CS205006B2 - Method of preparing n-acylamino-alpha-arylacetamido-cephalosporin - 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)

HO ~ A ~ CONH ~ CH-C onh

(I) 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 one or more substituents, comprising an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an alkanoyl group having 2 to 5 carbon atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms, an alkylthio group having a total number carbon atoms of 1 to 4, mercapto, hydroxyl, alkoxymethyl of 2 to 6, halogen, cyano, nitro, alkylsulfonyl of 1 to 4, phenylsulfonyl, pyridylsulfonyl, salt famoyl, carbamoyl, phenoxycarbonylamino, acetoacetylamino, C1-4 alkylamino, dialkylamino in which each alkyl has 1 to 4 carbon atoms, haloalkyl in 1 to 4 total, alkenyl 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 group of formula

R.

20S00B where

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 with a total carbon number 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 -OCOCH 3 or -S-Het, in which Het is 1-methyltetrazol-5-yl, 2-methyl-1,3,4-thiadiazol-5-yl, 1,2,3-triazole- 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 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.

Cephalosporin series compounds such as cephalothin and cefahzoline are known to be very potent and widely used chemotherapeutic 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 become widespread in recent years and which are 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.

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

UO-A-CONH-CH-CONH 1

O

in which

A represents a divalent heteroaromatic ring selected from the group consisting of quinoline, isoquinoline, cinnoline, naphthyridine, quinoxaline, pyrazolopyridine, pyridopyrazine, thiazolpyrimidine, 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 5 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, pyridylsulfo a phenyl group, a sulfamoyl group, a carbamoyl group, a phenoxycarbonylamino group, an acetoacetylamino group, an alkylamino group (1-4 carbon atoms total, a dialkylamino group in which each alkyl group has 1-4 carbon atoms), a halogenalkyl group total carbon atoms 1-4, 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 group

where

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 with a total carbon number 2-6, alkyl having 1-4 carbon atoms, alkoxy having 1-4 carbon atoms, chlorine, bromine, fluorine, iodine, trifluoromethyl, hydroxymethyl, and sulfamoyl,

X is -OCOCH 3 or -S-Het wherein Het is 1-methyltetrazol-5-yl, 2-methyl-1,3,4-thiadiazol-5-yl, 1,2,3-triazole -5-yl, 1,2,4-triazol-3-yl, tetrazol-5-yl, 2-methyltetrazol-5-yl, 2-mercapto-1,3,4-thiadiazol-5-yl a group, 2-hydroxymethyl-1,3,4-oxazol-5-yl, 3-hydroxypyridazin-6-yl, 2-hydroxymethyl-1,3,4-thiadiazol-5-yl, 1,3,4 a thiadiazol-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 a non-toxic physiologically harmless group thereof a salt comprising the step of forming an acylaminocarboxylic acid of formula VI

HO — A — CONH — CHCOOH

R (VI), wherein A and R are as defined above, or a reactive derivative thereof, derived from a carboxyl group and selected from the group consisting of acid halide, acid anhydride, acid azolid, active acid ester and acid azide, reacts with an acid VII

wherein X is as hereinbefore defined, or a derivative thereof, including a salt thereof, or a derivative in which the carboxyl group is protected, from the group consisting of a silyl ester and a tert-butyl ester, wherein in the silyl ester the amino group of the acid may also be silylated; in the case where X is -OCOCH 3, the optionally resulting reaction product may be reacted with a heterocyclic thiol of formula V wherein Het is as defined above.

Examples of non-toxic pharmaceutically acceptable salts derived from compounds of Formula I include sodium salt, potassium salt, calcium salt, magnesium salt, triethylamine salt, diethylamine salt, morpholine salt, procaine salt, L-arginine salt, L-lysine salt. etc.

Since the α-carbon atom of the side chain (phenylglycine residue), attached in formula I at position 7, is an asymmetric carbon atom, 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 diastereomer being the D-diastereomer.

The novel cephalosporins of formula (I) have been found to have potent antimicrobial activity against Gram-positive and Gram-negative bacteria and excellent pharmacological 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, amino, hydroxymethyl, or hydroxyl (- the general substituent R) are much better distributed in serum and urine than similar compounds without said substituents .

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

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, percentages by weight, and weight ratios, unless expressly stated otherwise.

Example 1, -3-Carboxamido-.alpha .- (p-hydroxyphenyl) acetamido] -cephalosporin

Preparation of 7- [D-a- (4-hydroxypyridine-)

OH

A stirred solution of 1.44 g of Da- (4-hydroxypyridine-3-carboxamidoyl-a- (p-hydroxyphenyl) acetic acid, 40 ml of acetonitrile and 1.01 g of triethylamine was cooled to -20 ° C and then added to the cooled solution. 1.08 grams of ethyl chloroformate and the resulting reaction mixture was allowed to react with stirring for 1.5 hours.

A solution of 1.35 g of 7-aminocephalosporanic acid tert-butyl ester [described in Journal of Medicinal Chemistry, 9, 444 (1966)] in 20 ml of acetonitrile is then added in one portion to the resulting reaction solution. This solution was precooled. The resulting reaction mixture was first stirred at -10 to -5 ° C for two hours and then overnight at -5 to 0 ° C.

The resulting reaction solution was concentrated to dryness under reduced pressure and the residue was dissolved in ethyl acetate. The ethyl acetate layer was then washed with water and concentrated and then purified by silica gel chromatography. Finally, trifluoroacetic acid is added to the purified product under ice-cooling to cleave the tert-butyl ester group.

To the resulting trifluoroacetic acid solution was added a large excess of diethyl ether to precipitate the desired product in crystalline form. The crystals obtained are then filtered off.

The melting point of the product obtained is 190 to 201 ° C.

Example 2

Preparation of 7- [N- (4-hydroxy-pyrimidin-3-carboxamido) -N- (p-hydroxyphenyl) acetamido] -3- (1-methyl-1,2,3,4-tetrazol-5-ylthiomethyl) 3-Cephem-4-carboxylic acid

cqnh-ch-conh-x-f>

OH

O'

CH ^ S

CQQH

A stirred solution of 1.44 g of D -? - (4-hydroxypyridine-3-carboxamido) -? - (p-hydroxyphenyl) acetic acid, 40 ml of acetonitrile and 1.01 g of triethylamine was cooled to -20 ° C and cooled to -20 ° C. of the solution was added 1.08 grams of ethyl chloroformate. Thereafter, the reaction mixture was stirred at -20 to -10 ° C for 1.5 hours.

In addition, a solution of 1.64 g of 7-amino-3- (1-methyl-1,2,3,4-tetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid, 2.5 ml of N, O -bis-trimethylsilylacetamide and 20 ml of acetonitrile were stirred at room temperature for 30 minutes. This solution is then cooled and added all at once to the first solution.

The reaction mixture is stirred at -10 to 0 ° C for two hours and then at 0 to 5 ° C for one hour, then 20 ml of methanol are added to the reaction mixture and the insoluble matter formed is removed by filtration.

The filtrate was concentrated under reduced pressure to obtain caramel crystals.

To 2 g of the caramel crystals thus obtained was added 10 ml of trifluoroacetic acid, which had previously been cooled to 0 ° C. After 15 minutes, 200 mL of diethyl ether was added dropwise to the resulting mixture. The separated crystals were collected by filtration.

Example 3

In the same manner as in Example 2, the product of formula is prepared

1 «

205008

The melting point of this product is 225 to 235 degrees Celsius.

Example 4

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

OH

CONH-CH

O

OOOH

CB ^ S

NHC0NH _z

A mixture of 1.21 g of the sodium salt of 7- [D-α- (4-hydroxypyridine-3-carboxamido) -? - (p-ureidophenyl) acetamide] cephalosporinic acid, prepared analogously to Example 1; 1.20 g of sodium bicarbonate, 0.36 g of 2-methyl-5-mercapto-1,3,4-thiadiazole and 25 ml of phosphate buffer (0.1 N H N NaHPCl; 2: 1 by volume; pH 6.3} was stirred for 6 hours at 60 [deg.] C. The resulting solution 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.

The melting point of this product is 233 to 240 degrees Celsius.

This compound can then be converted to the corresponding sodium salt in a manner known per se.

Example 1 a d 5

As described in Example 4 but using the corresponding starting materials, the product of the following formula was prepared

N - N CB ^ S-k ^

C00N &

'CH,

Melting point: 215-220 ° C.

Example 1 a d 6

As described in Example 4 but using the corresponding starting materials, the product of the following formula was prepared

The melting point of the product obtained is 212 to Example 7

217 ° C.

As described in Example 4, but using the corresponding starting materials, the product of the following formula nH was prepared

Mp 240 ° C.

Mp 242 ° C.

the product obtained is 233 to Example

As described in Example 4, but using the corresponding starting materials

As described in Example 4, but using the corresponding starting materials, a product of the following formula was prepared.

The melting point of the product obtained is 207 to Example 10

215 [deg.] C.

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

A mixture of 1.18 g of 7- [Da- (4-hydroxy-1,5-naphthyridine-3-carboxamido) -am-aminophenylacetamido] -cephalosporanic acid, prepared analogously to Example 1, 0.368 g of sodium bicarbonate, 0.32 g of 2-mercapto-1,3,4-thiadiazole and 25 ml of phosphate buffer (0.1 N KH2PO4-0, 1 N NaHPCl; 2: 1 by volume; pH 6.3) are stirred for 5.5 hours at a temperature of 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. 1.05 g of the sodium salt of the desired product is obtained.

The melting point of the product is 250-262 ° C.

Example 11

As described in Example 10, but using the corresponding starting materials, the product of formula is prepared

Melting point: 252-260 ° C.

Example 12

As described in Example 10, but using the corresponding starting materials, the product of formula is prepared

CONH-CH-CONH

i i

COON &.

^{CHI OH}

NM,

Melting point: 250-259 ° C. .

Example 13

As described in Example 10, but using the corresponding starting materials, the product of formula is prepared

CHf,

CONH-CH-CONH-j- (> N-ty

COON &.

CM,

The melting point of the product obtained is 257 to Example 14

266 ° C.

As described in Example 10, but using the corresponding starting materials, the product of formula is prepared

20500 «

The melting point of the product obtained is 253 to Example 15

260 [deg.] C.

As described in Example 10, but using the corresponding starting materials, a product of formula is prepared

The melting point of the product obtained is 240 to Example 16

245 ° C.

As described in Example 10, but using the corresponding starting materials, the product of formula is prepared

The melting point of the product obtained is 250 to Example 17

255 ° C.

As described in Example 10, but using the corresponding starting materials, the product of formula is prepared

C0NH ~ CH-CONH

NH n-f S n-N

COON.

Example18

As described in Example 10, but using the corresponding starting materials, the product of formula is prepared

The melting point of the product obtained is 262-62

267 ° C.

N-N 'tep' tep20500b

Λ4.

CH ^S- ^ ^J

NH *

CQ0N &. qu

The melting point of the product obtained is higher than that of Example 1

280 ° C.

As described in Example 10, but using the corresponding starting materials, the product of formula is prepared

Temperature 265 ° C.

As described in Example 10, but using the corresponding starting materials, the product of formula is prepared

The melting point of the product obtained is 264 to EXAMPLE 21.

270 ° C. ; /.

As described in Example 10, but using the corresponding starting materials, the product of formula is prepared

The melting point of the product obtained is 240 to Example 22

248 ° C.

As described in Example 10, but using the corresponding starting materials, the product of formula is prepared

Example 23

Temperature 245 ° C.

m.p.

As described in Example 10, but using the corresponding starting materials, the product of formula is prepared

m.p.

Temperature 250 ° C.

Example 24

As described in Example 10, but using the appropriate materials, the product of formula is prepared

Temperature 252 ° C.

m.p.

Example 25

As described in Example 10, but using the appropriate materials, the product of formula is prepared

m.p.

Ν — N

A _S A

CH _z m _z

Temperature 255 ° C.

Example 26

As described in Example 10, but using the corresponding starting materials, the product of formula is prepared

205008

Melting point: 249-261 ° C.

Example 27

As described in Example 10, but using the corresponding starting materials, the product of formula is prepared

OH? CONH-CH- CONHA X?

COON *

N — n ^CH z ^with xA

CH _Z OH

NH,

Melting point: 235-247 ° C.

Example 28

As described in Example 10, but using the corresponding starting materials, the product of formula is prepared

Melting point: 239-248 ° C.

Example 29

As described in Example 10, but using the corresponding starting materials, the product of formula is prepared

The melting point of the product obtained is 245 to 245 ° C

253 ° C.

Example 30

As described in Example 10, but using the corresponding starting materials, the product of formula is prepared

293916

The melting point of the product obtained is 230 to Ex

241 ° C.

As described in Example 10, but using the corresponding starting materials, the product of formula is prepared

OH aCONH-CH-CONH-

The melting point of the product obtained is 229 to Example 32

238 [deg.] C.

As described in Example 10, but using the corresponding starting materials, the product of formula is prepared

The melting point of the product obtained is 237 to Example 33

Mp 242 ° C.

As described in Example 10, but using the corresponding starting materials, the product of formula is prepared

The product obtained has a melting point of 234-240. Example 34 degrees Celsius.

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'-ephem-4-carboxylic acid

205008

A mixture of 3.03 grams of 7- [DL-α- (4-hydroxy-1,5-naphthyridine-3-carboxamido] -α-hydroxymethylphenylacetamido] cephalosporanic acid, prepared in a manner similar to that described in Example 1, 0.92 g. sodium bicarbonate, 0.90 g of 2-methyl-5-mercapto-1,3,4-thiadiazole and 60 ml of phosphate buffer (0.1 N KH2PO4-0.1N NaHPO3; 2: 1 by volume; pH 6.3) Stir 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 desired product are obtained.

The temperature of the product obtained is 236 to 243 degrees Celsius.

Example 1 5

As described in Example 34, but using the corresponding starting materials, the product of formula is prepared

CONH - CH - CQNH

O

CH £ H

COONa

Melting point: 240-246 ° C.

Example 36

As described in Example 34, but using the corresponding starting materials, the product of formula is prepared

OH ^ J ^ CONH-Oi-CONH 3 -

N '

/ V— / V

AND

H _Z HH

Melting point 232-235 ° C.

Example 37

As described in Example 34, but using the corresponding starting materials, the product of formula is prepared

OH

N — N

Also

AND

CH 2

205000

Mp 232-235. Example 3 8 degrees Celsius.

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

A mixture of 1.18 g of 7- [D - N- (4-hydroxy-1,5-naphthyridine-3-carboxamido) -α-hydroxyphenylacetamido] cep alosporanic acid, prepared in a manner similar to that described in Example 1, 0.368 g of bicarbonate sodium, 0.36 g of 2-methyl-5-mercapto-1,3,4-thiadiazole and 23 ml of phosphate buffer (0.1 Ν KH2PO4 -0.1 N NaHPCU; 2: 1 by volume; pH 6.3) Stir at 50-60 ° C for 5.5 hours. 20 ml of ethanol are then added to the reaction mixture and the mixture is maintained at 0-5 ° C overnight.

The precipitated crystals are collected, 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 39

As described in Example 38, but using the corresponding starting materials, the product of formula is prepared

CONH - CH - CONH

COONá

CH,

Melting point: 210-217 ° C.

Determination of the antimicrobial activity of the compounds produced according to the Examples (µg / ml) µ

rn OT

ŠSs 5 ®. Ρ w, o

CM

Cv .O toincocotocococo inNCNHHCNHHTH lOCMCOCDCOCDCOCO CM r-l

WHAT WHAT WHAT WHAT WHAT WHAT n Hï) Μ H ÍO M co

CO CM

CO CO CM CO CO CM CO CO rH rH

ΙΌ CO CO LO LO CO CM ID Η H N 04 Hlf)

CO CO

CO CM rH m m iri m m ιη ιη ιη ιηιη m mmrnmin o o o cm or cm cm ci ci ci ci ci ci o m ci ci ci ci ci o CJ

O tí o

O

Ό

Φ w

(. Th

Φ

CM co

Λ

Φ ca »» - * tí o

CZ) ca w

O

W) Those

CD ca ω

W) i-μ rS gE (X th three.

ce

WHAT

Φ ca three tí · φ

tí

Λ

CM σ

co il.

ω tí

CZ)

u o

O

CJ)

E) What did CM Φ n cn ca + -> ti ti φ three _Q three CD ca with Ti J2 three en) η O λ; r ^{ftjc> o} pj in the lo what what what tn as CM in ^ CM-CM ^ rH ^ rH rH ~ CM ^ rH what cm cd what what what what what

COeOCOLOLOCOLO10 rH tH ^ H CM ^ CM ^ rH ^ CM ^ CM ^ whats what, cd cd whats what cd

COLOCOCOCOCOCOLO ^ h what what what what what what what

CD cq rl Η Η CM CM CM H r Η r r r r r r r r r r r o o o o o o o

tn WHAT WHAT WHAT WHAT WHAT what WHAT WHAT what what tn what WHAT ID what WHAT WHAT WHAT WHAT WHAT WHAT CO tn ΙΌ CM rH rH tn ^ tn rH rH rH rH ^ tH rH ^ cq rH rH CM ^ rH ^ rH rH rH rH rH rH rH CM ~ cm rH what WHAT WHAT rH rH WHAT what what what what what what WHAT what what what what what what what what what what what

min pococococococococococomcomcococomcom inNCM WH WHW rH ^ rt m ^ lft N rH ^ in TH ^ C ^ m CM ^ r ^ TH rH_CSI_lf ^ N WHAT WHAT WHAT WHAT WHAT WHAT WHAT WHAT WHAT WHAT WHAT WHAT WHAT WHAT CD ri CO rH rH what mmm what HNCMNH what what what what mmmm CM ~ CMÍJ CM (í WHAT WHAT what what CM Η H what what 'mmmmm CM CM CM CM what' what what what mmmm mm cm m CM CM ~ cm_ in CM ~ CM what what what what what what

0) OTO) 0) OOOOCOCOCOCO coconnsMnw ^^ o o o o o o ri ri o o

CO 00 O) what what what what i o o m o o o r i ri θ O

COCOCOOOOOODCOO) c ^ in o. Ts tx tx m what θ C C O C C Í

0.78 6.25 3.13 3.13 0.2 3.13 12.5 3.13

1.56 6.25 1.56 3.13 0.1 3.13 12.5 3.13 rHcomcot ^ oooor-icMcoMcmcObsoomorHCMco ^ mco ^ cocn

HrlrlrirtrirZrlrlriNNNfMNCMNNNN

205QQ8

Product Staphylococcus Staphylo-Escherichia · Klebsiella Proteus Pseudomonas Serratia Enterobacter • by aureus coccus coli pneumoniae vulgaris aeruginosa No. 72 aerogeneus of Example 209 P aureus-Η NIHJ 602 HX 19 104 75 FS number 289 io Ω Ω 04 04 04 LO

04 * LO of CM * IO LO CO 04 * OOO rd

OO OO OO OO O O OO OO LO IO LO 04 LO 'O O rd 03 04 03

IO LO IO LO 03 ^ cm ^lr l · LO LO 04: WHAT* cc? CM * CM * 04 * LO CO * CD O O O rd rd rd 04 / O O O 04 / 03 / 04 /

o oo cr> oo cn co lo o o co · 'L 04 o o o o o o o o o o cm * co * co *

what co íd in © ισ r4 rH CM CM> IO> CM CO oo rd 00 ts WHAT WHAT WHAT cm cm r-what CO * o * O

rd rd

LO CO CO LO CO

04 ^ 04 LO LO IO LO ^ 04 ^ L0 ^ LO in

CO * CO * O * CM * 04 * LO rd * CO * 04 * 04 * rd * rd rd rd 04 rd rd

LO LO LO LO LO LO LO LO LO LO LO LO LO LO LO LO LO LO LO

CttCTjeocooooocoen co CO CO 0 * Cx t \ 0 »LO 'CO IO rd 04

O * O * O * O * O * O * O * O * O * O * O *

Sx .3 ’3> o a

o (Λ 'Φ and

J a

N

O Η N www o o u

OrdCMCOLOCOC ^ O

COCOCOCOCOCOCOCOCO

Legend to the previous table:

+ Staphylococcus aureus FS 289: Penicillin resistant strain.

CEG = Cephaloglycine

CET = Cephalothin:

HG-CH ^ _S ^ _Z CH CONH

CH ^ OCOCH ^ _{GEZ =} cefazoline:

COOH

CH-OCQCHa

COONa *

Claims (2)

SUBJECT A process for the preparation of N-acylamino-α-arylacetamidocephalosporin of formula (I) HO-A-CONH-CH-CONH COOH (U 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 from optionally comprising 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, an alkanoyl group having a total number of carbon atoms of 2 to 5, an alkoxycarbonyl group having a total number of carbon atoms of 2 to 5 1-4 atoms, mercapto group, hydroxyl group, alkoxymethyl group having 2 to 6 carbon atoms, halogen, cyano, nitro, alkylsulfonyl group having 1 to 4 carbon atoms, phenylsulfonyl group, pyridylsulfonyl group pin, sulfamoyl group, pin alloys, carbamoyl group, phenoxycarbonylamino group, acetoacetylamino group, 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 number of carbon atoms 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 represents a group of the formula wherein R1 is 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 with a total carbon number 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 -OCOCH 3 or -S-Het wherein Het is 1-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-thiadiazol-5-yl, 2 a methylamino-1,3,4-thiadiazol-5-yl group; 2-aminomethyl-1,3,4-thiadiazol-5-yl, and its physiologically harmless non-toxic salts, characterized in that the acylaminocarboxylic acid of the general formula VI HO — A — CONH — CHCOOH R (VI), wherein A and R are as defined above, or a reactive derivative thereof derived from a carboxyl group and selected from the group consisting of an acid halide, acid anhydride, acid azolid, active acid ester and acid azide, reacts with an acid or a derivative thereof, including a salt thereof, or a derivative in which the carboxyl group is protected by a protecting group selected from the group consisting of a silyl ester and a tert-butyl ester, wherein in the case of the silyl ester the amino group of the acid may also be silylated, then, when X is -OCOCH 3, the optionally resulting reaction product may be reacted with a heterocyclic thiol of formula V HS-Het (V), in which Het is as defined above and optionally cleaves the carboxyl protecting group in the compound obtained and / or converts the compound obtained to its non-toxic physiologically acceptable salt. severografia, n. p., plant 7, Most modification in printed descriptions of the invention In the printed description of the invention for the author's certificate S. 20S 006 (PV 7467-79) column 51, line 5 was not punched. Correctly, the β-S-Het in which Het is a 1-methyl-tetrazol-5-yl group,