JPH04103584A - 1-methylcarbapenem derivative - Google Patents

Abstract

NEW MATERIAL:2-(2-Oxopyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-- methylcarbapen-2-em-3-carboxylic acid pivaloyloxymethyl ester shown by formula I. USE:An antimicrobial agent having extremely excellent oral absorption, showing high stability to dehydropeptidase, having low toxicity and high safety. PREPARATION:First, the oxo group at the 2-position of carbapenem ring of a compound shown by formula II (Y is carboxyl-protecting group) is activated by reaction with benzenesulfonic anhydride in a solvent in the presence of a base and the resultant substance is reacted with a compound shown by formula III in a solvent in the presence of a base at-20 to 40 deg.C. Then the prepared compound shown by formula IV is deprotected and then reacted with a compound shown by formula V in a solvent in the presence of a base at 0-50 deg.C.

Description

[Detailed description of the invention] (Industrial application field) The present invention relates to 1-methylcarbapenem derivatives.

(Prior art) Chenamycin derivatives have attracted attention because they exhibit excellent antibacterial activity against a wide range of antigenic bacteria, including gram-positive and gram-negative bacteria, and have particularly strong antibacterial activity against cephem-resistant bacteria. There is. However, chenamycin derivatives are degraded by dehydropeptidase 1 present in the human body and lose their activity. Therefore, active research is being conducted in search of compounds that are relatively stable against dehydropeptidase and have a high recovery rate in urine.

For example, in JP-A-2-49783, the formula n is O-3, and R' is a hydrogen atom, a lower alkyl group with or without a substituent, or an alkanoyl group. ) 1-Methylcarbapenem derivatives are disclosed.

(Problems to be Solved by the Invention) As a result of various studies, the present inventors have discovered that the novel 1-methylcarbapenem derivative represented by the below-mentioned formula (I) is a conventionally known isomer thereof (i.e., the above-mentioned formula (A)). Quite surprisingly, compared to
It was discovered that it exhibits exceptionally excellent oral absorbability, and the present invention was achieved.

(Means for Solving the Problems) That is, the present invention provides 2-(2-year-old xobi-lysin-3-ylthio) having the general formula
-6-(1-hydroxyethyl)-1-methylcarbaben-2-em-3-carboxylic acid pivaloyloxymethyl ester.

The compound of the present invention represented by the above formula (1) has various isomers based on its asymmetric carbon atoms.6 Although the present invention includes either one or a mixture of these isomers, it may be used as a pharmaceutical. When using (IR15S, 6S)
A compound in which the a-position monohydroxyl group of the 6-position substituent is in the R coordination and the 2oxopyrrolidinyl group on the 2-position thio group is in the R coordination is preferred.

The novel 1-methylcarbapenem derivative (1) of the present invention has excellent antibacterial activity against a wide variety of microorganisms including Gram-negative bacteria and Gram-negative bacteria, and is a useful pharmaceutical compound as an antibacterial agent. For example, The derivative (I) can be used as a therapeutic agent for the Gram-negative bacteria and various infectious diseases caused by Gram-negative bacteria, as a chemotherapeutic agent for mammals including humans, or as an additive for animal feed.

The derivative of the present invention is produced by the method shown in the following reaction formula.

(In the above formula, Y represents a carboxyl group-protecting group, and X represents a halogen atom.) In the starting compound (IT), the carboxyl group-protecting group Y may be a lower group such as methyl, ethyl, or t-butyl. Examples include alkyl groups, substituted or unsubstituted phenyl lower alkyl groups such as benzyl, diphenylmethyl, and p-nitrivenzyl.

Activation of the oxo group at the 2-position of the carbapenem ring in compound (II) is carried out in the presence of a base in a solvent (e.g. acetonitrile, methylene chloride, dichloroethane, chloroform), for example, with diphenylphosphoryl chloride (diphenylphosphorochloridate), diphenylphosphorochloridate, etc. Diarylphosphoryl halides such as phosphoryl bromide; di-lower alkylphosphoryl halides such as dimethylphosphoryl chloride; lower alkanesulfonic anhydrides such as methanesulfonic anhydride; or arylsulfonic anhydrides such as benzenesulfonic anhydride and p-toluenesulfonic anhydride. and -2
This can be carried out by reacting at 0 to 40°C. As the base, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, etc. can be suitably used.

The compound thus obtained and the mercaptan compound (III
) in a solvent in the presence of a base at -20 to 40
It can be carried out at ℃. As the heating medium, those listed above can be used. In addition to the bases listed above, potassium carbonate, sodium carbonate, and the like can also be used. This reaction can be suitably carried out without isolating the intermediate product by adding the compound (1) to the activation reaction completed solution.

Removal of the protecting group from the compound (TV) can be carried out by conventional methods in this technical field, such as hydrolysis, acid treatment, solvolysis, and reduction, depending on the type of the protecting group.

The reaction between compound (V) or a salt thereof (e.g. potassium salt, sodium salt) and compound (Vl) can be carried out using a hot medium (e.g.
The reaction can be carried out in N,N-dimethylformamide, dimethyl sulfoxide) in the presence of a base at 0 to 50°C. As the compound (Vl), pivaloyloxymethyl halides such as pivaloyloxymethyl iodide can be suitably used. Examples of the base include potassium carbonate, sodium carbonate, 1,8-diazabicyclo[5,4
,0] undec-7-ene (DBU).

Note that one of the raw material compounds (III) is, for example, 3-
Hydroxy-2-oxopyrrolidine in a solvent, P-1-
3 by reacting with luenesulfonyl chloride and reacting the resulting product with an alkali metal salt of thioacetate.
-acetylthio-2-oxopyrrolidine, then
It can be produced by subjecting the compound to a deacetylation reaction.

The objective compound (I) of the present invention exhibits excellent antibacterial activity against a wide variety of bacteria. : (e.g. Salmonella typhi fS, typhi), Salmonella typhimurium (S, typhimurium)),
Shigella fshigella spp. (e.g. Shigella sonnei (S,
siella) genera (e.g. Klebsiella pneumoniae (K, pneumoniae), Proteusl K (e.g. Proteus vulgaris iP, vulgaris)), Morganella (e.g.
Morganella (e.g., Morganella morganii-fM, morganiill, Providencia (e.g., Providencia stuarti (P, 5tuarti il)).
), Citrobacter (for example, Citrobacter freundii (C, freu)
6 In addition, Bacteroides shows excellent antibacterial activity against bacteria belonging to the
sl genera (e.g., Bacteroides fragilis (B,
It also exhibits excellent antibacterial activity against anaerobic bacteria such as S. fragilis).

Additionally, Streptococcus
uslK (e.g. S. pneumoniae, S. pyogenes), Staphylococcus @
(For example, Staphylococcus aureus (S, a
ureusl, gram-positive bacteria such as Staphylococcus epidermizois (S, epidermidis) and Citrobacter freundei (C, freu
ndii), Morganella morgani fM, morg
aniil, Enterobacter cloacani (E,
cloacae) l, Ceresia marcescens (S
It also exhibits antibacterial activity against a wide range of bacteria, including Gram-negative bacteria such as S. marcescens).In particular, the target compound (I) exhibits high oral absorption, so it can be orally administered for the purpose of treating various bacterial infections. It has excellent characteristics.

Furthermore, the target compound (I) has the property of having high stability against dehydropeptidase I. Furthermore, the target compound (I) has low toxicity and is highly safe as a medicine.

The target compound (1) can be administered either orally or parenterally (eg, intravenously, intramuscularly, subcutaneously). The daily dose of the target compound (I) depends on the patient's age, weight,
Although it varies depending on the condition and type of disease, the daily dosage is usually about 0.001 to 0.1 g per kg of body weight.
, preferably about 0.01 to 0.04 g. Furthermore, when the target compound (I) is used as a medicine, it can be used as a pharmaceutical preparation in which it is combined or mixed with a pharmaceutical excipient suitable for oral or parenteral administration.

The pharmaceutical formulations may be solid formulations such as tablets, granules, capsules, or liquid formulations such as solutions, suspensions, emulsions.These pharmaceutical formulations may be sterilized and/or stabilized,
It may also contain auxiliary agents such as wetting agents and emulsifiers.

Compound (I) of the present invention is included in the general formula disclosed in JP-A No. 2-49783 for technical reasons, but compared to the compound specifically disclosed in the above-mentioned known document. , which has excellent oral absorption and constitutes a selected invention.

(Effects of the Invention) In order to prove the above, an experimental example in which the following compounds of the present invention and the compound described in JP-A-2-49783 were orally administered to mice and their blood concentrations were measured will be shown below.

(Compounds of the present invention) (IR,5S,6S)-2-(2-year-old xobyronodin-3-ylthio)-6-[(IR)-1-hydroxyethyl]-1-methylcarbapen-2-em-3 -Carboxylic acid pivaloyloxymethyl ester (comparative compound) (IR, 5S, 6S)-2-(2-year-old xovironodine-
(4-ylthio)-6-[(IR)-1-hydroxyethyl-1-methylcarbapen-2-em-3-carboxylic acid pivaloyloxymethyl ester (experimental example) (b) Bioassay method 1) Administration of 8i form The sample was diluted to 5 mg/- with distilled water, and 50 mg/kg per mouse body weight was orally administered to a group of 4 mice using an oral probe.

2) Sample preparation After administering the sample, 15.30.45.60
After 1 minute, the mice were exsanguinated by cutting the femoral artery and blood was collected. The collected blood was left at 4° C. for 2 hours. Serum was diluted 10 times with phosphate buffer (1/15M, pH 7.0) and filtered using a Millipore filter (MI) with a pore size of 0.45F.
(manufactured by LLIPORE), and this furnace solution was used as a measurement sample for the bioassay. All of the above 8 sample preparation operations were performed under water cooling.

b The concentration of the analyte in the bioassay serum is B, 5ubtilis ATCC
6633 as a test strain, the free carboxylic acid was measured by the standard curve method (8 mm paper disk) using a trypto soy agar medium (Eiken Chemical).

*Mean value ± SD As is clear from the above test results, the blood concentration of the compound of the present invention is about 3.5 times that of the comparative compound 15 minutes after administration, and the blood concentration is about 2.7 times that of the comparative compound even after 30 minutes. It can be seen that the absorbency is excellent.

(Example) Example (3S)-3-hydroxypyrrolidin-2-one (19
g) is suspended in chloroform (200+nl) and anhydrous potassium carbonate (28.6 g) is added.

Balatoluenesulfonyl chloride (362 g) was added under water cooling, and the mixture was stirred at room temperature overnight. Under water cooling, add water (140
Add d), stir for 15 minutes, and remove the precipitated product. After washing with water and isopropyl ether, the crystals were dried to obtain 35.9 g of (3S)-3-p-toluenesulfonyloxypyrrolidin-2-one. Yield: 75%.

mp, 145-148℃ (colorless prism crystal NMR (C
OOmu) δppm: 2, 12-2.32 (IH, ml, 2.44 f3)
1.31, 2.46-2.60 flH, ml, 3.21
-3.49f2H, ml, 4.92 (IH, tl, 7.
16 (IH, brsl, 7.35.7.85 (
2H,di[a]:' 16.9° (C1,MeO
H) Dissolve the compound (34.7 g) obtained in (1) in N,N-dimethylformamide (287 J), add potassium thioacetate (15.5 g) under water cooling, and stir at room temperature for 2 hours. The solvent was distilled off, and the residue was diluted with chloroform (300 d
) and wash with saline (400i). The aqueous layer is extracted with chloroform (3×100−), the chloroform layers are combined, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. Isopropyl ether (300-) is added to the residue for crystallization. Precipitated crystals? After washing with isopropyl ether, the crystals were dried under reduced pressure to obtain (3R)-3-acetylthiopyrrolidin-2-one (17.4 g).

Yield 81%.

mp, 85-87°C (colorless needle crystals) NMR (CDC) δppm: 2,0n-2,2OfLH,ml, 2.40 (3H,
S), 2, 59-2.78 flH, m), 3.33-
3.46 (2H, m), 4, 23 flH, tl, 7
．． 63 flH, brsl [a] P 2.3”
(C1, MeOH).

The compound (8 g) obtained in (2) was mixed with methanol (80C1-
) and diluted with IN-sodium hydroxide solution (5
0.2 g) and stirred at the same temperature for 1 hour. The solvent was distilled off under reduced pressure, and the aqueous layer was extracted with chloroform. After drying the chloroform layer over magnesium sulfate, the solvent was distilled off under reduced pressure. After crystallization by adding isopropyl ether to the residue, the precipitate was separated, washed with isopropyl ether, and dried to obtain (3R)-3-mercaptopyrrolidin-2-one (4.5 g). Yield 77%.

mp, 83-86°C (colorless needle crystals) NMR (DMSO-dB) δppm: 1, 76-1
．． 95 flH, m), 2.73-2.56 flH,
m), 2.89 (IH, dl, 3.10-3.31
(2H, m), 3.41-3.53 (IH, m], 7.
82 (IH, brsl[α]:'+11.2° (C
1, CHCff,) p-nitrobenzyl (IR, 3R,
5R.

6S)-6-[(IR)-1-hydroxyethyl]-1
-Methyl-2-year-old xocarbapenam-3-carboxylate (14.8 g) in anhydrous acetonitrile (100-)
diisopropylethylamine (5.7 g) and diphenylphosphorochloridate (11
, 8g) was added dropwise at below 0°C. After stirring for 30 minutes, (3)
(3R)-3-mercaptopyrrolidin-2-one (5.3 g) obtained in
) in anhydrous acetonitrile (loomt')
After dropwise addition at a temperature above 0.degree. C., water (100 J) was added to the reaction solution, which was stirred at the same temperature for 1.5 hours, and acetonitrile was distilled off under reduced pressure. The residue is extracted with ethyl acetate and washed with brine. The organic layer was dried with magnesium sulfate, and the solvent was distilled off under reduced pressure.
Add chloroform to the residue to crystallize it. Number of precipitated crystals,
By washing with isopropyl ether (IR,
5S, 6S)-2-[(3R)-2-xobi-lysin-3-ylthio]-6-[(IR)-1-hydroxyethyl]-1-methylcarbapene-2-emu-3-carboxylic acid - Obtain p-nitrobenzyl ester (14.5 g).

Yield 77%.

mp, 131-132℃ (colorless prism product) NMR (D
MSO-d, lδppm; 1, 1.6 FLH, dl
, 1.19 (3H, d), 1.89-2.08 fl
H, ml, 2.54-2.71 flH, ml, 3.1
9-3.35 f3H, m), 3.44-3.56 f
lH, ml, 3.93-4.15 f2H, m), 4.
23 (IH, d, dl, 5.09 (IH, dl, 5.
30.5, 47 (2H, d), 7.72.8.23
f2H, dl, 8.09 (IH, brs) water (280
tl'), tetrahydrofuran (14°-), and ethanol (140d), potassium hydrogen carbonate (140d) was added.
, 52 g) and the compound (7, oog) obtained in (4) are dissolved. Add 14,00 g of 10% palladium on carbon to this solution under a nitrogen stream and hydrogenate at room temperature and normal pressure for 2 hours. After removing the catalyst, the organic solvent in the solution is distilled off under reduced pressure. Water Wash the layer twice with chloroform (7ON!) and
Concentrate the aqueous layer under reduced pressure. Add N,N-dimethylformamide to the residue and concentrate again. Furthermore, the amorphous powder (lR) was obtained by performing two substitutional concentrations with N,N-dimethylformamide.

5S, 6S)-2-[(3R)-2-isobi-lysin-3-ylthioco-6-[(IR)-1-hydroxyethyl]-1-methylcarbaben-2-em-3-carboxylic acid Potassium salt (4.7 g) is obtained.

NMR (Dz01δppm; 1.22 (3H, d, J=7.3Hz), 1.29i3
H, d, J=6.3Hz), 2, 17 (IH, m), 2
．． 65 (IH, m), 3.35-3.52 (4H,
m), 4, 10-4.27 (3H, ml, to a suspension of the compound (11,72 g) obtained in (5) in N,N-dimethylformamide (6ON!) was added powdered potassium carbonate (1, 11 g) and stirred at room temperature for 30 minutes.

After adding pivaloyloxymethyl iodide (7.79 g) and stirring at room temperature for 30 minutes, ethyl acetate (100 d
) and remove the insoluble matter. The furnace solution was washed successively with pH 7, O phosphate buffer, and saline, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel flash column chromatography [CHC42s/E
tOH=20/1] and treated with ether to obtain amorphous powder (IR,556S)-2-[(3R
)-2-year-old xobimouth lysin-3-ylthio] -6-[
(IR) -1-Hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid pivaloyloxymethyl ester (9.63 g) was obtained. Yield 68%.

NMR (CDC1, lδppm:

Claims (1)

[Claims] 2-(2-oxopyrrolidin-3-ylthio) having the formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I)
-6-(1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylic acid pivaloyloxymethyl ester.