JPS5832886A - Cephalosporin - Google Patents

Abstract

NEW MATERIAL:A compound of formulaI(R1 is 2-thienyl, 3-thienyl, 2-pyridyl, 4-pyridyl, 2-imidazolyl; A is acetoxy; M is H, alkali metal, amine salt ion where the sulfinyl group has the R configuration in which R configuration means that, among optical isomers at the sulfiniyl group of the compound of formula II, it has the same configurational structure as that showing positive specific rotary power[alpha]d in an alcohol). EXAMPLE:7-(2-Thienylsulfinylacetamide)cephalosporanic acid. USE:Anbiotic: it shows strong antibiotic effect against gram-positive and-negative bacteria. For example, it is used to treat bronchitis, cholecystitis or sepsis. PREPARATION:The reaction of a compound of formula III or its reactive derivative such as silyl ester with a R-carboxylic acid of formula II or its reactive derivative such as acid chloride give an objective compound of formulaI.

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 compounds represented by the following general formula (1,1) and salts thereof.

0 (* ” L, R1ha2 chenyl, 3-f-enyl, 2-pyridyl, 4-pyridyl, 5-methyl-1,3
, 4-thiadiazol-2-yl, 1,3.4-thiadiazol-2-yl, 2-imidazolyl, 3-ynoxasilyl, 1-methyl-1H-tetrazol-5-yl, 1,2.4-) lyazol-3-yl, 2-pyrimidyl, phenyl, A represents acetoxy, M represents hydrogen, an alkali metal, or an amine salt ion. ) R which is the object of the present invention
The steric structure in the sulfinyl group of the compound of formula (I) above is the optical isomer of the sulfinyl group of the compound represented by the general formula (R1 is the same as above). ] It is defined as having the same three-dimensional structure as the three-dimensional structure where ゎ is positive.

The compound of 2I is asymmetric in the sulfinyl group,
Two types of optical isomers exist, and therefore, cephalosporins derived from this also have two types of isomers in the sulfinyl group. The inventors have discovered that these two
Cephalosporins derived from the optically active form of the compound of formula I, which is [α] positive in ethanol, or [α] positive in ethanol, among the isomers of the
] The cephalosporins derived from the mixture containing the compounds of 2I showing D are the formulas showing negative [α]D in the corresponding ethanol (than the cephalosporins derived from the compounds marked) It was also discovered that it has strong antibacterial activity.

Among the groups R1, preferred are 2-chenyl, 3-chenyl, 2-pyridyl, 4-pyridyl, 5-methyl-1
, 3,4-thiadiazol-2-yl, 1.3.4-thiadiazol-2-yl, 2-imidazolyl, 3-isoxasilyl, 1-methyl-I H-tetrazol-5
-yl, 1,2.4-triazol-3-yl, 2-pyrimidyl, phenyl, and especially 2-chenyl are preferred. Particularly preferred groups as A are acetoxy, 1-methyl-1H-tetrazol-5-ylthio, 5-methyl-
It is 1,3,4-thiadiazol-2-ylthio, and has the highest antibacterial activity.

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

A compound of the formula (21 (1)) 001M (wherein A and M are the same as above) or a reactive derivative thereof is reacted with the R-form carboxylic acid of 2I or a reactive derivative thereof.

Specific examples of the R-form carboxylic acid of formula (2) are the same as those in which -COOH is bonded to the moiety ↑ R1-8-CH, - -5= of the R-form of the object compound of the present invention, that is, [ α] is positive.

Reactive derivatives of compounds of formula (III) are, for example, silyl esters or amine salts.

Reactive derivatives of the carboxylic acids of 2I are, for example, acid chlorides, acid anhydrides, amides, azides, active esters or salts (e.g. alkali metal or alkaline earth metal,
salts formed with ammonia salts or organic bases).

The reaction between the compound of formula (m) and the compound of formula (2) 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 bicarbonate or potassium bicarbonate or a trialkylamine. , at room temperature or under cooling.

When the compound of formula (2) is reacted as a free acid or as a salt, dicyclohexylcarbodiimide, diphenylphosphoric acid azide, diethylphosphoric cyanide, hexachlorsif=6-lotrifosphatriazine is used as a condensing agent. It is preferable to carry out the reaction in the presence of triazine trichloride or the like.

The compound (I) of the present invention has a high degree of antibacterial activity against Durum-positive bacteria and Durum-negative bacteria in animals and humans, and therefore, the
-Ar infectious diseases, such as respiratory tract diseases such as bronchitis, bronchopneumonia, pleurisy, cholecystitis, hepatobiliary and abdominal diseases such as peritonitis, blood and cardiovascular diseases such as sepsis, pyelonephritis, cystitis, etc. It is useful in the treatment of otorhinolaryngal diseases such as urinary tract diseases, otitis media, and 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, physiological co-salt solutions, dextrose solutions or conventional intravenous fluids or electrolyte solutions, at approximately 1
It can be administered in an amount of 00m9 to about 20On+9. □The following examples describe the present invention in detail, but the present invention is not limited to these examples.

Reference Example 1 After refluxing 2-mercaptothiophene 11,6f and monochloroacetic acid 10,4S' with 8.82 g of caustic soda and 100 g of water for 6 hours, the mixture was adjusted to pH 2.0 with hydrochloric acid to precipitate an oily substance. This was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain pale yellow crystals 12.19. NMR (CDCl5) δ3,5 (2H.

S), δ6.9-7.4 (multi 3H), δ1
1,6 (S.

IH).

Reference Example 2 8.7y of 2-chenylthioacetic acid was dissolved in 30y of acetic acid,
Stir under water cooling and add 30% hydrogen peroxide solution 6.8 td.
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 give 2-
Chenylsulfinyl acetic acid 523f was obtained. Melting point 1.1
4-116°C, NMRl: (DMSO-da) δ4,1 (s, 2H),
7.15 (multi, 1H), 7.55 (t
, IH), 7.9 (d, IH), elemental analysis C6
Assuming Le S, 03, calculated value C: 57.88, H: 3
．． 18, S: 33,71, Actual value C:, 57,76
, i(: 3,3 1, S: 33,48° Reference Example 3 2-chenylsulfinyl acetic acid 1.00? ,!:
7'Rusine 2,57 TFC was dissolved in 25 ml of ethanol and then concentrated to dryness. After washing the residual powder with 35° hot benzene, 2.35 f of insoluble material is recrystallized from 20° of ethanol. The resulting crystals, 1.5 Or, were treated with hydrochloric acid, extracted with ethyl acetate, the organic layer was concentrated, and further crystallized from ethyl acetate to give J, 0.
359 optically active 2-chenylsulfinyl acetic acid was obtained. [α]B'+11.06C=1.0 in ethanol.

Example 1 2-chenylsulfinyl acetic acid ([
α 升'-4-11,0°C= 1.00 ethanol) 0
．． 58y is dissolved in dry acetone 8- and 3 drops of triethylamine 0.28- and N,N-dimethylbenzyl amine are added and stirred. Cool the solution to -10°C, and add 0.24 g of Pino(9-phosphate chloride) while stirring. After the dropwise addition, stir at -10°C for another 30 minutes, then stir vigorously at this temperature. From 7-
Aminocephalosporanic acid 0.54y.

Triethylamine 0.282 and acetone 3tnt.

Add the mixed solution of water 5- all at once. Then -10℃
Stir for 30 minutes at 0°C, 1 hour at 0°C, and 1 hour at room temperature. The reaction solution is concentrated at 40° C. or below, washed with ethyl acetate, adjusted to pH 5 with 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and then dried under reduced pressure to obtain 43f, a crude crystal containing optically active fxR form of 7-(2-chenylsulfinylacetamido)cephalosporanic acid in sulfoxide. In order to confirm that this is a pure product, the crude crystals were treated with Sephadex L H-20 (Pharmaira Fine Ch
It was obtained by fractionation by column chromatography (manufactured by chemical AB). NMR spectrum (DMSO-d
6) δ1114: 2,0 (s, 3H), 3.6 (
q, 2H), 4.1 (q, 2H), 4.8 (q,
2) 1), 5.1 (a, IH), 5.7 (q
, IH), 7.2 (t-, IH), 7.6 (d,
IH), 8. Q (d, IT(), 9.2-10
= (d, IH), elemental analysis Cl6H16N2078s”
'E HtO, calculated value C: 42,3 B,H
: 3.78, N: 6.18, S: 21,21
, Actual measurement value C: 42.52, H: 4,15, N:
5.78, S: 20J5゜This stuff\The minimum inhibitory concentration (MIC) against various Gram-positive and -negative bacteria is shown in Table 1. For comparison, the MIC of the cephalosporin obtained from 2-chenylsulfinyl acetic acid where [α] is −9.2° is shown in the ratio example below.

Table 1 Similarly, excellent effects were also obtained when coarse crystals were used in the trenches.

Comparative Example 2-Thhenylsulfinyl acetic acid ([αlj”: -9
, 2°C = 1.00 ethanol) 0.38 F was dissolved in dry acetone 8-, and triethylamine 0.38 F was dissolved in dry acetone 8-.
28m1! and 3 drops of N,N-dimethylbenzylamine and stir. The solution was cooled to -10°C, and 0.24 y of pivalic acid chloride was added with stirring.

After the dropwise addition, stirring was continued for 30 minutes at -10°C. [-After that, 0.549 p of 7-aminocephalosporanic acid, 0.28 p of ethylamine, and 5 me of acetone 3-1 water were mixed with vigorous stirring at the same temperature. Add the solution 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. Reaction liquid f: Concentrate at 40°C or lower to reduce the residue to 3%
Dissolve in aqueous sodium hydrogen carbonate solution, wash with ethyl acetate, adjust to pH 3 with 2N hydrochloric acid, and extract with ethyl acetate.

After concentrating the organic layer, by drying under reduced pressure,
0.38 ft of crude crystals of 7-(2-chenylsulfinylacetamido)cephalosporanic acid, which is optically active in sulfoxide, was obtained. NMR spectra are from Example 1.
It was identical to the compound of

Example 2 Substantially optically inactive 7-(2
150 mg of a diastereomeric mixture of cephalosporanic acid (chenylsulfinyl acetamide) was separated by reverse phase chromatography using a nonpolar coating resin as a carrier and a water-methanol mixed solution as a solvent. The main components of the two separated fractions are each optically active 2-thhenylsulfinyl sulfoxide.
The results were consistent with two types of 7-(2-chenylsulfinyl acetamido)cephalosporanic acids derived from acetic acid.

Among these, the optical rotation of the part containing a large amount of the compound of Example 1 is [
α seat': +115.9° (0.80° to C, chloroporum).

Example 6 0.52y of R-form 4-pyridylsulfinyl acetic acid was dissolved in 20 ml of dry acetone, and further triethyl 13
- Add 0.5- and 2 drops of N,N-dimethylbenzylamine and stir. Cool the solution to -20°C,
0.66 ml of pivalic acid chloride is added dropwise while stirring. After the dropwise addition, the mixture was further stirred at -20°C for 30 minutes, and then, while stirring vigorously at the same temperature, 81 g of 7-77 minocephalosboranic acid, 0.5 g of triethylamine, and 10 yd of methanol were added. Add the mixed solution at once. after that,
Stir at -20°C for 50 minutes, at 0°C for 1 hour, and at room temperature for 2 hours. Concentrate the reaction solution and dissolve the residue in water. After washing the solution with ethyl acetate and further washing with chloroform, the pH was adjusted to 2.0 with 2N hydrochloric acid, and the precipitate was filtered. The P solution was extracted with chloroform and further extracted with ethyl acetate, and the ethyl acetate layer was treated with activated carbon, dried, and concentrated under reduced pressure to obtain R-form 7-(4-pyridylsulfinylacetamido)cephalosporanic acid. 0.27 f was obtained.

NMR (DMSO-d,) δ Cape: 3,02 (s, 3H)
, 3.54 (dd, 2H), 4.12 (dd, 2H
), 4.82 (dd, 2H), 5.18 (d, IH)
, 5.74 (q, I H), 7.7 (m, 2H),
-14- 8.7 (m, 2H).

This one's \MIC is as shown in Figure 2.

Table 2 MIC (γ/-) Example 4 R-form phenylsulfinyl vinegar ri C (α square: +18
3°, C=1.00, x ta/-/l/m) 0.3
79 was dissolved in dry acetone 8- and triethylamine 0.28 m/! and 1 drop of N,N-dimethylbenzylamine and stir. The solution is cooled to -20°C and 0.242 g of pivalic chloride is added with stirring. After further stirring at -20°C for 30 minutes, while stirring vigorously at this temperature, 0.54% of 7-aminocephalosporanic acid was added.
r,) diethylamine 0.28 m and methanol 4 m
7! Add the mixed solution at once. Then at -20℃ 3
Stir for 0 min, 1 h at 0°C, and 2 h at room temperature. After the reaction,
Concentrate the solvent under reduced pressure and dissolve the residue in water. The solution was washed with ethyl acetate, and the aqueous layer was adjusted to pH'i 2. with 2N hydrochloric acid.
5, extracted with a small amount of chloroform, extracted with ethyl acetate, dried the ethyl acetate layer, and concentrated under reduced pressure to obtain 0.18 f of R-form 7-(phenylsulfinylacetamido)cephalosporanic acid. NMR (DMS)
O-d6) δPlil: 2.02 (s, 311)
, 3.56 (dd.

2H), 3.86 (dd, 2H), 4.84 (dd
, 2B) 5.10 (d, IH), 5.68 (q,
IH), 7.44-7.8 (m, 5H), 9.
10 (d, l11) This thing\various Gram-positive,
The minimum inhibitory concentration (MIC) against negative bacteria is shown in Table 3.

In addition, optical rotation [α] DI: l concentration in ethanol 1.0
Measured at 0%.

As a comparative example, the M TC of a cephalosporin obtained from phenyl A/finylacetic acid with [α] 1182° is shown.

Table 3 -17-

Claims (1)

[Claims] General formula (Tassoshi, R1 is 2-chenyl, 3-chenyl, 2-pyridyl, 4-pyridyl, 5-methyl-1,3,4-thiadiazol-2-yl, 1,5 .4-thiadiazole-
2-yl, 2-imidazolyl, 3-isoxasilyl,
1-Methyl-1H-tetrazol-5-yl, 1,2.
4-) Riazol-6-yl, 2-pyrimidyl, phenyl, A represents acetoxy, M represents hydrogen, an alkali metal, or an amine salt ion. ) A compound in which the sulfinyl group is in the R form among the cephalosporins. [Here, the R form refers to the specific optical rotation [α] in alcohol among the optical isomers of the sulfinyl group of the compound represented by R1-5-CH, cOoH (R1 is the same as above). It is defined as having the same three-dimensional structure as the three-dimensional structure in which is positive. ]