CS205007B2 - Process for preparing n-acylamino-alpha-arylacetamidocephalosporine - Google Patents

Description

The invention relates to a process for the preparation of a novel cephalosporin. In particular, it is a novel cephalosporin of the following general formula (I)

(Π in which

A is a divalent heteroaromatic ring selected from the group consisting of quinoline, isoquinoline, cinnoline, naphthyridine, quinoxaline, pyrazolopyridine, pyridopyrazine, thiazolopyrimidine, pyridopyrimidine, pyridine, pyrimidine, pyridazine, triazine and pyrazine, which may be substituted with at least one substituent selected C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 2 -C 5 alkanoyl, C 2 -C 5 alkoxycarbonyl, C 2 -C 2 alkylthio 1-4 carbon atoms, mercapto group, hydroxyl group, alkoxymethyl group having a total carbon number of 2 to 6, a halogen atom, a cyano group, a nitro group, an alkylsulfonyl group having a total carbon number of 1 to 4, a phenylsulfonyl group, pyridyl a sulfonyl group, a sulfamoyl group, a carbamoyl group, a phenoxycarbonylamino group, an acetoacetylamino group, an alkylamino group having a total carbon number of 1 to 4, a dialkylamino group in which each alkyl has 1 to 4 carbon atoms, a haloalkyl group having a total carbon number of 1 to 4 , an alkenyl group having a total carbon number of 2 to 6, a phenyl group, a pyridyl group and a cycloalkyl group having a total number of carbon atoms of 3 to 6,

R is a radical of formula

where

R 1 represents an amino group, a hydroxyl group, a trihydroxymethyl group, or an ureido group, and

R2 and R3, which may be the same or different, represent a hydrogen atom, a nitro group, an alkylamino group having a total carbon number of 1 to 4, an alkanoylamino group having a total carbon number of 2 to 6, an amino group, a hydroxyl group, an alkanoyloxy group with a total carbon number 2 to Θ atoms, an alkyl group having a total carbon number of 1 to 4, an alkoxy group having a total carbon number of 1 to 4, a chlorine atom, a bromine atom, a fluorine atom, an iodine, a trifluoromethyl group, a hydroxymethyl group and a sulfamoyl group;

X is -S-Het wherein Het is 1-methyltetrazol-S-yl, 2-methyl-1,3,4-thladiazol-5-yl, 1,2,3-triazol-5-yl 1,2,4-triazol-3-yl tetrazol-5-yl, 2-methyltetrazol-5-yl, 2-mercapto-1,3,4-thiadiazol-5-yl,

2-hydroxymethyl-1,3,4-oxazol-5-yl, 3-hydroxypyridazin-6-yl, 2-hydroxynlethyl-1,3,4-thiadiazol-5-yl, 1,3,4-thiadiazole A 5-yl group, a 2-methylamino-1,3,4-thiadiazol-5-yl group or a 2-aminomethyl-1,3,4-thiadiazol-5-yl group, and its nontoxic physiologically acceptable salts.

It is known that compounds of the cephalosporin series, such as cephalothin and cefazoline, are very potent and widely used ehemotherapeutic agents in the treatment of infectious diseases caused by Gram-positive and Gram-negative bacteria.

However, it is also known that said cephalosporins are virtually ineffective in the treatment of infectious diseases caused by Pseudomonas aeruginosa, which has been widespread in recent years and which are very difficult to treat. To date, compounds of the cephalosporin series that are effective in the treatment of an infectious disease caused by Pseudomonas aeruginosa are not commercially available. The invention solves this drawback.

Examples of non-toxic pharmaceutically acceptable salts derived from the compounds of Formula 1 include: sodium salt, potassium salt, calcium salt, magnesium salt, triethylamine salt, diethanolamine salt, morpholine salt, procaine salt, L-arginine salt, L-lysine salt. salt and the like.

Since the α-carbon atom of the side chain (phenylglycine residue), attached in formula I at position 7, is an asymmetric carbon, there are two optically active isomers of the compound of formula I. These two isomers (D-diastereomer and L- thus, the diastereomer) and the DL form are also within the scope of the invention, with the preferred diaesteromer being the D diastereomer.

The present invention provides a process for the preparation of N-acyl-α-arylacetamidocephalosporin of formula (I)

HO-A- CONH-CH-C ONH -, R ₀ U - f

N.

COOH ^C V (!) In which i

A is a divalent heteroaromatic ring selected from the group consisting of quinoline, isoquinoline, cinnoline, naphthyridine, quinoxaline, >

pyrazolopyridine, pyridopyrazine, thiazolopyrimidine, pyridopyrimidine, pyridine, pyrimidine, pyridazine, triazine and pyrazine, which may be substituted with at least one substituent selected from the group consisting of an alkyl group having a total carbon number of 1 to 4, an alkoxy group having a total carbon number 1-4, alkanoyl of 2 to 5, alkoxycarbonyl of 2 to 5, alkylthio of 1 to 4, mercapto, hydroxyl, alkoxymethyl of 2 to 6, halogen, cyano, nitro, alkylsulfonyl having a total carbon number of 1 to 4, phenylsulfonyl, pyridylsulfonyl, sulfamoyl, carbamoyl, phenoxycarbonylamino, acetoacetylamino, alkylamino an alkyl group having a total carbon number of 1 to 4, a dialkylamino group in which each alkyl has 1 to 4 carbon atoms, a haloalkyl group having a total carbon number of 1 to 4, an alkenyl group having a total carbon number of 2 to 6, a phenyl group, a pyridyl group and a * cycloalkyl group having a total carbon number of 3 to 6,

R is a radical of formula

where

R1 represents an amino group, a hydroxylow group, a hydroxymethyl group or aureido group

205067

R2 and R3, which may be the same or different, represent a hydrogen atom, a nitro group, an alkylamino group having a total carbon number of 1 to 4, an alkanoylamino group having a total carbon number of 2 to 6, an amino group, a hydroxyl group, an alkanoyloxy group with a total carbon number atoms of 2 to 6, an alkyl group having a total number of carbon atoms of 1 to 4, an alkoxy group having a total number of carbon atoms of 1 to 4, a chlorine atom, a bromine atom, an iodine, a trifluoromethyl group, a hydroxymethyl group and a sulfamoyl group;

X is -S-Het wherein Het is 1-methyltetrazol-5-yl,

2-methyl-1,3,4-thiadiazol-5-yl,

1,2.3-triazol-5-yl, 1,2,4-triazol-3-yl, tetrazol-5-yl,

2-methyltetrazol-5-yl, 2-mercapto-1,3,4-th ^; adiazol-5-yl, 2-hydroxymethyl-1,3,4-oxazol-5-yl, 3-hydroxypyridazin-6-yl, 2-hydroxymethyl-1,3,4-thiadiazol-5-yl,

1,3,4-thiadiazol-5-yl, 2-methylamino-1,3,4-thiadiazol-5-yl, or

2-aminomethyl-1,3,4-thiadiazol-5-yl, and is nontoxic physiologically harmless SOU, which is based on the fact that N-acylamino-.alpha. c onh

wherein A and R are as defined above, with a thiol of formula V

H — S — Het (V), wherein Het is as defined above.

The above reaction may be carried out at a temperature of 40 to 80 ° C.

The novel cephalosporins of formula (I) have been found to have potent antimicrobial activity against Gram-positive and Gram-negative bacteria and excellent pharmacokinetic properties, making them useful as chemotherapeutic agents for the treatment of infectious diseases in animals including human beings, poultry and cattle.

The compounds of formula (I) also have significant antimicrobial activity against bacteria against which known cephalosporin series compounds have little activity against bacteria such as Pseudomonas aeruginosa, indole-positive Proteus, Serratia and Enterobacter aerogeneus.

Cephalosporins of formula I having a phenyl group substituted with at least one substituent selected from the group consisting of ureido, amine, hydroxymethyl, or hydroxyl ("= common substituent R") are more readily distributable in serum and urine than similar compounds without said compounds. substituents.

GOQH (IV)

The compounds of formula I may be administered intramuscularly or intravenously, for example in the form of solutions, suspensions and the like.

Pharmaceutical formulations containing a compound of formula I as an active ingredient may be prepared by mixing a compound of formula I with one or more pharmaceutically acceptable carriers or diluents, for example, water.

A typical dose of a compound of formula I is 400 mg to 20 g / day, preferably about 500 mg to 2 g / day; this dose is administered in a single dose or in divided doses (usually in divided doses) and is calculated for an adult (about 60 kg of body weight).

In order that the invention may be more fully understood, the following non-limiting examples illustrate the invention. All parts, percentages and ratios herein are by weight, by weight, and by weight unless otherwise indicated.

He did

Preparation of 7- [D - N - (4-hydroxypyridine-3-carboxamido) - N - (p -ureidophenyl) acetamido] -3- (2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl -3-cephem-4-carboxylic acid

-Ιζ 1 _CH

COOH

A mixture of 1.21 g of sodium [α- (4-hydroxypyridine-3-carboxamido) -a- (p-ureidophenyl) acetamido] cef alosporate, 0.20 g of sodium hydrogen carbonate, 0.36 g of 2-methyl-5-mercapto -1,3,4-thiadiazole and 25 ml phosphate buffer (0.1 N KH2PO4-0.1N NaHPCl; 2: 1 v / v; pH 6.3) was stirred for 6 hours at 60 ° C. The reaction mixture was then cooled with ice and its pH adjusted to 2 by addition of aqueous hydrochloric acid (3 N).

The separated crystals were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure. 0.62 g of the expected product is obtained.

Melting point: 233-240 ° C.

This compound can then be converted to the corresponding sodium salt by a known method.

Example 2

In the same manner as described in Example 1, but using the corresponding starting materials, the product was prepared.

COON &

Melting point: 215-220 ° C.

Example 3

In the same manner as described in point 1, but using the corresponding starting materials, the product of the formula is prepared

OH ^^ NHCONH ^ COONd

Mp 212-217. Example 4 degrees Celsius.

In the same manner as described in Example 1, but using the corresponding starting materials, the product of formula is prepared

XI

The melting point of the product obtained is 233 to Ex

Mp 240 ° C.

In the same manner as described in Example 1, but using the corresponding starting materials, the product of formula is prepared

The melting point of the product obtained is 236 to Example 6

Mp 242 ° C.

In the same manner as described in Example 1, but using the corresponding starting materials, the product of formula is prepared

The melting point of the product obtained is 207 to Example 7

215 [deg.] C.

Preparation of 7- [D - N- (4-hydroxy-1,5-naphthyridine-3-carboxamido) -amino-phenylacetamido] -3- (1,3,4-thiadiazol-5-yl) thiomethyl-3-cephem -4-carboxylic acid

n -— n

AA

A mixture of 1.18 g of 7- [Da- (4-hydroxy-1,5-naphthyridine-3-carboxamido) -amino-phenylacetamido] -cephalosporanic acid, 0.368 g of sodium bicarbonate, 0.32 of 2-mercapto-1,3,4- of thiadiazole and 25 ml of phosphate buffer (0.1 N ΚΗζΡΟι-Ο, Ι N NaHPOi; 2: 1 by volume; pH = 6.3) are stirred for 5.5 hours at 60 ° C. 20 ml of ethanol are then added to the reaction mixture and the mixture is maintained at 0-5 ° C overnight.

The separated crystals were collected by filtration, washed with ethanol and dried over silica gel under reduced pressure. In this way 1.05 sodium salt of the desired product is obtained.

The melting point of the product is 250-265 ° C.

This compound can then be converted to the corresponding sodium salt.

Example 8

In the same manner as described in Example 7, but using the corresponding starting materials, the product of the formula was prepared

N = N

-O-OH

Melting point: 252-260 ° C.

Example 9

As described in Example 7, but using the corresponding starting materials, a product of formula is prepared

The melting point of the product obtained is 250 to Example

259 ° C.

As described in Example 7, but using the corresponding starting materials, a product of formula is prepared

The melting point of the product obtained is 257 to Example 1

266 ° C.

As described in Example 7, but using the corresponding starting materials, a product of formula is prepared

The melting point of the product obtained is 257 to EXAMPLE 1 and d 1 2

266 ° C.

As described in Example 7, but using the corresponding starting materials, a product of formula is prepared

Melting point: 240-245 ° C.

Example 13

In the same manner as described in Example 7, but using the corresponding starting materials, the product of the formula was prepared

COONi <1 _Hj

The melting point of the product obtained is 250 to Example 14

255 ° C.

In the same manner as described in Example 7, but using the corresponding starting materials, the product of the formula was prepared

Melting point: 262-267 ° C.

Example 15

In the same manner as described in Example 7, but using the corresponding starting materials, the product of the formula was prepared

The melting point of the product obtained is higher than Example 16

280 ° C.

As described in Example 7, but using the corresponding starting materials, a product of formula is prepared

The melting point of the obtained product is 260 to Example 17 ° -65 ° C.

As described in Example 7, but using the appropriate starting materials, a product of formula is prepared

Temperature 270 ° C.

In the same manner as described in Example 7, but using the corresponding starting materials, the product of the formula was prepared

The melting point of the obtained product is 240 to Example 19

248 ° C.

In the same manner as described in Example 7, but using the corresponding

The melting point of the product obtained is 237 to Ex

245 ° C.

In the same manner as described in Example 7, but using the corresponding starting materials, the product of the formula was prepared

N — N

-M ch ₃ ia

Melting point: 235-250 ° C.

Example 21

In the same manner as described in Example 7, but using the corresponding starting materials, the product of the formula was prepared

Mp 252 ° C.

the product obtained is 244 to

Example 22

In the same manner as described in Example 7, but using the corresponding starting materials, the product of the formula was prepared

The melting point of the product obtained is 247 to Ex

255 ° C.

In the same manner as described in Example 7, but using the corresponding starting materials, the product of the formula was prepared

This product has a melting point of 239-248 ° C. Example 24

In the same manner as described in Example 7, but using the corresponding starting materials, the product of the formula was prepared

CONH - CH - CONH

N-N

CHOON &

CH _Z OH

The melting point of the product obtained is 249 to Example 25

261 ° C.

In the same manner as described in Example 7, but using the corresponding starting materials, the product of the formula was prepared

Melting point: 245-253 ° C.

Example 26

In the same manner as described in Example 7, but using the corresponding starting materials, the product of the formula was prepared

The melting point of the product obtained is 235 to Example 27

247 ° C.

In the same manner as described in Example 7, but using the corresponding starting materials, the product of the formula was prepared

Melting point: 230-241 ° C.

Example 28

In the same manner as described in Example 7, but using the corresponding starting materials, the product of the formula was prepared

CONH-CH

Ň.

C00N *

The melting point of the product obtained is 229 to Example 29

238 ° C ^! .

In the same manner as described in Example 7, but using the corresponding starting materials, the product of the formula was prepared

Melting point: 237-242 ° C.

Example 30

In the same manner as described in Example 7, but using the corresponding starting materials, the product of the formula was prepared

ff

Ypn '

OH

Melting point: 234-231

Mp 240 ° C.

Preparation of 7- [DL-α- (4-hydroxy-1,5-naphthyridine-3-carboxamido) -α-hydroxymethylphenylacetamido] -3-2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl -3-cep-4-carboxylic acid

«>

A mixture of 3.03 g of 7- [DL-α- (4-hydroxy-1,5-naphthyridine-3-carboxamido) -α-p-hydroxymethylphenylacetamido] cep alosporanic acid, 0.92 g of sodium bicarbonate, 0.90 g

2-methyl-5-mercapto-1,3,4-thiadiazole and 60 ml of phosphate buffer (0.1 N KH2PCH-0.1 N NaHPO1; 2: 1 v / v; pH 6.3) are stirred for 5.5. hours at 50-60 ° C. Ethanol (40 ml) was then added and the reaction mixture was maintained at 0-5 ° C overnight.

The separated crystals are then isolated by filtration, washed with ethanol and dried over phosphorus pentoxide under reduced pressure. 2.5 g of the title compound are obtained.

Melting point: 236-243 ° C.

Example 32

In the same manner as described in Example 31, but using the corresponding starting materials, the product of formula oh was prepared

I CONH-CH-CONH-T-N-N-nitro

CH 2 OH

Melting point: 240-246 ° C.

Example 33

In the same manner as described in Example 31, but using the corresponding starting materials, the product of formula was prepared

_><6> - Ji _M /

COONá.

^CH 2? ^H

Melting point 232-235 ° C.

Example 34

In the same manner as described in Example 31, but using the corresponding starting materials, the product of formula was prepared

Melting point: 245-250 ° C.

Example 35

Preparation of 7- [Da- (4-hydroxy-1,5-naphthyridine-3-carboxamido) -α-p-hydroxyphenylacetamido] -3- (2-methyl-1,3,4-thiadiazol-5-yl) acid thiomethyl-3-cephem-4-carboxylic acid

N-N ch,

A mixture of 1; 18 g of 7- [Da- (4-hydroxy-1,5-naphthyridine-3-carboxamido) -ap-hydroxyphenylacetamido] cep alosporanic acid, 0.368 g of sodium hydrogen carbonate, 0.36 g of 2-methyl-5- mercapto-1,3,4-thiadiazole and 23 ml of phosphate buffer (0.1 N KH2PO4-0, 1 N NaHPOd; 2: 1 by volume; pH 6.3) is stirred at 50-60 ° C for 5, 5 hours, then 20 ml of ethanol are added to the reaction mixture and the mixture is maintained at 0-5 ° C overnight.

The separated crystals were collected by filtration, washed with ethanol and dried over phosphorus pentoxide under reduced pressure. 1 g of the sodium salt of the desired product is obtained.

Melting point: 223-232 ° C. ⁽

Example 36

In the same manner as described in Example 35, but using the corresponding starting materials, the product of the formula was prepared

203007

OH _n -chlor-ch-conh

^ CH _Z S COONa

The melting point of the product obtained is 210-217 ° C.

The results of the tests to determine the antimicrobial activity of the compounds produced in the preceding examples are shown in the following table.

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Example Minimum inhibitory concentration (µg / ml) Staphylo-Staphylo-Escherichia Klebsiella number Proteus Pseudomonas Serratia Enterobacter coccus coccus coli pneumoniae vulgaris aeruginosa No. 72 aerogeneus aureus 209 9 aureus -} - NIHJ 602 HX 19 104 75

FS 289

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Legend of the previous table: CET (Cefalothin):

+ Staphylococcus aureus FS 289: Penicillin resistant strain

CEG (Cephaloglycine):

^ X-ch-com-t-rS

NH.

CH ^ OCOCH ^ CHOON *

COOH CH ₂ OCOCH _of

CEZ (Cefalozinj:

Claims (2)

SUBJECT A process for the preparation of N-acylamino-.alpha.-arylacetamidocephalosporin of formula (I) wherein: A represents a divalent heteroaromatic ring selected from the group consisting of quinoline, isoquinoline, cinnoline, naphthyridine, quinoxaline, pyrazolopyridine, pyridopyrazine, thiazolopyrimidine, pyridopyrimidine, pyridine, pyrimidine, pyridazine, triazine and pyrazine, which may be substituted with at least one substituent selected; an alkyl group having a total carbon number of 1 to 4, an alkoxy group having a total number of carbon atoms of 1 to 4, an alkanoyl group having a total number of carbon atoms of 2 to 5, an alkoxycarbonyl group having a total number of carbon atoms. 2 to 5, alkylthio having 1 to 4 carbon atoms, mercapto, hydroxyl, alkoxymethyl having 2 to 6 carbon atoms, halogen, cyano, nitro, alkylsulfonyl having 1 to 4 carbon atoms, phenylsulfonyl a pyrimidylsulfonyl group, a sulfaynAlez moyl group, a carbamoyl group, a phenoxycarbonylamino group, an acetoacetylamino group, an alkylamino group having a total carbon number of 1 to 4, a dialkylamino group in which each alkyl has 1 to 4 carbon atoms, a haloalkyl group having a total carbon number 1-4, alkenyl having 2 to 6 carbon atoms, phenyl, pyridyl and cycloalkyl having 3 to 6 carbon atoms, R is a radical of formula wherein R 1 represents an amino group, a hydroxyl group, a hydroxymethyl group or an ureido group, R2 and R3, which may be the same or different, represent a hydrogen atom, a nitro group, an alkylamino group having a total carbon number of 1 to 4, an alkanoylamino group having a total carbon number of 2 to 6, an amino group, a hydroxyl group, an alkanoyloxy group 2-6, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, chlorine, bromine, fluorine, iodine, trifluoromethyl, hydroxymethyl, and sulfamoyl, and X is -S-Het wherein Het is 1-methyltetrazol-5-yl, 2-methyl-1,3,4-thiadiazol-5-yl, 1,2,3-triazol-5-yl , 1,2,4-triazol-3-yl, tetrazol-5-yl, 2-methyltetrazol-5-yl, 2-mercapto-1,3,4-thiadiazol-5-yl, 2-hydroxymethyl-1,3,4-oxazol-5-yl, 3-hydroxypyridazin-6-yl, 2-hydroxymethyl-1,3,4-thiadiazol-5-yl, 1,3,4-thiadiazole - 5-yl, 2-methylamino-1,3,4-thiadiazol-5-yl or 2-aminomethyl-1,3,4-thiadiazol-5-yl, and non-toxic physiologically acceptable salts thereof, N-acylamino-.alpha.-arylacetamidocephalosporin of the formula IV. COOH CH ₂ OCOCH ₃ (IV) wherein A and R are as defined above, with a thiol of formula V HS-Het (V) wherein Het is as defined above and the compound obtained is optionally converted to its non-toxic physiologically acceptable salt.