JPH06157544A - Carbapenem compound - Google Patents

Abstract

PURPOSE:To obtain a new compound useful as an antibacterial agent having a powerful antibacterial spectrum over a wide range. CONSTITUTION:The objective compound of formula I [A is R<1>CO, etc.; R<1> is (substituted)aliphatic hydrocarbon, alkoxy or aryl), e.g. (1R,5S,6S)-6-[(R)-1- acetyloxyethyl]-2-[(6,7-dihydro-5H-pyrazolo][1,2-a][1,2,4]triazolium-6 -yl)thio]-1- methylcarbapen-2-em-3-carboxylate. The compound of the formula I can be obtained by deprotecting the carboxyl-protecting group and amino-protecting group of a compound of formula II (R<5> is carboxyl-protecting group; R<6> is amino-protecting group) followed by reaction with a formimidoyl ester of the formula NH=CHOR (R is alkyl).

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to carbapenem antibiotics, and more specifically, β at the 1-position of the carbapenem skeleton.
-Having a methyl group and having a (6,7-dihydro-5H-pyrazolo [1,2-α] [1,2,4] triazolium-6-yl)] thio group at the 2-position , And further to a carbapenem compound having a 1-substituted hydroxyethyl group at the 6-position.

[0002]

Conventionally, the following formula (1) has been used for the purpose of various antibacterial activities.

[0003]

[Chemical 2]

A large number of carbapenem antibiotics having a basic skeleton of carba-2-penem-3-carboxylic acid represented by

Recently, as a novel antibacterial agent which overcomes the problems such as lack of chemical stability and inactivation by renal dehydropeptidase (DHF), which conventional carbapenem antibiotics have, the following formula ( 2)

[0006]

[Chemical 3]

The compound represented by the formula (1) was created by the present inventors and is disclosed in Japanese Patent Application Laid-Open No. 1-257979. The compound of the above formula (2) is an excellent antibacterial agent which does not need to be used in combination with a DHF inhibitor and has a wide-ranging strong antibacterial spectrum, and is currently undergoing clinical trials.

[0008]

[Problems and Means to be Solved by the Invention] While promising compounds such as those described above are being developed as carbapenem antibacterial agents, they are required to cope with resistant strains, establish new administration methods or simplify use. Therefore, it goes without saying that the development of new antibacterial agents is always required.

The inventors of the present invention have conducted extensive studies in order to meet this demand, and as a result, various hydroxyl groups of the 1-hydroxylethyl group bonded to the 6-position of the carbapenem skeleton of the compound represented by the formula (2) have been selected. The present inventors have succeeded in synthesizing a compound having an excellent antibacterial activity modified by the substituent of 1 and completed the present invention.

Thus, the present invention provides the formula (I)

[0011]

[Chemical 4]

Where: R ¹ represents a saturated or unsaturated aliphatic hydrocarbon group, an alkoxy group or an aryl group which may be substituted with a group selected from halogen, hydroxyl and phenyl, and R ² and R ³ each independently represent a hydrogen atom. Or an alkyl group optionally substituted with a carboxyl group, or R ² and R ³ may form a nitrogen-containing heterocycle together with the nitrogen atom to which they are attached; Wherein R ⁴ represents a hydrogen atom or an alkyl group, and a pharmaceutically acceptable salt thereof.

In the present specification, the "saturated or unsaturated aliphatic hydrocarbon group" may be linear or branched, and specifically, for example, methyl, ethyl, n-.
Or iso-propyl, n-, iso-, sec- or tert-butyl, n- or iso-pentyl,
Alkyl groups such as n- or iso-hexyl, n-octyl and 2-ethylhexyl; vinyl, n or iso-
Alkenyl such as propenyl, n-, iso or sec-butenyl; ethynyl, propargyl, 1-propynyl, n- or sec-butynyl, n- or iso-
Examples include alkynyl groups such as pentynyl, n- or iso-hexynyl. As these aliphatic hydrocarbon groups, lower ones having up to 6 carbon atoms are usually preferred.

An "alkoxy group" is an alkyloxy group in which the alkyl portion may be linear or branched and is, for example, methoxy, ethoxy, n- or i.
so-propoxy, n-, iso-, sec- or te
Examples thereof include rt-butoxy, n- or iso-pentoxy, n- or iso-hexoxy, n-octoxy and the like, and a lower alkoxy group is preferable.

The "aryl group" may be of any monocyclic or polycyclic type, and may have a lower alkyl group on the ring, specifically, phenyl, naphthyl, It includes tolyl, xylyl, cumenyl, mesityl and the like. Among them, phenyl is preferable.

The saturated or unsaturated aliphatic hydrocarbon group, alkoxy group and aryl group described above may be substituted with a halogen, for example, a group selected from fluorine, chlorine, bromine or iodine, hydroxy and phenyl. Examples of such substituted radicals include trifluoromethyl, 3-bromo-2-methylpropyl, 2,2-dimethyl-
Substituted alkyl groups such as 1-hydroxypropyl, benzyl, 1-methyl-1-phenylethyl group; 2,4-dichloro-1,
3-butadienyl, 2-hydroxy-1-methylvinyl, 3
-Substituted alkenyl group such as phenylallyl group; 4-chloro-
2-Pentynyl, substituted alkynyl groups such as 1-hydroxypropargyl group; 1-chloroethoxy, 4-hydroxypentyloxy, substituted alkoxy groups such as 1-phenylpropoxy group; 5-bromo-2-naphthyl, 3-hydroxy- Examples include substituted aryl groups such as m-tolyl and 4-biphenylyl groups.

In the above formula (I), the "nitrogen-containing heterocyclic group" formed by R ² and R ³ together with the nitrogen atom to which they are bonded is selected from O, S and N. Include a 3- to 8-membered, preferably 4- to 6-membered heterocycle which may further contain a heteroatom, specifically, azetidino,
Examples include pyrrolidino, piperidino, morpho, thiomorpholino, piperazinyl, pyrrolinino, pyrrolino, imidazolidinino, imidazolinino, imidazolino groups.

[0018] “A saturated heterocyclic group having 2” includes a saturated heterocyclic group having 3 to 8 atoms, preferably 4 to 6 atoms, and specifically includes, for example, oxetanyl, azetidinyl,
Tetrahydrofuryl, N-methylpyrrolidinyl, tetrahydrothienyl, tetrahydropyranyl, piperidyl,
Dioxacyclohexyl, imidazolidinyl, 1,2-oxathiolan-3-yl group and the like can be mentioned.

Typical examples of the compound of the above formula (I) provided by the present invention are as follows.

(1R, 5S, 6S) -6-[(R) -1-acetyloxyethyl] -2-[(6,7-dihydro-5H-pyrazolo [1,2-a] [1,2, 4] Triazolium-6-yl) thio] -1-methylcarbapene-2-em-3-carboxylate, (1R, 5S, 6S) -2-[(6,7-dihydro
-5H-Pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio] -1-methyl-6-[(R) -1-propionyloxyethyl] -carbapene-2-em -3-carboxylate, (1R, 5S, 6S) -2-[(6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio]- 1-methyl-6-[(R) -1-trifluoroacetyloxyethyl] -carbapene-2-em-
3-carboxylate, (1R, 5S, 6S) -6-
[(R) -1- (4-bromo-3-methylbutyryloxy)
Ethyl] -2-[(6,7-dihydro-5H-pyrazolo [1,
2-a] [1,2,4] triazolium-6-yl) thio]-
1-methylcarbapene-2-em-3-carboxylate,
(1R, 5S, 6S) -2-[(6,7-Dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio] -6-[(R) -1- (3,3-Dimethyl-2-hydroxybutyryloxy) ethyl] -1-methylcarbapene
-2-M-3-carboxylate, (1R, 5S, 6S)-
2-[(6,7-dihydro-5H-pyrazolo [1,2-a]
[1,2,4] Triazolium-6-yl) thio] -1-methyl-6-[(R) -1-phenylacetyloxyethyl)]
-Carbapene-2-em-3-carboxylate, (1R, 5
S, 6S) -2-[(6,7-dihydro-5H-pyrazolo [1,
2-a] [1,2,4] triazolium-6-yl) thio]-
6-[(R) -1- (2-Methyl-2-phenylpropionyloxy) ethyl] -1-methylcarbapene-2-em-3-carboxylate, (1R, 5S, 6S) -2- [ (6,7-Dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio] -6-[(R) -1- (3,3-dimethylacryloyloxy ) Ethyl] -1-methylcarbapene-2-em-carboxylate, (1R, 5S, 6S)-
6-[(R) -1- (3,5-dichloro-2,4-pentadienylyloxy) ethyl] -2-[(6,7-dihydro-5H-pyrazolo [1,2-a] [ 1,2,4] Triazolium-6-yl) thio] -1-methylcarbapene-2-em-3-carboxylate, (1R, 5S, 6S) -2-[(6,7-dihydro
-5H-Pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio] -6-[(R) -1- (3-hydroxymethacryloyloxy) ethyl] -1-methylcarba pen
-2-M-3-carboxylate, (1R, 5S, 6S)-
2-[(6,7-dihydro-5H-pyrazolo [1,2-a]
[1,2,4] Triazolium-6-yl) thio] -1-methyl-6-[(R) -1- (4-phenyl-3-butenylyloxy) ethyl] -carbapene-2-em-3-carboxy Rate, (1R, 5S, 6S) -6-[(R) -1- (3-butynylyloxy) ethyl] -2-[(6,7-dihydro-5H-pyrazolo [1,2-a] [1, 2,4] Triazolium-6-yl) thio] -1-methylcarbapene-2-em-3-carboxylate, (1R, 5S, 6S) -6-[(R) -1- (5-
Chloro-3-hexynylyloxy) ethyl] -2-[(6,
7-dihydro-5H-pyrazolo [1,2-a] [1,2,4]
Triazolium-6-yl) thio] -1-methylcarbapene
-2-M-3-carboxylate, (1R, 5S, 6S)-
2-[(6,7-dihydro-5H-pyrazolo [1,2-a]
[1,2,4] triazolium-6-yl) thio] -6-
[(R) -1- (2-hydroxy-3-butynylyloxy)
Ethyl] -1-methylcarbapene-2-em-3-carboxylate, (1R, 5S, 6S) -2-[(6,7-dihydro-
5H-Pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio] -6-[(R) -1-ethyloxycarbonyloxyethyl] -1-methylcarbapene-2- M-
3-carboxylate, (1R, 5S, 6S) -6-
[(R) -1- (1-Chloroethyloxycarbonyloxy) ethyl] -2-[(6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazolium-6- Il) thio] -1-methylcarbapene-2-em-3-carboxylate, (1R, 5S, 6S) -2-[(6,7-dihydro-5H-
Pyrazolo [1,2-a] [1,2,4] triazolium-6-
Il) thio] -6-[(R) -1- (4-hydroxypentoxycarbonyloxy) ethyl] -1-methylcarbapene
-2-M-3-carboxylate, (1R, 5S, 6S)-
2-[(6,7-dihydro-5H-pyrazolo [1,2-a]
[1,2,4] Triazolium-6-yl) thio] -1-methyl-6-[(R) -1- (1-phenylpropoxycarbonyloxy) ethyl] -carbapene-2-em-3-carboxy Rate, (1R, 5S, 6S) -6-[(R) -1-benzoyloxyethyl] -2-[(6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4 ] Triazolium-6-yl) thio] -1-methylcarbapene-2-em-3-carboxylate, (1R, 5S, 6S) -2-[(6,7-dihydro
-5H-Pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio] -6-[(R) -1-methylcarbonyloxyethyl] -1-methylcarbapene-2- Em-3-carboxylate, (1R, 5S, 6S) -6-[(R) -1-cumenylcarbonyloxyethyl] -2-[(6,7-dihydro-5H-pyrazolo [1,2-a ] [1,2,4] Triazolium-6-yl) thio] -1-methylcarbapene-2-em-
3-carboxylate, (1R, 5S, 6S) -6-
[(R) -1- (5-Bromo-naphth-2-ylcarbonyloxy) ethyl] -2-[(6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] Triazolium-6-yl) thio] -1-methylcarbapene-2-em-3-carboxylate, (1R, 5S, 6S) -2-[(6,7-dihydro-5H-
Pyrazolo [1,2-a] [1,2,4] triazolium-6-
Yl) thio] -6-[(R) -1- (1-hydroxy-m-tolu-5-ylcarbonyloxy) ethyl] -1-methylcarbapene-2-em-3-carboxylate, (1R, 5S, 6
S) -6-[(R) -1- (4-Biphenylenylcarbonyloxy) ethyl] -2-[(6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4 ] Triazolium-6-yl)
Thio] -1-methylcarbapene-2-em-3-carboxylate, (1R, 5S, 6S) -6-[(R) -1-carbamoyloxyethyl] -2-[(6,7-dihydro- 5H-pyrazolo [1,2-a] [1,2,4] triazolium-6-yl)
Thio] -1-methylcarbene-2-em-3-carboxylate, (1R, 5S, 6S) -6-[(R) -1-diethylcarbamoyloxyethyl] -2-[(6,7-dihydro- 5H-
Pyrazolo [1,2-a] [1,2,4] triazolium-6-
Iyl) thio] -1-methylcarbapene-2-em-3-carboxylate, (1R, 5S, 6S) -6-[(R) -1- (1
-Carboxyethylcarbamoyloxy) ethyl] -2-
[(6,7-Dihydro-5H-pyrazolo [1,2-a] [1,
2,4] Triazolium-6-yl) thio] -1-methylcarbapene-2-em-3-carboxylate, (1R, 5S,
6S) -6-[(R) -1-azetidinocarbonylethyloxy] -2-[(6,7-dihydro-5H-pyrazolo [1,2-
a] [1,2,4] triazolium-6-yl) thio] -1-
Methylcarbapene-2-em-3-carboxylate, (1
R, 5S, 6S) -2-[(6,7-Dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio] -1-methyl-6- [ (R) -1-Pyrrolidinocarbonyloxyethyl] -carbapene-2-em-3-carboxylate, (1R, 5S, 6S) -2-[(6,7-dihydro-5
H-pyrazolo [1,2-a] [1,2,4] triazolium-
6-yl) thio] -1-methyl-6-[(R) -1-piperidinocarbonyloxyethyl] -carbapene-2-em-3-
Carboxylate, (1R, 5S, 6S) -2-[(6,7-
Dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio] -6-[(R) -1-morpholinocarbonyloxyethyl] -1-methyl-carbapene-2
-M-3-carboxylate, (1R, 5S, 6S) -2-
[(6,7-Dihydro-5H-pyrazolo [1,2-a] [1,
2,4] Triazolium-6-yl) thio] -1-methyl-6
-[(R) -1-thiomorpholinocarbonyloxyethyl] -carbapene-2-em-3-carboxylate, (1
R, 5S, 6S) -2-[(6,7-Dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio] -1-methyl-6- [ (R) -1-Piperazinylcarbonyloxyethyl] -carbapene-2-em-3-carboxylate, (1R, 5S, 6S) -2-[(6,7-dihydro-
5H-pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio] -1-methyl-6-[(R) -1-pyrrolininocarbonyloxyethyl] -carbapene-2- M-3
-Carboxylate, (1R, 5S, 6S) -2-[(6,7
-Dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio] -1-methyl-6-[(R)
-1-Pyrrolinocarbonyloxyethyl] -carbapene-2
-M-3-carboxylate, (1R, 5S, 6S) -2-
[(6,7-Dihydro-5H-pyrazolo [1,2-a] [1,
2,4] Triazolium-6-yl) thio] -6-[(R)-
1-imidazolidininocarbonyloxyethyl] -1-methylcarbapene-2-em-3-carboxylate, (1
R, 5S, 6S) -2-[(6,7-Dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio] -6-[(R)- 1-Imidazolininocarbonyloxyethyl] -1-methylcarbapene-2-em-3-carboxylate, (1R, 5S, 6S) -2-[(6,7-dihydro-
5H-pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio] -6-[(R) -1-imidazolinocarbonyloxyethyl] -1-methylcarbapene-2- M-
3-carboxylate, (1R, 5S, 6S) -2-[(6,
7-dihydro-5H-pyrazolo [1,2-a] [1,2,4]
Triazolium-6-yl) thio] -1-methyl-6-
[(R) -1-oxetanyloxyethyl] -carbapene-2
-M-3-carboxylate, (1R, 5S, 6S) -6-
[(R) -1-azetidinyloxyethyl] -2-[(6,7-
Dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio] -1-methylcarbapene-2-
M-3-carboxylate, (1R, 5S, 6S) -2-
[(6,7-Dihydro-5H-pyrazolo [1,2-a] [1,
2,4] Triazolium-6-yl) thio] -1-methyl-6
-[(R) -1-Tetrahydrofuryloxyethyl] -carbapene-2-em-3-carboxylate, (1R, 5S, 6
S) -2-[(6,7-dihydro-5H-pyrazolo [1,2-
a] [1,2,4] triazolium-6-yl) thio] -1-
Methyl-6-[(R) -1- (N-methylpyrrolidinyloxy) ethyl] -carbapene-2-em-3-carboxylate, (1R, 5S, 6S) -2-[(6,7-dihydro -5H-
Pyrazolo [1,2-a] [1,2,4] triazolium-6-
Il) thio] -1-methyl-6-[(R) -1-tetrahydrothienyloxyethyl] -carbapene-2-em-3-carboxylate, (1R, 5S, 6S) -2-[(6, 7-Dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio] -1-methyl-6-[(R) -1-tetrahydropyranyloxyethyl]- Carbapen-2-em-3-carboxylate, (1R, 5S, 6S) -2-
[(6,7-Dihydro-5H-pyrazolo [1,2-a] [1,
2,4] Triazolium-6-yl) thio] -1-methyl-6
-[(R) -1-Piperidyloxyethyl] -carbapene-2-
M-3-carboxylate, (1R, 5S, 6S) -2-
[(6,7-Dihydro-5H-pyrazolo [1,2-a] [1,
2,4] Triazolium-6-yl) thio] -6-[(R)-
1-dioxan-2-yl-oxyethyl] -1-methylcarbapene-2-em-3-carboxylate, (1R, 5S, 6
S) -2-[(6,7-dihydro-5H-pyrazolo [1,2-
a] [1,2,4] triazolium-6-yl) thio] -6-
[(R) -1-Imidazolidinixethyl] -1-methylcarbapene-2-em-3-carboxylate, (1R, 5S,
6S) -2-[(6,7-dihydro-5H-pyrazolo [1,2-
a] [1,2,4] triazolium-6-yl) thio] -6-
[(R) -1- (oxathiolan-3-yloxy) ethyl] -1-methylcarbapene-2-em-3-carboxylate and the like.

The compound of formula (I) can be produced, for example, by method A or method B described below.

Method A : The compound of formula (I) has the following formula (I
I)

[0023]

[Chemical 5]

In the formula, R ⁵ represents a carboxyl-protecting group, R ⁶ represents an amino-protecting group, and A is as defined above. From the compound represented by the formula, a carboxyl-protecting group (R ⁵ ) and an amino-protecting group ( After removing R ⁶ ), the following formula (III)

[0025]

Embedded image NH = CHOR (III) In the formula, R represents an alkyl group which may be unsubstituted or substituted with a phenyl group, and can be produced by reacting with a formimidic acid ester represented by it can.

In the above formula (II), the "carboxyl protecting group" represented by R ⁵ may be any protecting group known per se as a protecting group for a carboxyl group in the field of peptide chemistry, for example, ester residue. A group can be exemplified. Such ester residues include methyl, ethyl, n-propyl, isopropyl, n-, i
Lower alkyl ester residues such as so-, sec-, tert-butyl, n-hexyl ester; araalkyl ester residues such as benzyl, p-nitrobenzyl, o-nitrobenzyl, p-methoxybenzyl; acetoxymethyl, propionyl Examples thereof include lower aliphatic acyloxymethyl residues such as oxymethyl, n-, iso-, butyryloxymethyl, pivaloyloxymethyl, etc., preferably an aralkyl ethithel residue, more preferably a p-nitrobenzyl group. is there.

The "amino protecting group" represented by R ⁶ can also be any protecting group known per se as a protecting group for an amino group in the field of peptide chemistry, for example an aromatic acyl group such as: , Phthaloyl;
Benzoyl or benzoyl substituted with halogen, nitro or lower alkyl such as chlorobenzoyl, p-nitrobenzoyl, p-tert-butylbenzoyl, toluoyl; naphthoyl; phenylacetyl; phenoxyacetyl; benzenesulfonyl, p-tert. -Aryl or halogenated aliphatic carboxylic acid acyl groups such as lower alkyl-substituted benzenesulfonyl such as butylbenzenesulphonyl and toluenesulphonyl: for example, camphorsulfonyl, methanesulfonyl, formyl, acetyl, valeryl, caprylyl, n -Esterified carboxy groups such as decanoyl, acryloyl, pivaloyl, halogenoacetyl (eg monochloroacetyl, monobromoacetyl, dichloroacetyl, trichloroacetyl): eg ethoxycarl Nyl, tert-butyloxycarbonyl, allyloxycarbonyl, isobornyloxycarbonyl, phenyloxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc., carbamoyl or thiocarbamoyl group: for example, methylcarbamoyl, Examples thereof include phenylcarbamoyl, naphthylcarbamoyl and the like, or thiocarbamoyl groups corresponding to these, and the like, preferably an esterified carboxy group,
More preferably, it is a p-nitrobenzyloxycarbonyl group.

The deprotecting group reaction of the compound of formula (II) can be carried out according to the leaving reaction of carboxyl protecting group and amino protecting group known per se in the art, for example,
In a suitable solvent, for example 0.1M phosphate buffer at pH 7, pH
H6.1 0.35M phosphate buffer, tetrahydrofuran containing sodium hydrogen carbonate, etc., dichloromethane, dioxane, dimethylformamide, dimethylsulfoxide, acetonitrile, hexamethylphosphoramide, tetrahydrofuran-water, tetrahydrofuran-ethanol-
Hydrogenation of platinum oxide, palladium-activated carbon, palladium hydroxide-activated carbon, etc. using hydrogen at about 1 to about 4 atm in a solvent such as water, dioxane-water, dioxane-ethanol-water, n-butanol-water. About 0 to about 50 ° C. in the presence of a catalyst
Can be carried out by treating at a temperature within the range of about 0.25 to about 5 hours.

The elimination reaction of the protecting group can also be carried out by treating with zinc in a buffer solution. For example, the compound of formula (II) is treated with zinc in a buffer of pH 5-7, such as phosphate buffer, acetate buffer, citrate buffer, morpholinopropane sulfonate buffer, N-methylmorphophosphate buffer. It can be done by processing. Examples of zinc that can be used include zinc powder, white zinc, and granular zinc. The amount used is not particularly limited, but generally 1 to 1 part by weight of the compound of the formula (II).
It can be in the range of 10 parts by weight. In this elimination reaction, if necessary, an organic solvent may be used in combination. Examples of such a solvent include alcohol solvents such as ethanol, propanol and n-butanol; ether solvents such as diethyl ethanol and tetrahydrofuran. Solvents: acetonitrile, dimethylformamide, dimethylacetamide and the like can be mentioned. The reaction is usually about -20
To about 50 ° C., preferably room temperature to about 30 ° C.
It can be completed by treating for about 1 to 5 hours.

The following formula (IV) formed by removing the protecting groups R ₅ and R ₆ in this way

[0031]

[Chemical 7]

In the formula, A is as defined above, and the compound of formula (I) is cyclized to form the compound of formula (I) by reacting with the formimidic acid ester of formula (III) or a salt thereof. You can

The reaction of the compound of the above formula (IV) with the formimidic acid ester of the formula (III) or a salt thereof is usually carried out by reacting the compound of the formula (IV) in an aqueous medium, for example, the above-mentioned deprotecting group reaction. The aqueous layer containing the compound of formula (IV), which is subsequently separated off, is made weakly basic with an alkali, such as potassium hydrogen carbonate, if necessary, and a formimidate ester of formula (III), such as ethyl formimidate hydrochloride, or Add benzyl formimidate hydrochloride and add about -1
It can be carried out by reacting at a temperature of 0 ° C. to room temperature.

The compound of formula (I) thus obtained is separated from the reaction mixture by a method known per se, for example, by means of crystallization, chromatography, filtration, washing and the like.
It can be purified.

The compound of formula (II) used as a starting material in the above-mentioned method is a novel compound which has not been described in the conventional literature, and will be described below according to the type of the substituent A (1). It can be produced by any of the methods (3) to (3).

(1) When A represents R ¹ CO, the compound of formula (II) can be produced, for example, by the reaction shown in the following reaction formula 1.

Reaction formula 1

[0038]

[Chemical 8]

In the formula, X represents a halogen atom, R ¹ ,
R ⁵ and R ⁶ are as defined above.

The reaction of the compound of the formula (V) with the acid halide of the formula (VI) is carried out, for example, by adding the compound of the formula (V) to tetrahydrofuran, methylene chloride, dioxane,
In an appropriate solvent such as dimethylformamide, dimethylsulfoxide, acetonitrile, hexamethylphosphoramide, the acid halide of the formula (VI) is used in an amount of about 0.5 to about 5 times, preferably about 1 to about 4 times. And preferably in the presence of a base such as sodium hydrogen carbonate, potassium carbonate, dimethylaminopyridine, propylene oxide, diisopropylethylamine, pyridine and triethylamine at a temperature in the range of ice cooling to reflux for about 30 minutes to about 2 days. This can be done by

The reaction is preferably carried out under a stream of an inert gas such as nitrogen gas or argon gas.

The compound of the formula (II-1) obtained by this reaction can be isolated and purified by a usual construction means if necessary, but it is the above method A or the following method (2). May be used as the starting material in.

The compound of formula (V) used as a starting material in the above reaction scheme 1 is known per se, and can be produced, for example, by the method described in JP-A-1-25779.

[0044] It can be produced by the reaction shown in Reaction formula 2.

Reaction formula 2

[0046]

[Chemical 9]

In the formula, R ⁷ represents an alkoxy group which may be substituted with a group selected from halogen, hydroxyl and phenyl, and R ² , R ³ , R ⁵ and R ⁶ are as defined above.

A compound of formula (II-1-a) and a compound of formula (VI
The reaction with the amine represented by the formula (I) can be carried out, for example, by the formula (II-1)
-A) compound in a solvent as exemplified in the above reaction (1), preferably in a solvent such as methylene chloride, about 0.
In the presence of about 5 to about 5 times, preferably about 1 to about 4 times the molar amount of the amine of formula (VII), and preferably in the presence of a base as described in the above reaction (1), about 0 ° C to about 50 ° C. It can be carried out by reacting at a temperature in the range of ° C for about 30 minutes to about 2 days.

By this reaction, the compound of formula (II-2) is obtained, and the reaction liquid can be used as it is as a starting material in the above-mentioned method (A). To the formula (I
The compound of I-2) can also be isolated and purified.

[0050] Compounds of formula (II) when representing a cyclic group are, for example:
It can be produced by the reaction shown in the following reaction formula 3.

Reaction formula 3

[0052]

[Chemical 10]

In the formula, a and b are single bonds or Is a hetero atom), R ⁵ and R ⁶ are as defined above.

The reaction of the compound of formula (V) with the heterocycloalkene of formula (VIII) is carried out by reacting the compound of formula (V) in about a solvent such as described in the above reaction formula (1). 0.5 to about 5 times, preferably about 1 to about 4 times the molar amount of the heterocycloalkene of formula (VIII) and a temperature in the range of about 0 ° C to about 50 ° C in the presence of an acid catalyst. The reaction can be performed for about 30 minutes to about 2 days. Specific examples of the acid catalyst that can be used here include inorganic acids such as hydrochloric acid, nitric acid, and sulfuric acid; organic acids such as acetic acid, propionic acid, benzoic acid, toluenesulfonic acid, and methanesulfonic acid; p-toluenesulfonic acid. Examples thereof include organic acid salts such as pyridine salts.

The compound of the formula (II-3) thus obtained can be used as it is as a starting material for the above-mentioned Method A, but it may be isolated and purified by a conventional purification means in some cases. Good.

Method B : The compound of formula (I) can also be produced by the route shown in Reaction Scheme 4 below.

Reaction formula 4

[0058]

[Chemical 11]

In the formula, R ^a represents an acyl group, X ⁻ represents a counter ion, and A and R ⁵ are as defined above.

In the above reaction formula 4, the "acyl group" represented by R ^a is not only the rest of the atomic groups obtained by removing OH from the carboxyl group of an organic carboxylic acid, but also, in a broad sense, an organic sulfonic acid or an organic phosphoric acid. And acyl groups derived from, for example, lower alkanoyl groups such as acetyl, propionyl, butyryl; (halo) lower alkylsulfonyl groups such as methanesulfonyl, trifluoromethanesulfonyl group; benzenesulfonyl, p-nitrobenzenesulfonyl, p- A substituted or unsubstituted arylsulfonyl group such as bromobenzenesulfonyl, toluenesulfonyl, 2,4,6-triisopropylbenzenesulfonyl and the like; a diphenylphosphoryl group and the like can be mentioned.

[0061] In addition, X ^- "counterion" represented by is an anion corresponding to the cationic quaternary ammonium, specifically, for example, hydroxy anion, methoxy anion, alkoxy anion such as ethoxy anion; chlorosulfonic Examples thereof include halogen anions such as anions, bromo anions, iodo anions, and fluorine anions; or “acid anions” described below. The "acid anion" means, in a broad sense, an atomic group remaining after removing a hydrogen atom from a proton donating molecule, and typical examples thereof include organic acid residues such as acetic acid, propionic acid, butyric acid,
Substituted or unsubstituted lower fatty acids such as trifluoroacetic acid, trichloroacetic acid, 4-cyclohexylbutyric acid; benzoic acid,
a substituted or unsubstituted benzoic acid such as p-nitrobenzoic acid;
(Halo) lower alkyl sulfonic acids such as methanesulfonic acid and trifluoromethanesulfonic acid; benzenesulfonic acid, p-nitrobenzenesulfonic acid, p-bromobenzenesulfonic acid, toluenesulfonic acid, 2,4,6-triisopropylbenzenesulfonic acid A substituted or unsubstituted aryl sulfonic acid such as; a residual atomic group obtained by removing a hydrogen atom from an organic phosphoric acid such as diphenyl phosphoric acid: an inorganic acid residue such as nitrous acid, nitric acid, sulfuric acid or perchloric acid, and hydrofluoric acid Examples of the remaining atomic groups obtained by removing a hydrogen atom from a hydrohalic acid such as

In the above reaction formula 4, first, the formula (IX)
The compound of formula (X) is modified by modifying the hydroxyl group of the 6-position side chain (1-hydroxyethyl group) of the compound (1) as described in the above reaction (1) to (3) in method A.

The compound of the formula (X) thus obtained is then 6,7-of the formula (XI) which is a mercapto reagent.
Dihydro-6-mercapto-5H-pyrazolo [1,2-a]
Reaction with a [1,2,4] triazolium salt yields a compound of formula (XI
This produces a compound of formula I).

The reaction of the compound of the formula (X) with the mercapto reagent of the formula (XI) is carried out, for example, by reacting the compound of the formula (X) with tetrahydrofuran, dichloromethane, dioxane, dimethylformamide, dimethylsulfoxide, acetonitrile, hexamethylphosphoramide. And the like in a suitable solvent such as about equimolar to about 5 times molar amount, preferably about 1.5 to about 3 times molar amount of the mercapto reagent of the formula (XI), and preferably sodium hydrogencarbonate. , Potassium carbonate, triethylamine, diisopropylethylamine and the like, at a temperature in the range of about -40 to about 25 ° C. for about 30 minutes to about 24 hours.

The desired compound of formula (I) can be obtained by subjecting the compound of formula (XII) produced by the above reaction to a deprotecting group reaction as described in Method A above.

The compound of formula (I) thus obtained can be isolated and purified by a purification method known per se, for example, crystallization, chromatography, filtration, washing and the like.

The compound of the formula (IX) and the mercapto reagent of the formula (XI) used as starting materials in the above Reaction Scheme 4 are known per se, and are described in JP-A Nos.
It can be produced by the methods described in JP-A-88578 and JP-A-4-230290. Further, the compound of formula (I) obtainable by the above method A or method B can exist in the form of a pharmacologically acceptable salt, and the salt is a compound of the formula (I). It can be obtained by treating with an acid or an inorganic acid to dissociate the inner salt and form a quaternary ammonium salt with the substituent at the 2-position of the carbapenem skeleton and an arbitrary acid residue. Examples of such an acid residue include the acid anion included in the above "counterion".

The carbapenem compound of the formula (I) provided by the present invention is modified by modifying the hydroxyl group of the 1-hydroxyethyl group bonded to the 6-position of the carbapenem skeleton of the compound of the formula (2) with various substituents. And a unique quaternary ammonium functional group at the 2-position side chain and a carboxylate at the 3-position form an intramolecular quaternary ammonium salt. Due to its structural characteristics such as the fact that it is extremely stable against attack by renal dehydropeptidase (DHP) and has high chemical and physical stability, it also has advantages in administration method and antibacterial spectrum, etc. Is a new compound expected.

[0069]

EXAMPLES Next, the production of the carbapenem compound of the present invention will be described in more detail by way of examples.

The symbols in the following description have the following meanings.

PNB: p-nitrobenzyl group PNZ: p-nitrobenzyloxycarbonyl group Ac: acetyl group DMAP: dimethylaminopyridine THF: tetrahydrofuran Ph: phenyl group Pd-C: palladium-activated carbon IPA: isopropanol Also, SP-207 Resin and HP-40 resin are SEPABEADS S manufactured by Mitsubishi Kasei Co., Ltd., respectively.
P207 and SEPABEADS HP40 are shown.

Example 1 P-nitrobenzyl (1R, 5S, 6S) -6-[(R) -1
-Acetyloxyethyl] -2- [N, N'-di (P-nitrobenzyloxycarbonyl) pyrazolidin-4-yl-thio] -1-methyl-carbapene-2-em-3-carboxylate

[0073]

[Chemical 12]

Compound (1) 10.0 g (12.4 mmo)
l) and DMAP 227 mg (1.86 mmol) were dissolved in anhydrous methylene chloride 150 ml, and diisopropylethylamine 3.24 ml (1
8.6mmol, 1.5eq), acetyl chloride 1.33m
1 (18.7 mmol, 1.5 eq) was added dropwise. After gradually returning to room temperature and stirring for 100 minutes, acetyl chloride 441 μl (6.2 mmol, 0.5 eq) diisopropylethylamine (1.08 ml) was added, and the mixture was reacted overnight. Ethyl acetate was added, 10% citric acid aqueous solution, saturated N
The solution was washed successively with an aHCO ₃ aqueous solution and saturated saline, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue is purified by silica gel column chromatography (SiO ₂ 34
It was then subjected to 0 g ethyl acetate: hexane = 2: 1) to obtain 9.74 g (11.5 mmol) of a pale yellow foamy solid (2). Yield 92.5% ¹ H-NMR (CDCl ₃ ): δ = 1.15-1.3 (m, 3
H), 1.42 (d, J = 6.3 Hz, 3H), 2.08
(S, 3H), 3.11 to 3.77 (m, 2H), 3.4
1 (m, 1H), 3.97 to 4.02 (m, 4H), 5.
15-5.55 (m, 8H), 7.4-7.6 (m, 4
H), 7.6 to 7.7 (m, 2H), 8.09 to 8.31
(M, 6H).

Example 2 (1R, 5S, 6S) -6-[(R) -1-Acetyloxyethyl] -2-[(6,7-dihydro-5H-pyrazolo [1,2-
a] [1,2,4] triazolium-6-yl) thio] -1-
Preparation of methylcarbapene-2-em-3-carboxylate

[0076]

[Chemical 13]

Compound (2) 9.0 g (10.6 mmol)
Was dissolved in 216 ml of THF, and 0.1M phosphate buffer (p
H7.0) 216 ml, 10% Pd-C (containing 50% water)
Add 4.14 g and NaHCO ₃ 1.77 g and add hydrogen gas 4
Catalytic reduction was performed at atmospheric pressure for 90 minutes at room temperature. Pd-C was filtered off and washed with 216 ml of ethyl acetate to separate the aqueous layer,
The pH was adjusted to 6.8 with 4N hydrochloric acid. The temperature of the solution is 5 ℃ ~ 1
While maintaining the temperature at 0 ° C., 3.70 g of KHCO _{3 and} 8.10 g (73.9 mmol) of ethylformimidate hydrochloride were added and vigorously stirred for 10 minutes to adjust the pH to 5.5. The reaction solution was concentrated under reduced pressure, desalted with 210 ml of SP-207 resin,
Purification (eluent: ion-exchanged water containing 7% IPA)
Freeze-dried pale yellow powder of compound (3) 1.74 g (4.
44 mmol) was obtained. Yield 41.9%.

¹ H-NMR (D ₂ O): δ = 1.25 (d,
J = 7.6Hz, 3H), 1.35 (d, J = 6.3H
z, 3H), 2.12 (s, 3H), 3.39 (dq, J
= 9.6, 7.6 Hz, 1H), 3.72 (dd, J = 4.
9, 3.0 Hz, 1H), 4.35 (dd, J = 3.0,
9.6 Hz, 1H), 4.70-5.17 (m, 5H),
5.29 (m, 1H), 9.01 (s, 1H), 9.03
(S, 1H).

Example 3 P-nitrobenzyl (1R, 5S, 6S) -6-[(R) -1
-(3,3-Dimethylacryloyloxy) ethyl] -2-
[N, N'-di (P-nitrobenzyloxycarbonyl)
Pyrazolidin-4-yl-thio] -1-methylcarbapene-2
-Production of M-3-carboxylate

[0080]

[Chemical 14]

4.5 g (5.58 mmol) of the compound (1)
Was dissolved in 50 ml of anhydrous methylene chloride, the reaction vessel was cooled with ice under a nitrogen stream, and then 1.15 ml of propylene oxide,
3,3-Dimethylacryloyl chloride 1.86ml
(16.7 mmol, 3 eq) was added dropwise and stirred for 3 hours. Furthermore, 0.62 ml (5.57 mmol, 1 eq) of 3,3-dimethylacryloyl chloride was added, and the mixture was stirred under ice cooling for 4 hours. Add ethyl acetate to the reaction mixture and
The extract was washed successively with 0% aqueous citric acid solution, saturated aqueous NaHCO ₃ solution and saturated saline solution, dried over magnesium sulfate, evaporated to remove the solvent, and the residue was subjected to silica gel chromatography (SiO ₂ 25
0 g, ethyl acetate: hexane = 3: 2). 3.67 g (4.13 m) of compound (4) as a pale yellow foamy solid.
mol) was obtained. Yield 74.1%.

¹ H-NMR (CDCl ₃ ): δ = 1.2
1.3 (m, 3H), 1.42 (d, J = 6.3Hz, 3
H), 1.91 (s, 3H), 2.17 (s, 3H),
3.14-3.80 (m, 2H), 3.44 (m, 1
H), 3.95 to 4.42 (m, 4H), 5.12 to 5.5
7 (m, 8H), 5.66 (s, 1H), 7.4 to 7.5
5 (m, 4H), 7.55-7.7 (m, 2H), 8.0
5-8.30 (m, 6H).

Example 4 (1R, 5S, 6S) -2-[(6,7-Dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio]- 6-[(R) -1- (3,3-dimethylacryloyloxy) ethyl] -1-methylcarbapene-2-em-
Production of 3-carboxylate

[0084]

[Chemical 15]

3.73 g (4.20 mmo) of compound (4)
l) is dissolved in 85 ml of THF and 85 ml of 0.1M phosphate buffer (pH 7.0), 10% Pd-C (containing 50% water).
1.64 g, NaHCO ₃ 702 mg was added, hydrogen gas 4
Stir vigorously at atmospheric pressure for 25 minutes at room temperature. Pd-C is removed by filtration, adjusted to pH 7 with 4N hydrochloric acid, and washed with 85 ml of ethyl acetate. The aqueous layer is separated and the organic layer is washed 5 times with a small amount of water. These aqueous layers are combined and stirred vigorously,
At 8 ° C. 1.47 g of KHCO ₃ are added, followed by 3.21 g (29.3 mmol) of ethylformimidate hydrochloride. 8
C. (after stirring for 10 minutes, adjusted to pH 5.5, concentrated the reaction solution under reduced pressure, desalted and purified with 150 ml of HP-40 resin. Fraction (eluent: ion-exchanged water containing 10% IPA)) After collected, concentrated under reduced pressure, and freeze-dried to obtain 486 mg (1.13 mmol) of compound (5) as a pale yellow powder, yield 26.9%.

¹ H-NMR (D ₂ O): δ = 1.20 (d,
J = 7.3Hz, 3H), 1.31 (d, J = 6.6H
z, 3H), 1.87 (s, 3H), 1.06 (s, 3
H), 3.33 (dq, J = 9.6, 7.3 Hz, 1
H), 3.70 (dd, J = 4.9, 3.0 Hz, 1
H), 4.30 (dd, J = 3.0, 9.6 Hz, 1
H), 4.62 to 4.74 (m, 2H), 4.85 to 5.1
0 (m, 3H), 5.27 (dq, J = 4.9, 6.6H
z, 1H), 5.72 (s, 1H), 8.95 (s, 1
H), 8.97 (s, 1H).

Example 5 P-Nitrobenzyl (1R, 5S, 6S) -2- [N, N'-
Di (P-nitrobenzyloxy-carbonyl) pyrazolidin-4-yl-thio] -6-[(R) -1-ethyloxycarbonyloxyethyl] -1-methylcarbapene-2-em-
Production of 3-carboxylate

[0088]

[Chemical 16]

Compound (1) 4.0 g (4.76 mmol)
And 182 mg of DMAP were dissolved in 40 ml of anhydrous methylene chloride, and while cooling with ice under a nitrogen stream, 3.02 ml of diisopropylethylamine and 1.65 ml of ethyl chlorocarbonate (1
7.3 mmol, 3.5 eq) was added dropwise. After gradually returning to room temperature and stirring for 2 days, ethyl acetate was added, and the mixture was washed successively with a 10% aqueous citric acid solution, a saturated NaHCO ₃ aqueous solution, and a saturated saline solution. After dehydration with magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel chromatography (SiO ₂ 1
80 g, ethyl acetate: hexane = 3: 2) was added, and 3.27 g (3.72 mmo) of pale yellow foamy solid compound (6).
l) was obtained. Yield 75.1%.

¹ H-NMR (CDCl ₃ ): δ = 1.23-
1.34 (m, 6H), 1.48 (d, J = 6.3Hz,
3H), 3.14 to 3.80 (m, 2H), 3.45
(M, 1H), 3.97 to 4.41 (m, 6H), 5.0
7 to 5.55 (m, 8H), 7.4 to 7.6 (m, 4
H), 7.55 to 7.7 (m, 2H), 8.10 to 8.30
(M, 6H).

Example 6 (1R, 5S, 6S) -2-[(6,7-Dihydro-5H-pyrazolo [1,2-a] [1,2,4] -triazolium-6-yl) thio] -6-[(R) -1-Ethyloxycarbonyloxyethyl] -1-methylcarbapene-2-em-3-carboxylate

[0092]

[Chemical 17]

3.0 g (3.42 mmol) of compound (6)
Was dissolved in 70 ml of THF, and 0.1M phosphate buffer (pH
7.0) 70 ml, 10% Pd-C (50% water content) 1.3
3 g and 571 mg of NaHCO ₃ were added, and the mixture was vigorously stirred at 4 atm of hydrogen gas at room temperature for 90 minutes. Pd-C was removed by filtration, adjusted to pH 7 with 4N hydrochloric acid, and washed with 70 ml of ethyl acetate. Adjust the pH of the collected water layer to 6.8 and adjust to 5-10.
While cooling to 0 ° C, 1.20 g of KHCO ₃ and 2.61 g (19.7 mmol) of ethylformimidate hydrochloride were added, and the mixture was vigorously stirred for 10 minutes. The reaction solution was adjusted to pH 5.5, concentrated under reduced pressure, and desalted and purified using 150 ml of HP-40 resin. (Eluent: ion-exchanged water containing 5% IPA) By freeze-drying, compound (7) 6 of white powder
77 mg (1.60 mmol) was obtained. Yield 47.0%.

¹ H-NMR (D ₂ O): δ = 1.19 (d,
J = 7.3Hz, 3H), 1.21 (t, J = 7.1H
z, 3H), 1.33 (d, J = 6.6Hz, 3H),
3.33 (dq, J = 9.6, 7.3 Hz, 1H) 3.7
0 (dd, J = 3.0, 5.1 Hz, 1H), 4.16
(Q, J = 7.1 Hz, 2H), 4.29 (dd, J =
9.6, 3.0 Hz, 1H), 4.62 to 4.85 (m, 2
H), 4.85 to 5.20 (m, 4H), 8.94 (s,
1H), 8.96 (s, 1H).

Example 7 P-nitrobenzyl (1R, 5S, 6S) -6-[(R) -1
-Benzoyloxyethyl] -2- [N, N'-di (P-nitrobenzyloxycarbonyl) pyrazolidin-4-yl-
Thio] -1-methylcarbapene-2-em-3-carboxylate preparation

[0096]

[Chemical 18]

1.0 g (1.24 mmol) of compound (1)
And 46 mg of DMAP were dissolved in 10 ml of anhydrous methylene chloride, and 325 μl of diisopropylethylamine and 216 μl of benzoyl chloride (1.86 g) while cooling with ice under a nitrogen stream.
(mmol, 1.5 eq) was added dropwise, and the mixture was stirred under ice cooling for 1 hour and at room temperature for 1 hour. Furthermore, 325 μl of diisopropylethylamine and 216 μl of benzoyl chloride (1.86 m
mol, 1.5 eq) was added, the mixture was stirred at room temperature for 16 hours, and then heated under reflux for 5 hours. 40 ml of ethyl acetate was added, 10% aqueous citric acid solution (15 ml), saturated NaHC
The mixture is washed successively with an O ₃ aqueous solution (15 ml, 10 ml) and saturated brine, dried over magnesium sulfate, and then the solvent is evaporated under reduced pressure. The obtained residue is subjected to silica gel chromatography (SiO 2
₂ 43 g, chloroform: acetone = 95: subjected to 5), a pale yellow compound foamy solid (8) 968 mg (1.0
5 mmol) was obtained. Yield 85.6%.

¹ H-NMR (CDCl ₃ ): δ = 1.28
(M, 3H), 1.55 (d, J = 6.6, 3H), 3.
12 to 3.75 (m, 2H), 3.58 (m, 1H),
3.94 to 4.44 (m, 4H), 5.15 to 5.4 (m,
6H), 5.35-5.5 (m, 1H), 5.55 (qu
intet, J = 6.6Hz, 1H), 7.35-7.6
7 (m, 9H), 8.03 (d, J = 7.9Hz, 2
H), 8.10-8.27 (m, 6H).

Example 8 (1R, 5S, 6S) -6-[(R) -1-benzoyloxyethyl] -2-[(6,7) -dihydro-5H-pyrazolo [1,2-a] [ Preparation of 1,2,4] triazolium-6-yl) thio] -1-methylcarbapene-2-em-3-carboxylate

[0100]

[Chemical 19]

921 mg (1.01 mmo) of compound (8)
l) was dissolved in 20.5 ml of THF, and 20.5 ml of 0.1 M phosphate buffer (pH 7.0), 395 mg of 10% Pd-C (containing 50% water) and 169 mg of NaHCO ₃ were added, and hydrogen gas at 4 atm was added to room temperature. The mixture was vigorously stirred under 90 minutes. Pd-C
Was filtered off and washed with 20.5 ml ethyl acetate. The aqueous layer was separated and the organic layer was washed twice with a small amount of water.
The aqueous layers were combined and stirred vigorously to produce KHCO ₃ 35
4 mg, ethylformimidate hydrochloride 774 mg
(7.06 mmol) was added. The mixture was stirred for 10 minutes while maintaining the temperature at 5 to 10 ° C, and adjusted to pH 5.5 with 4N hydrochloric acid. Concentrate under reduced pressure and use 23 ml of HP-40 resin,
It was desalted and purified. (Eluent: 10-15% IPA-containing ion-exchanged water) By freeze-drying, 128 mg (0.28 mmol) of white powder of compound (9) was obtained. Yield 2
7.9%.

¹ H-NMR (D ₂ O): δ = 1.26 (d,
J = 6.9Hz, 3H), 1.49 (d, J = 5.6H
z, 3H), 3.41 (dq, J = 9.2, 6.9 Hz,
1H), 3.89 (dd, J = 5.6, 2.6 Hz, 1
H), 4.51 (dd, J = 9.2, 2.6 Hz, 1
H), 4.7 to 4.9 (m, 2H), 4.9 to 5.2 (m,
3H), 5.55 (quintet, J = 5.6Hz, 1
H), 7.5-7.6 (m, 2H), 7.65-7.75
(M, 1H), 8.0-8.1 (m, 2H), 9.01
(S, 1H), 9.03 (s, 1H).

Example 9 P-Nitrobenzyl (1R, 5S, 6S) -2- [N, N'-
Preparation of di (P-nitrobenzyloxycarbonyl) pyrazolidin-4-yl-thio] -1-methyl-6-[(R) -1-propynyloxyethyl] -carbapene-2-em-3-carboxylate

[0104]

[Chemical 20]

Compound (1) 6.0 g (7.44 mmol)
And 273 mg of DMAP were dissolved in 60 ml of anhydrous methylene chloride, and while cooling with ice under a nitrogen stream, 1.56 ml of diisopropylethylamine and 776 μl of propionyl chloride.
(13.8 mmol, 2 eq) was added dropwise. After returning to room temperature and stirring for 2.5 hours, ethyl acetate was added, and the mixture was washed successively with a 10% aqueous citric acid solution, a saturated NaHCO ₃ aqueous solution, and a saturated saline solution. After dehydration with magnesium sulfate, the solvent was distilled off and the residue was subjected to silica gel chromatography. (SiO ₂ 2
50 g, ethyl acetate: hexane = 2: 1), 5.67 g (6.57 mmo) of compound (10) as a pale yellow foamy solid.
l) was obtained. Yield 88.3%.

¹ H-NMR (CDCl ₃ ) δ = 1.14
(T, J = 7.6 Hz, 3H), 1.20 to 1.36
(M, 3H), 1.41 (d, J = 6.3Hz, 3H),
2.34 (q, J = 7.6Hz, 2H), 3.14 to 3.8
0 (m, 2H), 3.44 (m, 1H), 3.93-4.
46 (m, 4H), 5.10 to 5.60 (m, 8H),
7.36 ~ 7.59 (m, 4H), 7.59 ~ 7.55
(M, 2H), 8.04 to 8.32 (m, 6H).

Example 10 (1R, 5S, 6S) -2-[(6,7-Dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio]- Preparation of 1-methyl-6-[(R) -1-propionyloxyethyl] -carbapene-2-em-3-carboxylate

[0108]

[Chemical 21]

Compound (10) 5.01 g (5.81 mmo)
1) was dissolved in 118 ml of THF, 118 ml of 0.1M phosphate buffer (pH 7.0), 2.27 g of 10% Pd-C (containing 50% water) and 972 mg of NaHCO ₃ were added, and hydrogen gas was added at 4 atm at room temperature. Stir vigorously for 90 minutes. Pd-C was filtered off, adjusted to pH 7 with 4N hydrochloric acid, and washed with 118 ml of ethyl acetate. Adjust the collected water layer to pH 6.8 and 5
While cooling to -10 ° C, 2.03 g of KHCO _{3 and} 4.44 g of ethylformimidate hydrochloride were added and vigorously stirred for 10 minutes. The reaction solution was adjusted to pH 5.5, concentrated under reduced pressure, and desalted and purified using 118 ml of SP-207 resin. (Ion-exchanged water containing 10% IPA as an eluate) 1.23 g of a pale yellow powder compound (11) by freeze-drying
(3.03 mmol) was obtained. Yield 52.1%.

¹ H-NMR (D ₂ O): δ = 1.10 (t,
J = 7.6Hz, 3H), 1.25 (d, J = 7.3H)
z, 3H), 1.35 (d, J = 6.3Hz, 3H),
2.43 (q, J = 7.6 Hz, 2H), 3.39 (d
q, J = 7.3Hz, 9.7Hz, 1H), 3.74
(M, 1H), 4.36 (dd, J = 2.5Hz, 9.7)
Hz, 1H), 4.60 to 4.85 (m, 2H), 4.8
5 to 5.20 (m, 3H), 5.20 to 5.38 (m, 1
H), 9.01 (s, 1H), 9.03 (s, 1H).

Example 11 P-nitrobenzyl (1R, 5S, 6S) -2- [N, N'-
Di (P-nitrobenzyloxycarbonyl) pyrazolidin-4-yl-thio] -1-methyl-6-[(R) -1-tetrahydropyranyloxyethyl] -carbapene-2-em-3
-Production of carboxylates

[0112]

[Chemical formula 22]

806 mg (1.0 mmo) of compound (1)
l) and 126 mg of dihydropyran (1.5 mmol, 1.
5eq) and 25.1 mg of tosylic acid pyridine salt were dissolved in anhydrous methylene chloride (10 ml), and the mixture was stirred at room temperature for 24 hours. The solvent was distilled off, and a silica gel column chromatograph (SiO ₂ 25 g, acetone: methylene chloride = 5: 9) was used.
Then, the compound (12) as a pale yellow powder was obtained as a diastereomer mixture to give 594 mg (66.7 mmol).
Yield 66.7%.

¹ H-NMR (CDCl ₃ ): δ = 1.31
(D, J = 6.3 Hz, 3H), 1.36 (d, J = 6.
6Hz, 3H), 1.5-1.9 (m, 6H), 3.2
4.4 (m, 10H), 4.7 (m, 1H), 5.15 ~
5.35 (m, 6H), 5.3 to 5.6 (m, 1H), 7.
3 to 7.7 (m, 6H), 8.2 (m, 6H).

Example 12 (1R, 5S, 6S) -2-[(6,7-Dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio]- Preparation of 6-[(R) -1-tetrahydropyranyloxyethyl] -carbapene-2-em-3-carboxylate

[0116]

[Chemical formula 23]

590 mg of compound (12) (0.66 mm)
sol) in 14 ml of THF, 14 ml of 0.1 M phosphate buffer (pH 7.0), 265 mg of 10% Pd—C (containing 50% water) and 113 mg of NaHCO ₃ are added, and catalytic reduction is carried out at 3 atm of hydrogen gas for 1 hour. went. Pd-C was removed by filtration, and while maintaining the filtrate at -4 ° C to 5 ° C, 570 mg of ethylformimidate hydrochloride was added and vigorously stirred for 10 minutes to adjust the pH to 6.7. The reaction solution is concentrated under reduced pressure,
Purified with 60 ml HP-40 resin. (Eluent: 2% T
HF-containing ion-exchanged water) lyophilized to give 163 mg (.
38 mmol) was obtained. Yield 57.0%.

¹ H-NMR (D ₂ O): δ = 1.2 to 1.4
(M, 6H), 1.4 to 1.9 (m, 6H), 3.4
(M, 1H), 3.5-3.7 (m, 2H), 3.9
(M, 1H), 4.2-4.4 (m, 2H), 4.7-5.
2 (m, 6H), 9.00 (s, 1H), 9.02 (s,
1H).

Example 13 P-nitrobenzyl (1R, 5S, 6S) -6-[(R) -1
-(1-Chloroethyloxycarbonyl) oxyethyl]
Preparation of 2- [N, N'-di (P-nitrobenzyloxycarbonyl) pyrazolidin-4-yl-thio] -1-methylcarbapene-2-em-3-carboxylate

[0120]

[Chemical formula 24]

3.28 g (4.07 mmo) of compound (1)
l) was dissolved in 80 ml of anhydrous methylene chloride, and pyridine (657 μl), 1-chloroethyl carbonic acid chloride (878 μl) (8.13 mmol, 2e) was cooled with ice under a nitrogen stream.
q) was added dropwise, and the mixture was stirred for 1 hour under ice cooling. To the reaction solution was added 240 ml of ethyl acetate, 10% citric acid aqueous solution, saturated NaHCO ₃ aqueous solution (80 ml), saturated saline solution (50,
It was washed with 30 ml) and dehydrated with magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (150 g of SiO ₂ , ethyl acetate: hexane = 2:
Then, the compound (14) was obtained as a pale yellow foamy solid to obtain 3.7 g (4.05 mmol) of a diastereo mixture. Yield 99.5%.

¹ H-NMR (CDCl ₃ ): δ = 1.27
(M, 3H), 1.53 (d, J = 6.4Hz, 3H),
1.83 (d, J = 5.6Hz, 1.5H), 1.84
(D, J = 5.9 Hz, 1.5 H), 3.15 to 3.77
(M, 3H), 3.95 to 4.44 (m, 4H), 5.1
2 to 5.57 (m, 8H), 6.35 to 6.47 (m, 1
H), 7.48 (m, 4H), 7.64 (m, 2H),
8.10-8.29 (m, 6H).

Example 14 P-nitrobenzyl (1R, 5S, 6S) -6-[(R) -1
-Diethylcarbamoyl-oxyethyl] -2- [N, N'-
Di (P-nitrobenzyloxycarbonyl) pyrazolidin-4-yl-thio] -1-methylcarbapene-2-em-3-
Carboxylate production

[0124]

[Chemical 25]

Compound (14) 549 mg (0.60 mm)
ol) was dissolved in 2.4 ml of DMF, and 124 μl (1.17 mmol) of diethylamine was added dropwise under a nitrogen stream. After stirring for 140 minutes at room temperature, add ethyl acetate,
Water, 10% citric acid aqueous solution, saturated NaHCO ₃ aqueous solution,
It was washed successively with saturated saline. After dehydration with magnesium sulfate, the solvent was distilled off, and the obtained residue was subjected to silica gel column chromatography to give compound (15) 5 as a pale yellow foamy solid.
02 mg (0.55 mmol) was obtained. Yield 92.2%.
¹ H-NMR (CDCl ₃ ): δ = 1.11 (m, 6H),
1.26 (m, 3H), 1.43 (d, J = 6.3Hz,
3H), 3.12 to 3.76 (m, 6H), 3.46 (d
d, J = 2.6, 6.9 Hz, 1H), 4.0-4.2
(M, 2H), 4.2-4.4 (m, 2H), 5.13-
5.54 (m, 8H), 7.3 to 7.5 (m, 4H), 7.
5 to 7.7 (m, 2H), 8.1 to 8.3 (m, 6H).

Example 15 (1R, 5S, 6S) -6-[(R) -1-Diethylcarbamoyloxyethyl] -2-[(6,7-dihydro-5H-pyrazolo [1,2-a] [ Preparation of 1,2,4] triazolium-6-yl) thio] -1-methylcarbapene-2-em-3-carboxylate

[0127]

[Chemical formula 26]

473 mg (0.52 mm) of compound (15)
ol) is dissolved in 16 ml of THF, 16 ml of 0.35M phosphate buffer (pH 6.1) and 3.8 g of zinc powder are added,
Stir vigorously at room temperature for 1 hour. The zinc powder was filtered off, washed with ethyl acetate, and the aqueous layer was separated. With 4N hydrochloric acid
After adjusting the pH to 6.9 and cooling the solution to a temperature of 5 to 10 ° C., 175 mg of KHCO ₃ and 382 mg (3.49 mmol) of ethylformimidate hydrochloride were added and vigorously stirred for 10 minutes. The reaction solution was adjusted to pH 5.4, concentrated under reduced pressure, desalted with 12 ml of HP-40 resin, and purified (eluent: 10% IPA-containing ion-exchanged water). White powder of compound (16) 63.
3 mg was obtained. Yield 26.9%.

¹ H-NMR (D ₂ O): δ = 1.12 (t,
J = 6.9Hz, 6H), 1.26 (d, J = 7.3H
z, 3H), 1.36 (d, J = 6.3Hz, 3H),
3.30 (q, J = 6.9 Hz, 4H), 3.16 to 3.4
5 (m, 1H), 3.77 (m, 1H), 4.40 (d
d, J = 3.0, 9.6 Hz, 1H), 4.67 to 5.21
(M, 6H), 9.01 (s, 1H), 9.02 (s, 1
H).

Example 16 P-Nitrobenzyl (1R, 5S, 6S) -6-[(R) -1
-Carbamoyloxyethyl] -2- [N, N'-di (P-nitrobenzyloxycarbonyl] pyrazolidin-4-yl
-Thio] -1-methylcarbapene-2-em-3-carboxylate preparation

[0131]

[Chemical 27]

Ammonia was saturated in anhydrous DMF, and 2.32 g (2.5 mmol) of the compound (14) was added to 15 ml thereof.
Was added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction solution, water, 10% citric acid aqueous solution, saturated NaHCO ₃
It was washed with an aqueous solution and saturated saline. After dehydration with magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is subjected to silica gel column chromatography. (SiO ₂ 100 g, chloroform: acetone = 3: 1) Compound (17) 6 as a pale yellow foamy solid
Obtained 63 mg (0.78 mmol). Yield 30.7%.

¹ H-NMR (CDCl ₃ ): δ = 1.26
(M, 3H), 1.42 (d, J = 6.3Hz, 3H),
3.14-3.80 (m, 2H), 3.44 (m, 1
H), 3.9 to 4.2 (m, 2H), 4.2 to 4.4 (m,
2H), 4.79 (s, 2H), 5.10 to 5.56
(M, 8H), 7.4 to 7.6 (m, 4H), 7.6 to 7.
7 (m, 2H), 8.08 to 8.30 (m, 6H).

Example 17 (1R, 5S, 6S) -6-[(R) -1-carbamoyloxyethyl] -2-[(6,7-dihydro-5H-pyrazolo [1,2-a] [1 , 2,4] Triazolium-6-yl) thio] -1-methylcarbapene-2-em-3-carboxylate

[0135]

[Chemical 28]

Compound (17) 642.6 mg (0.76 m)
mol) in THF 15 ml, 0.1 M phosphate buffer (pH 7.0) 15 ml, NaHCO ₃ 126 mg,
296 mg of 10% Pd-C (containing 50% water) was added, and the mixture was vigorously stirred at 4 atm of hydrogen gas at room temperature for 1 hour. Pd-C
Was removed by filtration, washed with 15 ml of ethyl acetate, the aqueous layer was ice-cooled to 5 to 10 ° C, and the mixture was vigorously stirred to KH.
CO ₃ 264 mg, ethylformimidate hydrochloride 57
8 mg (5.2 mmol) was added, and after stirring for 10 minutes, the pH was 5.
Adjusted to 5. The reaction solution was concentrated under reduced pressure, and HP-40 resin 1
Desalination and purification (eluent: ion-exchanged water) were performed using 5 ml. Compound (18) 4 was obtained as a white powder by freeze-drying.
Obtained 5.8 mg (0.11 mmol). Yield 15.3
%.

¹ H-NMR (D ₂ O): δ = 1.26 (d,
J = 7.3Hz, 3H), 1.35 (d, J = 6.3H)
z, 3H), 3.40 (m, 1H), 3.73 (m, 1)
H), 4.35 (m, 1H), 4.65 to 4.90 (m,
2H), 4.90 to 5.18 (m, 4H), 9.01
(S, 1H), 9.03 (s, 1H).

Example 18 P-Nitrobenzyl (1R, 5S, 6S) -2- [N, N'-
Di (P-nitrobenzyloxycarbonyl) pyrazolidin-4-yl-thio] -6-[(R) -1-((1S) -1-P-
Preparation of nitrobenzyloxycarbonylethyl) carbamoyloxyethyl] -1-methylcarbapene-2-em-3-carboxylate

[0139]

[Chemical 29]

Paranitrobenzyl oxyalanine tosylate 434.0 mg (1.10 mmol, 1 eq) and triethylamine 152.6 μl were added to anhydrous DMF 4.5 ml, and the mixture was stirred under a nitrogen stream while cooling with ice to give compound (14).
1.0 g (1.10 mmol) was added. After stirring for 40 minutes with ice-cooling and 2 hours at room temperature, 434 mg (1.10 mmol) of para-nitrobenzyloxyalanine tosylate was added to 4%.
What was treated with aqueous NaHCO ₃ solution was added. After stirring for 1 hour, 100 μl of triethylamine was further added, and the mixture was reacted overnight. Ethyl acetate was added to the reaction solution, which was washed with 10% citric acid aqueous solution, 4% NaHCO ₃ aqueous solution, and saturated saline, and then subjected to silica gel column chromatography (SiO ₂ 50 g Ac
Purification by OEt: Hexane = 3: 1) was performed.
747 mg (0.71 mmo) of light yellow foamy solid compound
l) was obtained. Yield 64.5%.

¹ H-NMR (CDCl ₃ ): δ = 1.25
(D, J = 6.9 Hz, 3H), 1.43 (d, J = 6.
6Hz, 3H), 1.47 (d, J = 7.3Hz, 3
H), 3.10 to 3.75 (m, 3H), 3.95 to 4.5
0 (m, 5H), 5.12 to 5.56 (m, 10H),
7.38 to 7.56 (m, 6H), 7.64 (m, 2
H), 8.10-8.26 (m, 8H).

Example 19 (1R, 5S, 6S) -6-[(R) -1-((1S) -Carboxyethylcarbamoyloxy) ethyl] -2-
[(6,7-Dihydro-5H-pyrazolo [1,2-a] [1,
Preparation of 2,4] triazolium-6-yl) thio] -1-methylcarbapene-2-em-3-carboxylate

[0143]

[Chemical 30]

709 mg (0.61 mm) of compound (19)
is dissolved in 14 ml of THF, 14 ml of 0.1M phosphate buffer (pH 7.0), 112 mg of NaHCO ₃ and 1
262 mg of 0% Pd-C (containing 50% water) was added, and the mixture was vigorously stirred at 4 atm of hydrogen gas at room temperature for 90 minutes. After removing Pd-C by filtration and adjusting the pH to 7.0, the aqueous layer washed with 23 ml of ethyl acetate was separated and cooled to 5 to 10 ° C., then 234 mg of KHCO ₃ and form 513 mg (4.68 mmol) of imidate hydrochloride was added, and the mixture was vigorously stirred for 10 minutes, and the pH was adjusted to 5.5. The reaction solution was concentrated and purified with 18 ml of SP-207 resin. Lyophilized to give 169 mg of compound (20) as a pale yellow powder.
(0.37 mmol) was obtained. Yield 54.2%.

¹ H-NMR (D ₂ O): δ = 1.25 (d,
J = 6.9Hz, 3H), 1.32 (d, J = 6.9H
z, 3H), 1.0 to 1.42 (m, 3H), 3.3 to 3.
5 (m, 1H), 3.72 (m, 1H), 3.97 (m,
1H), 4.21 to 4.44 (m, 1H), 4.60 to 4.
9 (m, 2H), 4.9 to 5.2 (m, 4H), 9.02
(S, 2H).

─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] July 9, 1993

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0001

[Correction method] Change

[Correction content]

[0001]

FIELD OF THE INVENTION The present invention relates to a carbapenem antibiotic, more specifically, β- at the carbapenem skeleton 1-position.
Having a methyl group of configuration and a (6,7-dihydro-5H-pyrazolo [1,2- a ] [1,2,4] triazolium-6-yl)] thio group at the 2-position, Furthermore, it relates to a carbapenem compound having a 1-substituted hydroxyethyl group at the 6-position.

[Procedure Amendment 2]

[Document name to be amended] Statement

[Name of item to be corrected] 0005

[Correction method] Change

[Correction content]

Recently, as a novel antibacterial agent which overcomes the problems such as lack of chemical stability and inactivation by renal dehydropeptidase (DH P ) which the conventional carbapenem antibiotics have, the following formula (2)

[Procedure 3]

[Document name to be amended] Statement

[Correction target item name] 0007

[Correction method] Change

[Correction content]

The compound represented by the formula (1) was created by the present inventors and is disclosed in JP-A-1-25779. The compound of formula (2) is not only does not require a combination with DH P inhibitor is an excellent antimicrobial agent having potent antimicrobial spectrum extensive, it is currently undergoing clinical trials.

[Procedure amendment 4]

[Document name to be amended] Statement

[Correction target item name] 0017

[Correction method] Change

[Correction content]

Further, in the above formula (I), R ² and R ³
The "nitrogen-containing heterocyclic group" which is formed together with the nitrogen atom to which they are bonded is a 3 to 8 membered member which may further contain a hetero atom selected from O, S and N, preferably encompasses 4-6-membered heterocycle, can azetidino, pyrrolidino, piperidino, Moruho Li Roh, thiomorpholino, piperazinyl, Pirorinino, pyrrolino, Imidazorijinino, Imidazorinino, be exemplified a imidazolino group.

[Procedure Amendment 5]

[Document name to be amended] Statement

[Correction target item name] 0020

[Correction method] Change

[Correction content]

(1R, 5S, 6S) -6-[(R) -1
-Acetyloxyethyl] -2-[(6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio] -1-methylcarbapene-
2-M-3-carboxylate, (1R, 5S, 6
S) -2-[(6,7-Dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio] -1-methyl-6-[(R)- 1-propionyloxyethyl] -carbapene-2-em-3-carboxylate, (1R, 5S, 6S) -2-[(6,7
-Dihydro-5H-pyrazolo [1,2-a] [1,2,
4] Triazolium-6-yl) thio] -1-methyl-
6-[(R) -1-trifluoroacetyloxyethyl] -carbapene-2-em-3-carboxylate,
(1R, 5S, 6S) -6-[(R) -1- (4-Bromo-3-methylbutyryloxy) ethyl] -2-
[(6,7-Dihydro-5H-pyrazolo [1,2-a]
[1,2,4] Triazolium-6-yl) thio] -1
-Methylcarbapene-2-em-3-carboxylate, (1R, 5S, 6S) -2-[(6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazolium -6-yl) thio] -6-[(R) -1-
(3,3-dimethyl-2-hydroxybutyryloxy)
Ethyl] -1-methylcarbapene-2-em-3-carboxylate, (1R, 5S, 6S) -2-[(6,7
-Dihydro-5H-pyrazolo [1,2-a] [1,2,
4] Triazolium-6-yl) thio] -1-methyl-
6-[(R) -1-phenylacetyloxyethyl)]
-Carbapene-2-em-3-carboxylate, (1
R, 5S, 6S) -2-[(6,7-dihydro-5H-
Pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio] -6-[(R) -1- (2-methyl-2-phenylpropionyloxy) ethyl] -1- Methylcarbapene-2-em-3-carboxylate,
(1R, 5S, 6S) -2-[(6,7-dihydro-5
H-pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio] -6-[(R) -1- (3,3
-Dimethylacryloyloxy) ethyl] -1-methylcarbapene-2-em-carboxylate, (1R, 5
S, 6S) -6-[(R) -1- (3,5-dichloro-
2,4-Pentadienylyloxy) ethyl] -2-
[(6,7-Dihydro-5H-pyrazolo [1,2-a]
[1,2,4] Triazolium-6-yl) thio] -1
-Methylcarbapene-2-em-3-carboxylate, (1R, 5S, 6S) -2-[(6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazolium -6-yl) thio] -6-[(R) -1- (3
-Hydroxymethacryloyloxy) ethyl] -1-methylcarbapene-2-em-3-carboxylate,
(1R, 5S, 6S) -2-[(6,7-dihydro-5
H-pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio] -1-methyl-6-[(R)-
1- (4-phenyl-3-butenylyloxy) ethyl]
-Carbapene-2-em-3-carboxylate, (1
R, 5S, 6S) -6-[(R) -1- (3-butynylyloxy) ethyl] -2-[(6,7-dihydro-5H
-Pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio] -1-methylcarbapene-2-em-3-carboxylate, (1R, 5S, 6S) -6
-[(R) -1- (5-chloro-3-hexynylyloxy) ethyl] -2-[(6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] Triazolium-6
-Yl) thio] -1-methylcarbapene-2-em-3
-Carboxylate, (1R, 5S, 6S) -2-
[(6,7-Dihydro-5H-pyrazolo [1,2-a]
[1,2,4] Triazolium-6-yl) thio] -6
-[(R) -1- (2-Hydroxy-3-butynyloxy) ethyl] -1-methylcarbapene-2-em-3
-Carboxylate, (1R, 5S, 6S) -2-
[(6,7-Dihydro-5H-pyrazolo [1,2-a]
[1,2,4] Triazolium-6-yl) thio] -6
-[(R) -1-Ethyloxycarbonyloxyethyl] -1-methylcarbapene-2-em-3-carboxylate, (1R, 5S, 6S) -6-[(R) -1-
(1-Chloroethyloxycarbonyloxy) ethyl]
-2-[(6,7-dihydro-5H-pyrazolo [1,2
-A] [1,2,4] triazolium-6-yl) thio] -1-methylcarbapene-2-em-3-carboxylate, (1R, 5S, 6S) -2-[(6,7- Dihydro-5H-pyrazolo [1,2-a] [1,2,4]
Triazolium-6-yl) thio] -6-[(R) -1
-(4-Hydroxypentoxycarbonyloxy) ethyl] -1-methylcarbapene-2-em-3-carboxylate, (1R, 5S, 6S) -2-[(6,7-dihydro-5H-pyrazolo [ 1,2-a] [1,2,4]
Triazolium-6-yl) thio] -1-methyl-6-
[(R) -1- (1-Phenylpropoxycarbonyloxy) ethyl] -carbapene-2-em-3-carboxylate, (1R, 5S, 6S) -6-[(R) -1-
Benzoyloxyethyl] -2-[(6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio] -1-methylcarbapene-
2-M-3-carboxylate, (1R, 5S, 6
S) -2 - [(6,7-dihydro -5H- pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio] -6 - [(R)-1-eyes were Cylcarbonyloxyethyl] -1-methylcarbapene-2-em-3-
Carboxylate, (1R, 5S, 6S) -6-
[(R) -1-Cumenylcarbonyloxyethyl] -2
-[(6,7-Dihydro-5H-pyrazolo [1,2-
a] [1,2,4] triazolium-6-yl) thio]
-1-Methylcarbapene-2-em-3-carboxylate, (1R, 5S, 6S) -6-[(R) -1- (5
-Bromonaphtho-2-ylcarbonyloxy) ethyl] -2-[(6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio] -1- Methylcarbapene-2-em-3-carboxylate, (1R, 5S, 6S) -2-[(6
7-dihydro-5H-pyrazolo [1,2-a] [1,
2,4] Triazolium-6-yl) thio] -6-
[(R) -1- (1-hydroxy-m-tolu-5-ylcarbonyloxy) ethyl] -1-methylcarbapene-
2-M-3-carboxylate, (1R, 5S, 6
S) -6-[(R) -1- (4-Biphenylylcarbonyloxy) ethyl] -2-[(6,7-dihydro-5
H-pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio] -1-methylcarbapene-2-
M-3-carboxylate, (1R, 5S, 6S)-
6-[(R) -1-carbamoyloxyethyl] -2-
[(6,7-Dihydro-5H-pyrazolo [1,2-a]
[1,2,4] Triazolium-6-yl) thio] -1
- Mechirukaru Bas pen-2-em-3-carboxylate, (1R, 5S, 6S) -6 - [(R)-1-diethylcarbamoyloxy-ethyl] -2 - [(6,7-dihydro -5H- Pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio] -1-methylcarbapene-2-em-3-carboxylate, (1R, 5S,
6S) -6-[(R) -1- (1-Carboxyethylcarbamoyloxy) ethyl] -2-[(6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] Triazolium-6-yl) thio] -1-methylcarbapene-2-em-3-carboxylate, (1R, 5S, 6
S) -6-[(R) -1-azetidinocarbonylethyloxy] -2-[(6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazolium-6- Yl) thio] -1-methylcarbapene-2-em-3-carboxylate, (1R, 5S, 6S) -2-[(6,6
7-dihydro-5H-pyrazolo [1,2-a] [1,
2,4] Triazolium-6-yl) thio] -1-methyl-6-[(R) -1-pyrrolidinocarbonyloxyethyl] -carbapene-2-em-3-carboxylate, (1R, 5S, 6S ) -2-[(6,7-Dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio] -1-methyl-6-
[(R) -1-Piperidinocarbonyloxyethyl]-
Carbapene-2-M-3-carboxylate, (1
R, 5S, 6S) -2-[(6,7-dihydro-5H-
Pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio] -6-[(R) -1-morpholinocarbonyloxyethyl] -1-methyl-carbapene-2
-M-3-carboxylate, (1R, 5S, 6S)
-2-[(6,7-dihydro-5H-pyrazolo [1,2
-A] [1,2,4] triazolium-6-yl) thio] -1-methyl-6-[(R) -1-thiomorpholinocarbonyloxyethyl] -carbapene-2-em-3
-Carboxylate, (1R, 5S, 6S) -2-
[(6,7-Dihydro-5H-pyrazolo [1,2-a]
[1,2,4] Triazolium-6-yl) thio] -1
-Methyl-6-[(R) -1-piperazinylcarbonyloxyethyl] -carbapene-2-em-3-carboxylate, (1R, 5S, 6S) -2-[(6,7-dihydro-5H -Pyrazolo [1,2-a] [1,2,4]
Triazolium-6-yl) thio] -1-methyl-6-
[(R) -1-pyrrolininocarbonyloxyethyl]-
Carbapene-2-M-3-carboxylate, (1
R, 5S, 6S) -2-[(6,7-dihydro-5H-
Pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio] -1-methyl-6-[(R) -1-
Pyrrolinocarbonyloxyethyl] -carbapene-2-
M-3-carboxylate, (1R, 5S, 6S)-
2-[(6,7-dihydro-5H-pyrazolo [1,2-
a] [1,2,4] triazolium-6-yl) thio]
-6-[(R) -1-imidazolidininocarbonyloxyethyl] -1-methylcarbapene-2-em-3-carboxylate, (1R, 5S, 6S) -2-[(6
7-dihydro-5H-pyrazolo [1,2-a] [1,
2,4] Triazolium-6-yl) thio] -6-
[(R) -1-imidazolininocarbonyloxyethyl] -1-methylcarbapene-2-em-3-carboxylate, (1R, 5S, 6S) -2-[(6,7-dihydro-5H- Pyrazolo [1,2-a] [1,2,4]
Triazolium-6-yl) thio] -6-[(R) -1
-Imidazolinocarbonyloxyethyl] -1-methylcarbapene-2-em-3-carboxylate, (1
R, 5S, 6S) -2-[(6,7-dihydro-5H-
Pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio] -1-methyl-6-[(R) -1-
Oxetaniloxyethyl) -carbapene-2-em-3
-Carboxylate, (1R, 5S, 6S) -6-
[(R) -1-azetidinyloxyethyl] -2-
[(6,7-Dihydro-5H-pyrazolo [1,2-a]
[1,2,4] Triazolium-6-yl) thio] -1
-Methylcarbapene-2-em-3-carboxylate, (1R, 5S, 6S) -2-[(6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazolium -6-yl) thio] -1-methyl-6-
[(R) -1-Tetrahydrofryloxyethyl] -carbapene-2-em-3-carboxylate, (1R,
5S, 6S) -2-[(6,7-Dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazolium-6
-Yl) thio] -1-methyl-6-[(R) -1- (N
-Methylpyrrolidinyloxy) ethyl] -carbapene-2
-M-3-carboxylate, (1R, 5S, 6S)
-2-[(6,7-dihydro-5H-pyrazolo [1,2
-A] [1,2,4] triazolium-6-yl) thio] -1-methyl-6-[(R) -1-tetrahydrothienyloxyethyl] -carbapene-2-em-3-carboxylate, (1R, 5S, 6S) -2-[(6
7-dihydro-5H-pyrazolo [1,2-a] [1,
2,4] Triazolium-6-yl) thio] -1-methyl-6-[(R) -1-tetrahydropyranyloxyethyl] -carbapene-2-em-3-carboxylate, (1R, 5S, 6S ) -2-[(6,7-Dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio] -1-methyl-6-
[(R) -1-piperidyloxyethyl) -carbapene-
2-M-3-carboxylate, (1R, 5S, 6
S) -2-[(6,7-Dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio] -6-[(R) -1-dioxane- 2-yl-oxyethyl] -1-methylcarbapene-2-em-
3-carboxylate, (1R, 5S, 6S) -2-
[(6,7-Dihydro-5H-pyrazolo [1,2-a]
[1,2,4] Triazolium-6-yl) thio] -6
- [(R) -1- Imidazorijini b Kishiechiru] -1-
Methylcarbapene-2-em-3-carboxylate,
(1R, 5S, 6S) -2-[(6,7-dihydro-5
H-pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio] -6-[(R) -1- (oxathiolan-3-yloxy) ethyl] -1-methylcarbapene -2-M-3-carboxylate and the like.

[Procedure correction 6]

[Document name to be amended] Statement

[Correction target item name] 0026

[Correction method] Change

[Correction content]

In the above formula (II), the "carboxyl protecting group" represented by R ⁵ may be any protecting group known per se as a protecting group for a carboxyl group in the field of peptide chemistry, for example, ester residue. A group can be exemplified. Such ester residues include methyl, ethyl, n-propyl, isopropyl, n-,
lower alkyl ester residues such as iso, sec-, tert-butyl, n-hexyl ester; benzyl, p-
Araalkyl ester residues such as nitrobenzyl, o-nitrobenzyl, p-methoxybenzyl and the like; lower aliphatic acyloxymethyl such as acetoxymethyl, propionyloxymethyl, n-, iso-, butyryloxymethyl, pivaloyloxymethyl and the like. residues and the like, preferably Ararukirue scan ether residues, more preferably p- nitrobenzyl group.

[Procedure Amendment 7]

[Document name to be amended] Statement

[Name of item to be corrected] 0029

[Correction method] Change

[Correction content]

The elimination reaction of the protecting group can also be carried out by treating with zinc in a buffer solution. For example, the compound of formula (II) is treated with zinc in a buffer having a pH of 5 to 7, such as phosphate buffer, acetate buffer, citrate buffer, morpholinopropane sulfonate buffer, N-methylmorphophosphate buffer. It can be done by processing. Examples of zinc that can be used include zinc powder, white zinc, and granular zinc. The amount used is not particularly limited, but generally 1 to 1 part by weight of the compound of the formula (II).
It can be in the range of 10 parts by weight. In this elimination reaction, an organic solvent may be used in combination, if necessary, and as such a solvent, an alcohol solvent such as ethanol, propanol or n-butanol; diethyl.
Ether, ether solvents such as tetrahydrofuran;
Acetonitrile, dimethylformamide, dimethylacetamide and the like can be mentioned. The reaction can usually be completed by treatment at a temperature of about -20 to about 50 ° C, preferably room temperature to about 30 ° C for about 0.1 to 5 hours.

[Procedure Amendment 8]

[Document name to be amended] Statement

[Correction target item name] 0038

[Correction method] Change

[Correction content]

[0038]

[Chemical 8]

[Procedure Amendment 9]

[Document name to be amended] Statement

[Correction target item name] 0042

[Correction method] Change

[Correction content]

The method of formula obtained by the reaction (II-1) compound is isolated in the usual refining means necessary, can be purified, described as the A method or following the (2) May be used as the starting material in.

[Procedure Amendment 10]

[Document name to be amended] Statement

[Correction target item name] 0046

[Correction method] Change

[Correction content]

[0046]

[Chemical 9]

[Procedure Amendment 11]

[Document name to be amended] Statement

[Correction target item name] 0064

[Correction method] Change

[Correction content]

The reaction of the compound of formula (X) with the mercapto reagent of formula (XI) is carried out, for example, by reacting the compound of formula (X) with tetrahydrofuran, dichloromethane, dioxane, dimethylformamide, dimethylsulfoxide, acetonitrile, hexamethylphosphoramide. And the like in a suitable solvent such as about 1 to about 5 times, preferably about 1.5 to about 3 times the molar amount of the mercapto reagent of the formula (XI), and preferably sodium hydrogencarbonate. , Potassium carbonate, triethylamine, diisopropylethylamine and the like at a temperature in the range of about −40 to about 25 ° C. for about 30 minutes to about 24 hours.

[Procedure Amendment 12]

[Document name to be amended] Statement

[Correction target item name] 0085

[Correction method] Change

[Correction content]

3.73 g (4.20 mmo) of compound (4)
l) is dissolved in 85 ml of THF, 85 ml of 0.1 M phosphate buffer (pH 7.0), 1.64 g of 10% Pd-C (containing 50% water), and 702 mg of NaHCO ₃ are added, and hydrogen gas is added at 4 atm at room temperature. Stir vigorously for 25 minutes. Pd-C
Is filtered off and adjusted to pH 7 with 4N hydrochloric acid, then 85 ml
Wash with ethyl acetate. The aqueous layer is separated and the organic layer is washed 5 times with a small amount of water. The aqueous layers are combined and stirred vigorously, and 1.47 g of KHCO ₃ at 8 ° C. are added, followed by 3.21 g (29.3 mmol) of ethylformimidate hydrochloride. After stirring at 8 ° C for 10 minutes, the pH was adjusted to 5.5,
The reaction solution was concentrated under reduced pressure and desalted and purified with 150 ml of HP-40 resin. Fractions (eluate: 10% IPA-containing ion-exchanged water) were collected, concentrated under reduced pressure, and then freeze-dried to obtain 486 mg (1.13 mmol) of pale yellow powdery compound (5). Yield 26.9%.

[Procedure Amendment 13]

[Document name to be amended] Statement

[Correction target item name] 0089

[Correction method] Change

[Correction content]

The compounds (1) 4.0g (4. 9 6mmo
l) and 182 mg of DMAP, 40 m of anhydrous methylene chloride
Dissolve in 1 l, while cooling with ice under a nitrogen stream, diisopropylethylamine 3.02 ml, ethyl chlorocarbonate 1.65 m
1 (17.3 mmol, 3.5 eq) was added dropwise. After gradually returning to room temperature and stirring for 2 days, ethyl acetate was added to 1
It was washed successively with 0% aqueous citric acid solution, saturated aqueous NaHCO ₃ solution, and saturated saline. After dehydration with magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel chromatography (S
iO _{2 (} 180 g, ethyl acetate: hexane = 3: 2) was added, and 3.27 g (3.7) of a compound (6) as a pale yellow foamy solid.
2 mmol) was obtained. Yield 75.1%.

[Procedure Amendment 14]

[Document name to be amended] Statement

[Correction target item name] 0103

[Correction method] Change

[Correction content]

Example 9 P-nitrobenzyl (1R, 5S, 6S) -2- [N,
N'-di (P-nitrobenzyloxycarbonyl) pyrazolidin-4-yl-thio] -1-methyl-6-
[(R)-1-propyl o oxy ethyl] - carbapen-2-em-3-carboxylate

[Procedure Amendment 15]

[Document name to be amended] Statement

[Correction target item name] 0140

[Correction method] Change

[Correction content]

Paranitrobenzyloxyalanine tosylate (434.0 mg, 1.10 mmol, 1 eq) and triethylamine (152.6 μl) were added to anhydrous DMF (4.5 m).
In addition to 1, the mixture was stirred under a nitrogen stream while cooling with ice to give the compound (1
4) 1.0 g (1.10 mmol) was added. Ice cold 40
After stirring for 2 minutes at room temperature for 2 hours, 434 mg (1.10 mmol) of para-nitrobenzyloxyalanine tosylate
Treated with 4% aqueous NaHCO ₃ solution was added. 1
After stirring for an hour, 100 μl of triethylamine was further added, and the mixture was reacted overnight. Ethyl acetate was added to the reaction mixture to give 10
% Citric acid aqueous solution, 4% NaHCO ₃ aqueous solution, and saturated saline solution, and then washed with silica gel column chromatography (SiO ₂ 50
Purification by gAcOEt: Hexane = 3: 1) was performed. 747 mg of the compound (19) as a light yellow foamy solid.
(0.71 mmol) was obtained. Yield 64.5%.

[Procedure Amendment 16]

[Document name to be amended] Statement

[Name of item to be corrected] 0142

[Correction method] Change

[Correction content]

Example 19 (1R, 5S, 6S) -6-[(R) -1-((1S)
− 1 -carboxyethylcarbamoyloxy) ethyl]
-2-[(6,7-dihydro-5H-pyrazolo [1,2
-A] [1,2,4] triazolium-6-yl) thio] -1-methylcarbapene-2-em-3-carboxylate

[Procedure Amendment 17]

[Document name to be amended] Statement

[Correction target item name] 0144

[Correction method] Change

[Correction content]

709 mg (0.61 mm) of compound (19)
is dissolved in 14 ml of THF, 14 ml of 0.1M phosphate buffer (pH 7.0), 112 mg of NaHCO ₃ and
262 mg of 10% Pd-C (containing 50% water) was added, and the mixture was vigorously stirred at 4 atm of hydrogen gas at room temperature for 90 minutes. After removing Pd-C by filtration and adjusting the pH to 7.0, the aqueous layer washed with 23 ml of ethyl acetate was separated and cooled to 5 to 10 ° C, and then KHCO ₃ 234 mg, form imidate by addition of hydrochloric acid salt 513 mg (4.68 mmol) 1
Stir vigorously for 0 minutes and adjust to pH 5.5. The reaction solution was concentrated and purified with 18 ml of SP-207 resin. Compound (20) 16 which is a pale yellow powder upon freeze-drying
9 mg (0.37 mmol) was obtained. Yield 54.2%.

Claims (1)

[Claims] 1. Formula (I): In the formula, R ¹ represents a saturated or unsaturated aliphatic hydrocarbon group, an alkoxy group or an aryl group which may be substituted with a group selected from halogen, hydroxyl and phenyl, and R ² and R ³ each independently represent a hydrogen atom. Or an alkyl group optionally substituted with a carboxyl group, or R ² and R ³ may form a nitrogen-containing heterocycle together with the nitrogen atom to which they are attached; Wherein R ⁴ represents a hydrogen atom or an alkyl group, and a pharmacologically acceptable salt thereof.