SU1340590A3 - Method of producing 2-azacycloalkylthiopenem derivatives as salts with alkali metals - Google Patents

Abstract

The invention relates to heterocyclic compounds, in particular, antibiotics of the 2-azacycloalkylthiopenem (AP) series of the formula H C- (H) C (-OH) CH-C () -SC-SR, 11 II I -N c-c (o ) it is in the form of their salts with alkali metals, where R, is the group XB-TSR -lCH-i -CH (CH2) group-CH2-C (OHHH-C (0) -tH--, 1;; 2; ; S; CHj; B - CHj; B - H; C (0) H, which as antibacterial agents can be used in medicine. For the detection of antibiotics of this series with lower values of minimum inhibitory concentrations, an AP analysis method was developed Obtaining AP lead from acc. of an ester (preferably p-nitrobenzyl) by catalytic (Pd) hydrogenolysis in tetrahydrofuran and water at room temperature, followed by treatment with an aqueous base solution () and isolation of the alkaline salt of AP. AP tests show that they have antibacterial activity at lower concentrations, than 2-ethyltyopenem. In addition, AP is more stable in the aquatic environment than 2-ethylthiopenem. 3 tab. CO from 4 About

Description

134

This invention relates to a process for the preparation of novel antibiotics, derivatives of 2-azacycloalkylthiopenem in

the form of their salts with alkali metals,

which can be used as antibacterial agents in medicine.

The aim of the invention is to obtain novel antibiotics with lower minimum inhibitory concentrations.

Example 1. (5R, 6S) -6-G (Yu-1-hydroxyethyl -2- (2-pyrrolidone-3-yl) sodium thio-2-penem-3-carboxylate.

The pH of the suspension 73 mg of 10% palladium on diatomaceous earth in a mixture of 20 ml of tetrahydrofuran and 20 ml of distilled water was adjusted to 8.3 with 0.02 M aqueous sodium bicarbonate solution. A solution of 73 mg of p-nitrobenzyl (5R, 6S) - t (R) -1 -oxyethyl -2- (2-pyrrolidon-3-yl) thio-2-penem-3-carboxylate in a mixture of 8 ml is added. tetrahydrofuran and 8 ml of water and the resulting mixture is hydrogenated at 55 lb / KB 2, (3.867 atm) of hydrogen for 75 minutes, then another 73 mg of 10% palladium is added on diatomaceous earth and the pH of the mixture is adjusted to 7.0 with 0.02 m sodium bicarbonate aqueous solution. The mixture was hydrogenated at 55 psi for 75 minutes; the catalyst is then removed by filtration and the filtrate is concentrated in vacuo to remove tetrahydrofuran. The pH of the resulting aqueous solution was adjusted to 7.0, and the solution was extracted with two 15 ml portions of ethyl acetate. The aqueous solution is then lyophilized and 38 mg (69%) of the title compound are obtained as an amorphous solid.

The infrared spectrum of the target compound (on the potassium bromide disk) has absorption at 2.94, 5.65 and 6.3 microns.

Example 2 The procedure of example 1 is applied using the corresponding starting compounds and sodium salts of compounds of the formula I are obtained, the output of which is the IR spectrum (on a KBr disk, unless otherwise specified

what) and R are shown in table. one

Example 3. (5R, 6S) -6-t (R) - 1-Hydroxyethyl -2- (pyrrolidine-2,5-dione

5 o

five

five

0

five

3-yl) thio-2-penem-3-carboxol sodium.

The procedure of Example 1 is repeated, except that the initial pH is 7.5 and in the starting compound of formula (II) R is pyrrolidine-2,5-dione-3-yl. The compound is obtained in 90% yield. It has infrared absorption bands (on a disk of potassium bromide) at 2.92; 5.63; 5.8 and 6.2 microns.

Example 4. The procedure of example 3 is repeated using the corresponding compounds of formula (II) to obtain the sodium salts of compounds of formula (I), the output of which is, the IR spectrum using potassium bromide disks and R of which are given in table. 2

The in vitro antibacterial activity of the compounds of formula (I) in the form of their salts was tested by measuring their minimum inhibitory concentrations (MIC) in µg / ml with respect to various microorganisms.

Tests were performed using heart-brain stretching (BHI) with agar. The tubes that grew overnight were diluted 100 times to obtain a standard sample (20,000-10000 cells in approximately 0.002 ml were placed on an agar surface; 20 ml of BHI agar / dish). Twelve twofold dilutions of the test compounds were used, the initial concentration of the test preparation being 200 µg / ml. When checking the plates after 18 hours at 37 ° C, the single colonies are not taken into account.

A known 2-ethyl-thiopenem is taken as a reference: (5R, 6S, 8R) -6- (1-oxystil) -2-ethylthiopenem-3-carboxylic acid (R., - ethyl). The test results of the antibacterial activity of the compounds of formula I are given in table. 3

From a comparison of the above data it can be seen that the proposed compounds have advantages over the known 2-ethylthiopenem. In addition, it was found that 2-ethylthiopene is unstable in an aqueous medium and produces an unpleasant odor, most likely due to the formation of ethyl mercaptan.

Form-pa invention

The ability to obtain 2-azacycloalkylthiopenem derivatives of formula

he

.S.SR, (I)

B Q- -TSh-kcoOH

where R is a radical of the formula

(cH.v and .;

m / o

g

where n is O or 1; p "1 or 2;

X is oxygen, sulfur or methylene; B is carbonyl or methylene;

2-Pyrrolidone-4-sh1

1-formyl-2-pyrrolidinyl

(3-methyl-1,3-oxazolidin-2-one-5-yl) methyl

(3-methyl-1,3-oxazolidin-2-one-4-yl) methyl

2-Piperidone-5-Ш1

Piperidine-2-on-3-pcs

1-Methylpiperidine-2-on-3-yl

1-formylpiperidin-3-yl

R is hydrogen, methyl or formyl.

1340590

7

In the form of their salts with alkali metals, characterized in that

compound of formula (II)

HE TT

four.

 1-lsoo1;

(Ii)

where R, has the indicated meanings; The R - group protecting the carboxyl group, which is removed by hydrogenolysis, preferably p-nitrobenzyl, is subjected to catalytic hydrogenolysis and the desired product is isolated as an alkali metal salt.

Table 1

2.92; 5.68; 6.0 and 6.15

2.92,6,64

6.03 and 6.3

2.94, 5.7 and 6.25

2.94, 5.7 and 6.28

5.64, 6.02

and 6.3 (DMSO)

2.94, 5.66,

6.06 and 6.25

2.93,5,64

and 6.15

2.9, 5.65 and 6.03

Z-Methyl-perhydro-1,3oxazine 2-one-5-yl

(less soluble)

diastereomer)

Z-Methyl-Perhydro-1,3oxazin-2-one-5-yl

(from the more soluble

diastereomer)

table 2

R IR spectrum, Vymkmkhod,

%

(1,3-oxazolidin2-on-4-yl) methyl5.7 (br.) 95

(1,3-oxazolidin2-OH-5-IL) -methyl 5.72 (br.) 87

(1,3-diazolidin2-OH-4-IL) -methyl 5.65 100

Table 3 RMIK, µg / ml

Staphylo- Escheri- Klebsi- cocus chia. ella aureus coli pneumo- 01A005 51A266 niae

53A009

2 3 4

3-Methyl-1,3-oxazoidin-2-one-4-yl) -methyl 0.05 0.05 0.10

0, 20,781,56

0.781,563.12

0, 393,123,12

0.050,100.20

Continuation of table 1

2.92, 5.63 5.99 and 6.08

5.65 (DMSO)

1340390

8 Continuation of table 3

Claims (1)

Claim A method of obtaining derivatives of 2azacycloalkylthiopenem of the formula SR1 С00Н (I) where R, is a radical of the formula where η ° 0 or 1; p "1 or 2; X is oxygen, sulfur or methylene; B is carbonyl or methylene; Rj is hydrogen, methyl or formyl, in the form of their salts with alkali metals, characterized in that the compound of formula (II) wherein R, has the indicated meanings; - the group protecting the carboxyl group, removed by hydrogenolysis, preferably η-nitrobenzyl, is subjected to catalytic hydrogenation and the target product is isolated in the form of a salt with an alkali metal. Table 1 R IR spectrum, microns Exit, % 1 2 3 2-pyrrolidone-4-yl 2.92; 5.68; 88 6.0 and 6.15 1-Formyl-2-pyrrolidine- NILE 2.92, 6.64 6.03 and 6.3 89 (3-Methyl-1,3-oxazo- lidin-2-one-5-yl) methyl 2.94, 5.7 and 6.25 78 (3-Methyl-1,3-oxazo- lidin-2-one-4-yl) methyl 2.94, 5.7 and 6.28 90 2-piperidone-5-yl 5.64, 6.02 and 6.3 (DMSO) 93 Piperidin-2-one-z-yl 2.94, 5.66, • 6.06 and 6.25 79 1-Methylpiperidin-2- he-3-yl 2.93, 5.64 and 6.15 98 1-Formylpiperidin-3-yl 2.9, 5.65 and 6.03 73 Continuation of table 1 --------------------1- 1 --------------1------------------------- 2 3 3-Methyl-perhydro-1,3oxazin-2-one ~ 5-yl (from a less soluble diastereomer) 2.92, 5.63 5.99 and 6.08 57 3-Methyl-perhydro-1,3oxazin-2-one-5-yl (from a more soluble diastereomer) 5.65 (DMSO) 84 table 2 ——————— IR spectrum You- μm move % (1,3-oxazolidin2-one-4-yl) methyl 5.7 (w) 95 (1,3-oxaolidin- 2-on-5-yl) methyl 5.72 (w) 87 (1,3-diazolidine- 2-on-4-yl) methyl 5.65 100 Table 3 R MIC, μg / ml Staphylo-  COCUS aureus 01A005 Escherichia. coli 51A266 Klebsiella pneumoniae 53A009 1 2 3 4 (3-Methyl-1,3-oxazolidin-2-one-4-yl) methyl 0.05 0.05 0.10 (3-Methyl-1,3-oxazoLIDIN-2-OH-5-IP) methyl 0.2 0.78 1,56 Piperidin-2-one-z-yl 0.78 1,56 3.12 1-Methylpiperidin-2-on3-yl 0.39 3.12 3.12 Piperid-2-on-5-ip 0.05 0.10 0.20 Continuation of table.Z 1 1 3 4 2-pyrrolidone-3-yl 0.10 0.05 0.10 1-Formyl-3-pyrrolidinyl 0.05 0.20 0.39 2-pyrrolidone-4-yl 0.05 0.20 0.39 1-Formylpiperidin-3-yl 0.20 6.25 12.5 Pyrrolidin-2,5-dion-3-yl 0.39 0.78 1,56 (1, 3-Thiazolidin-2-one- 4-yl) methyl 0.05 0.78 0.78 3-Methyl-perhydro-1,3oxazin-2-one-5-yl 0.05 0.10 0.20 (1, 3-Oxaeolidin-2-one5-yl) methyl 0.05 0.39 0.39 (1,3-0xazolidin-2-one- 4-yl) methyl 0.10 0.39 0.39 Ethyl 0.05 0.78 0.78