Method of producing 7/beta-/(z)-2-(2-aminothiazol-4-yl)-2 oxyiminoacetamido/-3-cephem-4-carboxylic a

专利摘要:
The invention relates to compounds characterised by the formula: <CHEM> The invention also includes methods of preparing such compounds.
公开号:SU1324586A3
申请号:SU843697655
申请日:1984-01-27
公开日:1987-07-15
发明作者:Ойне Тоенари；Сугано Хироси；Ямада Есихиса；Ямагути Тотаро；Осима Сатоси
申请人:Танабе Сейяку Ко,Лтд (Фирма)；
IPC主号:

专利说明:

The invention relates to the field of production of new cephalosporin derivatives, namely, 7 - - (Z) -2- (2-aminothiazol-4-yl) -2-oxy-imino-ethotamido-3-cethem-4-carboxylic acid derivatives of the general formula
 N-T-C-CONft
 ° h
R is hydrogen or methyl;
R. - (1-methyl-1H-tetrazol-5-yl) - - thio group;
R, is a carboxy group, Rj is a radical of the formula
-N
.Y
where Y is in position 3 or 4 and is hydrogen, hydroxymethyl or carbamoyl ;.
Rj -
n 2 or 3, or their alkali metal salts with antimicrobial activity.
The aim of the invention is to develop a process for the preparation of novel compounds with high pharmacological activity with low toxicity.
Example 1. 1). 3.2 g (Z) 2). 1.0 g of tert-butyl-7 / h-Z (Z) -2- - (2-tritylaminothiazol-4-yl) 2- (2-pyrrolidon-3-yl) oxyimino acetamido cephalosporonate is added to the mixture 20 ml of trifluoroacetic acid and 1 ml of anisole, and stir the resulting reaction mixture at room temperature for 20 minutes. The reaction mixture is then concentrated under reduced pressure in order to remove trifluoroacetic acid. Ether is added to the residue and the resulting powder is collected by filtration. The specified powder is suspended in 10 ml of water and sodium bicarbonate is added to the resulting suspension, resulting in dissolving the powder. The solution is washed with ethyl acetate and chromatographed on a column filled with Amberlite XAD-2 non-ionic polymer resin (trade name, manufactured by Rohm and Haas, U.S.A.) using water as eluent. The fractions containing the cephalosporin derivative are collected 35 and concentrated under reduced pressure to remove the solvent. Acetone is then added to the residue obtained, and
x “/ 1 / o powder is collected by filtration. AT
- (2-tritylaminothiazol-4-yl) -2 - (. 2-pyr-4P ";;., .. / ggl
t h „the result is 320 mg of 7a - (. Z) ririntTTTnH- -t-MT) ptgg ygtmmipl / tsp vr HnM Tcwrnn-jjj
-2- (2-aminothiazol-4-yl) -2- (2-pyrrolidone-3-yl) oxyiminoacetamido Sodium phosphorosporanate as a colorless powder.
3). A mixture of 13 g
rolidon-3-yl) oxyiminoacetic acid is suspended in 60 ml of tetrahydrofuran, and 2.05 g of tert-butyl-7-aminoacephalosporanate, 1.27 g of 1-hydroxybenzotriazole and 1, are added to the resulting suspension 93 g of dicyclohexylcarbodiimide. The resulting reaction mixture is stirred at room temperature for 3 hours. Insoluble products are filtered off and the filtrate is concentrated to dryness under reduced pressure. The residue is dissolved in ethyl acetate and the resulting solution is washed with 1% hydrochloric acid, and then successively with a 5% aqueous solution of sodium bicarbonate and water. The solution in ethyl acetate is dried and concentrated to dryness under reduced pressure. Obtained by
45
50
sodium iodide
and 4 ml of water was stirred at, after which 3.6 g of pyridine and 3.2 g of 7 / i- (Z) -2- - (2-aminothiazol-4-yl) -2- (2- pyrrolidone-3-yl) -oxyiminoacetamido cephalosporanic acid and stir the resulting mixture for 1 hour at 75-80 ° C. After cooling, the reaction mixture is poured into 150 ml of water and concentrated to dryness under reduced pressure. The residue is dissolved in 150 ml of water and the pH of the solution is adjusted to 1 with 2N hydrochloric acid. Not
This residue is purified by gel chromatography (chloroform – methanol 98.5: 1.5 solvent). As a result, 4.3 g of tert-butyl 7 1b - t (Z) -2- (2-tritylaminothiazol-4-yl) -2- (2-pyrrolidon-3-yl) oxyminoacetamido cephalosporanate are presented as pale yellow powder, so pl. 135-145 with (with decomposition).
2). 1.0 g of tert-butyl-7 / h-Z (Z) -2- - (2-tritylaminothiazol-4-yl) 2- (2-pyrrolidon-3-yl) oxyimino acetamido cephalosporonate is added to the mixture 20 ml of trifluoroacetic acid and 1 ml of anisole, and stir the resulting reaction mixture at room temperature for 20 minutes. The reaction mixture is then concentrated under reduced pressure in order to remove trifluoroacetic acid. Ether was added to the residue and the resulting powder was collected by filtration. This powder was suspended in 10 ml of water and sodium bicarbonate was added to the resulting suspension, whereby the powder was dissolved. The solution is washed with ethyl acetate and chromatographed on a column filled with Amberlite XAD-2 non-ionic polymer resin (commercial
title, made by Rohm and Haas, USA) using water as eluent. The fractions containing the cephalosporin derivative are collected 35 and concentrated under reduced pressure to remove the solvent. Acetone is then added to the residue obtained, and
3). A mixture of 13 g
0
sodium iodide
and 4 ml of water was stirred at, after which 3.6 g of pyridine and 3.2 g of 7 / i- (Z) -2- - (2-aminothiazol-4-yl) -2- (2- pyrrolidone-3-yl) -oxyiminoacetamido cephalosporanic acid and stir the resulting mixture for 1 hour at 75-80 ° C. After cooling, the reaction mixture is poured into 150 ml of water and concentrated to dryness under reduced pressure. The residue is dissolved in 150 ml of water and the pH of the solution is adjusted to 1 with 2N hydrochloric acid. The insoluble materials are filtered off and the filtrate is washed with ethyl acetate, the pH is adjusted to 6 with 2N. sodium hydroxide solution and concentrated to a total volume of 30 ml under reduced pressure. The solution obtained in this way is chromatographed on a column containing neon polymer resin Dialon HP-20 (the trade name is produced by Mitsubishi Chemical Industries Limited Japan). The column was washed with water, after which it was eluted with a 20% aqueous solution of methanol. The fractions containing the cephalosporin derivative are collected and concentrated to dryness under reduced pressure. Acetone is added to the residue and the resulting powder is collected by filtration. The result of 0.67 g of 7/5 - - (2) -2- (2-aminothiazol-4-yl) -2- (2- -pyrrolidon-3-yl) oxyiminocetamido-3- (1-pyridinomethyl) - Z-cephem-4-carboxyloxylate, m.p. .
PRI mme R 2. 1). 4.0 g of (Z) -2- .- (2-tritylaminothiazol-4-yl) -2- (2-pyrolidin-3-yl) oxyiminoacetic acid is dissolved in a mixture of 30 ml of tetrahydrofuran and 10 ml of N, N-dimethyl acetamide and 1.27 g of 1-hydroxybenzotriazole and 1.93 g of dicyclohexylcarbodiimide are added to the resulting solution. After stirring the obtained reaction mixture for 2 hours at a temperature from 0 to 5 seconds, it is introduced into 30 ml of a mixture of N, N-dimethyl acetate-amide with water (water content 15%) containing 2.12 g of 7-aminocephalosporanic acid and 4 g of triethylamine, while cooling with ice. The mixture was then stirred at the same temperature for 1.5 hours. The insoluble products were filtered off and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was poured into 300 ml of water. The mixture was adjusted to pH 8 with sodium bicarbonate, the mixture was washed with ethyl acetate, the pH was adjusted to 3 with 2N. hydrochloric acid and extracted with ethyl acetate. - The extract is dried and concentrated to dryness under reduced pressure. Ether is then added to the residue and the powder thus obtained is collected by filtration. 3.1 g of 7 / i - (2) -2- (2-tritylaminothiazol-4

five
0
0
0

-yl) -2- (2-pyrrolidon-3-yl) oxyimino-acetamido cephalosporanic acid.
2). 40 ml of an 80% aqueous formic acid solution are added to 3.0 g 7 /} - (E) -2- (2-tritylaminothia-ZOL-4-IL) -2- (2-pyrrolidon-3-yl) hydroxyminoacetamido cephalosporanic acid and stir the resulting mixture for 2 hours at room temperature. Insoluble products are filtered off and the filtrate is concentrated to dryness under reduced pressure. Water is added to the resulting residue, and the aqueous mixture is neutralized with sodium bicarbonate, then washed with ether. Then the specified aqueous mixture is chromatographed on a column filled with non-ionic polymeric resin Dialon HP-20, using water as the eluent. The fractions containing the cephalosporin derivative are collected and concentrated to dryness under reduced pressure. As a result, 1.5 g of 7 / J - (7) -2- (2-aminothiazole-4-yl) -2 -; (2-pyrrolidone -3-yl) hydroxyiminoacetamido-sodium cephalosporanate.
3. The product obtained above is treated as described in Example 1 to give 7 1 - {(g) -2- (2-aminothiazol-4-yl) -2- (2-pyrrolidon-3-yl) -oximino -acetamido -3- (1-pyridinomethyl) -Z-cephem-4-carboxylate.
Example 3) .18.2 g of phosphorus oxychloride is added dropwise to 9.2 ml of dimethylformamide under ice cooling, after which the mixture is stirred for 30 minutes at 25-35 ° C. After cooling, to the mixture is added 100 ml of chloroform and cooled to. 20 g (g) -2- (2-tritylaminothiazole-4-yl) -2- (2-pyrrolidon-3-yl) oxyiminoacetic acid is added dropwise to the mixture at a temperature of from -35 to -25 ° C. acids (t-isomer) and 5.6 ml of triethylamine in 160 ml of K, K-dimethyl acetamide, after which the reaction mixture is stirred at the same temperature for 20 minutes. Then, with stirring, a solution of 7-aminocephalosporanic acid is added to the reaction mixture dropwise at -35 to -20 ° C to the slots (this solution is obtained by stirring a mixture of 16 g of 7-aminocephalosporanic acid, 48 g of trimethylchlorosilane, 35, 6 ml of pyridine and 160 ml
five
0
five
N, N-dimethyl ethers at 10-20 C
five
for 2 h-). After stirring the reaction mixture for 20 minutes at the same temperature, it is drunk in 2 liters of ice-water and stirred vigorously. The crystalline precipitates are collected by filtration, washed with water, ethyl acetate and ether, and then dried in vacuo. As a result, 26.5 g of 7 / s- (Z) -2- (2- -tritylaminothiazol-4-yl) -2- (2-pyrrolidone-3-yl) -oxyiminoacetamide cephalum sporadic acid (i-eomer ) in the form of a colorless powder.
2). 67.5 g of sodium iodide and 10.9 g of pyridine are added to a mixture of 18 ml of water and 18 ml of dimethylformamide, after which the mixture is heated to 80 ° C. 11.5 g of 7 p- (E) -2- (2-tritylaminothiazol-4- -yl) 2- (2-pyrrolidon-3-yl) oxyiminoacetamido cephalosporanic acid (1-isomer) and stir the reaction mixture for 35 minutes at 80 ° C. After cooling, 90 ml of an ice-water mixture are added to the reaction mixture and the mixture is washed with ethyl acetate, then it is distilled under reduced pressure to remove ethyl acetate and adjusted to pH 2 with 10% hydrochloric acid. The crystalline precipitates are collected by filtration, washed with water and dried in vacuo. The result is 11.9 7 ft - (Z) -2- (2-tritylaminothiazol-4- -yl) -2- (2-pyrrolidone-3-yl) oxyimino - acetamido-3- (1-pyridinomethyl) -3-tsefem-4-carboxylate (1-isomer) in the form of a crude pale yellow powder.
3). 5.5 g 7 / 1- (Z) -2- (2-trityl-aminothiazol-4-yl) -2- (2-pyrrolidon-3-yl) oxyiminoacetamido-3- (1-pyridinomethyl) - 3-cephem-4-carboxylate (J-isomer) is dissolved in 90 ml of 80% formic acid. The resulting solution was stirred at room temperature.
work for 1 h, then concentrate under reduced pressure and add 200 ml of water to the residue. The insoluble materials are filtered off, the aqueous filtrate is washed with ethyl acetate, concentrated under reduced pressure to remove ethyl acetate, and introduced into a column filled with 200 ml of non-ionic adsorption resin Dialon HP-20. Then the column is washed with water and the product is eluted with 20% aqueous pacTj3opoM methanol. The eluted solution is concentrated under reduced pressure, added
324586
five
0
, O
0
five
five
0
45
50
55
acetone to the resulting residue and collect the precipitates that form after filtration. The result is 1.6 g 7 /} - (E) -2- (2-aminothiazole-4-yl) -2- (2-pyrrolidon-3-yl) oxyiminoacetamido 3- (1-pyridinomethyl) - - Z-cephem-4-carboxylate (1-isomer) as a pale yellow powder (another name for the levorotatory isomer is 7/5-C (g) -2- (2-aminothiazol-4-yl) -2-C (3S) - -2-pyrrolidone-3-yl oxyiminoacetamido-3- (1-pyridinomethyl) -3-cephem-4-carboxylate).
Example 4: 2.5 g 7 / i - H (E) -2- - (2-tritylaminothiazol-4-yl) -2- (2-pyrrol. Idon-3-yl) oxyiminoacetamido cephalosporanic acid (1-isomer), prepared according to Example 3.1, was dissolved in 50 ml of 80% formic acid and the resulting solution was stirred at room temperature for 1 hour. Insoluble products were filtered, the filtrate was concentrated under reduced pressure, and water to the residue is obtained and the aqueous mixture is neutralized with sodium bicarbonate. Then, this aqueous mixture was washed with ethyl acetate, concentrated under reduced pressure, and introduced into a column filled with 200 ml of non-ionic adsorption resin Dialon HP-20. After washing the tank with water, further processing is carried out according to Example 3.3. The result is 1.0 g of (Z) -2- (2-aminothiazol-4-yl) -2- (2-pyrrolidone-3-yl) oxyiminoacetamido} sodium cephalosporanate in the form of a pale yellow powder (1- isomer). Another name for this levorotatory isomer is 7 f, - (Z) -2- (2-aminothiazol-4-yl) -2- (3S) -2-pyrrolidone-3-yl oxyiminocetamidoDeptospalosporanate sodium.
The resulting product is treated as in Example 7, whereby 7 and - (Z) -2- (2-aminothiazol-4- -yl) -2- (2-pyrrolidon-3-yl) oxyimino-acetamido-3- (1 -pyridinomethyl) -3-cephem-4-carboxylate (1-isomer).
Example 5. A mixture of 960 mg of 7 jj - (Z) -2- (2-aminothiazol-4-yl) -2- (2- -pyrrolidon-3-yl) oxyiminoacetamido - cephaloposmic acid, 730 mg of iso-nicotinamide, 4.5 g of sodium iodide and 3 ml of water are stirred at 65-70 ° C for 6 hours. After cooling the reaction mixture, 20 ml of water is added to it and insoluble products are filtered off. The filtrate is introduced into the column.
7 1324586 g
filled with 100 ml of non-ionic adsorb-amido1-3- (1-methyl-1H-tetrazol-5-yl)
Dialon NR-20, and dipropylamine-3-cephem-A-carboxylate resin was stretched over the column with water. Then do it.
is elution with 20% aqueous Example B. one). 7-aminocephalic solution of methanol, and the resulting eluasporanic acid (4 g) of the suspended solution is concentrated and concentrated in M, H-dimethylacetamide (40 ml),
reduced pressure. To the results of the suspension, trimethylchloropropane is added to receive 175 mg of 7 - (g) -2- (2-amino-forces (12 g) and pyridine (8.9 ml).
thiazol-4-yl) -2- (2-pyrrolidon-3-yl) -The mixture is stirred at 10-20 0 in theoxyiminoacetomyo-3- (4-carbamoyl-Chunia 2 h in order to obtain rast-1-pyridinomethyl) -3-cephem-4-carbox-thief trimethylsilyl ester
silat in the form of pale yellow powder, 7-aminocephalosporic acid in
m.p. 163-166 0 (with decomposition) .N, N-dimethyl acetamide.
PRI me R 6. A mixture of 960 mg 7 / 5- Separately (7.) - 2- (2-tritylaminothia- (E) -2- (2-aminothiazol-A-yl) -2- (2-15zol -4-yl) -2- (2-pyrrolidon-3-yl) oxy. -Pyrrolidon-3-yl) oxyiminoacetamido imino acetic acid (1-isomer, 5 g)
cephalosporanic acid, 650 mg suspended in K, N-dimethylacetamide
A-hydroxymethylpyridine, 4.5 g of iodis- (40 ml) and add sodium salt and 3 ml of water to the suspension, stirring ethylamine (1.6 ml). The resulting plant is 65770 ° C for 7 hours. Then the solution is added dropwise phosphorous
. the mixture is processed according to oxychloride (4.8 g) at a temperature of
Example 12. The result is -35 to and the mixture is stirred.
150 mg of 7 - (g) -2- (2-aminothiazol-4-at the same temperature for
-yl) -2- (2-pyrrolidon-3-yl) oxyimino-20 min. A solution of trimethylsilylidinomethyl) -3-cephem-4-carboxylate of the second 7-aminocephalospic acid ester of pale yellow powder, mp, is added dropwise to the reaction mixture (etamido-3- (4-hydroxymethyl-1-pyri-25 l). of ranic acid in N, N-dimethyl acetate 162-184 C (with decomposition). The mide obtained above at temperature Example 7 A mixture of 960 mg of 7 d-re from -35 to within about - (2) -2- (27 aminothiazole-4 -yl) -2- (2-30 minutes. The reaction mixture is poured into -pyrrolidon-3-yl) oxyiminoacetamido ice-water mixture (500 ml) and cephalosporanoic acid mixture 650 is stirred for 30 minutes to be removed. -Hydroxymethylpyridine, 4.5 g of iodis-trimethylsilyl ether with this sodium and 3 ml of water are treated with hydrolysis power, and the resultant precipitate is collected by filtration, resulting in 83 mg of 7 / j- (E) -2- (2-aminothia), whereby 7 (Z) -sol-4-yl) -2- (2-pyrrolidon-3-yl) oxy-2- (2-tritylamine thiazole-4- yl) -2- (2-imino-acetamido-3- (3-hydroxymethyl-pyrrolidon-3-yl) oxyimino-cetamine-1-pyridinomethyl) -3-cephem-4-carboxy-to cephalosporinic acid (1-isolate m.p. 128-135 C (with decomposition) .40mer) as a colorless powder. Using the method of reduced chemical and chemical properties of this pre-examples, the following co-products were obtained are similar to those of the product,
unity: obtained in example 3.1.
7 pG (2) -2- (2-aminothiazol-4-yl) -2). The product obtained above, obra-2- (2-pyrrolidon-3-yl) yuksiminoacetat- 45, is processed according to example 3.2 and 3.3, in ream1-3- (1-methyl-2H-tetrazol-5-yl) .. as a result, 7 / j- (Z) -2-.
thiomethyl-3-cephem-4-carboxylate nat - (2-aminothiazol-4-yl) 2- (2-pyrroli-don-3-yl) oxyimino acetamido-3- (17 (i- (Z) -2 (2 α-aminothiazol-4-yl) -2-pyridinomethyl) -3-cephem-4-carboxylate
- ((ZU-2-pyrrolidone 3-yl) oxyimino-50 (1-isomer). Acetamido-3- (pyridinomethyl) -3-cephem-4-carboxylate; Example 9.1). Example 8.1,
7 - (2) -2- (2-aminothiazol-4-yl) -ab except that thionyl chloride -2- (1-methylpyrrolidon-3-yl) oxyimino- (3.5 g) is used instead of phosphorous acetamido - 3- (1-methyl-1H-tetrazole-55 ™ oxychloride (4.8 g), give -5-Sh1) thiomethyl-3-cephem-4-carboxy-7 - {(Z) -2-tritylaminothiazol-4- (yl) - sodium lat; -2- (2-pyrrolidon-3-yl) oximemino-7 d- (g) -2- (2-aminothiazol-4-yl) -acetamido cefapospororanic acid -2- (2-piperidone- 3-yl) oxyiminoacetic acid (1-isomer).
ten
2) “The product obtained above is treated in accordance with Example 3.2 and 3.3. In this way, 7 (j - {(2) -2- (2-amino thiazol-4-yl) -2- (2-pyrrolidon-3-yl) oxyimino acetamido) is obtained } -3- (1-pyridino-methyl) -3-cephem-4-carboxylate (1-isomer).
Example 10. 1). In Example 8.1, with the exception that oxalyl chloride (3.7 g) is used instead of phosphate) 0 7 p - (g) -2- (2-aminothiazol-4-yl) .- 2 - foric oxychloride (4.8 g) to obtain - - (2-pyrrolidon-3-yl) oxyimino acetic acid - {(g) -2- (2-tritylaminothiazole-amido cephalosporic acid -4-yl) -2- ( 2-pyrrolidone-3-yl) oxyimino-acetamido cephalosphoranic acid 15
Amberlite HLB-2 resins, and then the column was eluted with water. The fraction containing the desired product was collected and distilled under reduced pressure to obtain a dry residue. Acetone was added to the residue and the resulting powdered material was separated by filtration, resulting in get salt
(780 mg). The physicochemical properties of this product are similar to those of the product obtained in Example 1.2.
2). The resulting product is treated as in example 1, thus obtaining 1 fb (Z) -2- (2-aminothiazol-4-yl) -2- - (2-pyrrolidon-3-yl) oxymino-J acetone (1-isomer).
2). The resulting product is treated according to example 3.2 and 3.3, thus receive 7l- (E) -2- (2-aminothiazol-4-yl) -2- (2-pyrrolidon-3-yl) oxyimino acetamido-3- (1- pyridinomethyl) - 20 amido 1-3- (1-pyridinomethyl) 3-cephem- -3-cephem-4-carboxylate (1-isomer). -4-carboxylate.
Example 11. 1). (g) -2- (2-chloro-prim ep 12. 1). For example, acetamidothiazol-4-yl) -2-t (2-pyrpole-11.1, with the exception that (Z) -2- don 3-yl) oxyimino acetic acid - (2-chloroacetamidothiazol-4-yl) -2- (2- (2.07 g) is suspended in tetrahydro-25-pyrrolidone-3-yl) oxyimino acetic furan (60 ml) , added acid to the suspension (1-isomer) is used instead of
7-Aminocephalosporoinic acid t-butyl ester (1.97 g) and dicyclohexylcarbodiimide (1.8 g) are added and the mixture is stirred at room temperature for 10 hours. The precipitated crystals are separated by filtration, and the filtrate is distilled under reduced pressure to obtain a dry mass. Ethanol (30 ml) and tetrahydrofuran (10) are added to the residue, and thiourea (1.1 g) and sodium acetate trihydrate (1.6 g) are added to the resulting solution and the mixture is stirred at room temperature for 4 hours. The reaction mixture is distilled under reduced pressure to obtain a dry residue, trifluoroacetic acid (40 ml) is added to the residue and the mixture is stirred at room temperature for 20 minutes. The reaction mixture is concentrated under reduced pressure to remove trifluoroacetic acid.
45 of a wide range of microorganisms, including microorganisms belonging to the genus of streptococci (for example, St..faecal is, St. pneumonial), the genus staphylo cocci (eg, S. aurens, S. epi acid, and 50-dermidis are added to the residue) and the pseudomonium species (sodium ether, and the resulting powdery material is recovered by filtration. The powder is suspended in water (20 ml) and the mixture is dissolved by neutralization with acidic carbonate sodium. A small amount of non-dissolved material is separated by filtration, and the filtrate passed through a column of non-ionic polymer
1324586
ten
Amberlite HLB-2 resins, and then the column was eluted with water. The fraction containing the desired product was collected and distilled under reduced pressure to obtain a dry residue. Acetone is added to the residue and the resulting powdery material is separated by filtration, resulting in a sodium salt.
7 p - (g) -2- (2-aminothiazol-4-yl) .- 2- - (2-pyrrolidon-3-yl) oxyimino acetamido cephalosporic acid
(780 mg). The physicochemical properties of this product are similar to those of the product obtained in Example 1.2.
2). The resulting product is treated as in example 1, thus obtaining 1 fb (Z) -2- (2-aminothiazol-4-yl) -2- - (2-pyrrolidon-3-yl) oxyminoJ acetamido 1-3- (1-pyridinomethyl ) 3-cephem-4-carboxylate.
(Z) -2- (2-chloroap: etamidothiazol-4-yl) -. -2- (2-pyrrolidone-3-sh1) oxyimino acetic acid, sodium salt is obtained
7 and - (g) -2- (2-aminothiazol-4-yl) -2- (2-pyrrolidone-3-yl) oxyimino acetamido cephalosporinic acid (1-isomer).
2). The resulting product is treated according to Example 1.3, with this being 7 - (g) -2- (2-aminothiazol-4-yl) -2 -2 (2-pyrrolidon-3-yl) oxyimino-acetamido | -3- (1- pyridinomethyl) -3-cephem-4-carboxylate (1-isomer).
Cephalosporin derivatives of general formula I, as well as pharmaceutical salts suitable for pharmaceutical use, possess antimicrobial activity against
a wide range of microorganisms, including microorganisms belonging to the genus of streptococci (for example St..faecal is, St. pneumonial), the genus of staphylococci (for example S. aurens, S. epidermidis) and the genus of pseudo-mones (for example PS. aeruginosa, Ps. putida, PS. Stutzevi) and are distinguished, in particular, by the presence of anti-microbial activity both in relation to gram-positive and in relation to
Gram-negative bacteria. For example, 7 - (g) -2- (2-aminothiazol-4-yl) -2- (2-pyrrolidon-3-yl) oxy-acetamido 3- (1-pyridinomethyl) - -3-cephem-4-carboxylate (1-isomer) and 7b - (Z) -2- (2-aminothiazo-A-and JI) -2- - (1-methyl-2-pyrrolddon-3-yl) -oximinoacetamido-3- (1 methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carbonate with respect to the effect of times
acid have a minimum inhibitory concentration (MIC) (determined by diluting agar during cultivation for 20 hours at 37 ° C) equal to 12.5 and 25 μg / ml, respectively, relative to Streptococcus faecalis, CN-478, while MIC for Cefmenoxime (chemical name 7 / J-C (Z) -2- (2-aminothiazol-4-yl) 2- (methoxyiminoacetamido) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl - -Z-cephem-4-carboxylic acid) and Zeftazidime (chemical name 7-p-G (Z) -2- (2-vminothiazol-4-yl) -2- (2-4 "„ formulas I can be used for -carboxyprop-2-yl) oxyiminoacetam- 20 j, „„ „„ „„ .-. „„ to „
(1-pyridinomethyl) -3-cephem-4-β-carboxylate) for the respective microorganisms has a value in excess of 100 μg / ml. Antimicrobial activity of 7 J1 - t (Z) -2- (2-aminothiazol-4-yl) -2- (2-pyrrolidon-3-yl) hydroxyimino sodium, potassium, calcium, aluminum,
ammonium salts, salts of these compounds with non-toxic amines, for example with trialkylamines (triethylamine and procaine), salts with inorganic acids, in particular with hydrochloric or hydrobromic acid, salts with organic acids, for example
salts have noticeable antimicrobial, oxalic or succinic acid, and
Noah activity against bacte- These salts may be semi-poly, belonging to the genus Bacillus
(for example B. subtilis), the genus Escherichia (for example E. Coli), Klebsiella
40
personal microorganisms producing / i-lactamase, especially in relation to the effects of / s-lactamase produced by Proteus vulgaris, and low toxicity. For example, none of the rats died when administered subcutaneously with 7 ft - {(E) -2- (2-aminothiazol-4 yl) - -2- (2-pyrrolidon-3-yl) oxyiminoacetate-amido-3- (1 -pyrrolidinomethyl)} - 3-ce-15 fem-4-carboxylate (1-isomer) to male rats at a dose of 1000 mg / kg for 14 days.
Derivatives of cephalosporin total
pharmaceutical purposes, either as a free substance or as its salt. Salts of the compounds of general formula I suitable for pharmaceutical use include, for example.
acetamido1-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid with respect to Staphylococcus aureus 252R is also more than 16 times higher than the activity of Cefmenoxime and Ceftazidime.
Compounds of general formula I and their
thirty
i (for example, K. pneumoniae), Enterobacter (for example, E. aerogenes, E. clocal) and Serratia (for example, S. marcescens).
Treatment of compound I with a stoichiometric equimolar amount of the corresponding alkaline agent or acid at room temperature in an aqueous solvent. The cephalosporin derivatives of general formula I and their salts can be administered orally or parenterally (for example, in addition, the cephalospore derivatives intravenously, intramuscularly, and the general formula I can have skin). The daily dose of the compound is significant antimicrobial activity against other bacteria belonging to the genus Citrobacter, Proteus, Shigella, Hemophilis and Salmonella. Cephalosporin derivatives of general formula I and their salts have significant positive protection50
Formula I or a salt thereof may vary widely depending on the age, weight and condition of the patient, as well as on the degree of development of the disease to be treated. In general, daily doses of the compounds of general formula I or their salts are about 0.002-0.2, preferably 0.01-0.04 g / kg body weight per day. The compounds of general formula I and their salts can be used in the form of pharmaceutical formulations containing these compounds in a mixture
effect on infections caused by microbes. This applies to various types of bacteria, including both Staphylococcus aureus and Pseudomonas aeruginosa, due to the high absorption capacity of these compounds or the long-term therapeutic effect in living tissues; The compounds are also highly stable.
Formulas I can be used for j, „„ „„ „„ .-. „„ To „
personal microorganisms producing / i-lactamase, especially in relation to the effects of / s-lactamase produced by Proteus vulgaris, and low toxicity. For example, none of the rats died when administered subcutaneously with 7 ft - {(E) -2- (2-aminothiazol-4 yl) - -2- (2-pyrrolidon-3-yl) oxyiminoacetate-amido-3- (1 -pyrrolidinomethyl)} - 3-tsefem-4-carboxylate (1-isomer) to male rats at a dose of 1000 mg / kg for 14 days.
Derivatives of cephalosporin total
Formulas I can be used for j, „„ „„ „„ .-. „„ To „
pharmaceutical purposes, either as a free substance or as its salt. Suitable for pharmaceutical use salts of the compounds of general formula I include, for example.
thirty
Treatment of compound I with a stoichiometric equimolar amount of the corresponding alkaline agent or acid at room temperature in an aqueous solvent. Cephalosporin derivatives of general formula I and their salts can be administered orally or parenterally (for example, intravenously, intramuscularly, subcutaneously). The daily dose of the compound is about
0
five
Formula I or a salt thereof may vary widely depending on the age, weight and condition of the patient, as well as on the degree of development of the disease to be treated. In general, daily doses of the compounds of general formula I or their salts are about 0.002-0.2, preferably 0.01-0.04 g / kg body weight per day. The compounds of general formula I and their salts can be used in the form of pharmaceutical formulations containing these compounds in a mixture
13
with a pharmaceutical carrier suitable for oral or parenteral use.
Experience 1. Antimicrobial activity in vitro.
A MIC (µg / ml) was determined for the test compounds using the standard agar dilution method. Mueller-Hinton agar (MNA, Nissui) was used as the medium in these experiments.
The results are shown in table 1.
Test II, Protective effect on bacterial infections in mice.
Groups of 10 male mice were taken for each dose. The mice were injected intraperitoneally with bacteria in an amount sufficient to achieve a lethal outcome in the case of all untreated animals within 24 hours. All bacteria were administered as a suspension in mucin (6% concentration). Test compounds were administered intramuscularly 1 hour after infection was applied. After 7 days, the number of surviving animals was determined. The average effective doses were determined for 50% of the surviving animals (ED 50 mg / kg).
The results are shown in Table 2 along with the CC value (μg / ml), which was found in a manner similar to that described in Experiment I.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining the derivative 7) i - C (g) -2- (2-amino-thiazol-4-yl) -2-oxyiminoacetamido-3-cephem-4-carboxylic acid of formula
S
Nn-C-CONH -, - t 0 v / -CH2-B,
Ri
WcCH2) n 0.
14
R is hydrogen or methyl;
RJ -. (1-Methyl-1H-tetrazol-5-yl) -thio group; RJ is a carboxy group, RI is a radical of the formula
where Y is in position 3 or 4 and is hydrogen, hydroxymethyl or carbamoyl; . Rj -
n 2 or 3;
or an alkali metal salt thereof, characterized in that the compound of the general formula
N-T-C-CONH-r-r jlj Yiwu-CH rsOS p.S. GTN
0
About CH - (CH2) p
.
where R is hydrogen or a protecting group,
taka-trityl; R and p have the indicated meanings, or its alkali metal salt is reacted with pyridine derivatives of the general formula
40
f
T
where Y has the indicated values, or with 1-methyl-5-mercaptotetrazole in water or an aqueous organic solvent at a temperature of from 65 to followed by removal of the protective group when R is a protective group and separation of the desired product in free form or in. as an alkali metal salt.
15
Staphylococcus aureus
 7 / i - (Z) -2- (2-aminothiazol-4-yl) -2- (2-pypropyldon-3-yl) oxyiminoacetamido-3- (1-pyridinomethyl) -3- -cepheme-4-carboxylate (1 isomer).
Table 2
Staphylococcus aureus Smith
Escherichia coli, KS-14
1324586
16 Table 1
1.71 5.32 7.85 (1.56) (1.56) (12.5)
0.05 0.16 0.08
1 rogaaizm
Offered socescesns,
freundii,
dynamic
one
(0.05) (0.025) (0.05)
0,140,880,54
(0.05) (0.2) (0.2)
0,060,190,15
(0.1) (0.05) (0.39)
Enterobacter aerogenes, 816
By experience I.
ED-50, ng / kg (MIC, µg / kp)
Cefmenocime
CeftazDIM
1.37 23.85 26.38 (0.39) (1.56) (6.25)

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同族专利:

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DK361587D0|1987-07-10|

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JPH0360803B2|1991-09-17|

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FI74972C|1988-04-11|

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US4727071A|1988-02-23|

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JPH0246588B2|1990-10-16|

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ES531296A0|1985-08-01|

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PL140023B1|1987-03-31|

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US4598154A|1986-07-01|

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NO161068C|1989-06-28|

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DE3381734D1|1990-08-16|

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ES8603496A1|1985-12-16|

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FI832770A|1984-02-08|

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IE55406B1|1990-09-12|

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CS196483A2|1985-08-22|

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IL69246A|1986-07-31|

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US4742174A|1988-05-03|

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DD210053A5|1984-05-30|

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IE831648L|1984-02-07|

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SU1227116A3|1986-04-23|

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EP0245619A1|1987-11-19|

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AU562248B2|1987-06-04|

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CS243484B2|1986-06-12|

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PL249964A1|1985-05-07|

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ES8502121A1|1984-12-16|

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GR78864B|1984-10-02|

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PT77166A|1983-09-01|

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PT77166B|1986-01-28|

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PL243329A1|1985-02-13|

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AU1710483A|1984-02-09|

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ES8506707A1|1985-08-01|

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DK358983D0|1983-08-05|

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JPS62294615A|1987-12-22|

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NO161068B|1989-03-20|

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IL69246D0|1983-11-30|

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JPS5951292A|1984-03-24|

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ZA835411B|1984-03-28|

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US4598075A|1986-07-01|

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PL139932B1|1987-03-31|

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BG37838A3|1985-08-15|

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JP4773154B2|2005-07-29|2011-09-14|小澤物産株式会社|Lever type coupling|

法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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GB8222823|1982-08-07|

---