JPS5814440B2 - Cephalosporins - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel cephalosporins and salts thereof having broad spectrum antibacterial activity and processes for their production.

Although cephalosporin derivatives are known to be substances with antibacterial activity, the known cephalosporin derivatives must be used in large quantities.

Therefore, in order to obtain a cephalosporin derivative having higher antibacterial activity, the present inventors conducted repeated research on various derivatives, and as a result, arrived at the present invention.

The objects of the present invention are cephalosporins in which the sulfinyl group is in the R form among the compounds represented by the following general formula (I) and salts thereof.

[However, R1 is chenyl, A is 1-methyl-1H-
Tetrazol-5-ylthio, 5-methyl-1,3,4
-thiadiazol-2-ylthio, M represents hydrogen, alkali metal, or amine salt ion.

) The R form, which is the object of the present invention, means that the steric structure of the sulfinyl group of the compound of the above formula (I) is of the general formula
(R,
is the same as above) Among the optical isomers of the sulfinyl group of the compound represented by, it is defined as having the same steric structure as the steric structure in which the specific rotation [α]D in alcohol is positive.

The compound of formula (II) is asymmetric in its sulfinyl group and has two types of optical isomers, and therefore, cephalosporins derived therefrom also have two types of isomers in its sulfinyl group.

Among these two types of isomers, cephalosporins derived from an optically active form of the compound represented by formula (■) in which [α]D is positive in ethanol, or Cephalosporins derived from mixtures containing compounds of the formula (■) exhibiting a positive [α]D in ethanol each have a compound of the formula (■) exhibiting a negative [α]D in the corresponding ethanol.
It was discovered that this compound has more antibacterial activity than cephalosporins derived from the compound II).

Among the groups of R1, preferable groups are 2-chenyl, 3-
Chenyl is particularly preferred, and 2-chenyl is particularly preferred.

Particularly preferred groups as A are 1-methyl-11H-tetrazol-5-ylthio and 5-methyl-1,3,4-thiadiazol-2-ylthio, which have the most antibacterial activity.

The compounds according to the invention can be produced as follows.

(a) A compound of formula (■) (wherein A and M are the same as above) or a reactive derivative thereof is reacted with R-carbonic acid of formula (II) or a reactive derivative thereof.

Specific examples of the R-carboxylic acid of formula (II) are the same as those in which -COOH is bonded to the moiety R1-S-CH2- of the R-form of the compound of interest of the present invention, that is, [α]D in the ethanol.
is positive.

Reactive derivatives of compounds of the formula are, for example, silyl esters or amine salts.

Reactive derivatives of carboxylic acids of formula (■) are, for example, acid chlorides, acid anhydrides, amides, azides, active esters or salts (formed, for example, by alkali metals or alkaline earth metals, ammonia or organic bases). salt)
It is.

The reaction between the compound of formula (■) and the compound of formula (■) is
in a suitable solvent such as acetone, dioxane, tetrahydrofuran, acetonitrile, chloroform, methylene chloride, and if desired in the presence of a base such as sodium or potassium bicarbonate or a trialkylamine, at room temperature or cooled. Do it below.

When the compound of formula (II) is reacted as a free acid or as a salt, the condensing agent may be dicyclohexycarbodiimide, diphenyl phosphate azide, diethyl phosphate cyanide, hexachlorocyclotriphosphatriazine, triazine trichloride, etc. It is desirable to carry out the reaction in the presence of.

Compound (I) of the present invention has a high degree of antibacterial activity against Gram-positive bacteria and Gram-negative bacteria in animals and humans, and therefore prevents infectious diseases caused by the bacteria.
For example, respiratory tract diseases such as bronchitis, bronchopneumonia, pleurisy, hepatobiliary and abdominal diseases such as cholecystitis, peritonitis, blood and cardiovascular diseases such as sepsis, urinary tract diseases such as pyelonephritis, cystitis, otitis media. , useful in the treatment of otorhinolaryngal diseases such as parotitis.

The compounds of the present invention are effectively absorbed by oral or parenteral administration.

In the latter case, these compounds may be dissolved in a suitable solvent, such as sterile water, saline solution, dextrose solution, or conventional intravenous fluids or electrolyte solutions, for example, in a dosage format for adults. It can be administered in an amount of about 100 mg to about 200 mg.

The following examples illustrate the invention in detail, but the invention is not limited to these examples.

Reference Example 1 11.6 g of 2-mercaptothiophene and 10.4 g of monochloroacetic acid were mixed with 8.8 g of caustic soda and 100 ml of water.
After refluxing for a period of time, the pH was adjusted to 2.0 with hydrochloric acid to precipitate an oily substance.

This was extracted with ethyl acetate, dried over anhydrous sodium sulfate,
Upon concentration, 121 g of pale yellow crystals were obtained.

NMR (CDCI3) δ3.5 (2H,S), δ
6. 9-7. 4 (multi, 3H), δ
1 1.6 (s, IH).

Reference Example 2 8.7 g of 2-chenylthioacetic acid was dissolved in 30 ml of acetic acid, and while stirring under water cooling, 6.8 ml of 30% hydrogen peroxide solution was added.
and further stirred at room temperature for 5 hours.

Acetic acid was removed from the reaction solution under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain 5.3 g of 2-chenylsulfinyl acetic acid.

Melting point 114-116°C, NMR (DMSO-d6) δ4
．． 1 (s12H), 7. 1 5 (multi, I
H), 7.55 (t, IH), 7.9 (d, IH), elemental analysis C6H6S203, calculated value C: 37.88
, H: 3.18, S: 33.71, Actual value C: 37, 7
6, H: 3.31, S: 33, 48.

Reference example 3 2-chenylsulfinyl acetic acid 1.00g and brucine 2
．． After dissolving 57 g in 25 ml of ethanol, it was concentrated to dryness.

After washing the residual powder with 35 ml of hot benzene, the insoluble material 2,351 is recrystallized from 20 ml of ethanol.

By treating 1.50 g of the obtained crystals with hydrochloric acid, extracting with ethyl acetate, concentrating the organic layer, and further crystallizing from ethyl acetate, 0.35 g of optically active 2-chenylsulfinyl acetic acid was obtained. I got it.

In ethanol [α] ■ Exhalation +11.0°C - 1. 0
Met.

Reference example 4 2-thhenylsulfinyl acetic acid ([
α)': +11.0°C=1. OO ethanol) is dissolved in 8 ml of dry acetone, and further 0.28 ml of triethylamine and 3 drops of N-N-dimethylbenzylamine are added and stirred.

The solution is cooled to -10°C and 0.24y of pivalic chloride is added while stirring.

After the dropwise addition, the mixture was further stirred at -10°C for 30 minutes, and then 7-aminocephalosporanic acid was added while stirring vigorously at the same temperature.
．． 54g, triethylamine 0. 28 g, a mixed solution of 3 ml of acetone, and 3 ml of water are added all at once.

Thereafter, the mixture was stirred at -10°C for 30 minutes, at 0°C for 1 hour, and at room temperature for 1 hour.

The reaction solution was concentrated below 40°C, washed with ethyl acetate, and then
Adjust the pH to 3 with normal hydrochloric acid and extract with ethyl acetate.

The organic layer was concentrated under reduced pressure and then dried under reduced pressure to obtain 7-(2-
Thienylsulfinyl acetamide) cephalosporanic acid? 0.43 g of crude crystals were obtained.

In order to confirm that this is a pure product, the crude crystals were treated with Sephadex L H-20 (
Pharmaira F ineChemicaljqls
AB) column chromatography.

NMR spectrum (DMSO-d6) δppm: 2.
O (s, 3H), 3.6 (q, 2H),
4.1 (q12H), 4.8 (q, 2H), 5. Dd
, IH), 5.7 (q, IH), 7.2 (t, IH),
7.6 (d, IH), 8.0 (d, IH), 9.2 (d
, IH), elemental analysis C16H16N20S3・%H20, calculated value C:
42.38, H: 3.78, N: 6. l8, S:21.
21, Actual value (::42.52, H:4.15, N:5
．． 78, S: 20.85.

Example 1 In the sulfoxide synthesized according to Reference Example 4, optically active R-form 7-(2-thienylsulfinylacetamido)cephalosporanic acid 300~, sodium hydrogen carbonate 130~ and 2-mercapto-5- 140 mg of methyl-1,3,4-thiadiazole was added to pH 6.
Heat and stir at 60° C. for 5 hours in 6 ml of the phosphate buffer solution prepared in Step 5.

After the reaction, the pH is adjusted to 2.5, the precipitate is collected, and the precipitate is dried to obtain optically active R in the sulfoxide.
7-(2-thienylsulfinyl acetamide)-
3-(5-methyl-1,3,4-thiadiazole-2-
220 mg of crude crystals of ylthiomethyl-3-cefemu-4-carboxylic acid were obtained.

A pure product was obtained by recrystallizing from water and acetone.

NMR spectrum (DMSO da ) δppm
: 2.7 (s, 3H), 3.7 (q, 2H), 4
．． 1 (q, 2H), 4.5 (q, 2H), 5.1
(d, IH), 5.7 (q, IH), 7.2 (t, IH
), 7.6 (a, IH), 8.0 (d, IH), 9, 2
(d, IH).

The minimum inhibitory concentration of this product against bacteria is shown in Table 1.

7-amino-3-(1-methyl-IH-tetrazole-
154 mg of 5-ylthiomethyl)-3-cephem-4-carboxylic acid-1-butyl ester and 83 cm of dicyclohexylcarbodiimide were dissolved in 5 ml of benzene, and 2-thhenylsulfinyl acetic acid ([α)',;'
: 10a 5.0°c=i. oo Ethanol] 76~
Add.

The reaction mixture is stirred at 25° C. for 2 hours, then filtered and adsorbed onto 2 g of silica gel.

Benzene-ethyl acetate (50:50) silica gel 2
Chromatography on 0g yields a white foamy 7-(
2-chenylsulfinyl acetamide)-3-(1-
Methyl-IH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid t-butyl ester 1
Obtain 45 mg.

This ester was dissolved in 1d of trifluoroacetic acid and heated at 25°C.
The mixture was stirred for 5 minutes and then added dropwise to 70 ml of ether.

The precipitate was collected, dissolved in 5% sodium bicarbonate, and 100 m
Let it be l.

After extraction with ethyl acetate, the aqueous phase is brought to pH 2.0 and extracted with ethyl acetate.

Dry the organic layer and concentrate to 5rnl, leaving 30%
A solution of sodium 2-ethylhexanoate in propanol is added followed by ether.

The precipitated salts were collected, reprecipitated from methanol-ether, and dried under reduced pressure to obtain optically active R in the sulfoxide.
Body 71 (2-thienylsulfinyl acetamide) -
3-(1-Methyl-IH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid sodium salt 51η was obtained.

NMR spectrum (DMSO d6) δppm:
3.70 (dd, 2H), 3.94 (s,
3I{), 4. +2 (dd, 2H), 4.3 2 (m
, 2H), 5.0 8 (d, IH), 5.8
(q, IH), 7.2 (m, IH), 7.56 (d, 1
}{), 7.96 (d, IH), 9.30 (d, IH)
.

The MIC of this product against bacteria is shown in Table 2.

Claims (1)

[Claims] 1 General formula (Ty, R1 is chenyl, A is 1-methyl-IH-
Tetrazol-5-ylthio, 5-methyl-1,3,4
-thiadiazol-2-ylthio, M represents hydrogen, alkali metal, or amine salt ion. ) A compound in which the sulfinyl group is in the R form among the cephalosporins. [Here, the R form is (R1 is the same as above) Among the optical isomers of the sulfinyl group of the compound represented by, the same three-dimensional structure as the three-dimensional structure in which the specific optical rotation [α]D in alcohol is positive Defined as having . ].