JPS5967291A - Novel cephalosporin compound - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula (R1 is groups shown by the formula II formula VII, NCCH2SCH2-, or CF3SCH2-; R2 is H, or methoxy; X is S, or O; R3 is H, salt of organic group, or metallic ion) and its salt. EXAMPLE:7-[1-(1H)Tetrazolylacetamide]-3-[(2'-amino-2'-carboxy)ethyl-im idazol-2- ylthiomethyl]-3-cephem-4-carboxylic acid. USE:An antibacterial agent. Having high blood concentration in organisms and its durability. PROCESS:For example, a compound shown by the formula R1-COOH is reacted with a 7-aminocephalosporanic acid derivative (7-ACA for short) shown by the formula VII in the presence of a binder such as dicyclo-hexylcarbodiimide, etc., or an active derivative (e.g., active ester, etc.) of a compound shown by the formula R1-COOH is reacted with 7-ACA shown by the formula VII, to give a compound shown by the formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel cephalosporin derivative, and more particularly to a novel cephalosporin compound represented by the following general formula (■).

In the general formula (II O H2 H R7 represents hydrogen or a methoxy group, X represents S or 0, R3 represents hydrogen or a salt with an organic base [- or represents a physiologically acceptable metal ion)] The cephalosporin compounds and physiologically acceptable inorganic to organic salts are shown.

The purpose of the present invention is to have excellent antibacterial activity against a wide range of pathogenic bacteria, mainly including gram-space bacteria and gram-positive bacteria;
Another object of the present invention is to provide a cephalosporin that has excellent blood concentration and persistence after being administered to living organisms.

Cephalosporin compounds are widely used in the treatment and prevention of infections caused by pathogenic bacteria.

In many cases, it is desirable to use cephalosporin antibiotics that are active against both Gram-positive and Gram-space bacteria, and various types of broad-spectrum cephalosporins are being developed.

The cephalosporin of the present invention is a novel cephalosporin having an S bond at histidine at the 3rd position, and these cephalosporins have high antibacterial activity against Gram-positive bacteria and Gram-spacific bacteria, and are It has the characteristics of high blood concentration in the body and excellent persistence. Histidine Hari, L.

Any DL can be used.

Next, regarding the method for synthesizing the compound of the present invention, it is possible to synthesize it roughly by the following two routes.

0OH R+ 0OH R9 Nti R, -C0OHR2 Ntl = 5- Y In the method for synthesizing the protective group z: H or trimethylsilyl group (1) for the niamino group, R, -COOH-i is a suitable bonding agent, such as dicyclohexyl. In the presence of carbodiimide, the 7-ACA derivative is fully reacted or R1-C
There is a method in which 0OH'i is converted into an active form, such as an active ester, mixed acid anhydride, etc., and then reacted with a 7-ACA derivative. Furthermore, it is also possible to react after converting it into an acid chloride like R,-COCl. In the above condensation,
Organic solvents that do not participate in the reaction, such as tetrahydrofuran, dioxane, ethyl acetate, dimethylformamide,
Methylene chloride, acetone, etc. are selected. Also,
In reactions such as acid chloride, it is also possible to use all aqueous systems.

6- Next, the conversion reaction of the acetoxymethyl group at the 3-position with thiolhistidine is carried out using sodium bicarbonate or triethylamine as a base in a mixed solvent system such as water, methanol, acetone, etc. , p of the reaction system
Hf 30-10 while controlling around 6-7
In the range of 0 ° C., for 1 to 20 hours, 2 to 1
By reacting for 0 hours, the 3-position conversion reaction can be carried out. During this time, the reaction system is preferably under a nitrogen atmosphere.

Next, regarding route (i+), to give one example, after protecting the amino group of thiolhistidine and, for example, t-butyloxycarbonylation, the acetoxymethyl group at the 3-position of 7-ACA (or its derivative) is in a mixed solvent system of water and acetone, using hydrogen carbonate as a base) I
The reaction is carried out at 30 to 100° C. for 1 to 20 hours while controlling the pH to 6 to 7 using Jum or the like. During this time, the reaction system must be under a nitrogen atmosphere. The carboxyl group at the 4-position of the obtained compound 7-ACA derivative and the carboxyl group of histidine at the 3-position are trimethylsilylated, or even the free residue is converted to R, -COO.
It is condensed with T (or its carboxylic acid active form (e.g., active ester, mixed acid anhydride, acid chloride, etc.). Thereafter, BOC is removed with trifluoroic acid e, formic acid, etc., and the entire target product can be obtained.

The compounds of the present invention have excellent blood concentration and persistence in vivo. For example, as an example, the blood concentration of the following compound (I) and cephaloglycin after intravenous injection in rats. When the values were compared, as shown in Table 1, it was found that the concentration in the dish was more persistent than that of cephaloglycin.

Table 1 Blood concentration value after intravenous injection □'j 7 ml rats are Wistar female rats, 14 [weight 180-220 g, drug dosage is 20-/1 (9 Compounds (■): Furthermore, the following compounds Comparing the blood concentration values of (II) and cefazolin after intravenous injection in rats, it was confirmed that the blood concentration and persistence were superior to cefazolin, as seen in Table 2. .

Table 2 Blood concentration values after intravenous injection pf//me administration conditions were the same as for compound (Il).

Compound (III: = 9 - As shown in Table 3, the following compound (m) also showed excellent results in blood concentration and persistence after intravenous injection.

Compound (III): As shown in the above compounds (Il, ffI) and (nI), cephalosporin derivatives with histidine attached at the 3-position have excellent blood concentration and long-lasting effects. discovered.

= 1 lo - Example 1 41 of Tellasol acetic acid was placed in 301 nt of thionyl chloride, and 17! of dimethylformamide and boiled at reflux for 1 hour. Next, thionyl chloride is distilled off under reduced pressure, and the residue is dissolved in 10 ml of acetone.

Next, put 8.5 g of 7-ACA into 701 n11 of water and 70 g of acetone, and add 7.9 yi of sodium bicarbonate to form a homogeneous solution. The above acetone solution of tetrazole acetic acid chloride was added dropwise to this solution under water cooling, and 1
Let's do a time reaction. After the reaction, the pH was adjusted to 3 with INHC4, the acetone was distilled off, and extraction was performed with 100% ethyl acetate.The ethyl acetate was washed with water, dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off. 7 of 27-[
1-(IH)tetrazolylacetamide]cephalosporanic acid is obtained.

A similar product was obtained in condensation of 7-ACA with the triethylamine salt after the tetrasole acetic acid kp-nitrophenyl ester.

Next, 2-thiono L/-L-histidine 17 was added to 1.76 ml of sodium bicarbonate water, and further 7-[1-(IH)tetrazolylacetamide]cephalosporanic acid 17 was added. The reaction is carried out for 6 hours at °C. During this time, the reaction is carried out under a nitrogen atmosphere while controlling the pH to 16.4. After the reaction is completed, the p solution is filtered under heat, part of the water is distilled off, and the p solution is purified by XAD-IIO column chromatography.

7-[1-(1)1)tetrazolylacetamide]-3
-[(2'-amino-2'-carboxy)ethylimidazol-2-ylthiomethylcy-3-cephem-4-carboxylic acid 1.11 was obtained.

The target product was confirmed by NMR (measured in DMSO).

chemical shift PPM (measured in DMSO) N.H.

0OH 5,17H6d 572H-7m -13 Example 2 Thiolhistidine 4,7ff Dissolved in 50ml dimethyl sulfoxide, 'l'+313-Tetramethylated guanine 5,89, t-butylphenyl carbonate) 5.4
f'ft was added and the reaction was carried out at 20°C for 300 hours.

After the reaction is completed, 200-ml water is added and extracted with 100-ml ethyl acetate. The aqueous phase was adjusted to pH 2, extracted twice with 100 ml of ethyl acetate, dried over anhydrous magnesium sulfate, and ethyl acetate was distilled off, leaving a residue of 4.
．． 61 remain.

Next, 7-ACA3 f and t obtained by the above method
-Butyloxycarbonylated thiol histidine 4.67 ml was added to 100 ml of water. The mixture was placed in 50ml of acetone, 5,57ml of hydrogen carbonate was added, and the reaction was carried out at 65°C under a nitrogen atmosphere. After 6 hours of reaction, the acetone in the reaction solution was distilled off and the target product was isolated by XAD-■ column chromatography to obtain 2.17.

Next, 7-amino-3-[2'-1 obtained by the above method
-butyloxycarbonylamino-2'-carboxy
14-cy)ethylimidazol-2-ylthiomethylcou-3-
2.17i of cephem-4-carboxylic acid are placed in 60% of tetrahydrofuran, and 1.2 equivalents of bis(trinotylsilyl)acetamide, which is a trimethylsilylation agent, is added.

Then trifluoromethylthioacetic acid 0.81 and N,N
1.45' of -dicyclohexylcarbodiimide is added to the reaction system and allowed to react at 15°C for 10 hours. After separating the precipitate and adding 10% of water to the P solution, the solvent was distilled off under reduced pressure, and the residue was dissolved in 60% of formic acid and heated at 5°C.
The reaction is carried out for a period of time, and the formic acid is distilled off. When ether is added to the oily residue, crystals are precipitated, and this is ftXA.
Purify by D-TI column chromatography.

7-()lifluoromethylthioacetamide)-3-[:
1.27 of (2'-amino-2'-carboxy)ethylimidazol-2-ylthiomethylcou-3-cephem-4-carboxylic acid is obtained.

PPM (measured in DMSO, ) lifluoroacetic acid) 3.9
1 F, C3CH2-S5.1 1
H-6d 5.69) I-7d Example 3 Cephaloglycin 4.17 and triethylamine 2.
1 yd'i 50'% dioxane 65fnI! 2-tert-butyloxycarbonyloxyimino-2-phenylacetonitrile 2
．． Add 79f and stir at 25°C for 2 days.

After the reaction is complete, dioxane is distilled off under reduced pressure, extracted three times with 20 ml of ethyl acetate, and the pH of the aqueous layer is adjusted to 2. Next, the mixture is extracted with ethyl acetate and ethyl acetate is distilled off to obtain tert-butyloxycarbonylated cephaloglycin j11/i.

Next, 2.61 2-thiol-L-histidine and 5.5 tf sodium bicarbonate were dissolved in 130 ml of water after heating to 50°C, and the tert-butyloxycarbonylated cephaloglycine 2, obtained by the above method, was dissolved. 1ff was added, and the reaction was carried out at 60° C. for 6 hours under a nitrogen atmosphere. During this time, the pH of the reaction solution was controlled at 6.4 to 7.0. Next, after adjusting the reaction solution f to pH 5, XAD
- When purified by TIO column chromatography, the target product 12
I got it. Next, this product -17- was dissolved in 40% of total formic acid and reacted at 20°C for 1 hour.The formic acid was then distilled off under reduced pressure and 20% of 1-1 ethyl acetate was added to precipitate crystals. However, as a result of NHR measurement, 7-(D-α-amino-α-phenylacetamide)-3-[(2'-amino-2'-hydroxy)ethylimidazole-2 was obtained. -ylthiomethyl]
It was confirmed that it was -6-cephem-4-carboxylic acid.

PPM (measured in DMSO,) lifluoroacetic acid) H2 -18- 5.84 H-7d Example 4 The following compound was synthesized by a known method, and the acetoxymethyl group at the 3-position was replaced with a thiol according to OOH Example 1. The target compound was obtained by reacting with histidine, and NM
The chemical structure was confirmed by R measurement.

PPM (DMSO-da, measured in trifluoroacetic acid)
jl 7 H-6d 567 H-7d -21- PPM (DMSO-d, measured in trifluoroacetic acid) 5
．． 1 6 H-6d 5.69 H-7d -22= 3.8 1 NCCH25CH2-SPPM (DM
Measured in SO) 0OH 5,1D H-66 5,62H-7m 8.5 0 -CONH-d PPM (DMSO-d,,) Measured in lifluoroacetic acid) 0
OH 509H-6d 556H-7m

Claims (1)

[Claims] With the general formula (Il H R2 hydrogen or methoxy group, X represents S or 0, and R3 represents hydrogen, a salt with an organic base, or a physiologically acceptable metal ion). Cephalosporin compounds and physiologically acceptable inorganic or organic salts as indicated.