Can be mentioned,
It is preferably a C2-C5 alkanoyl group, more preferably an acetyl, propionyl, butyryl or isobutyryl group, particularly preferably an acetyl, propionyl or butyryl group, most preferably an acetyl group.

The "C1-C10 alkanoyl group" may have a substituent, and examples include substituents such as amino, methylamino, dimethylamino, hydroxyl, and phenyl.

The "substituted C1-C10 alkanoyl group" is preferably a substituted C2-C6 alkanoyl group (the substituent represents an amino, methylamino, dimethylamino, hydroxyl or phenyl group). And more preferably an α or β-amino acid residue, such as glycyl, alanyl, β-alanyl, valyl, leucyl, isoleucyl, seryl, threonyl, phenylalanyl and the like. Alanyl, β
-Alanyl, leucyl, isoleucyl or phenylalanyl group, more preferably glycyl, alanyl, β
-Alanyl, leucyl or isoleucyl.

The "C1-C10 alkoxy-carbonyl group" is a carbonyl group substituted with an alkoxy group having 1 to 10 carbon atoms, for example, methoxycarbonyl,
An ethoxycarbonyl, propyloxycarbonyl, butyloxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl or decyloxycarbonyl group can be mentioned, and a C1-C4 alkoxycarbonyl group is preferred. And more preferably a methoxycarbonyl or ethoxycarbonyl group, and most preferably an ethoxycarbonyl group.

"C6-C10 aryl-carbonyl group"
Is, for example, a benzoyl, 1-naphthoyl or 2-naphthoyl group, and is preferably a benzoyl group.

The "5- (C1-C4 alkyl) -2-oxo-1,3-dioxolen-4-ylmethyl group" is, for example, 5-methyl-2-oxo-1,3-dioxolen-
4-ylmethyl, 5-ethyl-2-oxo-1,3-dioxolen-4-ylmethyl, 5-propyl-2-oxo-1,3-dioxolen-4-ylmethyl or 5-
And a butyl-2-oxo-1,3-dioxolen-4-ylmethyl group.
-Oxo-1,3-dioxolen-4-ylmethyl group.

When the “pharmacologically acceptable derivative” of the compound (I) of the present invention has a basic amino group or the like,
If necessary, it can be made into "pharmacologically acceptable salt".

"Pharmacologically acceptable salts" include, for example, hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate,
Minerates such as nitrates; sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate; oxalate, tartrate, citrate, maleate , Succinate, acetate,
Acid addition salts such as organic acid salts such as benzoate, mandelate, ascorbate, lactate, gluconate, malate, glycine, lysine, arginine, ornithine, ornithine, glutamate, asparagine Examples include amino acid salts such as acid salts, preferably hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, p-
Toluenesulfonate, oxalate, tartrate, citrate, acetate, lactate, glutamate, aspartate, more preferably hydrochloride, sulfate, methanesulfonate, citrate, Acetate or lactate, particularly preferably hydrochloride or sulfate.

The compound (I) of the present invention absorbs water by leaving it in the air, freeze-drying from an aqueous solution, or recrystallizing to form adsorbed water,
A hydrate may be formed, or a solvate may be formed by handling with an organic solvent, and such a salt is also included in the present invention.

The compound (I) of the present invention has an asymmetric carbon in the molecule and has various optical isomers based on its configuration. The present invention relates to individual isomers and mixtures of isomers. Include. Among these isomers, preferred are carbapenem skeletons having the R configuration at the 1-position, the 5-position and the 6-position having the same configuration as thienamycin (5S, 6S), and having a hydroxyl group at the 6-position substituent. Compounds in which the configuration of α-carbon is R configuration can be given.

Among the compounds represented by the general formula (I) which are the active ingredients of the present invention, the following compounds are preferred.

(1) A compound in which the substitution position of the group represented by formula (IIa) of R ¹ is the 4-position.

(2) A compound wherein R ^{3 of the} group represented by formula (IIa) of R ¹ is a hydrogen atom.

(3) The compound wherein R ¹ is a 2-oxo-4-pyrrolidinyl or 1-methyl-2-oxo-4-pyrrolidinyl group.

(4) The compound wherein R ¹ is a 2-oxo-4-pyrrolidinyl group.

(5) The compound wherein R ² is a C1-C20 alkyl group.

(6) The compound wherein R ² is a C1-C10 alkyl group.

(7) The compound wherein R ² is a C2-C6 alkyl group.

(8) The compound wherein R ² is an ethyl, propyl, butyl, isobutyl, 3-methylbutyl or pentyl group.

(9) The compound wherein R ² is an ethyl or propyl group.

R ¹ is selected from the groups (1) to (4),
Compounds obtained by selecting R ² from groups (5) to (9) and arbitrarily combining them are more preferred. Examples of such compounds include the following compounds.

(10) A compound wherein R ¹ is a 2-oxo-4-pyrrolidinyl group or a 1-methyl-2-oxo-4-pyrrolidinyl group, and R ² is a C1-C10 alkyl group.

(11) A compound wherein R ¹ is a 2-oxo-4-pyrrolidinyl group and R ² is a C2-C6 alkyl group.

(12) The compound wherein R ¹ is a 2-oxo-4-pyrrolidinyl group and R ² is an ethyl or propyl group.

Table 1 shows specific examples of compounds having the general formula (I) or compounds suitable as pharmaceutically acceptable derivatives thereof.

[0042]

[Table 1]

[0043]

Embedded image -------------------------------------------------- -------------------- Compound No R ¹ p R ² R ⁴ p -------------------- -------------------------------------------------- 1 2-oxo-4-pyrr Me H 2 2-oxo-4-pyrr Me Ac 3 2-oxo-4-pyrr Et H 4 2-oxo-4-pyrr Et Ac 5 2-oxo-4-pyrr Et EtCO 6 2-oxo-4-pyrr Et PnCO 7 2-oxo-4-pyrr Et EtOCO 8 2-oxo-4-pyrr Et Gly 9 2-oxo-4-pyrr Et Ala 10 2-oxo-4-pyrr Et Leu 11 2-oxo-4-pyrr Et Ile 12 2-oxo-4-pyrr Et b-Ala 13 2-oxo-4-pyrr Et MODM 14 2-oxo-4-pyrr Pr H 15 2-oxo-4-pyrr Pr Ac 16 2-oxo-4-pyrr Pr EtCO 17 2-oxo-4-pyrr Pr PrCO 18 2-oxo-4-pyrr Pr Gly 19 2-oxo-4-pyrr Pr Ala 20 2-oxo-4-pyrr Pr Leu 21 2-oxo-4-pyrr Pr Ile 22 2-oxo-4-pyrr Pr b-Ala 23 2-oxo-4-pyrr Pr MODM 24 2-oxo-4-pyrr Me EtCO 25 2-oxo-4 -pyrr Me EtOCO 26 2-oxo-4-pyrr Bu H 27 2-oxo-4-pyrr Bu Ac 28 2-oxo-4-pyrr Pen H 29 2-oxo-4-pyrr Pen Ac 30 2-oxo-4 -pyrr Hex H 31 2-oxo-4-pyrr Hex Ac 32 2-oxo-4-pyrr iPr H 33 2-oxo-4-pyrr iPr Ac 34 2-oxo-4-pyrr 3-Pen H 35 2-oxo -4-pyrr 3-Pen Ac 36 2-oxo-4-pyrr iBu H 37 2-oxo- 4-pyrr iBu Ac 38 2-oxo-4-pyrr 3-Me-Bu H 39 2-oxo-4-pyrr 3-Me-Bu Ac 47 2-oxo-4-pyrr cPen H 48 2-oxo-4- pyrr cPen Ac 49 2-oxo-4-pyrr cHex H 50 2-oxo-4-pyrr cHex Ac 51 2-oxo-4-pyrr cHex-Me H 52 2-oxo-4-pyrr cHex-Me Ac 54 2- oxo-4-pyrr Hep H 55 2-oxo-4-pyrr Oct H 56 1-Ac-2-oxo-4-pyrr Me H 57 1-Ac-2-oxo-4-pyrr Me Ac 58 1-Ac- 2-oxo-4-pyrr Et H 59 1-Ac-2-oxo-4-pyrr Et Ac 60 1-Ac-2-oxo-4-pyrr Et EtCO 61 1-Ac-2-oxo-4-pyrr Et PnCO 62 1-Ac-2-oxo-4-pyrr Et EtOCO 63 1-Ac-2-oxo-4-pyrr Et Gly 64 1-Ac-2-oxo-4-pyrr Et Ala 65 1-Ac-2- oxo-4-pyrr Et Leu 66 1-Ac-2-oxo-4-pyrr Et Ile 67 1-Ac-2-oxo-4-pyrr Et b-Ala 68 1-Ac-2-oxo-4-pyrr Et MODM 69 1-Ac-2-oxo-4-pyrr Pr H 70 1-Ac-2-oxo-4-pyrr Pr Ac 71 1-Ac-2-oxo-4-pyrr Pr EtCO 72 1-Ac-2- oxo-4-pyrr Pr PrCO 73 1-Ac-2-oxo-4-pyrr Pr Gly 74 1-Ac-2-oxo-4-pyrr Pr Ala 75 1-Ac-2-oxo-4-pyrr Pr Leu 76 1-Ac-2-oxo-4-pyrr Pr Ile 77 1-Ac-2-oxo-4-pyrr Pr b-Ala 78 1-Ac-2-oxo-4-pyrr Pr MODM 79 1-Ac-2- oxo-4-pyrr Me EtCO 80 1-Ac-2-oxo-4-pyrr Me EtOCO 81 1-Ac-2-oxo-4-pyrr Bu H 82 1-Ac-2- oxo-4-pyrr Bu Ac 83 1-Ac-2-oxo-4-pyrr Pen H 84 1-Ac-2-oxo-4-pyrr Pen Ac 85 1-Ac-2-oxo-4-pyrr Hex H 86 1-Ac-2-oxo-4-pyrr Hex Ac 87 1-Ac-2-oxo-4-pyrr iPr H 88 1-Ac-2-oxo-4-pyrr iPr Ac 89 1-Ac-2-oxo- 4-pyrr 3-Pen H 90 1-Ac-2-oxo-4-pyrr 3-Pen Ac 91 1-Ac-2-oxo-4-pyrr iBu H 92 1-Ac-2-oxo-4-pyrr iBu Ac 93 1-Ac-2-oxo-4-pyrr 3-Me-Bu H 94 1-Ac-2-oxo-4-pyrr 3-Me-Bu Ac 102 1-Ac-2-oxo-4-pyrr cPen H 103 1-Ac-2-oxo-4-pyrr cPen Ac 104 1-Ac-2-oxo-4-pyrr cHex H 105 1-Ac-2-oxo-4-pyrr cHex Ac 106 1-Ac-2- oxo-4-pyrr cHex-Me H 107 1-Ac-2-oxo-4-pyrr cHex-Me Ac 109 1-Ac-2-oxo-4-pyrr Hep H 110 1-Ac-2-oxo-4- pyrr Oct H 111 1-Me-2-oxo-4-pyrr Me H 112 1-Me-2-oxo-4-pyrr Me Ac 113 1-Me-2-oxo-4-pyrr Et H 114 1-Me- 2-oxo-4-pyrr Et Ac 115 1-Me-2-oxo-4-pyrr Et EtCO 116 1-Me-2-oxo-4-pyrr Et PnCO 117 1-Me-2-oxo-4-pyrr Et EtOCO 118 1-Me-2-oxo-4-pyrr Et Gly 119 1-Me-2-oxo-4-pyrr Et Ala 120 1-Me-2-oxo-4-pyrr Et Leu 121 1-Me-2- oxo-4-pyrr Et Ile 122 1-Me-2-oxo-4-pyrr Et b-Ala 123 1-Me-2-oxo-4-pyrr Et MODM 124 1-Me-2-oxo-4-pyrr Pr H 125 1-Me-2-oxo-4-pyrr Pr Ac 126 1-Me-2-oxo-4-pyrr Pr EtCO 127 1-Me-2-oxo-4-pyrr Pr PrCO 128 1-Me-2- oxo-4-pyrr Pr Gly 129 1-Me-2-oxo-4-pyrr Pr Ala 130 1-Me-2-oxo-4-pyrr Pr Leu 131 1-Me-2-oxo-4-pyrr Pr Ile 132 1-Me-2-oxo-4-pyrr Pr b-Ala 133 1-Me-2-oxo-4-pyrr Pr MODM 134 1-Me-2-oxo-4-pyrr Me EtCO 135 1-Me-2- oxo-4-pyrr Me EtOCO 136 1-Me-2-oxo-4-pyrr Bu H 137 1-Me-2-oxo-4-pyrr Bu Ac 138 1-Me-2-oxo-4-pyrr Pen H 139 1-Me-2-oxo-4-pyrr Pen Ac 140 1-Me-2-oxo-4-pyrr Hex H 141 1-Me-2-oxo-4-pyrr Hex Ac 142 1-Me-2-oxo- 4-pyrr iPr H 143 1-Me-2-oxo-4-pyrr iPr Ac 144 1-Me-2-oxo-4-pyrr 3-Pen H 145 1-Me-2-oxo-4-pyrr 3-Pen Ac 146 1-Me-2-oxo-4-pyrr iBu H 147 1-Me-2-oxo-4-pyrr iBu Ac 148 1-Me-2-oxo-4-pyrr 3-Me-Bu H 149 1- Me-2-oxo-4-pyrr 3-Me-Bu Ac 157 1-Me-2-oxo-4-pyrr cPen H 158 1-Me-2-oxo-4-pyrr cPen Ac 159 1-Me-2- oxo-4-pyrr cHex H 160 1-Me-2-oxo-4-pyrr cHex Ac 161 1-Me-2-oxo-4-pyrr cHex-Me H 162 1-Me-2-oxo-4-pyrr cHex -Me Ac 164 1-Me-2-oxo-4-pyrr Hep H 165 1-Me-2-oxo-4-pyrr Oct H 166 1-EtOCO-2-oxo-4-pyr r Et H 167 1-EtOCO-2-oxo-4-pyrr Et Ac 168 1-MODM-2-oxo-4-pyrr Et H 169 1-MODM-2-oxo-4-pyrr Et Ac ----- -------------------------------------------------- --------------- The abbreviations used in Table 1 above are as follows.

Ac acetyl, Me methyl, Et ethyl, Pr propyl, iPr isopropyl, iBu
Isobutyl, Pen pentyl, Hex hexyl,
Hep heptyl, Oct octyl, cPen cyclopentyl, cHex cyclohexyl, Bz benzyl, MODM 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl, Pyrr pyrrolidinyl,
Gly glycyl, Ala alanyl, Leu leucyl, Ile isoleucyl, b-Ala β-alanyl.

Of the compounds exemplified in Table 1 above, compound numbers 3, 4, 5, 6, 8, 9, 10, 12, 12
14, 15, 26, 27, 32, 33, 36, 37, 4
9, 51, 52, 58, 59, 113 or 114, more preferably 3, 4, 8, 14, 15, 2
6, 27, 36, 37, 52, 58, 59, 113 or 114.

Among the above-mentioned compounds, the compounds specified by the following chemical names are particularly preferred.

Compound No. 3: ethyl 6- (1-hydroxyethyl) -1-methyl-2- (2-oxo-4-
Pyrrolidinylthio) -1-carbapene-2-em-3-
Carboxylate Compound No. 4: Ethyl 6- (1-acetoxyethyl) -1-methyl-2- (2-oxo-4-pyrrolidinylthio) -1-carbapen-2-em-3-carboxylate Compound No. 14: Propyl 6- (1-hydroxyethyl) -1-methyl-2- (2-oxo-4-pyrrolidinylthio) -1-carbapen-2-em-3-carboxylate Compound No. 15: propyl 6- (1- (Acetoxyethyl) -1-methyl-2- (2-oxo-4-pyrrolidinylthio) -1-carbapen-2-em-3-carboxylate Compound No. 26: butyl 6- (1-hydroxyethyl) -1- Methyl-2- (2-oxo-4-pyrrolidinylthio) -1-carbapen-2-em-3-carboxylate Compound No. 27: butyl 6- (1-acetate) Toxylethyl) -1-methyl-2- (2-oxo-4-pyrrolidinylthio) -1-carbapen-2-em-3-carboxylate Compound No. 36: isobutyl 6- (1-hydroxyethyl) -1-methyl -2- (2-oxo-4-pyrrolidinylthio) -1-carbapen-2-em-3-carboxylate Compound No. 37: isobutyl 6- (1-acetoxyethyl) -1-methyl-2- (2- Oxo-4-pyrrolidinylthio) -1-carbapen-2-em-3-carboxylate Compound No. 58: Ethyl 6- (1-hydroxyethyl) -1-methyl-2- (1-acetyl-2-oxo-
4-pyrrolidinylthio) -1-carbapen-2-m-
3-carboxylate Compound No. 59: ethyl 6- (1-acetoxyethyl) -1-methyl-2- (1-acetyl-2-oxo-
4-pyrrolidinylthio) -1-carbapen-2-m-
3-carboxylate Compound No. 113: Ethyl 6- (1-hydroxyethyl) -1-methyl-2- (1-methyl-2-oxo-
4-pyrrolidinylthio) -1-carbapen-2-m-
3-carboxylate Compound No. 114: Ethyl 6- (1-acetoxyethyl) -1-methyl-2- (1-methyl-2-oxo-
4-pyrrolidinylthio) -1-carbapen-2-m-
3-carboxylate.

Among the above, the most preferred compounds are the following compounds.

Ethyl (1R, 5S, 6S) -6
[(1R) -1-hydroxyethyl] -1-methyl-2
-[(4R) -2-oxo-4-pyrrolidinylthio]-
1-carbapene-2-em-3-carboxylate ethyl (1R, 5S, 6S) -6-[(1R) -1-
Acetoxyethyl] -1-methyl-2-[(4R) -2
-Oxo-4-pyrrolidinylthio] -1-carbapene-
2-M-3-carboxylate propyl (1R, 5S, 6S) -6-[(1R) -1
-Hydroxyethyl] -1-methyl-2-[(4R)-
2-oxo-4-pyrrolidinylthio] -1-carbapen-2-em-3-carboxylate propyl (1R, 5S, 6S) -6-[(1R) -1
-Acetoxyethyl] -1-methyl-2-[(4R)-
2-oxo-4-pyrrolidinylthio] -1-carbapene-2-em-3-carboxylate butyl (1R, 5S, 6S) -6-[(1R) -1-
Hydroxyethyl] -1-methyl-2-[(4R) -2
-Oxo-4-pyrrolidinylthio] -1-carbapene-
2-M-3-carboxylate butyl (1R, 5S, 6S) -6-[(1R) -1-
Acetoxyethyl] -1-methyl-2-[(4R) -2
-Oxo-4-pyrrolidinylthio] -1-carbapene-
2-M-3-carboxylate.

Isobutyl (1R, 5S, 6S) -6
[(1R) -1-hydroxyethyl] -1-methyl-2
-[(4R) -2-oxo-4-pyrrolidinylthio]-
1-carbapene-2-em-3-carboxylate isobutyl (1R, 5S, 6S) -6-[(1R)-
1-acetoxyethyl] -1-methyl-2-[(4R)
-2-oxo-4-pyrrolidinylthio] -1-carbapen-2-em-3-carboxylate.

[0051]

BEST MODE FOR CARRYING OUT THE INVENTION The carbapenem compound having the general formula (I) of the present invention is produced by introducing a group represented by R ² into the carboxyl group at the 3-position of the carbapenem compound represented by the formula (III). (A
Law).

[0052]

Embedded image In the above, R ¹ and R ² are the same as described above. In addition,
Compounds represented by the formula (III) as starting materials are described in JP-A-2-49783, JP-A-7-165759, JP-A-2-223587 and JP-A-4-27.
9588, JP-A-8-53453, The Jo
Urnal of Antibiotics 50 (5), 429-439 (1997) and the like or a method analogous thereto. Hereinafter, the above manufacturing method will be described in detail.

Step A-1 is achieved by reacting compound (III) with a compound represented by R ² L in a solvent in the presence of a base.

[0054] As the compound represented by R ² L, there may be mentioned chloride R ^2, bromide, methanesulfonate halide or R ^2, such as iodide, trifluoromethanesulfonate, the sulfonates such as toluene sulfonate, Preferably it is a halide of R ² . Among halides, iodide has high reactivity and is suitable, and chloride or bromide can be used in the presence of sodium iodide.

The solvent used is not particularly limited as long as it dissolves the starting materials to some extent and does not participate in the reaction. For example, n-pentane, n-hexane, n-hexane
Aliphatic saturated hydrocarbons such as heptane and n-octane; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran and dioxane; ethyl formate, methyl acetate;
Esters such as ethyl acetate; nitriles such as acetonitrile; halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform, chlorobenzene and dichlorobenzene; N, N-dimethylformamide, N, N- Examples include amides such as dimethylacetamide and N-methyl-2-pyrrolidone. Also, a mixed solvent in which these are appropriately combined can be used. Preferred solvents among these are esters, nitriles or amides, more preferably amides (especially N, N-dimethylformamide or N, N-formamide).
N-dimethylacetamide).

The base to be used is not particularly limited as long as it is used as a base in a usual reaction, and examples thereof include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate and potassium carbonate. Inorganic bases or N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline,
-(N, N-dimethylamino) pyridine, quinoline,
2,6-di (t-butyl) -4-methylpyridine, N,
Organic bases such as N-dimethylaniline and N, N-diethylaniline can be mentioned. Of these, inorganic bases such as sodium carbonate, sodium bicarbonate and potassium carbonate or organic bases such as triethylamine, diisopropylethylamine and dicyclohexylamine are preferred.

The reaction temperature is usually -10 to 50 degrees, preferably 0 to 30 degrees.

The reaction time varies depending on the solvent, base, reaction temperature and the like to be used, but is usually 10 minutes to 10 hours, preferably 0.5 to 3 hours.

After completion of the reaction, the desired product can be obtained by a conventional method, for example, by appropriately combining techniques such as concentration, extraction, activated carbon treatment, and crystallization.
For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration. Then, an immiscible organic solvent such as water and ethyl acetate is added. And the solvent is distilled off. The target compound can be purified, if necessary, by a method commonly used for separation and purification of organic compounds such as activated carbon treatment, recrystallization, reprecipitation, and column chromatography.

The compound (II) previously prepared and isolated
Compound (I) can also be obtained by dissolving the salt of I) in a solvent and reacting with a compound represented by R ² L.

A pharmacologically acceptable derivative of compound (I) can be produced by the following method.

Method B is a method for producing a derivative (IV) in which a group R ⁴ which can be decomposed in vivo is introduced into the hydroxyl group at the 6-position hydroxyethyl group of compound (I).

[0063]

Embedded image Step B-1 is achieved by reacting compound (I) with a reactive derivative of R ^{4 in} a solvent in the presence of a base.

[0064] As the reactive derivative of the R ^4, R ⁴ is alkanoyl, substituted alkanoyl or arylcarbonyl group, an acid halide, acid anhydride, mixed acid anhydride, etc. can be mentioned an acid imidazole compound, Preferably, it is an acid anhydride. When R ⁴ is an alkoxycarbonyl group, examples thereof include an alkoxycarbonyl halide, a dialkyl carbonate and the like, and preferably an alkoxycarbonyl halide. R ⁴ is 5-
In the case of a (C1-C4 alkyl) -2-oxo-1,3-dioxolen-4-ylmethyl group, a halide is preferred.

The solvent used is not particularly limited as long as it dissolves the starting material to some extent and does not participate in the reaction. For example, n-pentane, n-hexane, n-hexane
Aliphatic saturated hydrocarbons such as heptane and n-octane; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran and dioxane; ethyl formate, methyl acetate;
Esters such as ethyl acetate; nitriles such as acetonitrile; halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform, chlorobenzene and dichlorobenzene; N, N-dimethylformamide, N, N- Examples include amides such as dimethylacetamide and N-methyl-2-pyrrolidone. Also, a mixed solvent in which these are appropriately combined can be used.

The base to be used is not particularly limited as long as it is used as a base in a usual reaction. For example, N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine,
Dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N,
Organic bases such as (N-dimethylamino) pyridine, quinoline, 2,6-di (t-butyl) -4-methylpyridine, N, N-dimethylaniline and N, N-diethylaniline can be mentioned. Of these, pyridine, 4- (N, N-dimethylamino) pyridine or a combination thereof is most preferred.

The base is usually used in an amount of 1 to 1.1 molar equivalents with respect to the reactive derivative of R ⁴ , but can be used in a large excess as a solvent. In addition, 4- (N, N-dimethylamino) pyridine or 4-pyrrolidinopyridine can be used in a catalytic amount in combination with another base.

The reaction temperature is usually from -10 to 50 degrees, preferably from 0 to 30 degrees.

The reaction time varies depending on the solvent, base, reaction temperature and the like to be used, but is usually 10 minutes to 10 hours, preferably 0.5 to 3 hours.

After completion of the reaction, the desired product can be obtained by a conventional method, for example, by appropriately combining techniques such as concentration, extraction, activated carbon treatment, and crystallization.
For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration. Then, an immiscible organic solvent such as water and ethyl acetate is added. And the solvent is distilled off. The target compound can be purified, if necessary, by a method commonly used for separation and purification of organic compounds such as activated carbon treatment, recrystallization, reprecipitation, and column chromatography.

In the method C, a derivative (VI) in which a group R ⁵ capable of being degraded in vivo is introduced into the amide nitrogen residue of R 1 of the compound (I)
This is a method for producing I).

[0072]

Embedded image In the above, R ¹ and R ² are as defined above, and R ⁶
Represents a hydroxyl-protecting group. As the “hydroxyl protecting group” for R ⁶ , any of those commonly used in the field of synthetic organic chemistry can be used, but triprotective groups such as trimethylsilyl, triethylsilyl and t-butyldimethylsilyl can be used. A -C1-C4 alkylsilyl group is preferred, most preferably a triethylsilyl group. The compound represented by formula (V) starting material is obtained by a protecting group R ⁶ in a conventional manner a hydroxy group of the compound of the aforementioned (I).

In the step C-1, the compound (V) is dissolved in a solvent,
This is a step of producing a compound (VI) by reacting with a reactive derivative of R ^{5 in} the presence of a base.

[0074] As the reactive derivative of R ^5, when R ⁵ is alkanoyl group, acid halide, acid anhydride, mixed acid anhydride, acid imidazole compounds can be exemplified, preferably an acid anhydride It is. When R ⁵ is an alkoxycarbonyl group, examples thereof include an alkoxycarbonyl halide, a dialkyl carbonate and the like, and preferably an alkoxycarbonyl halide. R
⁵ is alkyl or 5- (C1-C4 alkyl) -2-
In the case of an oxo-1,3-dioxolen-4-ylmethyl group, a halide is preferred.

The solvent used is not particularly limited as long as it dissolves the starting material to some extent and does not participate in the reaction. For example, n-pentane, n-hexane, n-hexane
Aliphatic saturated hydrocarbons such as heptane and n-octane; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran and dioxane; ethyl formate, methyl acetate;
Esters such as ethyl acetate; nitriles such as acetonitrile; halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform, chlorobenzene and dichlorobenzene; N, N-dimethylformamide, N, N- Examples include amides such as dimethylacetamide and N-methyl-2-pyrrolidone. Also, a mixed solvent in which these are appropriately combined can be used. Preferably it is methylene chloride.

The base to be used is not particularly limited as long as it is used as a base in a usual reaction. For example, N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine,
Dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N,
Organic bases such as (N-dimethylamino) pyridine, quinoline, 2,6-di (t-butyl) -4-methylpyridine, N, N-dimethylaniline and N, N-diethylaniline can be mentioned. Of these, 4-
(N, N-dimethylamino) pyridine.

The base is usually used in an amount of 1 to 1.1 molar equivalents relative to the reactive derivative of R ⁵ , but can be used in a large excess as a solvent. In addition, 4- (N, N-dimethylamino) pyridine or 4-pyrrolidinopyridine can be used in a catalytic amount in combination with another base.

The reaction temperature is usually -10 to 50 degrees, preferably 0 to 30 degrees.

The reaction time varies depending on the solvent, base, reaction temperature and the like used, but is usually from 10 minutes to 10 hours, preferably from 0.5 to 3 hours.

After completion of the reaction, the desired product can be obtained by a conventional method, for example, by appropriately combining techniques such as concentration, extraction, activated carbon treatment, and crystallization.
For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration. Then, an immiscible organic solvent such as water and ethyl acetate is added. And the solvent is distilled off. The target compound can be purified, if necessary, by a method commonly used for separation and purification of organic compounds such as activated carbon treatment, recrystallization, reprecipitation, and column chromatography.

Step C-2 is a step of removing a hydroxyl-protecting group of compound (VI) to obtain compound (VII).

When the protecting group is a tri-C1-C4 alkylsilyl group, usually, tetrabutylammonium fluoride,
It is removed by treatment with a compound that produces fluoride anions, such as potassium fluoride (preferably tetrabutylammonium fluoride).

The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but ethers such as tetrahydrofuran and dioxane are preferred.

The reaction temperature and the reaction time are not particularly limited, but are usually at room temperature for 6 hours to 3 days (preferably 10 to 1 day).
8 hours).

After completion of the reaction, the desired product can be obtained by a conventional method, for example, by appropriately combining techniques such as concentration, extraction, activated carbon treatment, and crystallization.
For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration. Then, an immiscible organic solvent such as water and ethyl acetate is added. And the solvent is distilled off. The target compound can be purified, if necessary, by a method commonly used for separation and purification of organic compounds such as activated carbon treatment, recrystallization, reprecipitation, and column chromatography.

In the method D, a derivative (VII) in which the groups R ⁴ and R ⁵ which can be decomposed in vivo are introduced into the hydroxyl group at the 6-position hydroxyethyl group of the compound (I) and the amide nitrogen residue of R 1 respectively.
This is a method for producing I).

[0087]

Embedded image Step D-1 is achieved by reacting compound (VII) with a reactive derivative of R ^{4 in} a solvent in the presence of a base. This step can be achieved in the same manner as described in Method B described above.

The thus obtained carbapenem compound having the general formula (I) and its pharmacologically acceptable derivatives (IV), (VII) and (VIII) may be optionally used in medicinal chemistry, -It can be purified as a pharmacologically acceptable salt according to methods or techniques known in the field of lactam antibiotics.

When compound (I) and its pharmacologically acceptable derivatives are used as a medicine (especially an antibacterial agent),
As such or mixed with appropriate pharmacologically acceptable excipients, diluents, etc., and administered orally with tablets, capsules, granules, powders or syrups or parenterally with injections, etc. can do.

These preparations contain excipients (eg, lactose,
Sugar derivatives such as sucrose, glucose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, α-starch, dextrin, carboxymethyl starch; crystalline cellulose, low-substituted hydroxypropyl cellulose, hydroxy Cellulose derivatives such as propylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally cross-linked carboxymethylcellulose sodium; gum arabic; dextran; pullulan; light anhydrous silicic acid, synthetic aluminum silicate; Silicate derivatives such as magnesium metasilicate aluminate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate; Agent Gelatin; polyvinylpyrrolidone;
Macrogol, etc.), disintegrants (for example, the above-mentioned excipients; croscarmellose sodium, carboxymethyl starch)
Disodium, chemically modified starch such as crosslinked polyvinylpyrrolidone, starch, cellulose derivatives, etc.), lubricants (eg, talc; stearic acid; metal stearate such as calcium stearate, magnesium stearate; colloidal silica) Bee gum; beeswax;
Waxes such as gay wax; boric acid; glycol; carboxylic acids such as fumaric acid and adipic acid; sodium carboxylate salts such as sodium benzoate; sulfate salts such as sodium sulfate; leucine; Lauryl sulfates such as magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; starch derivatives in the above-mentioned excipients); stabilizers (eg, paraoxybenzoic acid esters such as methylparaben and propylparaben) Chlorobutanol, benzyl alcohol
Alcohols such as phenylethyl alcohol;
Benzalkonium chloride; phenols such as phenol and cresol; thimerosal; acetic anhydride; sorbic acid, etc.) and flavoring agents (for example, commonly used sweeteners).
Additives such as acidulants, flavors, etc., suspending agents (eg, polysorbate 80, carboxymethyl cellulose sodium, etc.), diluents, formulation solvents (eg, water, ethanol, glycerin, etc.). And manufactured by a well-known method.

The dosage depends on symptoms, age, etc., but in the case of oral administration, the lower limit is 10 mg (preferably 50 mg) and the upper limit is 2000 mg (preferably 10 mg).
In the case of intravenous administration, the lower limit is 10 mg (preferably 100 mg) and the upper limit is 3000 mg per dose.
(Preferably 2000 mg) is desirably administered to an adult 1 to 6 times a day depending on the symptoms.

[0092]

The following examples, reference examples and test examples are given below.
The present invention will be described in more detail, but the scope of the present invention is not limited thereto. In addition, regarding the nuclear magnetic resonance spectrum, tetramethylsilane was used as an internal standard substance.

Example 1 Ethyl (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(4R) -2-oxo-4-
Pyrrolidinylthio] -1-carbapen-2-em-3-
Carboxylate

[0094]

Embedded image Under a nitrogen stream, (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(4R) -2-oxo
-4-pyrrolidinylthio] -1-carbapen-2-m-
3.48 g of 3-carboxylic acid sodium salt was dissolved in 35 ml of N, N-dimethylacetamide, and ethyl iodide 4.68 g was dissolved at room temperature.
g was added and stirred for 1 hour. 35 ml of saturated saline was added to the reaction solution, extracted with 500 ml of ethyl acetate, and the aqueous layer was again extracted with 500 ml of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and methanol and isopropyl ether were added to the obtained crude product to obtain 3.11 g of the title compound as a colorless powder.

Infrared absorption spectrum (KBr) ν cm ^-1 : 3
334, 3293, 2965, 1742,1688, 1542, 1373, 1335, 122
3, 1157. Nuclear magnetic resonance spectrum (400MHz, DMSO-d ₆ ) δ ppm: 1.1
4 (3H, d, J = 7.3Hz), 1.15 (3H, d, J = 5.9Hz), 1.21 (3H,
t, J = 7.0Hz), 2.11 (1H, dd, J = 17.0, 4.2Hz), 2.78 (1H,
dd, J = 17.0, 7.9Hz), 3.09 (1H, dd, J = 10.9, 3.9Hz),
3.23 (1H, dd, J = 6.3, 2.7Hz), 3.41 (1H, dq, J = 9.3, 7.
3Hz), 3.70 (1H, dd, J = 10.9, 7.5Hz), 3.96 (1H, dq, J =
6.3, 5.9Hz), 4.07-4.00 (1H, m), 4.17 (2H, q, J = 14.0,
7.3Hz), 4.20 (1H, dd, J = 9.3, 2.7Hz), 5.07 (1H, br),
7 84 (1H, br s). Melting point 189-191 ° C.

Example 2 propyl (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(4R) -2-oxo-4
-Pyrrolidinylthio] -1-carbapene-2-em-3
-Carboxylate

[0097]

Embedded image (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio] -1-carbapen-2-em Using 2.00 g of sodium-3-carboxylate and 1.44 g of propyl iodide, 1.15 g of the title compound as a colorless powder was obtained in the same manner as in Example 1.

Infrared absorption spectrum (KBr) ν cm ^-1 : 3
342, 3286, 2967, 1750, 1691, 1549, 1334. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 1.00
(3H, t, J = 7.4Hz), 1.28 (3H, d, J = 7.3Hz), 1.37 (3H,
d, J = 6.1Hz), 1.75 (2H, qd, J = 7.4, 6.5Hz), 1.84 (1H,
d, J = 4.6Hz), 2.41 (1H, dd, J = 17.1, 5.4Hz), 2.79 (1H,
dd, J = 17.1, 8.1Hz), 3.22-3.32 (2H, m), 3.35 (1H, d
d, J = 10.6, 4.9Hz), 3.82 (1H, dd, J = 10.6,7.8Hz), 3.9
5-4.05 (1H, m), 4.16 (1H, dt, J = 10.5, 6.5Hz), 4.20-4.
36 (3H, m), 5.78 (1H, brs) mp 188-190 ° C.

Example 3 Butyl (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(4R) -2-oxo-4-
Pyrrolidinylthio] -1-carbapen-2-em-3-
Carboxylate

[0100]

Embedded image (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio] -1-carbapen-2-em Using 4.50 g of sodium -3-carboxylate and 3.56 g of butyl iodide,
By the same method as in Example 1, the title compound was obtained as a colorless powder.
1.93 g were obtained.

Infrared absorption spectrum (KBr) ν cm ^-1 : 3
350, 3239, 2966, 1750, 1693, 1547, 1345, 1223, 114
5. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 0.94
(3H, t, J = 7.4Hz), 1.27 (3H, d, J = 7.3Hz), 1.36 (3H,
d, J = 6.1Hz), 1.37-1.55 (2H, m), 1.65-1.76 (2H, m), 2.
05 (1H, d, J = 4.6Hz), 2.41 (1H, dd, J = 17.2, 5.4Hz),
2.80 (1H, dd, J = 17.2, 8.1Hz), 3.22-3.32 (2H, m), 3.3
4 (1H, dd, J = 10.5, 5.0Hz), 3.83 (1H, dd, J = 10.5, 7.8H
z), 3.95-4.05 (1H, m), 4.16-4.35 (4H, m), 5.96 (1H, br
s) Melting point 194-198 ° C.

Example 4 Pentyl (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(4R) -2-oxo-4
-Pyrrolidinylthio] -1-carbapene-2-em-3
-Carboxylate

[0103]

Embedded image (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio] -1-carbapen-2-em Using 2.20 g of sodium -3-carboxylate and 1.82 g of pentyl iodide, 2.37 g of the title compound as a colorless powder was obtained in the same manner as in Example 1.

Infrared absorption spectrum (KBr) ν cm ^-1 : 3
346, 3282, 2964, 1754, 1690, 1548, 1341, 1223, 114
8. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 0.89
(3H, t, J = 7.1Hz), 1.27 (3H, d, J = 7.3Hz), 1.28-1.46
(4H, m), 1.36 (3H, d, J = 6.0Hz), 1.72 (2H, m), 2.08 (1
H, d, J = 4.7Hz), 2.41 (1H, dd, J = 17.3, 5.4Hz), 2.80
(1H, dd, J = 17.3,8.1Hz), 3.21-3.32 (2H, m), 3.34 (1H,
dd, J = 10.7, 4.9Hz), 3.83 (1H, dd, J = 10.7, 7.8Hz),
3.95-4.05 (1H, m), 4.16-4.35 (4H, m), 5.99 (1H, brs) melting point 180-183 ° C.

Example 5 Hexyl (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(4R) -2-oxo-4
-Pyrrolidinylthio] -1-carbapene-2-em-3
-Carboxylate

[0106]

Embedded image (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio] -1-carbapen-2-em Using 2.10 g of sodium -3-carboxylate and 1.94 g of pentyl iodide, 2.22 g of the title compound as a colorless powder was obtained in the same manner as in Example 1.

Infrared absorption spectrum (KBr) ν cm ^-1 : 3
359, 3300, 2964, 1749, 1693, 1551, 1340, 1221, 114
6. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 0.89
(3H, t, J = 7.1Hz), 1.21-1.47 (6H, m), 1.27 (3H, d, J =
(7.3Hz), 1.36 (3H, d, J = 6.4Hz), 1.66-1.78 (2H, m), 1.9
7 (1H, d, J = 4.6Hz), 2.41 (1H, dd, J = 17.3, 5.4Hz), 2.
80 (1H, dd, J = 17.3, 8.1Hz), 3.21-3.32 (2H, m), 3.34
(1H, dd, J = 10.5, 5.1Hz), 3.82 (1H, dd, J = 10.5, 7.9H
z), 3.95-4.05 (1H, m), 4.15-4.35 (4H, m), 5.89 (1H, br
s) Melting point 176-178 ° C.

Example 6 Isopropyl (1R, 5S, 6S) -6-[(1R) -1-
Hydroxyethyl] -1-methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio] -1-carbapen-2-em-3-carboxylate

[0109]

Embedded image (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio] -1-carbapen-2-em Using 2.40 g of sodium -3-carboxylate and 1.71 g of isopropyl iodide, 1.70 g of the title compound as a colorless powder was obtained in the same manner as in Example 1.

Infrared absorption spectrum (KBr) ν cm ^-1 : 3
341, 2979, 1766, 1706, 1673, 1543, 1366, 1215, 110
4. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 1.27
(3H, d, J = 7.2Hz), 1.27 (3H, d, J = 6.7Hz), 1.35 (3H,
d, J = 6.7Hz), 1.36 (3H, d, J = 6.5Hz), 2.03 (1H, br), 2.
41 (1H, dd, J = 17.2, 5.3Hz), 2.75 (1H, dd, J = 17.2, 8.
1Hz), 3.21-3.32 (2H, m), 3.34 (1H, dd, J = 10.6, 4.9H
z), 3.77 (1H, dd, J = 10.6, 7.8Hz), 3.95-4.05 (1H, m),
4.21-4.30 (2H, m), 5.15 (1H, m), 5.91 (1H, br s) mp 178-182 ° C.

Example 7 3-pentyl (1R, 5S, 6S) -6-[(1R) -1-
Hydroxyethyl] -1-methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio] -1-carbapen-2-em-3-carboxylate

[0112]

Embedded image (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio] -1-carbapen-2-em Using 2.09 g of sodium-3-carboxylate and 3.48 g of 3-pentyl iodide, 1.65 g of the title compound was obtained as a colorless powder in the same manner as in Example 1.

Infrared absorption spectrum (KBr) ν cm ^-1 : 3
350, 3301, 2969, 1748, 1694, 1546, 1457, 1335, 122
2, 1143. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 0.91
(3H, t, J = 7.5Hz), 0.97 (3H, t, J = 7.3Hz), 1.28 (3H,
d, J = 7.3Hz), 1.66 (3H, d, J = 6.1Hz), 1.55-1.74 (4H,
m), 1.90-1.97 (1H, m), 2.42 (1H, dd, J = 17.3, 5.4Hz),
2.80 (1H, dd, J = 17.3, 8.1Hz), 3.23-3.35 (1H, m), 3.
26 (1H, dd, J = 7.3, 2.7Hz), 3.40 (1H, dd, J = 10.4, 5.1H
z), 3.82 (1H, dd, J = 10.4, 7.9Hz), 3.97-4.03 (1H, m),
4.22-4.30 (1H, m), 4.24 (1H, dd, J = 9.4, 2.7Hz), 4.90
(1H, m), 5.82 (1H, br s) mp 182-185 ° C.

Example 8 Isobutyl (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(4R) -2-oxo
-4-pyrrolidinylthio] -1-carbapen-2-m-
3-carboxylate

[0115]

Embedded image (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio] -1-carbapen-2-em Using 2.30 g of sodium -3-carboxylate and 1.80 g of isobutyl iodide, 0.73 g of the title compound as a colorless powder was obtained in the same manner as in Example 1.

Infrared absorption spectrum (KBr) ν cm ^-1 : 3
336, 3285, 2965, 1745, 1690, 1550, 1350, 1335, 122
2, 1157. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 0.99
(6H, d, J = 6.7Hz), 1.28 (3H, d, J = 7.3Hz), 1.37 (3H,
d, J = 6.4Hz), 1.77 (1H, br s), 2.04 (1H, septet, J = 6.7
Hz), 2.41 (1H, dd, J = 17.2, 5.4Hz), 2.79 (1H, dd, J = 1
7.2, 8.2Hz), 3.21-3.32 (2H, m), 3.34 (1H, dd, J = 10.
4, 5.1Hz), 3.82 (1H, dd, J = 10.4, 7.8Hz), 3.93 (1H, dd,
J = 10.7, 6.5Hz), 3.97-4.06 (1H, m), 4.14 (1H, dd, J =
10.7, 6.8Hz), 4.20-4.31 (2H, m), 5.60 (1H, br s) mp 209-212 ° C.

Example 9 Isopentyl (1R, 5S, 6S) -6-[(1R) -1-
Hydroxyethyl] -1-methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio] -1-carbapen-2-em-3-carboxylate

[0118]

Embedded image (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio] -1-carbapen-2-em Using 2.09 g of sodium -3-carboxylate and 3.56 g of isopentyl iodide, 2.03 g of the title compound as a colorless powder was obtained in the same manner as in Example 1.

Infrared absorption spectrum (KBr) ν cm ^-1 : 3
338, 3286, 2963, 1754, 1691, 1546, 1343, 1221, 114
7. Nuclear magnetic resonance spectrum (400MHz, DMSO-d ₆ ) δ ppm: 0.8
7 (3H, d, J = 6.6Hz), 0.88 (3H, d, J = 6.6Hz), 1.14 (3H,
d, J = 7.3Hz), 1.14 (3H, d, J = 6.6Hz), 1.43-1.57 (2H,
m), 1.65-1.78 (1H, m), 2.10 (1H, dd, J = 17.0, 4.3Hz),
2.78 (1H, dd, J = 17.0, 7.7Hz), 3.08 (1H, dd, J = 10.9,
3.7Hz), 3.24 (1H, dd, J = 6.3, 2.5Hz), 3.40 (1H, dq,
J = 9.2, 7.3Hz), 3.70 (1H, dd, J = 10.9, 7.5Hz), 3.92-
3.99 (1H, m), 3.99-4.07 (1H, m), 4.08-4.14 (1H, m), 4.1
8-4.25 (2H, m), 5.07 (1H, br), 7.84 (1H, br s) mp 192-193 ° C.

Example 10 Cyclopentyl (1R, 5S, 6S) -6-[(1R) -1
-Hydroxyethyl] -1-methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio] -1-carbapen-2-em-3-carboxylate

[0121]

Embedded image (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio] -1-carbapen-2-em 2.24 g of sodium-3-carboxylate and 3.78 g of cyclopentyl iodide
In the same manner as in Example 1 to obtain 2.00 g of the title compound as a colorless powder.

Infrared absorption spectrum (KBr) ν cm ^-1 : 3
342, 3289, 2965, 1743, 1692, 1549, 1370, 1224, 114
7. Nuclear magnetic resonance spectrum (400MHz, DMSO-d ₆ ) δ ppm: 1.1
4 (6H, d, J = 6.6Hz), 1.89-1.49 (8H, m), 2.10 (1H, dd,
J = 17.1, 4.1Hz), 2.77 (1H, dd, J = 17.1, 7.7Hz), 3.07
(1H, dd, J = 10.9, 3.7Hz), 3.24 (1H, dd, J = 6.2, 2.7H
z), 3.39 (1H, m), 3.69 (1H, dd, J = 10.9, 7.5Hz), 3.96
(1H, dq, J = 6.6, 6.2Hz), 3.94-4.06 (1H, m), 4.20 (1H, J
= 9.4, 2.7Hz), 5.23-5.13 (1H, m), 7.84 (1H, br s) melting point 217-218 ° C.

Example 11 Cyclohexylmethyl (1R, 5S, 6S) -6-[(1
R) -1-Hydroxyethyl] -1-methyl-2-[(4R)
2-oxo-4-pyrrolidinylthio] -1-carbapene-2
-M-3-carboxylate

[0124]

Embedded image (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio] -1-carbapen-2-em 2.05 g of sodium-3-carboxylate and bromomethylcyclohexane
In the same manner as in Example 1 using 1.56 g, 0.60 g of the title compound was obtained as a colorless powder.

Infrared absorption spectrum (KBr) ν cm ^-1 : 3
338, 3284, 2930, 1751, 1689, 1546, 1450, 1340, 122
2, 1146. Nuclear magnetic resonance spectrum (400MHz, DMSO-d ₆ ) δ ppm: 0.9
9-1.33 (6H, m), 1.15 (3H, d, J = 6.5Hz), 1.15 (3H, d, J
= 7.3Hz), 1.50-1.80 (5H, m), 2.10 (1H, dd, J = 17.0, 4.
2Hz), 2.78 (1H, dd, J = 17.0, 7.9Hz), 3.08 (1H, dd, J =
10.9, 3.5Hz), 3.24 (1H, dd, J = 6.2, 2.6Hz), 3.41 (1H,
dq, J = 9.4, 7.3Hz), 3.70 (1H, dd, J = 10.9, 7.5Hz), 3.
85 (1H, dd, J = 10.7, 6.2Hz), 3.97 (1H, dq, J = 6.5, 6.2H
z), 4.00-4.08 (2H, m), 4.21 (1H, J = 9.4, 2.6Hz), 5.06
(1H, br), 7.84 (1H, br s) mp 196-199 ° C.

Example 12 Ethyl (1R, 5S, 6S) -6-[(1R) -1-acetoxyethyl] -1-methyl-2-[(4R) -2-oxo-4-
Pyrrolidinylthio] -1-carbapen-2-em-3-
Carboxylate

[0127]

Embedded image 1.55 g of the compound obtained in Example 1 was added to 60 ml of dichloromethane.
Dimethylaminopyridine 568 under ice-cooling.
g and 475 mg of acetic anhydride were added and stirred for 2 hours. After concentrating the reaction solution, the obtained crude product was purified by silica gel column chromatography to obtain 1.35 g of the title compound in an amorphous state.

Infrared absorption spectrum (KBr) ν cm ^-1 : 3
369, 3241, 2980, 1778, 1738, 1703, 1554, 1447, 137
2, 1242, 1140, 1042. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 1.27
(3H, d, J = 7.3Hz), 1.35 (3H, t, J = 7.0Hz), 1.41 (3H,
d, J = 6.4Hz), 2.08 (3H, s), 2.40 (1H, dd, J = 17.2, 5.5
Hz), 2.79 (1H, dd, J = 17.2, 8.2Hz), 3.25 (1H, dq, J =
9.4, 7.3Hz), 3.35 (1H, dd, J = 10.4, 5.1Hz), 3.39 (1H,
dd, J = 10.4, 7.8Hz), 3.82 (1H, dd, J = 10.4, 7.8Hz),
3.95-4.04 (1H, m), 4.19 (1H, dd, J = 9.4, 2.7Hz), 4.26
-4.39 (2H, m), 5.26 (1H, dq, J = 7.6, 6.4Hz), 5.93 (1H,
br s).

Example 13 butyl (1R, 5S, 6S) -6-[(1R) -1-acetoxyethyl] -1-methyl-2-[(4R) -2-oxo-4-
Pyrrolidinylthio] -1-carbapen-2-em-3-
Carboxylate

[0130]

Embedded image By acetylating 2.00 g of the compound obtained in Example 1 in the same manner as in Example 12, 1.23 g of the title compound in an amorphous state was obtained.

Infrared absorption spectrum (KBr) ν cm ^-1 : 3
360, 3240, 2962, 1779, 1739, 1703, 1553, 1452, 124
0, 1140, 1041. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 0.94
(3H, t, J = 7.5Hz), 1.27 (3H, d, J = 7.4Hz), 1.41 (3H,
d, J = 6.5Hz), 1.36-1.51 (2H, m), 1.64-1.77 (2H, m), 2.0
7 (3H, s), 2.40 (1H, dd, J = 17.1, 5.5Hz), 2.79 (1H, d
d, J = 17.1, 8.1Hz), 3.24 (1H, dq, J = 9.0, 7.4Hz), 3.3
4 (1H, dd, J = 10.6, 5.0Hz), 3.39 (1H, dd, J = 7.4, 2.6H
z), 3.82 (1H, dd, J = 10.6, 7.8Hz), 3.94-4.05 (1H, m),
4.14-4.24 (2H, m), 4.31 (1H, dt, J = 10.8, 6.7Hz), 5.
21-5.32 (1H, m), 6.02 (1H, br s).

Test Example Oral Absorption Test The compound of Example 7 of the present invention and one of the closest prior art documents, The Journal of Antibiotics 50 (5),
Compound 14 described in 429-439 (1997) was orally administered to dogs, and the active substance concentration in plasma was measured by high performance liquid chromatography to compare absolute bioavailability (BA). (1) Sample Compound of Example 1 of the present application: ethyl (1R, 5S, 6)
S) -6-[(1R) -1- (hydroxyethyl)]-
1-methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio] -1-carbapen-2-em-3-carboxylate Compound of Example 2 of the present application: propyl (1R, 5S,
6S) -6-[(1R) -1- (hydroxyethyl)]
-1-Methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio] -1-carbapen-2-em-3-carboxylate Comparative compound (The Journal of Antibiotics 50 (5), 429)
-439 (1997) Compound 14): 1- (isopropoxycarbonyloxy) ethyl (1R, 5S,
6S) -6-[(1R) -1-hydroxyethyl] -1
-Methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio] -1-carbapen-2-em-3-carboxylate Active form: (1R, 5S, 6S) -6-[(1R) -1
-Hydroxyethyl] -1-methyl-2-[(4R)-
2-oxo-4-pyrrolidinylthio] -1-carbapen-2-em-3-carboxylic acid (2) Administration of specimen 10 mg titer / kg of specimen (ester compound) was propylene glycol-polysorbate 80-water 5 mg / kg each.
0:15:35 (v: v: v) Dissolved in a mixture, fasted overnight and orally administered to male beagle dogs (n = 3, body weight 10-14 kg) administered ranitidine (2.5 mg / kg) intramuscularly Was administered. (3) Blood collection and measurement of plasma active substance concentration After sample administration, blood is collected every 0.25, 0.5, 1, 1.5, 2, 3, 4, and 6 hours, and plasma is obtained by centrifuging the obtained blood. The concentration of the active substance in plasma was measured by a high performance liquid chromatography method. (4) Calculation of bioavailability The measured values in plasma concentration were plotted against the time after administration of the sample, and the area under the plasma concentration-time curve (AUC) was determined.
On the other hand, AUC when the active substance was intravenously administered to dogs was determined. BA (%) = (AUC at oral administration / A at intravenous administration)
The absolute bioavailability (BA) was calculated using UC) x100, and is shown in Table 2 together with the separately calculated pharmacological parameters.

[0133]

[Table 2] ---------------------------------------------- ------------------------ Specimen Cmax Tmax AUC _0-6 BA (μg / ml) (hr) (μg · hr / ml) (%) -------------------------------------------------- -------------------- Compound of Example 1 5.61 1.2 15.06 58.8 Compound of Example 2 5.54 1.7 15. 07 58.9 Comparative compound 4.53 0.8 10.92 42.6 -------------------------------- -------------------------------------- In Table 2, Cmax is the maximum plasma concentration, Tmax Indicates the time at which Cmax was given, and AUC _0-6 indicates the AUC from 0 to 6 hours after the administration of the sample.

The compounds of Examples 1 and 2 of the present invention were compared with the comparative compounds described in the closest prior art literature.
It showed excellent oral absorption and pharmacokinetics in oral administration.

[0135] The powders of the above formula are mixed, wet-granulated using corn starch paste, dried, and then tableted with a tableting machine to make one tablet of 200 mg. The tablets can be sugar-coated as needed.

[0136]

According to the present invention, the carbapenem ester compound having the above general formula (I) or a pharmaceutically acceptable derivative thereof exhibits excellent absorption and sustained pharmacokinetics when administered to a living body. Therefore, the compound having the general formula (I) or a pharmacologically acceptable salt thereof according to the present invention is effective for a drug (particularly an antibacterial agent) for treating or preventing (preferably treating) bacterial infections caused by various pathogenic bacteria. Useful as an ingredient.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Osamu Kanno 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Akihiko Nakagawa 2-7-12 Ginza, Chuo-ku, Tokyo Sankyo (72) Inventor Toshio Terao 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. F-term (reference) 4C050 KA02 KB05 KB13 KB16 KC08 4C086 AA01 AA02 CC08 MA01 MA04 NA14 ZB35

Claims (14)

[Claims] 1. A compound of the general formula (I) [Wherein, R ¹ represents the following general formula (IIa)] (Wherein R ³ represents a hydrogen atom or a C1-C4 alkyl group), and R ² represents a C1-C20 alkyl group, a C3-C7 cycloalkyl group or a C3-C7 cycloalkyl-C1- C6
Shows an alkyl group. An antibacterial agent comprising, as an active ingredient, a carbapenem ester compound having the formula: or a pharmacologically acceptable derivative thereof. 2. The antibacterial agent according to claim 1, which comprises, as an active ingredient, a compound represented by the formula (IIa) wherein the substitution position of the group is 4-position. 3. The antibacterial agent according to claim 1, wherein the compound represented by the formula (IIa) wherein R ³ is a hydrogen atom is contained as an active ingredient. 4. The method according to claim 1, wherein R ¹ is 2-oxo-4-pyrrolidinyl or 1
-An antimicrobial agent containing, as an active ingredient, a compound which is a methyl-2-oxo-4-pyrrolidinyl group. 5. The antibacterial agent according to claim 1, wherein R ¹ is a 2-oxo-4-pyrrolidinyl group as an active ingredient. 6. The antibacterial agent according to claim 1, wherein R ² is a C1-C20 alkyl group as an active ingredient. 7. The antibacterial agent according to claim 1, wherein R ² is a C1-C10 alkyl group as an active ingredient. 8. The antibacterial agent according to claim 1, wherein R ² is a C2-C6 alkyl group as an active ingredient. 9. An antibacterial agent according to any one of claims 1 to 5, comprising a compound wherein R ² is an ethyl, propyl, butyl, isobutyl, 3-methylbutyl or pentyl group as an active ingredient. 10. The antibacterial agent according to claim 1, wherein R ² is an ethyl or propyl group as an active ingredient. 11. The method according to claim 1, wherein R ¹ is a 2-oxo-4-pyrrolidinyl group or a 1-methyl-2-oxo-4-pyrrolidinyl group, and R ² is An antibacterial agent containing a compound that is a C1-C10 alkyl group as an active ingredient. 12. The compound according to claim 1, wherein R ¹ is a 2-oxo-4-pyrrolidinyl group and R ² is a C2-C6 alkyl group as an active ingredient. Antibacterial agent. 13. The active ingredient according to claim 1, wherein R ¹ is a 2-oxo-4-pyrrolidinyl group and R ² is an ethyl or propyl group. Antibacterial agent. 14. The antibacterial agent according to claim 1, comprising a compound selected from the following compound group as an active ingredient. Ethyl (1R, 5S, 6S) -6-[(1R) -1-
Hydroxyethyl] -1-methyl-2-[(4R) -2
-Oxo-4-pyrrolidinylthio] -1-carbapene-
2-M-3-carboxylate ethyl (1R, 5S, 6S) -6-[(1R) -1-
Acetoxyethyl] -1-methyl-2-[(4R) -2
-Oxo-4-pyrrolidinylthio] -1-carbapene-
2-M-3-carboxylate propyl (1R, 5S, 6S) -6-[(1R) -1
-Hydroxyethyl] -1-methyl-2-[(4R)-
2-oxo-4-pyrrolidinylthio] -1-carbapen-2-em-3-carboxylate propyl (1R, 5S, 6S) -6-[(1R) -1
-Acetoxyethyl] -1-methyl-2-[(4R)-
2-oxo-4-pyrrolidinylthio] -1-carbapene-2-em-3-carboxylate butyl (1R, 5S, 6S) -6-[(1R) -1-
Hydroxyethyl] -1-methyl-2-[(4R) -2
-Oxo-4-pyrrolidinylthio] -1-carbapene-
2-M-3-carboxylate butyl (1R, 5S, 6S) -6-[(1R) -1-
Acetoxyethyl] -1-methyl-2-[(4R) -2
-Oxo-4-pyrrolidinylthio] -1-carbapene-
2-M-3-carboxylate isobutyl (1R, 5S, 6S) -6-[(1R)-
1-hydroxyethyl] -1-methyl-2-[(4R)
-2-oxo-4-pyrrolidinylthio] -1-carbapene-2-em-3-carboxylate isobutyl (1R, 5S, 6S) -6-[(1R)-
1-acetoxyethyl] -1-methyl-2-[(4R)
-2-oxo-4-pyrrolidinylthio] -1-carbapen-2-em-3-carboxylate.