DE2857816C2 - 7β- (Substituted-isothiazole) thioacetamido-7-methoxy (alkyl-substituted-tetrazolyl) thiomethyl-Δ → 3 → -cephem-4-carboxylic acids, processes for their preparation and their use - Google Patents

Description

wherein Ri is a hydrogen atom, a carboxyl, a cyano, a carbamoyl, a hydroxymethyl or a Represents carbazoyl group and R 1 is a lower alkyl-substituted tetrazolyl group, and its pharmazeu-2ü table permissible salts.

2. 7X4-Carboxy-3-hydroxyisothiazol-5-yl) thioacetamido-7a-methoxy-3- (1-methyItetrazol-5-yl) thiomethyl-zl "-cephem ^ -carboxylic acid.

3. 7> (4-Amino-3-hydroxyisothiazol-5-yl) thioacetamido-7> methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-Λ'-cepherTHl-carboxylic acid.

4. 7j8- (3-Amino-4-cyanoiscthiazol-5-yl) thioacetamido-7a-methoxy-3- (l-methyltetrazol-5-yl) thiomethy! -

j'-cephem-4-carboxylic acid.

5. 7 / - (3-HydroxyisothiazoI-4-yI) thioacetamido-7e-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-j'-cephem-4-carboxylic acid.

6. A process for the preparation of 7 _{j /} ß- (substituted-isothiazole) -thioacetamido-7-methoxy (alkylsubstitu-; -ΰ ierter-tetrazolvIUhiomethyl-zT-cephenM-carboxylic acid according to claim 1, characterized in that Ία- amino-7_ / <- halogenacetaniido-3-heterocyclic-thiomethyl-j'-cephem-4-carboxylic acid with the general formula II

OCHj

X-CH ₂ COH

where X represents a halogen atom and R-, which has the meaning already mentioned, with the connection with the general Formula III

HO

or its alkali compound, in which R, which has the meaning already mentioned, is reacted and optionally is converted in a known manner into a pharmaceutically acceptable salt.

7. Use of the compounds mentioned in claim for combating bacterial infections.

This invention relates to new 7yj- (substituted-isothiazole) thioacclamido-7-methoxy (alkyl-substituted-c-! Etrazolyl) -lhioinethy! -. R-cephcm-4ciirboxylic acids of the general formula I.

SCH ₂ CONH

wherein R _{2 represents} a hydrogen atom, a carboxyl, a cyano, a carbamoyl, a hydroxymethyl or a carbazoyl group and R _{3 is} a lower alkyl-substituted tetrazolyl group, and their pharmaceutically acceptable salts as well as those in claims 3-5 named compounds.

A particularly preferred compound is T / J - ^ - CarboxyO-hydroxyisothiazoI-S-yOthioacetamido ^ amethoxy-S-il-methyltetrazole-S-yOthiomethyl-j'-cephem ^ -carboxylic acid and their pharmaceutically acceptable salts.

The invention also comprises a process for the preparation of 7j8- (substituted-isothiazole) thioacetamido-7-methoxyialkylsübstituierten-tetrazolyOthiomethyl- ^ j'-cephem ^ -carboxylic acids of the general formula I, characterized in that 7 "-amino-7y ^ haloacetamido- 3-heterocyclic-thiomethyl- / l ^3- cephein-4-carboxylic acid with the general formula II

X - CH ₂ COH-1

wherein X represents a halogen atom and R _{3 has} the meaning already mentioned, with the compound with the general formula III

HO R ₂

N Η W

S ^X _SH

or its alkali compound, in which R _{2 has} the meaning already mentioned, is reacted and optionally converted into a pharmaceutically acceptable salt in the usual way.

Finally, the invention includes the use of the compounds mentioned in general formula 1 to fight bacterial infections.

The claimed compounds of this invention having the general formula (I) and their pharmaceuticals Permissible salts have a better antibacterial effect than all known cephalosporins. Both The tests carried out were the compounds according to the invention in comparison with CS-1170 and cefoxitin compared.

The lower alkyl group in the general formula (I) is a straight chain or branched chain alkyl group with 1 -4 carbon atoms such as methyl group, ethyl group, isopropyl group, n-butyl group, tert-butyl group.

The compounds according to the invention with the general formula (I) are prepared by reaction a compound with the general formula (II) with a compound of the general formula! (III) under basic conditions.

The. The reaction is usually carried out in a solvent at room temperature or under cooling. Any solvent that does not take part in the reaction can be used without limitation but usually water, methanol, acetone, tetrahydrofuran, dimethylformamide or theirs Mixtures used as solvents. The compound of formula III can usually be used as its alkali metal salt can be used on the mercapto group, but when the compound of formula III is in the form in which it is is present, is used, the reaction in the presence of an aliphatic, aromatic or heterocyclic Base, e.g., triethylamine, N, N-dimethylaniline, N-ethylmorpholine, pyridine, collidine, 2,6-lutidine. or an alkali metal carbonate or alkali metal hydrogen carbonate, such as sodium carbonate, potassium carbonate, Sodium hydrogen carbonate, potassium hydrogen carbonate.

The isolation and purification of the product from the reaction mixture is carried out according to customary methods, 7 B. Extraction with organic solvent, crystallization, column chromatography, carried out.

The compounds of general formula I obtained in this way are new compounds. Own the connections an isothiazolylacetamide group in the 7-position, as it has been in the chemistry of cephalosporins, both

for example in US-PS 34 64 999 is described, but the compounds with the specific structure with an isothiazolylthioacetamide group have not yet become known.

The compounds of the invention have excellent antibacterial activity, especially against gray-negative ones Bacteria as shown in Table I below.

Table I.

Example no. (M l.C.) (µg / ml) 1.56 Escheri ?. Klebsieila Proteus Proteus Serratia Escheria 0.78 CoIi Ebara pneumoniae V-17 vulgaris OXK US rettegeri Y-I marcescens CoIi NlHJ 0.39 0.19 1.56 0.78 0.78 1 0.19 0.78 1.56 3.13 12.5 6.25 2 G, 78 1.56 1.56 3.13 3.13 6.25 3 0.78 0.78 0.39 50 25th 5 0.78 3.13 1.56 1.56 6th 1.56 1.56 7th 0.39 1.56 0.78 1.56 12.5 6.25 8th 0.39 1.56 0.78 3.13 2.5 12.5 9 0.78 0.19 0.39 1.56 12.5 3.13 10 0.19 Known connections 0.78 12.5 6.25 50 50 Cefoxitin 0.78 0.78 3.13 50 6.25 CS-1170

The compounds of the formula I of this invention can easily be converted into their pharmaceutically acceptable non-toxic or effective salts are transferred. These salts include the alkali metal salts such as sodium or Potassium salt or salts (e.g. using sodium or potassium 2-ethylhexanoate), ammonium salt or salts and organic amine salt or salts such as those with procaine or ethanolamine which are known by those skilled in the art can be produced by known methods.

The pharmaceutical preparations have antibacterial activity and have a pharmaceutical Carriers and an active, but nontoxic, amount of the compound of Formula I, and they are well suited door Method of combating bacterial infections by administering such a pharmaceutical preparation to an infected human or animal in a non-toxic amount that is sufficient. about such To fight infections, which also belong to the subject of the invention.

The compounds of this invention can be administered orally, rectally, or by subcutaneous, intramuscular, or intravenous Injection.

The injections are made from suitably prepared sterile solutions or suspensions that are effective, but contain non-toxic amount of the cephelosporin compound of this invention, manufactured and manufactured preferred form of administration.

The doses of the cephalosporin compound of this invention are usually 250-3000 mg / day for an adult and can vary according to the type of disease, age, weight and status of the patient be adjusted accordingly.

The invention will now be described in more detail by referring to the following examples will.

example 1

270 mg of 4-carboxy-5-ethylthio-3-hydroxyisothiazole were suspended in 10 ml of liquid ammonia. After cooling the suspension to-5O ⁰ C and addition of; 0C mg of metallic sodium, the mixture was

Stirred for> 5 for 30 minutes at temperatures from -50 ° C to -33 ° C.

Liquid ammonia was distilled off from the reaction mixture. The residue obtained was each in 20 ml Dissolved methanol. Then 10 ml methanol solution of 600 mg 7 /? -Bromoacetamido-7ff-methoxy-3- (1-methyItetrazol-5-yl) thiomethyl-J '-cephem ^ -carboxylic acid was added dropwise to the solution under ice-cooling. After stirring the mixture for 30 minutes with ice cooling, the mixture was still for

> Stirred for 30 minutes at room temperature. After completion of the reaction, the reaction mixture was on pH 4 adjusted with 4 η hydrochloric acid. Then the reaction solvent was reduced under reduced pressure Distilled pressure.

Water was added to the residue formed. After adjusting the mixture to pH 1 with 4 η hydrochloric acid, the product with 50 ml of a mixture of butanol and ethyl acetate in volume

ό ratio 1: 1 extracted. The organic layer formed was ^zwe: washed twice each with water and then washed once with saturated aqueous sodium chloride solution. It was dried over anhydrous magnesium sulfate. Then the solvent was distilled off under reduced pressure. To the residue obtained, 30 ml of ether was added. The precipitates formed were removed by filtration

collected and washed three times with 20 ml of ether each time. Then it was dried under reduced pressure, 560 mg of powdery 7 / M4-Carbo \ y-3-hydroxyisothia / ol-5-yl) lhio; icotaniido-7 </ - melhoxy-3- (I-methyI-lclrii / ol-5-y I) Ih ionic thy I-.1'-cc ρ he m-4-carbon sii ure obtained.

Nuclear magnetic resonance spectrum (D ₁₁ -DMSO)

f5 (p. p. m.): 3.41 (3 II). 3.58 (2 II). 3.93 (3 II), 3.99 (2 II). 4.28 (2 II), 5.10 (I II).

Example 2

HO-! T-NH ₂

Ν —Ν
SCH ₂ CONH-

After cooling, 40 ml of liquid ammonia at - 70 ⁰ C were back / ugclugt 183 mg 4-Amino-5-ethylthio-3-hydroxyisothia / ol and then 55 mg of sodium to the liquid ammonia. The mixture was stirred for 10 minutes at the same temperature. Then liquid ammonia was distilled off. 15 ml of methanol were added to the residue, followed by cooling to 2 ° C. 15 ml of meth; inol solution of 300 mg of 7>'- bromoacetamido-7tf-methoxy-3- (l-methyitetrazoi-5-yi) thiomcihyi- / i'-cephem-4-carboxylic acid were added dropwise to the mixture over a period of 30 seconds added. It was stirred for 10 minutes at the same temperature. The solvent was distilled off under reduced pressure. After adding 15 ml of water to the residue, the mixture was adjusted to pH 2.5 by adding 5% hydrochloric acid. The precipitates formed were extracted with 100 ml of a mixture of NH, anol and ethyl acetate in a volume ratio of 1: 1. The extracts were washed with water and then rewashed with saturated aqueous sodium chloride solution. It was dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue formed was subjected to silica gel column chromatography. 180 mg of 7jS- (4-amino-3-hydroxyisothiazol-5-yl) thioacetamido-7yS-methoxy-3- (1 -methyltetrazol-5-yl) thiomethyl- / ⁱ -eephem-4-carboxylic acid were added using a Mixture of chloroform, methanol and formic acid in a volume ratio of 8: 2: 0.2 obtained as eluent.

Nuclear Magnetic Resonance _{Spectrum (D 6} -DMSO)

<5 (ppm): 3.36 (3 H), 3.54 (2 H), 3.58 (2 H), 3.94 (2 H), 4.30 (2 H), 5.09 ( IH).

Example 3
HO

The procedure indicated in Example 2 was followed. 100 mg of 7jβ- (4-carbazoyl-3-hydroxyisothiazol-5-yI) thioacetamido-7ff-methoxy-3- (1-methyltetra2ol-5-yl) thiomethyl-J ³ -cephem-4-carboxylic acid were obtained from 220 me 4 -Carbazoyl-5-ethylthio-3-hydroxyisothiazole and 400 mg of 7 _J ö-bromoacetamido-7a'-methoxy-3- (1-methyltetrazo! -5-yl) thiomethyl- ^ ³ -cephem ^ l-carboxylic acid.

Nuclear Magnetic Resonance _{Spectrum (D 6} -DMSO)

<5 (p. P-m.): 3.39 (3 H), 3.63 (2 H). 3.90 (2 H), 3.93 (3 H), 4.30 (2 H), 5.13 (I H).

HO

N-N

(a) In 60 ml of methanol, 6.1 g of 7j3-bromoacetamido-7a-methoxycephalosporanic acid was dissolved. Then, 15 ml of ice-cooled aqueous solution of 4.3 g trisodium salt (trihydrate) of 4-carboxy-3-hydroxy-5-mercuptoisothiazol dropwise added to the solution at 0-5 ⁰ C. The mixture was stirred for 30 minutes at the same temperature, and methanol was distilled off under reduced pressure. The residue was mixed with 40 ml of water, adjusted to pH 3 with 2η hydrochloric acid and washed with ethyl acetate. The watery layer was continued on pil! adjusted with hydrochloric acid and extracted twice: o each time with a mixture of n-butanol and ethyl acetate in a volume ratio of 1: 1. The organic layer was washed with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. Then the solvent was distilled off. A powdery crude product was obtained. The product was dissolved in a small amount of methanol and then cooled with ice to crystallize. The crystals were separated by filtration. 4.8 g (64.2% yield) of purified white crystals of 7 / <- (4-carhoxy-3-hydroxyisothiazol-5-yl) thioacetamido-7a-methoxycephalosporanic acid were obtained.

Nuclear Magnetic Resonance _{Spectrum (D 6} -DMSO)

(5 (p. P. M.): 5.20

4.84

1 H,

H S \

-N

S H

2 H. K. ql.
// ^ H )

4.02 12 H, SCH ₂ CO-, SJ,

3.52

2 H, CH ₂ O-, q,

50

3.44

OCH ₃ 3H ₁ -J- /, s

2.04 (3H, -OCOCH ₃ , s).

60 65

(b) 300 mg of 7j8- (4-carboxy-3-hydroxyisothiazol-5-yl) thioacetamido-7a-methoxy-cephalosporanic acid, 67.2 mg of 5-mercapto-1-methyltetrazole and 146 mg of sodium hydrogen carbonate were added to 6 ml of water. The mixture was stirred for 16 hours at 60-62 ⁰ C. The reaction mixture was adjusted to pH 1 with 2 η hydrochloric acid while cooling with ice. The formed precipitates were separated by filtration, dried over phosphorus pentoxide under reduced pressure. 7jJ- (4-carboxy-3-hydroxyisothiazol-5-yl) thioacetamido-7a-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-2f ³ -cephem-4-carboxylic acid mg were obtained.

By the same procedure outlined in Example 1, the following compounds were made:

I I

Example 5

7yM4-cyano-3-hydroxyisothiazol-5-yl) thioacctamido-7ij'-methoxy-'i- (1-methyltetrazol-5-yl) -thiomethyl- / 1 ¹ -cephem-4-carboxylic acid

Nuclear Magnetic Resonance _{Spectrum (D 6} -DMSO) (5 (pp m>. 3.39 (3H), 3.59 (2 H), 3.92 (3 11), 4.11 (2 H), 4.28 (2H) , 5.10 (1H).

Example 6

7j? - (3-Amino-4-cyanoisothiazol-5-yl) thioacetamido-7a-methoxy-3- (1-methyltetrazol-5-yl) -thiomethyl-j'-cephem ^ -carboxylic acid

Nuclear Magnetic Resonance _{Spectrum (D 6} -DMSO) (5 (ppm): 3.40 (3 H), 3.60 (2 H), 3.95 (3 H), 4.08 (2 H), 4.31 ( 2H), 5.11 (1H).

Example 7

7> (3-Hydroxyisothiazol-4-yl) thioacetamido-7a-methoxy-3- (1-methyltetrazol-5-yl) -thiomethyl-j'-cephem ^ -carboxylic acid

Nuclear Magnetic Resonance _{Spectrum (D 6} -DMSO) δ (p. Pm): 3.39 (3 H), 3.48 (2 H), 3.66 (2 H), 3.94 (3 H). 4.26 (2H), 5.11 (1H). 7.59 (1H).

Example 8

7X4-carbamoyl-3-hydroxyisothiazol-5-yl) thioacetamido-7a-methoxy-3- (l-methyltetrazol-5-yl) -

thiomethyl - ^ '- cephem ^ -carboxylic acid

Nuclear Magnetic Resonance _{Spectrum (D 6} -DMSO) <5 (ppm): 3.39 (3 H), 3.49 (2 H), 3.64 (2 H). 3.93 (3H). 4.28 (2H). 5.07 (1H).

Example 9

7X3-Hydroxy-4-hydroxymethylisothiazol-5-yl) thioacetamido-7ff-methoxy-3- (l-methyltetrazol-5-yl-

thiomethyl-j'-cephem-1-carboxylic acid

Nuclear Magnetic Resonance _{Spectrum (D 6} -DMSO) <5 (ppm): 3.40 (3 H), 3.58 (2 H), 3.83 (2 H), 3.92 (3 H). 4.12 (2H), 4.30 (2H). 5.10 (1H).

40

Example 10

45

Ν —Ν

50 55

^{A solution of 250 mg of 7j5-bromoacetamido-7e-methoxy-3- (1-methyltetrazol-5-yI) thiomethyl-J 3 was added} to a solution of 123 mg of the sodium salt of 3-hydroxy-5-mercaptisothiazole in 6 ml of methanol, while cooling with ice -cephem-4-carboxylic acid in 4 ml of methanol was added dropwise and then stirred at room temperature for 2 hours.

When the reaction had ended, the procedure indicated in Example 1 was followed. 153 mg of 7jβ- (3-hydroxyisothiazoI-5-yl) thioacetamido-7ff-methoxy-3- (1-methyltetraiZoI-5-yl) thiomethyl- ^ l ³ -cephem-4-carboxylic acid were obtained.

Nuclear Magnetic Resonance _{Spectrum (D 6} -DMSO) (ρ. Σ., M.) 3.38 (3 H), 3.60 (2 H), 3.90 (3 H), 3.94 (3 H), 4 , 30 (2H), 5.10 (1H), 6.61 (1H).

Claims (1)

Patent claims: 1. TjS-t-substituted-isothiazole-thioacetamido-T-methoxyialkyl-substituted-tetrazolyhthiomelhyl-.d'-cephem ^ t-carboxylic acids of the general formula I. HO OCH ₃ SCH ₂ CONH