DE2065621C3 - 3-Thiadiazolylmercaptomethyl- and 3-tetrazolylmercaptomethyl-cephalosporins and processes for their preparation - Google Patents

Description

The invention ^{relates to:} I-thiadiazo] yl mercaptomethyl and 3-tetrazolyl mercaptomethyl cephalosporins of the general formula Ii

is atoms, and X is a group of the general formula

/ -. Il

/ V-CH-C-NH

or the formula

(D

COOH
wherein R ^{1 is} a group of the general formulas

N-N

'5 -NHR ²
O

Il

—O — C — H

denotes in which R ^{2 represents} a Rtst of the formulas
O

—C

c-z

Ν — Ν

/ ft \

- C ^ N

N
Z

is. in which Z is an alkyl radical with I to 3 carbon

or

2S stands.

Il

-CO-CH ₂ -CC!.,
O

Il

-C = CH — C —Ο — CH ₃
CH ₃

The cephalosporins according to the invention can be prepared by using a cephalosporin of the general formula II

(II)

COOH

wherein X has the above meaning, with a thiol of the general formulas lilac or HIb

Ν — Ν

y \

HS-C C-Z

la)

Patent 20 18 600 protected compounds used can be.

From BE-PS 6 17 687 is already a method for Preparation of cephalosporin C derivatives known by using compounds of the general formula

R ²

HS-C

N-N

I. ζ

-N

CH ₂ -OR ¹

(HIb)

in which Z has the above meaning, with repression the Acetoxygruppc in position 3 reacts.

The compounds of the general invention Formula I are valuable intermediates, for example for the production of the German COOH

where R ^{1 is} an acyl radical and R ² and R ³ are hydrogen atoms or R ^{2 is} a hydrogen atom and R ^{3 is} an acyl group or an alkanoyl radical substituted by a triaryl group, or where R ² and R ³ together are a dicarboxylic acid derived from a dicarboxylic acid Form a residue or salts of such compounds in a polar solvent with a strong nucleophilic agent, for example a thiol, to displace the group —O — R ¹ in position 3.

This known process is similar to that for the preparation of the compounds according to the invention applied working method, but it assumes different starting products and leads therefore also to other products. Both types of connection differ fundamentally in terms of their substituents of positions 3 and 7.

The intermediates according to the invention also lead to cephalosporin antibiotics which are known Compounds cephalothin, cephalexin and cephaloridin are superior in their effects, as can be seen from the The following test report emerges later.

The invention is explained in more detail with reference to the following examples.

example 1

a) A mixture of 27.2 g (0.1 mol) of 7-aminocephalosporanic acid in 200 ml of water and 100 ml Acetone is stirred with a saturated sodium bicarbonate solution to a pH of 7.9 offset. This solution is placed in a bath of 80 C, and when the internal temperature reaches 45 C. has. with a solution of 19.6 g (1.15MoI) 2-methyl-1,3,4-thiadiazole-5-thiol in 200 ml acetone offset. The mixture is heated in the 80 ° C bath for 3 hours, then cooled to 10 ° C and adjusted to pH 3.9 by adding 6η-hydrochloric acid. The cold mixture will last for 15 minutes stirred, and the solid is filtered off, with acetone washed and dried. There are 24 g (70%) 7-amino-3- (2-methyl-1,3,4-thiadiazolyl-5-thiomethyD-

I obtained ^3- cephem-4-carboxylic acid. The expected structure is confirmed by nuclear magnetic resonance and ultraviolet spectroscopy.

b) 15.2 g (0.1 mol) »-mandelic acid are in 250 ml Formic acid is stirred in and the mixture is left to stand at room temperature for 2 days. Man the solution is concentrated in vacuo, the residue is dissolved in benzene, the benzene solution is washed with water, dried over magnesium sulfate, filtered and evaporated to dryness, giving 13.2 g of n-mandelic acid formal ester can be obtained.

A solution of 3.6 g (0.02 mol) of the D-mandelic acid formate test in 25 ml of dry benzene at room temperature, 5 ml of oxal chloride and 1 drop of dimethylformamide are added. After 2 hours Long stirring at room temperature, the solution is concentrated in vacuo, whereby the formate ester is obtained from D-mandclyl chloride as an oil.

c) The above oil is dissolved in 40 ml of acetone, and the acid chloride solution is added to an ice-cold solution of 3.44 g (0.01 mol) of the product from a) and 5 g of sodium bicarbonate in 100 ml of water and 100 ml of acetone . This mixture is stirred in the cold for 1 hour and then at room temperature for 2 hours. The acetone is below. removed under reduced pressure, and the aqueous mixture obtained is added with stirring to a cold mixture of 100 ml of water and 200 ml of ethyl acetate. The pH is adjusted to 2.0 by adding 6N hydrochloric acid. After filtering through a filter aid, the aqueous layer is discarded and the ethyl acetate layer is washed with water, dried over magnesium sulfate and concentrated in vacuo to an oil. The oil is triturated with ether, causing it to solidify, and the solid is filtered off and dried. 4 g of 7- (D-2-formyloxy-2-phenyl-acetamido) -3- (2-methyl -1.3.4 - thiomethyl thiadiazolyl - - 5) - obtained ccphem-4-carboxylic acid - I. ³ NMR spectrum: 2.7 (singlet). 3.4 (quartet). 4.7 (quartet), 4.93 (doubles |. 5.64 (doubles). 6.2 (singlet), 7.45 (multiples) and 8.3 (singlet) ppm.

From the formate-protected thiadiazoles cephalosporanic acid obtained, the formyl protective group can be split off in the usual way by treatment with sodium bicarbonate solution, 7-i> -mandelamido-3- (2-methyl-1,3.4-thiadiazolyl-5-thiometInI) -l ³ -cephem-4-carbonsüiirc receives.

Sodium 7-D-almondamido-3- (2-methyl-1.3.4-thiadia / olyl-5-thiomethyl) -l ³ -ccphcm-4-carboxylate has a pKa of 4.9.

Example 2

a) The procedure of Example la) is repeated using 1-methyl-1,2,3,4-tctrazole-5-thiol instead of the thiadiazole. 25 g (76%) of 7-amino-3- (1-methyl-1,2,3,4-tetrazo! Yl-5-thkv methyl) ^{-1 3} -ccphcm-4-carboxylic acid are obtained. NMR spectrum: 3.3 to 4.0 (quartet), 4.1 (single), 3.9 to 4.5 (quartet). 5.1 (singlet) and 5.5 (singlet) ppm.

b) The procedure of Example Ib) to Ic) is repeated using the product from Example 2a). I: s are 2 g of 7- (i) -2-formyioxy-2-phenyI-acetamido) -3- (I -methyl- l ^^^ - tctrazolyl-S-thiomethvl) -l ³ -cephcm-4-carboxylic acid receive. NMR spectrum: 3.3 to 3.8 (quartet). 4.0 (singlctt), 3.9 to 4.5 (quartet). 5.1 (singlet). 5.35 (singlet), 5.7 (singlet) and 7.55 (singlet) ppm.

Trial report

Testing of various cephalosporins against gram-positive and gram-negative organisms (gradient plate test)

connection

Cephalothin

Cephalexin

Cephaloridin

Sodium-7-D-almondamido-

3- (1-methyl-1.2.3.4-telrazolyl-

5-thiomethyl) - l'-cephcm-

Grief +. MK. .0 VM Grief . MIC N 26 X 26 X 528 X 61 \ M2 X 400 .4 0.4 N9 NlO 10.4 0.75 > 200 2.4 0.5 > 2 (l 3.8 8.S 6.4 9.3 6.6 > 2 (X) 6.4 4.8 > 2M 0.8 10.4 9.7 3.3 > 200 2.9 1.0 12th 0.6 3.4 3.3 0.6 0.6 > 50 0.5 0.8 13th 0.5 1.3 I.

continuation

connection

Grief +. MIC V 32 X 4 (X)

V

MIC

N 2 (p

X? 6

X52X

Sodium 7-D-almondamido 4.3> 20 4.2

3- (2-methyl-1,3,4-thiadiazolyl-

5-yl-thiomethyl) ^{-1 3} -cephem-4-carboxylate

3- (2-MethyI-1.3.4-thiadiazolyl-4,2> 20 6.9

5-yl-thiomethy!) - 7-i> phenylglycylamidol ³ -cephem-4-carboxylic acid

MIC = Minimal Inhibitory Concentration.

V 32 = Staphylococcus aurcus. X 4 (X) = Staphylococcus aurcus. V 84 = Staphylococcus aurcus. N9 = Shigella sp. NOK = E. coli. N 26 = E. coli. X 26 = Klebsielia pneumoniae X 528 = Pseudomonas sp. X 68 = Enterobacter aerogencs

1.9

5.2

1.7

1.2

> KX) 3.4

> HX)

comparison

some cephalosporins Sodium- Cephalo 0.5 C'cpha lo 0.25 30th organism Sodium-
7-D-man- Cephalo
ridin CephaU
tin 7-n-man- ridin 0.5 tin 0.5 del- for different organisms dcl- 4.0 1.0 amido amido 4.0 0.5 3h I-me 3- (1 -me ethyl-1.2. Organisms ethyl 1.2. 3.4-tclra- 3.4-tctra- 4.0 32 .,. zolyl zolyl ZO 8.0 5 thio 5 thio ZO 16 methyl) - melhyll- ZO 4.0 ^ -eephem- l ^J -ccphcm-
4-carb 4-carb oxylai oxylate 4.0 1.0 ZO 0.5 40 0.03 > 128 > 128 Mima pohmorpha 0.06 MP 1 0.25 1.0 0.5 0.125 ZO 1.0 45 Proteus mirabilis 0.125 4.0 ZO PR 6
PR 10 1.0
10 8.0
8.0 4. (1
8. (1 Li -
Clostridium
perfringens P. morganii CP 23 50 PR 1 1.0 > 128 > 12S CP 24 1.0 PR 15 1.0 > 128 > 128 Neisseria gonorrhoeae 1.0 G - N. meningitidis OS 1.0 P. rettgeri G - 0.5 55 PR 7 0.5 > 128 > 128 Escherichia coli PR 9 ZO 128 > 128 EC 9th variant P. vulgaris EC 31 0.5 PR 27 32 > 128 > 128 EC 35 0.5 6o PR 28 8.0 > 128 > 128 EC 38 32 Salmonella sp. Haemophilus SA 4, typhimurium 1.0 4.0 4.1 influenzae 0.5 SA IZ typhosa 1.0 4.0 4y St. 1 1.0 6s Shigella sp. HI 2 SH 3, flexneri 2a ZO 8.0 8.1 Herellea sp. HE 28 SH 10. Sonnei I ZO 8.0 8.1 Klebsieila pneumoniae Ci -► - gram positive. KL 3 G = gram-neutral.

Toxicity study

To determine the toxicity of the Λη-ca which can be prepared from the erlingemous intermediate products, the corresponding compounds are administered enosely to mice. The ι D ₅₁ , for

Nauium-7-i) -mandelamido-3- (I-melh) 1-1.2.3.4-letra- / olyl-5-thiomethyl) -l'-cephem ^ -carboxylate is therefore 4047 to 5301 mg / kg. This value moves within the generally recognized low toxicity range for cephalosporins.

Claims (2)

Patent claims: 1. 3-thiadiazolyl mercaptomethyl and 3-tetrabtoITatomen, and X is a group of the general zolyliTiercaptomethylcephalosporins of the general formula
nen formula I NHR ² / ~ VcH-C-NH -CH, -S-R COOH (I) wherein R ^{1 is} a group of the general formulas Ν — Ν - C C-Z or the formula IO Il —O — C — H is where R ^{2 is} a radical of the formulas Il —C — O — C (CH,)., ! I or Ν — Ν C N -CO-CH ₂ -CCl ₃ Il C = CH-C-O-CH., CH, N I
Z stands. 2. Process for making compounds according to claim I, characterized in that a cephalosporin is used in a manner known per se is. in which Z is an alkyl group with 1 to 3 carbons of the general formula 11 O <- Il ^ j ~> ^ Il / \ <f> - CH- C — NH- -N -CH ₁ -OC-CH ₃ Il ο COOH wherein X has the meaning given in claim 1, with a thiol of the general formula III a or HIb N-N Ν - Ν HS-C C-Z (purple) or HS-C (1Mb) I ζ in which Z has the meaning given in claim I. tiniset / t.