JPS6126999B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel cephalosporins and salts thereof having a wide range of antibacterial activity and a method for producing the same. 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 () and salts thereof. (However, R ₁ is 2-thienyl, 4-pyridyl, phenyl, A is acetoxy, and M is hydrogen, alkali metal, or amine salt ion.) ()
The three-dimensional structure of the sulfinyl group of the compound is
general formula (R ₁ is the same as above) Among the optical isomers at the sulfinyl group of the compound represented by, the specific optical rotation in alcohol [α] _D
It is defined as having the same three-dimensional structure as the three-dimensional structure in which is positive. The compound of formula () is asymmetric in the sulfinyl group and has two types of optical isomers, and therefore, the cephalosporins derived therefrom also have two types of isomers in the sulfinyl group. Among these two types of isomers, the cephalosporins derived from the optically active form of the compound represented by the formula () in which [α] _D is positive in ethanol, or Cephalosporins derived from mixtures containing compounds of formula () exhibiting a positive [α] _D exhibiting a negative [α] _D in the corresponding ethanol ()
discovered that it has stronger antibacterial activity than cephalosporins derived from compounds of Among the R ₁ groups, preferred are 2-thienyl, 4-pyridyl, and phenyl, with 2-thienyl being particularly preferred. Particularly preferred groups as A are:
Acetoxy, 1-methyl-1H-tetrazole-
5-ylthio and 5-methyl-1,3,4-thiadiazol-2-ylthio, which have the highest antibacterial activity. The compounds according to the invention can be produced as follows. (a) Formula () (In the formula, A and M are the same as above) The compound or its reactive derivative is reacted with the R-carboxylic acid of the formula () or its reactive derivative. Specific examples of the R-form carboxylic acid of the formula () are the parts of the R-form of the object compound of the present invention. It is the same as when −COOH is bonded to , that is, [α] _D in the ethanol is positive. Reactive derivatives of compounds of 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, with alkali metals or alkaline earth metals, ammonia or organic bases). salt). The reaction between a compound of formula () and a compound of formula () can be carried out in a suitable solvent such as acetone,
It is carried out in 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 under cooling. When reacting the compound of formula () as a free acid or as a salt, as a condensing agent,
The reaction is preferably carried out in the presence of dicyclohexylcarbodiimide, diphenylphosphoric azide, diethylphosphoric cyanide, hexachlorocyclotriphosphatriazine, triazine trichloride, or the like. The compound () of the present invention has a high degree of antibacterial activity against Gram-positive bacteria and Gram-negative bacteria in animals and humans, and is therefore effective against infectious diseases caused by these bacteria, such as bronchitis and bronchopneumonia. , respiratory tract diseases such as 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, parotitis, etc. Useful in the treatment of ear, nose and throat diseases. 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 saline solution, dextrose solution, or conventional intravenous fluids or electrolyte solutions, at a dosage of, for example, about 100 mg per dose for adults. ~about 200
It can be administered in an amount of 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 are refluxed with 8.8 g of caustic soda and 100 ml of water for 3 hours, and then the pH is adjusted to 2.0 with hydrochloric acid to precipitate an oily substance. This was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to yield 12.1 g of pale yellow crystals.
I got it. NMR (CDCl ₃ ) δ3.5 (2H, s), δ6.9
~7.4 (multi 3H), δ11.6 (s, 1H). Reference Example 2 Dissolve 8.7 g of 2-thienylthioacetic acid in 30 ml of acetic acid, stir under ice cooling, and add 6.8 g of 30% hydrogen peroxide solution.
ml 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-thienylsulfinyl acetic acid.
I got it. Melting point 114-116℃, NMR (DMSO-d ₆ ) δ
4.1 (s, 2H), 7.15 (multi, 1H), 7.55 (t,
1H), 7.9 (d, _1H ) _, elemental analysis _C6H6S2O3 , calculated values C: _37.88 , H: 3.18, S: 33.71, actual values C: 37.76, H: 3.31, S: 33.48. Reference Example 3 1.00 g of 2-thienylsulfinyl acetic acid and 2.57 g of brucine are dissolved in 25 ml of ethanol, and then concentrated to dryness. After washing the residual powder with 35 ml of hot benzene, 2.35 g of insoluble matter 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-thienylsulfinyl acetic acid was obtained. In ethanol [α] ²² ° _D +11.0°C=
It was 1.0. Example 1 2-thienylsulfinylacetic acid obtained according to Reference Example 3 ([α] ²² ° _D + 11.0°C = 1.00 ethanol)
Dissolve 0.38 g in 8 ml of dry acetone, add 0.28 ml of triethylamine and 3 drops of N.N-dimethylbenzylamine and stir. -10 solution
Pivalic acid chloride while stirring and cooling to °C.
Add 0.24g. After the dropwise addition, the mixture was further stirred at -10℃ for 30 minutes, and then stirred at that temperature with vigorous stirring.
A mixed solution of 0.54 g of aminocephalosporanic acid, 0.28 g of triethylamine, 3 ml of acetone, and 3 ml of water is added all at once. Then, at -10℃ for 30 minutes, 0
Stir for 1 hour at ℃ and 1 hour at room temperature. 40% reaction solution
Concentrate at below ℃, wash with ethyl acetate, adjust the pH to 3 with 2N hydrochloric acid, and extract with ethyl acetate. The organic layer is concentrated under reduced pressure and then dried under reduced pressure to obtain the optically active R-7-
0.43 g of crude crystals containing (2-thienylsulfinyl acetamide) cephalosporanic acid were obtained. In order to confirm this as a pure product, the crude crystals were washed with methanol as a solvent using Sephadex LH-20.
(manufactured by Pharmaira Fine Chemicals AB) Column chromatography was used to obtain the fraction. NMR spectrum (DMSO-d ₆ ) δppm: 2.0 (s, 3H),
3.6 (q, 2H), 4.1 (q, 2H), 4.8 (q, 2H),
5.1 (d, 1H), 5.7 (q, 1H), 7.2 (t, 1H),
7.6 (d, 1H), 8.0 (d, 1H), 9.2 (d, 1H),
Elemental analysis: _{Calculated value} C: _42.38 , H: _3.78 , N: _6.18 , S: _21.21 , actual value C: 42.52, H: 4.15, N: 5.78, S:
20.85. Table 1 shows the minimum inhibitory concentration (MIC) of this product against various Gram-positive and -negative bacteria. For comparison, [α] ²⁰ ° _D is -9.2° shown in the comparative example below.
- Shows the MIC of cephalosporin obtained from thienylsulfinylacetic acid.

【table】

[Table] Furthermore, even when the crude crystals were used as they were, similar excellent effects were obtained. Comparative example 2-thienylsulfinyl acetic acid ([α] ²² ° _D :-
9.2°C = 1.00 ethanol) is dissolved in 8 ml of dry acetone, and 0.28 ml of triethylamine and 3 drops of N·N-dimethylbenzylamine are added and stirred. The solution is cooled to -10°C and 0.24 g of pivalic chloride is added with stirring. After the dropwise addition, the mixture was further stirred at -10°C for 30 minutes, and then a mixed solution of 0.54 g of 7-aminocephalosporanic acid, 0.28 g of triethylamine, 3 ml of acetone, and 3 ml of water was added all at once while stirring vigorously at the same temperature.
Then, it was heated to -10℃ for 30 minutes, 0℃ for 1 hour, and room temperature for 1 hour.
Stir for an hour. The reaction solution is concentrated at below 40°C, the residue is dissolved in a 3% aqueous sodium bicarbonate solution, washed with ethyl acetate, adjusted to pH 3 with 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was concentrated and then dried under reduced pressure to obtain 0.38 g of crude crystals of 7-(2-thienylsulfinylacetamido)cephalosporanic acid, which is optically active in sulfoxide. The NMR spectrum was almost identical to that of the compound of Example 1. Example 2 Substantially optically inactive 7-(2-thienylsulfinyl acetamide) in sulfoxide
Diastereomeric mixture of cephalosporanic acid
150mg using non-polar coating resin as carrier,
Separation was performed by reverse phase chromatography using a water-methanol mixed solution as a solvent. The two main components of the separated fractions corresponded to two types of 7-(2-thienylsulfinylacetamido)cephalosporanic acid derived from 2-thienylsulfinyl acetic acid, each of which is optically active in its sulfoxide. Among these, the light intensity of the part containing a large amount of the compound of Example 1 was [α] ²⁵ ° _D : +115.9° (C = 0.80,
chloroform). Example 3 0.52 g of R-form 4-pyridylsulfinyl acetic acid is dissolved in 20 ml of dry acetone, and 0.5 g of triethylamine and 2 drops of N.N-dimethylbenzylamine are added and stirred. The solution is cooled to -20°C and 0.36 ml of pivalic acid chloride is added dropwise with stirring. After the dropwise addition, the solution was further stirred at -20℃ for 30 minutes.
While stirring vigorously at this temperature, a mixed solution of 0.81 g of 7-aminocephalosporanic acid, 0.5 ml of triethylamine, and 10 ml of methanol is added all at once. Thereafter, the mixture was stirred at -20°C for 30 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 with chloroform, the pH was adjusted to 2.0 with 2N hydrochloric acid, and the precipitate was filtered. The liquid 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. 0.27g was obtained. NMR (DMSO-d ₆ ) δppm: 3.02 (s,
3H), 3.54 (dd, 2H), 4.12 (dd, 2H), 4.82
(dd, 2H), 5.18 (d, 1H), 5.75 (q, 1H), 7.7
(m, 2H), 8.7 (m, 2H). The MIC of this product is as shown in Table 2.

【table】

[Table] Example 4 R-form phenylsulfinyl acetic acid ([α] ²⁰ _D :+
183°, C=1.00, in ethanol) was dissolved in 8 ml of dry acetone, and then triethylamine was added.
0.28ml and N-N-dimethylbenzylamine 1
Add drops and stir. Cool the solution to −20°C,
Add 0.24 g of pivalic acid chloride while stirring. After further stirring at -20°C for 30 minutes, a mixed solution of 0.54 g of 7-aminocephalosporanic acid, 0.28 ml of triethylamine, and 4 ml of methanol is added all at once while stirring vigorously at that temperature. After that-
Stir at 20°C for 30 minutes, at 0°C for 1 hour, and at room temperature for 2 hours. After the reaction, the solvent is concentrated under reduced pressure and the residue is dissolved in water. The solution was washed with ethyl acetate and the aqueous layer was
Adjust the pH to 2.5 with normal hydrochloric acid, extract with a small amount of chloroform, extract with ethyl acetate, dry the ethyl acetate layer, and concentrate under reduced pressure to obtain 0.18 g of R-form 7-(phenylphinylacetamido)cephalosporanic acid. I got it. NMR (DMSO−d ₆ ) δppm:
2.02 (s, 3H), 3.56 (dd, 2H), 3.86 (dd,
2H), 4.85 (dd, 2H), 5.10 (d, 1H), 5.68
(q, 1H), 7.44−7.8 (m, 5H), 9.10 (d,
1H) Table 3 shows the minimum inhibitory concentration (MIC) of this product against various Gram-positive and -negative bacteria. The light intensity [α] _D was measured at a concentration of 1.00% in ethanol. As a comparative example, the MIC of cephalosporin obtained from phenylsulfinylacetic acid with [α] ²⁰ _D of −182° is shown.

【table】

Claims (1)

[Claims] 1. General formula (However, R ₁ is 2-thienyl, 4-pyridyl, phenyl, A is acetoxy, and M is hydrogen, alkali metal, or amine salt ion.) In the cephalosporins represented by, the sulfinyl group is in the R form. Compound. [What is R body here? (R ₁ is the same as above) Among the optical isomers of the sulfuryl 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. ]