CS196261B2 - Method of producing new compounds of 1-ureidosubstituted 3-thiomethylcephalosporine - Google Patents

Abstract

A process is described for the preparation of novel cephalosporin compounds of the formula I, which are substituted by a ureido radical, by reaction of a compound of the formula II with a compound of the formula (III) R''-NH-CO-N(R')-CO-A. These can be converted into the esters of the formula IV which are likewise new. The substituents in the compounds of the formula I and IV have the meanings stated in Claim 1 and Claim 10 respectively. The compounds of the formula I and IV have a high activity and a broad spectrum of action as antibiotics and are particularly suitable for the treatment of infections caused by Gram-negative microorganisms. <IMAGE>

Description

The invention relates to a process for the preparation of novel ureidosubstituted cephalosporins. which are antibiotics with a broad spectrum of activity, particularly suitable against infections caused by a Gram-negative microorganism.

Cephalosporin compounds with an ureide group or substituted. an ureide group at the α position and the 7-acylamide side chain have already been described. U.S. Patent No. 3,673,183, issued June 27, 1972, describes α-ureidocephalosporanic acids. U.S. Pat. No. 3,708,479 discloses acyloxymethyl esters of α-ureidocyclohexadienyl and acetamidophalosporins, and U.S. Pat. No. 3,697,507, the same esters, derived, have been described. by α-aminobenzylpenicillin. Penicillins and cephalosporins. with α- (3-imidoylureido) arylacetamide side chain have been described in U.S. Patents 3,634,405 and 3,646,024. Also known are α-3-acylureidobenzylpenicillins, U.S. Pat. wherein the various acyl groups are bonded to the terminal nitrogen atom of the α-ureide group in the 6-arylacetamide side chain.

Compounds that can be produced. by the method of the invention. The cephalosporinedihydrazine ring is substituted at the 3-position by a heterocyclic thiomethyl group, in addition to these, they have a broader spectrum of activity because of their usual high activity against Gram positive microorganisms, but they are also highly effective against A wide range of gram - negative micro - organisms,. which distinguishes them from previously known compounds.

The invention therefore provides a process for the preparation of 1-ureidosubstituted 3-thiomethylcephalosporin compounds of formula I

where

R is a 3-substituted ureido group of the formula

where

R 'is hydrogen, methyl, phenyl, benzyl or furfuryl,

R ‘is hydrogen or methyl,

R 1 is phenyl, hydroxyphenyl, or thienyl; R 2 is acetoxy, Groups

N - N fy — n z

where

Z is C 1 -C 4 alkyl, as well as pharmaceutically acceptable non-toxic salts of these compounds, characterized in that the compounds of formula (II) and (R ') are different from hydrogen, acylation of cephalosporin of formula (II) with the corresponding carbamoyl chloride II

R — N — C — N — C — Cl,

СНз

Compounds of formula I wherein R is

3-Substituted urea -

Him

I II. R '-N — C — Nr-,

AND

H can be prepared by acylating a compound of formula II with p-nitrophenylcarbamate

where

R 1 and R 2 are as defined above, with a compound of formula

O

II r-c-a, ·

where

R is as defined above, and

A represents a chlorine atom or a group

The starting compounds of formula II in which R 1 is phenyl, substituted phenyl or thienyl and R 2 is 1-lower alkyl-1H-tetrazol-5-yl or 5-lower-alkyl-1H-thiadiazobZ-yl have been described in U.S. Patent No. 3,641,021.

The starting materials of formula II in which R2 is acetoxy may be prepared by acylation of 7-aminocephalosporanic acid with phenylglycine. thienylglycine or furylglycine. Compounds of formula II in which R is phenyl and R ₂ is acetoxy, include known antibiotic cephaloglycin.

Acylation of compounds of formula II with 1,3-disubstituted ureidocarbamoyl chloride and optionally converting the acid thus obtained into a non-toxic salt.

The term "halogen atom" means a fluorine, chlorine and bromine atom, preferably a chlorine atom. .

The term "C 1 -C 4 alkyl" in the meaning of Z means methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and other straight and branched chain hydrocarbon radicals having 1 to 4 carbon atoms.

Compounds of formula I wherein R is a 1,3-disubstituted ureide group

HIM ...

R '—N — C — N “,

Wherein R 1 is as defined above, includes acylation of the free α-amino group at position 7 of the side chain. This acylation is carried out in an inert solvent in the presence of a substance capable of binding hydrogen halide at a temperature of -5 to 20 ° C, preferably 0 to 5 ° C. Acylation may be, for example, acetonitrile, tetrahydrofuran, dimethylformamide and dimethylacetamide, the preferred solvent being acetonitrile. If the starting material is insoluble or partially insoluble in the chosen solvent, it can be dissolved by adding a silylating agent, for example bis- (trimethylsilyl) acetainide (BSA) before addition of carbamoyl chloride.

6,261 ⁵

Suitable hydrogen halide-capable substances are, for example, tertiary amines, such as triethylamine and pyridine, or alkylene oxides, such as propylene oxide or butylene oxide.

Carbamoyl chlorides of formula

- \, Ί .11'II R‘ — N — C — N — C — Cl,

- Л |

It can be prepared by reacting 1,3-disubstituted urea with a phosgene-VT anhydrous inert solvent such as dichloroethane, dichloromethane or tetrahydrofuran. The reaction is preferably carried out at a temperature of 0 to 5 ° C.

Symmetrical 1,3-dimethylurea gives rise to only one of the carbamoyl chloride, N-methylaminocarbonyl-N-methylcarbamoyl chloride

H O O .1 H 7. II

СНз — N — C — N — C — Cl, • СНз (R “= methyl), because both nitrogen atoms in urea are equivalent. '

Unsymmetrical ureas in which R 'is a quaternary group other than a methyl group can form two types of carbamoyl chloride by reaction with phosgene · Desired N-methylcarbamoyl chloride

H o ··· O

I II II

R ^u —N — C — N — C — Cl,

AND

Separate from the undesired isomeric chloride by fractional crystallization from a mixture of a polar and a non-polar organic solvent, for example a mixture of diethyl ether and petroleum ether, or a mixture of acetone or ethyl acetate and hexane or petroleum ether.

The 1,3-disubstituted ureas may be prepared by known methods or are commercially available.

Examples of N-substituted aminocarbonyl-N-methylcarbamoyl chlorides are those of the above formula wherein R 1 is phenyl, benzyl or 2-furfuryl.

The preparation of the compounds of formula I in which R <is methyl is illustrated by the process for the preparation of 7- [α- (3-methylcarbamoyl-3-methyl-1-ureido) -phenylacetamido] -3- (1-methyl-). 1H-Tetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid. 7- (D-6-amino-α-phenylacetamido) -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid is suspended in acetonitrile containing excess propylene oxide. A small excess of bis- (trimethylsilyl) acetamide was added to the suspension while stirring to facilitate dissolution. The resulting solution was cooled to 5 ° C and a molar equivalent of N-methylaminocarbonyl-N-methylcarbamoyl chloride was added dropwise with stirring. The mixture was stirred in the cold for 2-4 hours, then allowed to warm to room temperature. The product is preferably isolated by extraction with an organic solvent such as ethyl acetate and then the reaction mixture is poured into ethyl acetate / water, the aqueous phase is separated, acidified and the resulting product is extracted with ethyl acetate.

Compounds of formula (I) in which R‘ represents a hydrogen atom may be prepared by acylation of the t-aminocephalosporin starting material of formula (II) with a pmitrophenylcarbamate of formula (I):

R ~ N-C-N-C- o wherein R 'is as defined above.

These esters are prepared by reacting urea or monosubstituted urea in an inert solvent such as tetrahydrofuran with p-nitrophenyl chloroformate to form R rozpouště-NH-C (O) -NHs. For example, methyl urea is reacted in anhydrous tetrahydrofuran at 0 ° C with p-nitrophenyl chloroformate to give p-nitrophenyl-N- (methylcarbamoyl) carbamates.

As in the reaction of the above carbamoyl chlorides, two isomeric p-nitrophenylcarbamates are formed in the reaction of urea or monosubstituted urea with β-nitrophenyl chloroformate.

Desired carbamates are formed by acylation of urea, unsubstituted on Ni, while the undesired ester is formed by acylation of the N3 nitrogen atom when substituted, or by acylation at the R &apos; -N &apos; group. Usually · I h.

both of these products form in equal quantities.

The desired p-nitrophenyl-N- (substituted carbamoyl) carbamates form isocyanate by the action of silylating agents such as bis- (trimethylsilyl) acetamide (BSA) or mono- (trimethylsilyl acetamide) (MSA).

196281

Unwanted p-nitrophenylcarbamate

O

C = O, which is formed together with the above-mentioned desired carbamate, is unable to form an isocyanate by the action of a silylating agent.

In the acylation of α-aminoarylacetamidocephalosporin of formula II to give cephalosporin of formula I wherein R R is hydrogen, a mixture of the two formed carbamates can be used. The acylation is carried out in an inert anhydrous solvent in the presence of an excess of a silylating agent such as BSA or MS A. The p-nitrophenyl-N- (substituted carbamoyl) carbamate forms an isocyanate in the reaction mixture, which then reacts with the α-amino group of the compound .

Examples of p-nitrophenyl carbamate, which can be used in preparing compounds of formula I in which R ¹ represents a hydrogen atom may be p-nitrophenyl N- (ethylcarbamoyl) carbamate, p-nitrophenyl N- (cyclopropylcarbamoyl) carbamate, p- nitrophenyl-N- (phenylcarbamoyl) carbamate, p-nitrophenyl-N- (phenylcarbamoyl) carbamate, p-nitrophenyl-N- (propargylcarbamoyl) carbamate, p-nitrophenyl-N- (allylcarbamoyl) carbamate, p-nitrophenyl- N- (benzylcarbamoyl) carbamate and 'p-nitrophenyl-N- (carbamoyl) carbamate (R' = H).

The acylation of the .alpha.-aminoarylacetamidophthalosporin of formula II by treatment with p-nitrophenylcarbamate is usually carried out in anhydrous acetonitrile at a temperature of 20 to 25 DEG C. To provide anhydrous conditions, the acylation is preferably a gas such as nitrogen or argon. A sizing agent such as BSA or MSA is added in excess and has two purposes. On the one hand, it facilitates the dissolution of the α-aminoarylcephalosporin of the formula II by the formation of soluble silyl derivatives, for example the silyl esters of the compound of the formula II, and in addition an excess of this compound reacts with p-nitrophenylcarbamate.

The acylation is carried out as follows. A suspension of α-aminoarylacetamidophalosporin of formula II in anhydrous acetonitrile is mixed with an excess of BSA. After obtaining a homogeneous solution, the mixture of p-nitrophenylcarbamate is added in an amount sufficient to produce at least one molar equivalent of the desired p-nitrophenylcarbamate isomer per equivalent of the compound of Formula III.

The reaction mixture was stirred at room temperature for 1 to 3 hours, whereupon the resulting product was isolated.

The product of formula (I) in which R * is hydrogen is readily isolated by extracting the reaction mixture, after dilution with water, with a water-immiscible organic solvent such as ethyl acetate, amyl acetate or another suitable solvent. The reaction is carried out at acidic pH, preferably at pH 2.5. The extract is washed, dehydrated and evaporated to give the cephalosporin antibiotic of the invention.

An example of this reaction is the preparation of a cephalosporin of formula I in which R 'is a hydrogen atom which is carried out by reacting 7- [α-amino-α- (2-thienyl) acetamido] -3- (5-methyl- 1,3,4-thiadiazol-2-ylthiomethyl) -3-cephem-4-carboxylic acid reacts in anhydrous acetonitrile in excess of bis- (trimethylsilyl) acetamide with p-nitrobenzyl N- (methylcarbamoyf) carbamate to give 7- [α- (3-methylcarbamoyl-1-ureido) -α- (2-thienyl) acetamido) -3- (5-methyl-1,3,4-thiadlazol-2-ylthiomethyl) -3-cephem-4- carboxyl.

Compounds of formula (I) wherein R is a 1,3-disubstituted ureide group of formula (I) may also be prepared as described above.

_Chapter 11

R - N - C - N -,. · <. . J J 1 '; СНЗ (R. ‘= СНз) using the above carbamoyl chlorides. Compounds of formula I wherein R, is hydrogen may be prepared by treatment with p-nitrophenyl-N- (substituted carbamoyl) carbamate

19..9.2 81

· Ο Η 0 · 4-1 I R-N-C-N'C-0

An example. cephalosporin of formula I are the following:

Ri

HIM

I II

CH3N — G — N—

........ _; | CH 3 H. O

I. II

CHsN — C — N—

I. . CH3 H O

I C

CH3N — C — N—

AND

GH3

HIM

I II

CH3N — C — N—. AND

CH3 phenyl

4-hydroxyphenyl

2-thienyl

3-thienyl

Him

I II

CHsN — C — N—

AND

CH3

HIM

I II

CHN-C — N—

AND

СНз

HIM

I II

CH3N — C — N—

CH3 H O

I II

CHj — N — C — N—

AND

CH3

HIM

I II

CH3 — N — C — N—

AND

CH3

H O • N II

CIH-N-C —ΜΙ CH5

II

R 1 -N-C 1 N phenyl

4-hydroxyphenyl

2-thienyl phenyl

4-hydroxyphenyl

2-thienyl

acetoxy group. acetoxy

9 2'61

..... females! .....

benzyl H

4-hydroxyphenyl

2-furfuryl H

TABLE I

Antibiotic activity of ureidosubstituted cephalosporins - minimal inhibitory concentration (Og / ml)

The cephalosporin compounds of the invention form pharmaceutically acceptable salts with inorganic bases such as alkali metal carbonates and acid carbonates. For example, sodium and potassium carbonate can be used to obtain sodium and potassium salts of the acid in a conventional manner.

Salts can also be prepared with basic organic amines such as methylamine, diethylamine, cyclohexylamine, dicyclohexylamine, ethanolamine, diethanolamine and tris (hydroxymethyl) aminomethane. These salts can be used in a suitable dosage form for parenteral administration.

The cephalosporin antibiotics of the present invention are highly effective in inhibiting the growth of a broad spectrum of pathogenic microorganisms, both gram positive and gram negative.

A variety of cephalosporin antibiotics are known to be effective against Gram positive microorganisms but with a limited spectrum of activity against Gram-positive microorganisms.

CH., Gative. Other cephalosporin antibiotics are effective against gram-negative microorganisms, but again have reduced activity against gram-positive microorganisms. The antibiotics of the invention are effective against both of these groups and therefore have. extended spectrum of efficacy over previously known antibiotics.

The cephalosporins according to the invention are particularly active against Pseudomonas, Enterobacter, both indolpositive and indolnegative strains, Proteus, Aerobacter, Serratia and Klebsiella. In addition, they are active against penicillin resistant strains of Staphylococcus and Streptococcus, for example S. faecalis.

The antibiotic activity of the cephalosporin compounds of formula I is given, for example, in Table 1, where the minimum inhibitory concentrations of MIC for some of the compounds are reported according to the results of the gradient method on the plates.

Microorganism ¹ ) AND (B) Test substance ² ) CD E F Shlgella sp. 1.0 3 7 7 10 3 Escherichia coli 1.0 4 11 12 18 4 Klebsiella pneumoniae 3.5 4 14 7 12 1 Aerobacter aerogenes 1.0 4 14 12 10 3 Salmonella heidelberg 1.0 2 13 6 11 3 Pseudomonas aeruginosa 18 28 80 90 24 22nd Serratia marcescens 8 19 Dec 80 70 42 22nd V41 4.0 8 1 6 2 5 V32 4.8 10 1 7 5 5 X400 20 May 20 May 20 May 20 May 20 May 20 May V84 0.6 0.6 0.5 0.9 0.4 4

Table I - continued

Microorganism ¹ ) H AND Test substance ² ) L M AND К Shigella sp. 9.5 3.0 4.0 1.0 5.5 4.0 Escherichia coli 16 5.5 7.5 2.5 7.5 10.0 Klebsiella pneumoniae 35 6.8 10 0.9 16 0.6 Aerobacter aerogenes 15 Dec 4.3 4.3 1.0 15.5 15.5 Salmonella heidelberg 12 4,5 4.3 1.0 6.5 7.8 Pseudomonas aeruginosa 60 16 22.3 21.5 19.5 19.5 Serratia marcescens > 200 35 130 19.5 > 200 24 V41 2.5 0.6 2,0 3.0 6.5 0.5 V32 4.0 0.7 3.0 3.0 7.5 0.5 X400 > 20 13 > 20 > 20 > 20 10.0 V84 1.0 0.6 5.0 3.0 0.6 0.5

1) The Val, V32 and V84 microorganisms are Staphylococcus resistant to penicillin. X400 is Staphylococcus resistant to methcilin.

2) Test substances:

A. 7- [α- (3-Methylcarbamoyl-3-methyl-1-ureido) -a- (4-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazole-)

-5-ylthenyl-3-carboxy-4-carboxylic acid,

B. 7- [α- (3-Methylcarbamoyl-3-methyl-1-ureido) - (4-hydroxyphenyl) acetamido] -3- (5-methyl-1,3,4-thladiazole-2-) 3-Cephem-4-carboxylic acid

C. 7- [α- (3-methylcarbamoyl-3-methyl-1-ureido] - α -phenylacetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid,

D. 7- [N - (imidazolidin-2-one-1-ylcarbonylamino) -α-phenylacetamido] -3- [1-methyl-1H-tetrazol-5-yl-thienyl] -3-chloro-4- carboxyl,

E. 7- [α- (imidazolidin-2-one-1-ylcarbonylamino-α-phenylacetamido) -3-acetoxymethyl-3-cephem-4-carboxylic acid,

F. 7- [α- (3-methylcarbamoyl-3-methyl-1-ureido) -α-thietylacetamido] -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid,

H. 7- [N- (3-carbamoyl-1-ureido-α-phenylacetamido) -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid,

I. 7- [α- (3-Methylcarbamoyl-1-ureido) -a- (2-thienyl) acetamido] -3- (1-methyl-1H-tetrazol-5-ylthlomethyl) -3-cephem-4-carboxylic acid ,

J. 7- [α- (3-methylcarbamoy-1-ureido) -α-phenylacetamido] -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid,

K. 7- [α- (3-Methylcarbamoyl-3-methyl-1-ureido] -α- (2-thienyl) acetamido] -3-

- [1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid,

L. 7- [α- (3-methylcarbamoyl-1-ureido) -ιϊ-

- (4-hydroxyphenyl) acetamido] -3- (5-methyl-1,3,4-thiadiazol-2-ylthiomethyl) -3-cephem-4-carboxylate,

M. 7- [α- (3-Phenylcarbamoyl-1-ureido) -α-phenylacetamido] -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid.

In the standard dilution method, the MICs for Compounds A to Z against Stahpylococcus aureus were as follows:

A: 2, V: 1, C: 0.5, D: 2 and E: 0.5 micrograms / ml.

The cephalosporin antibiotics of formula I and their pharmaceutically acceptable salts can be used to control infections in warm-blooded mammals by parenteral administration at non-toxic doses of 10 to 500 mg / kg body weight.

A preferred class of cephalosporin antibiotics of formula I are those wherein R is

where

R‘ is hydrogen or methyl, R, is phenyl, hydroxyphenyl or 2-thienyl,

R @ 2 is <4 and pharmaceutically acceptable salts of these compounds.

Another preferred class of antibiotics of the formula I are those in which

R is

O

II

СНз — N — C — N—,

N R ‘

R ‘represents a hydrogen atom or methyl

N — or

-s-ψ -sA _with > -CH ₃ CH ₃ and a pharmaceutically acceptable salt of these compounds.

Examples of preferred antibiotics are 7- [N- (3-methylcarbamoyl-3-methyl-1-ureido) -α-phenylacetamido] -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3 -cephem-4-carboxylic acid 7- [α- (3-methylcarbamoyl-3-methyl-1-ureido) -α- (4-hydroxyphenyl) acetamido] -3- (5-methyl-1,3,4- thladlazol-2-ylthlomethyl) -3-cephem-4-carboxylic acid 7- [α- (3-methylcarbamoyl-3-diethyl-1-ureldo) - N - (4-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-2-ylthiomethyl) -3-cephem-4-carboxylic acid 7- [α- (3-methylcarbamoyl-o-urido) -α-phenylacetamido] -3- (1-methyl- 1H-Tetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid 7- [α- (3-methylcarbamoyl-3-methyl-1-ureldo) -a- (2-thlenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-ylthlomethyl) -3-cephem-4-carboxylic acid 7- [α- (3-methylcarbamoyl-1-ureldo) -via] - (2-thienyl} acetamldo] -3 - (1-Methyl-1H-tetrazazol-5-ylthlomethyl-3-cephem-4-carboxylic acid 7- [α- (imidazol-4-yn-2-one-1-ylcarbonylamino) -) - phenyl ac etamldo] -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid 7 - [.alpha .- (3-methylcarbamoyl-3-methylmethyl-1-ureldo)] N- (3-chloro-4-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-methyl-4-carboxylic acid 7- [α- (3-methylcarbamoyl) -3-ethyl-1-ureldo) - N- (3,5-dichloro-4-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid and pharmaceutically acceptable non-toxic salts thereof.

The effective in vivo dose (ED 50) in mg / kg for some antibiotics of Formula I was determined on experimental infections in mice. Table II shows the ED 50 for Streptococcus pyogenes and Escherlchla coli infections. The following table shows the meaning of the symbols R ', R ‘and Ri and Rž in formula I.

TABLE II. Test substance ED50. (mg / kg x 2) i.p.

R 'R' Ri R S. S. pyogenes E. coli

CHs Н phenyl tet ¹ 0.7 72 СНз СНз 4-hydroxyphenyl tet 0.7 72 Η Н phenyl tet 0.7 <72 СНз Н 4-hydroxyphenyl thlad ² 0.7 <72 СНз Н 2-thienyl tet <7.2 <72 СНз СНз phenyl acetoxy <7.2 <7.2

1) tet = 1-methyl-1H-tetrazol-5-ylthio2) thlad = 5-methyl-1,3,4-thiadlazol-2-ylthio-.

1S

The invention will be illustrated by the following examples.

He did

N-methylcarbamoyl-N-methylcarbamoyl chloride

To a cold suspension of 22.0 g (0.25 mol) of sym-dimethylurea in dichloromethane, a cold solution of 30.0 g (0.3 mol) of phosgene in 90 ml of dichloroethane was added dropwise with stirring. Upon completion of the addition of the phosgene solution, the reaction mixture was allowed to stir for one hour at room temperature and then heated to 80 ° C and purged with nitrogen for one hour. The reaction mixture was evaporated under reduced pressure and the resulting gummy residue was extracted twice with 350 mL of ether. The extracts were combined and evaporated to give 25.0 g of carbamoyl chloride.

Example2.

Imidazoldin * 2-on-1-ylcarbonyl chloride

To a stirred suspension of 35.0 g of 2-imidazolidine in 500 ml of anhydrous tetrahydrofuran cooled in an ice bath was added a cold solution of 40 g of phosgene in 100 ml of anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature for about 16 hours and filtered to remove insoluble materials. The filtrate was concentrated under reduced pressure and the reaction product precipitated from the concentrate after addition of acetone and petroleum ether. The product is obtained by filtration and filter drying.

Example 3

Preparation of 7- [α- (3-methylcarbamoyl-3-methyl-1-ureido] -α- (4-hydroxyphenyl) acetamido) -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cef em-4-carboxylic acids

To a suspension of 483 mg (1 mmol of 7- [Da-amino-ar- (4-hydroxyphenyl) acetamido) -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid in 8 ml of anhydrous acetonitrile containing 2 ml of propylene oxide held under an anhydrous argon atmosphere is added with 1 ml of bis- (trimethylsilyl) acetamides. After the solution is formed, the reaction vessel and the solution are cooled to 0-5 ° C. A solution of 150 mg (1 mmol) of N-methylaminocarbonyl-N-methylcarbamoyl chloride in 2 ml of anhydrous acetonitrile was added dropwise with stirring. The reaction mixture was stirred for 2 hours and allowed to warm to room temperature. The reaction mixture was poured into a mixture of water and ethyl acetate and the pH of the mixture was adjusted to pH 9. The aqueous layer was separated and re-stratified with fresh ethyl acetate. The aqueous layer was adjusted to pH 2.5, and the ethyl acetate layer was separated, washed twice with brine, and dried over sodium sulfate. The anhydrous ethyl acetate solution containing the reaction product was evaporated to dryness in vacuo to give the product as a pale yellow powder. The product was dissolved in ethyl acetate and partially precipitated by adding petroleum ether to the solution. The product precipitate was filtered and dried to give 138 mg. Another part of the product is obtained by evaporating the filtrate.

NMR (60 MHz, DMSO d6):

9.8 (d, J = 7, 1 H),

9.3 (d, J = 8, 1 H),

7.4 to 6.5 (m, 5H),

5.85 to 5.50 (g, 1H),

5.50 to 5.30 (d, J = 7, 1H);

4.9 (d, J = 5, 1 H),

4.3 (broad, 2H),

Δ (s, 3H),

3.6 (broad, 2H),

3.1 (s, 3H);

2.65 (d, J = 3,3H);

For C 22 H 25 N 9 O 7 S 2 calculated:

% C, 44.66;% H, 21.31%.

H, 4.34; N, 19.32.

Example 4

Preparation of 7- [α- (3-methylcarbamoyl-3-methyl-1-ureido) -α- (4-hydroxyphenyl) acetamido] -3- (5-methyl-1, 4-thiadiazol-2-ylthiomethyl) -3-cep-4-carboxylic acid

To a suspension of 2.12 g (4 mmol) of 7- (Da-amino-α- (4-hydroxyphenyl) acetamido] -3- (5-methyl-1,3,4-thiadiazol-2-ylthiomethyl) -3- cefem-4-carboxylic acid in 32 ml of anhydrous acetonitrile containing 8 ml of propylene oxide and maintained under an anhydrous argon atmosphere, 4 ml of bls (trimethylsilyl) acetamides are added with stirring, the solution is cooled to 0 ° C and added dropwise with stirring. 600 mg (4 mmol) of N-methylaminocarbonyl-N-methylcarbamoyl chloride in 8 ml of anhydrous acetonitrile was stirred for 2 hours, during which time the mixture was allowed to warm to room temperature and poured into water / ethyl acetate and aqueous pH. The pH of the aqueous layer was then adjusted to about 2.5, and the ethyl acetate layer was separated, washed with brine and dried over sodium sulfate. drought for reduced Pressure to give about 1.6 g of product as a light yellow solid. The product was triturated with ethyl acetate and the insoluble product (645 mg) was filtered off. The filtrate is concentrated by evaporation, 9.2. 423 mg of precipitated product was obtained. The last filtrate. se. Evaporate to dryness to obtain 5.130 mg. . All three fractions were shown to be the same in the chromatography. on silica gel thin-layer chromatograms - using a mixture of chloroform, methanol: (7: 3, v / v) for iodine and iodine vapor or ultraviolet light k. . visualization of developed spots. · '; - ’.... ....

For C25H25N7O7S3;

calculated:: '

% C, 45.40;% H, 4.15;% N, 16.13%.

% C, 45.53;% H, 4.47;

Electrometric titration in 66% dimethylformamide shows the presence of two ^; pK _and 4.8 and 12.2 and the apparent molecular weight as calculated from the titration data of 587 (calculated

m. h. = 607) · The infrared absorption spectrum (mull with mineral oil) shows a characteristic (-actamcarbonyl absorption at a wavelength of about 2920 and · the NMR spectrum is in agreement with the expected product.

UV absorption spectrum (methanol):

Amax 303 · · ε ·· = 9,247 ·

A _m ax ^; .27.5 · · = 9.273

A _ma > x-229 · ε = 10.254 ·

Example 1 and d '5

· Preparation .'7 -. ^[A- (3-methylcarbamoyl-3-methyl-1-ureíido) -α-phenylacetamido] -3-acetoxy- ·.

methyl 3-cephem-4-carboxylic acid The above compound is prepared by reaction. 7- (D-.alpha.-amino-phenyl-acetamido) -3-acetoxymethyl-3-methyl-1-carboxylic acid (cephaloglycine) p. N - methylaminocarbones - N - methylcarbamoyl chloride. using the reaction conditions of one example. 158 mg of the product obtained is a white crystalline solid. .

NMR (60 MHz, DMSO d6):

7.45 (s, 5H).

5.9 to 5.4 (m, 2H);

5.2 to 4.4 (m, 3H);

3.6 (broad, 2H).

3.15 (s, 3H).

2.7 (s, 3H) and 2.05 (s, 3H) delta.

Example · 6 ·. ..... '·' ·. ···. ; ______

Preparation of 7- [D-d- (imidazolidin-2-on-1-ylcarbonylamino) -α-phenylac etamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid

A suspension of 17.66 g of cephaloglycine dihydrate in 150 ml of tetrahydrofuran with water (80% tetrahydrefuran) is cooled in an ice bath and the pH of the suspension is adjusted to 7.8-8.2 by addition of triethylamine. To a cold (0 ° C) suspension. add in small parts. 5.94 · g. . . N-chlorocarbonylimidazolidin-2-one; During the addition of the acid chloride, the pH of the reaction mixture is maintained. keeps between. 7.5 'to 8.0. by adding triethylamine according to. needs. .Po. adding. of the acid chloride is stirred in the reaction mixture. at 0 ° C .30 minutes and then 20 minutes at room temperature. Reaction. mixture.·; (pH = 7.5). Dilute 130. · Ml. water; and then . se. . evaporates,. to remove it. most tetrahydrofuran. Vodná-. the phase is extracted once with ether. and then stratified with ethyl acetate. pH · aqueous. The layers were adjusted to pH 1.5-2.0 with dilute hydrochloric acid. The ethyl acetate layer was separated and washed with water. dried over magnesium sulfate. Evaporation of the anhydrous ethyl acetate solution under pressure gave the product as an amorphous solid. - .. ·· .. ··. ·· · 7

Example · 7. .

Following the acylation procedure and conditions described in Example 6. 7- (D-.alpha.-amino-2-phenylacetamido) -3- (1-methyl-1H-tetrazo-5-ylthi-methyl) -3-cephem-4-carboxylic acid is reacted. With N-chloro-carbonylimidazolidin-2-one to give acid 7- [D- (α- (imidazolidin-2-one-ylcarbonylamino)) - (phenylacetamido) -3- (1-methyl-1H) tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid.

Monitoring procedures and. using the solvent and the conditions described in the acylation of Example 6, were carried out. Reaction of 7- (D-α-amino-α-phenylacetamido) -3- (5-methyl-1,3,4-thiadiazol-2-ylthiomethyl) -3-cephem-4-carboxylic acid. with chlorocarbonylimidazolidin-2-one to give 7- [Da - (imidazolidin-2-on-1-ylcarbonylamino) -arphenylacetamido] -3- (5-methyl-1,3,4- thiadiazol-2-ylthiophthyl) -3-cephem-4-carboxylic acid.

Examples

Preparation of 7- [a '- (3-methylcarbamoyl-1-ureido) -a- (4-hydroxyphenyl) acetamido] -3- (5-methyl-1,3,4-thadadiazol-2-ylthiomethyl) Sodium -3-cephem-4-carboxylate:

K .. suspension · 2.88. . g (6 mmol of 7- [D-N-amino-α- (4-h-hydroxyphenyl) · acetamido] -3- (5-methyl-1 *)

Sodium 1,3-thiadiazole-2-yl-1,3-thiadiazole-4-carboxylate in 48 ml of anhydrous acetyl piperidine at room temperature is added. ·

198281

-ml '- (BSA).

After homogeneous formation. solution is added

5.2 g · :. nit-nitrophenylmethyl carbonate. ..Reaction ... mixture. The mixture was stirred for 1 hour and poured into a mixture of water and ethyl acetate. The pH is adjusted to 6 and the ethylation phase is separated. and replaced with fresh ethyl acetate. The pH of the water phase is adjusted to 2.5. The aqueous layer was separated and / discarded. · Ethyl acetate. phase is washed with dilute hydrochloric acid (pH; = 2.0) and fresh water is added. The pH is adjusted to 5.5 at the end and the "aqueous" phase is lyophilized to give 1.3 g of product as a pale yellow powder.

NMR (DMSO d6):?

2.7 (s, 6H, NHCH3 $ thiadiazole CH3),

3.5 (Sroka, 2H, C2-H?) ^·:

5.0 (d, J = 5, 1H, C 6 -H);

5.4 to 5.9 (m, 2H, C7-H δ side chain CH),

6.9 (d, J = 9, 2H, aromatic) a

7.4 (d, J = 9, 2H, aromatic) .delta.

Example 10 .....

Preparation of 7- [α- (3-methylcarbamoyl-3-).

sodium methyl-1-ureido) -α-phenylacetamido] -3- (5-methyl-1,3,4-thiadiazol-2-ylthiomethyl) -3-cephem-4-carboxylate

To a suspension of 2.78 g of sodium 7- (N-amino-α-phenylacetamido) -3- (5-methyl-1,3,4-thiadiazol-2-ynehomeethyl) -3-cephem-4-carboxylate in 48 ml of anhydrous acetonitrile containing 12 ml of propylene oxide is added with 6 ml of bis- (trimethylsilyl) acetamide. After obtaining a homogeneous solution, the solution is cooled to about 0 ° C and a solution of 6 mmol of N-methylaminocarbonyl-N-methylcarbamoyl chloride in 12 ml of anhydrous acetonitrile is added. The reaction mixture was stirred for 2 hours.

The product was obtained according to the procedure described in Example 9 to give 11 g of the sodium salt of the product. IR (muI) / β-lactamcarbonyl absorption at about 2920 cm -1.

NMR · (DMSO d 6):

2.7 (broad, 6H, NHCH 3 thiadiazole CH 3),

3.1 (s, 3H, N-CH 3),

4.4 (broad, 2H, C (3 ') H ₂ ),

4.9 [d, J = 4.5, 1Ή; C (6) H].

5.4 to 5.9 [m, 2H, C (7) H and side chain CH],

9.4 (d, J = 9, 1H, NH);

10.0 (d, J = 7, 1H, NH) delta.

Example 11

Preparation 7 - [- (3-Methylcarbamoyl-3-methyl-1-ureido) -a- (2-thienyl) acetamido) -3- (1H-methyl-1H-tetrazol-5-ylthiomethyl) -3- · · '

-cephem-4-carboxylic acid.

To a suspension of 234 mg of 7- [α-amino-α- (2-thienyl) acetamido] -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid in 4- · Ml of anhydrous acetonitrile · containing · 1 ml of propylene oxide under argon is added · 0.5 · ml of bis- (trimethylsilyl) acetamide to form a homogeneous solution The solution is cooled to 0 ° C and solution 75 is added mg of N-methylaminocarbonyl-N-methylcarbamoyl chloride in 1 ml of acetonitrile was stirred for 2 hours and then poured into a mixture of water and ethyl acetate, the pH of the aqueous phase was adjusted to 6 and the organic layer was separated. The aqueous phase is adjusted to pH 2.5 with dilute hydrochloric acid, the organic phase is separated, dried and evaporated to dryness to give the product.

For C20H23N9O6S3 * - ·· calculated:

% C, 41.30;% H, 3.99;% N, 21.68; found: · <

41.78 ° / o C, 4.14% ·· H, “21.73“ ·% · N. ··

UV (Methanol): λ max 238 ε 17,475.

λ max 270 ε 9,000 '

Example 1 a d 1 2

Preparation of p-nitrophenylmethylcarbamoylcarbamate ^:

Methylurea (3.7 g, 50 mmol) and p-nitrophenyl chloroformate (50 mmol) were reacted under nitrogen in 10 ml of anhydrous tetrahydrofuran. The reaction mixture initially becomes clear and the product begins to precipitate from the clear solution: The mixture is stirred for 18 hours and the precipitated product is filtered. The product is washed with water and diethyl ether to obtain 5.9 g of an approximately 50:50 mixture of p-nitrophenylmethylcarbamoylcarbamate and p-nitrophenylcarbamoyl N-methylcarbamate, as shown by nuclear magnetic resonance. .. ’·. · '

Example 1 1 ^{: 3}

Preparation of 7- [α (3-methylcarbamoyl-11-ureido) -α-phenylacetamido) -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid

A suspension of 2 mmol of 7- (α-amino-arphenylacetamido) -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid v · 16 held under argon Ml of anhydrous acetonitrile are solubilized by addition of 2 ml of bis (trimethylsilylacetamide) 4 mmol of the product mixture obtained as described in Example 12 (mixture of p-nitrophenylmethylcarbamoylcarbamate and p-nitrophenylcarbamoyl-N) are added under stirring. The reaction mixture became clear in a few minutes and stirred for about 2 hours.

The reaction mixture was poured into a mixture of water

The ethyl acetate layer was separated and discarded. The aqueous phase was again stratified with fresh ethyl acetate and the pH of the aqueous phase. -is adjusted to 2.5. The organic layer was separated, washed with water, dried and evaporated in vacuo. The residue is triturated with diethyl ether to give 600 mg of product as a pale yellow powder.

For C21H23N9O6S2 calculated:

C 44.91, H 4.13, N 22.45, S 11.42; found ·

44.66%. C ⁴ 34 θ / ο H, ^22, 29 ° / of the 11.28% P.

UV (methanol): λ max 272 ε 11.091

NMR (DMSO d6):

2.6 (d, J 5Hz, 3H, NHCH 3),

3.9 (S, 3H, -CH4 tetrazole),

3.55 (broad, 2H, CH 2), 5.0 '[d, J = 5, 1H, C (6) H],

5.4 to 5.9 [m, 2H, C (7) H and side chain CH],

7.3 (s, 5H, Q)

8.4 (d, J = 7, 1H, NH)

8.8 (S, 1H, NH);

9.4 (d, J = 9, 1H, NH) .delta.

Example 14

Preparation of 7- [α- (3-methylcarbamoyl-1-ureido) -α- (4-hydroxyphenyl) acetamido] -3- [5-methyl-1,3,4-thiadiazol-2-ylthiomethyl) -3-cephein -4-carboxylic acids

K. suspension of 988 mg (2 mmol) of 7- [α-amino-α- (4-hydroxyphenyl) acetamido] -3- (5-methyl-1,3,4-thiadiazol-2-ylthiomethyl) -3-cephem 4-Carboxylic acids in 16 ml of anhydrous acetonitrile are added under argon - 2 ml of bis- (trimethylsilyl) acetamide are added. A homogeneous solution was obtained and 1.43 g (6 mmol) of a product mixture containing 50% of p-nitrophenylmethylcarbamoylcarbamate (Example 12) was added. After stirring for 1 hour, the product was obtained from the reaction mixture according to the procedure described in Example 13. 524 mg of the product was obtained in the form of a pale yellow powder.

UV (methanol):

λ max 232 ε 16.072 λ max 275 ε 14 309

IR (mull): [0068] M-Cyclohexyl absorption at about 2900 cm &^lt; -1 & gt ^; .

Example 15

Preparation of 7- [α- (3-methylcarbamoyl-1-ureldo) -a- (2-thienyl) acetamido] -3- (1-methyl-1H-tetrahydro-5-ylthiomethyl) -3-cephem-4- carboxylic acids

To 'suspension' 435 mg (0.93 mmol) of 7- [Da-amino-cis- (2-thienyl) acetamido) -3- (1-methyl-1H-tetrazol-5-ylthlomethyl) -3-cephem Of 4-carboxylic acid in 8 mL of anhydrous acetonitrile was added 1 mL of bis- (trimethylsilyl) acetamide. After obtaining a homogeneous solution, 1.4 g of p-nitrophenylmethylcarbamoylcarbamate is added.

The reaction mixture was stirred at room temperature for 90 minutes. The product was obtained from the reaction mixture according to the procedure described in Example 11. 341 mg of the product was obtained as a white powder.

For C 29 H 21 N 9 O 6 S 3: ·. .

calculated:

40.20% C, 3.73 θ / ο'.Η, 22.21 θ / ο N, '16.95%' S; found:

.39.86% C, 4.02 θ / ο H, 22.88 θ / ο N, 14.66 θ / ο S.

IR (mull) (β-Laccaimcarbonyl absorption at about 2920 cm -1).

UV (methanol):

λ max 235 ε 14,450 λ max 272 ε 9,360.

NMR (DMSO-d6): 1

2.6 (d, J = 4.5, 3H, NHCH 3),

3.6 (broad, 2H, C (-2.) H2),

3.9 (5, 3H, tetrazole CH3),

4.25 [broad, 2H, C (3 ‘) H2],

5.1 [d, J = 5, 1H, C (6) H]

5.6 to 5.9 [m, 2H, C (7) H and side chain CH],

6.9 to 7.6 (m, 4H, thiophene 1NH),

8.4 (d, J = 8, 1H, NH)

8.9 (S, 1H, NH); and P

9.5 (d, J = 8.5, 1H, 1H) delta.

Example 16 ',

Preparation of p-nitrophenylphenylcarbamoylcarbamate:

To a stirred solution of 6.8 g of phenyl urea in 50 ml of anhydrous tetrahydrofuran kept at 0 ° C under nitrogen was added 5.05 g of p-nitrophenyl chloroformate. The reaction mixture was allowed to warm to room temperature and stirred for about 18 hours. The mixture is evaporated to dryness and dried. the residue was dissolved in ethyl acetate. The solution was washed twice with water, twice with 'sodium chloride' solution and filtered 'over sodium hydroxide. The filtrate was evaporated to dryness to give 4.9 g of the product as a white powder.

Example 17 / л

Preparation of 7- [α- (3- [1,3] [1,2,3] arbamoyl-1-ureido) -α-phenylacetamido. 3R- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid

Suspension 950 'mg: (2' mmol) 7- (D-a-ami196261)

Example 20

Preparation of p-nitrophenylcarbamoylcarbamate

Example 1 and 1 8

Example 21

Example 19

For C20H21N9OGS2

Following the procedures described in Example 17, 2 mmol of 7- (α-amino-α-phenylacetamido) -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid was reported at 0 °. C in anhydrous acetonitrile to

Preparation of 7- [N - (3-carbamoyl-ureido) -phenylacetamido] -3- (1-methyl-1H-tetrazole-5 - [(4-trifluoromethyl) -1H-tetrazole] -2H-tetrazole] -1H-4 H]]. -3-chloro-4-carboxylic acid

Preparation of 7- [1- (3-benzylcarbamoyl-1-ureldo) -α-phenylacetamido] -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid

Preparation of 7- [α- (3-furfurylcarbamoyl-1-ureido) -α-phenylacetamido] -3- (1-methyl-1H-tetrazol-5-ylthlomethyl) -3-cep-4-carboxylic acid calculated:

% H, 3.87;% N, 23.02;% S, 11.71.

H, 4.00; N, 22.86; S, 11.41.

treatment with bis- (trimethylsilyl) acetamide and 1.22 g of plnitrophenyl-N-furfurylcarbamoylcarbamate to give the title compound.

No-af enylacetamido) -3- (1-methyl-1H-tetrazol-4-ylthiomethyl-4-cephem-4-carboxylic acid) in 16 ml of anhydrous acetonitrile at 0 ° C is solubilized under nitrogen by addition of 2 ml of bis- (trimethylsilyl) 1.2 g of p-nitrophenyl-N-phenylcarbamoylcarbamate prepared according to the method described in Example 16 are added with stirring. The reaction mixture is stirred for 1 hour and the product is obtained according to the operating procedures described in Example 11. - 839 mg of the product as a pale yellow powder.

NMR (DMSO d6):

3.6 [broad, 2H C (2) -H2],

3.95 (S, 3H, tetrazo-CH5),

4.3 [broad, 2H, -C (3 ‘) - H2], -

5.0 [d, J = 5.1G, C (6) -H],

5.5 to 5.9 [m, - 2H, C (7) -H, side chain CH],

7.0 to 7.6 (broad, 10H, aromatic)

8.4 (d, J = 7.5, 1H, NH).

9.1 (s, 1H, NH).

9.6 (d, J = 9, 1H, NH); 9.8 (S, 1H, -NH).

Following the procedures described in Example 17, 2- (α-amino-α-phenylacetamido) -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid was dissolved in acetonitrile. with bis- (trimethylsilyl) acetamide and treated with 1.26 g of p-nitrophenyl-N-benzylcarbamoylcarbamate to give the title compound.

NMR (DMSO d6):

3.6 [broad, 2H, C (3) H2],

3.9 (S, 3H, tetrazole CH 3),

4.3 [broad, 4H, C (3 ‘) - H 2 and benzyl CH 2],

5.0 [d, J = 5, 1H, C (6) H];

5.4 to 5.9 [m, 2H, C (7) H side chain CH],

7.2 to 7.6 (m, 10H, aromatic),

7.8 (t, J = 5.5, 1H).

8.4 (d, J = 7, 1H, NH).

8.95 (s, 1H, NH).

9.5 (d, J = 8, 1H, NH).

NMR (DMSO d6): ......

3.55 [broad, 2H, C (2) -H 2],

3.9 (S, 3Η, tetrazole CH3),

4.3 [broad, 4H, - C (3 ‘) - H and thiophene CH2],. 5.0 (d, J = 5.1, C (6) H),

5.4 to 5.9 [m, 2H, C (7) -H and CH side chain],

6.3 [m, 2Η, aromatic thiophene),

7.2 to 7.9 (m, 7H, - aromatic NH),

8.4 (d, J = 7, 1H, NH).

8.9 (s, 1 H, -NH),

9.4 (d, J = 8, 1H, NH).

To a mixture of 1.20 g (20 mmol) of urea and 2.02 g (10 mmol) of p-nitrophenylchloroformate in a dry flask under nitrogen was added 10 ml of anhydrous acetonitrile. The reaction mixture immediately becomes clear and then a precipitate is formed. The mixture was stirred at room temperature for 18 hours and the precipitate was filtered, washed with water and dried in vacuo. The dried product is triturated with ether 0 and dried again to obtain 1.0 g of crystalline product.

To a suspension of 2 mmol of 7- (α-amino-α-phenylacetamido) -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid in 20 mL of anhydrous acetonitrile under argon is added A ml of bis- (trimethylsilyl) acetamide. After forming a homogeneous solution, the resulting solution is evaporated to dryness. The residual dried white powder is dissolved in dimethylformamide and the solution is added under argon to 20 mmol of p-nitrophenylcarbamoylcarbamate - (Example 20) - in 10 ml of dimethylformamide containing 20 mg of - 1-hydroxybenzotriazole monohydrate. The reaction mixture was stirred at room temperature for 72 hours and then diluted with water and the product was extracted with ethyl acetate at a pH of about 2.5. The extract was washed, dried and evaporated to give the product as an amorphous powder.

UV (methanol):

Amax 250 ε 8.957.

NMR (DMSO d6):

3.55 [broad, 2H, C (2) Hz],

3.95 (s, 3H, tetrazole-CH3),

4.45 [broad, 2H, C (3 ‘) H2],

5.0 [d, J = 5, 1H, C (6) H]

5.4 to 5.9 [m, 2H, C (7) H and side chain CH],

6.75 (broad S, 2H, —NHz),

7.4, (S, 5H, phenyl),

8.51 (d, J = 7, 1H, NH).

8.8 (S, 1H, NH);

9.5 (d, J = 10, 1H, NH) [delta] .delta.

Example 23

Example 22

For C4H8N2O3S e 9 328 e 15 995.

UV methanol: Amax 270 Amax 233

Preparation of 3- (methylsulfonyl) imidazolidin-2-one-ylcarbonyl chloride

Preparation of 7- [α- (3-methylsulfonylimidazolidin-2-one-1-ylcarbonylamino) -ce- (2-thienyl) acetamido) -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3- cef em-4-carboxylic acids τίαΊρτρτίλ *

% C, 29.47;% H, 4.96;% N, 17.17;% S, 19.50.

H, 4.91; N, 17.06.

19,53% S,

To a suspension of 10.7 g of imidazolid-2-one in 100 ml of anhydrous tetrahydrofuran was added dropwise with stirring at room temperature 15.7 g of methanesulfonyl chloride. The reaction mixture is stirred at about 40 ° C for 1 hour and then heated to reflux using a reflux condenser for one hour.

The reaction mixture was evaporated in vacuo, the thick syrup consistency residue was dried under vacuum for about 18 hours. The dried residue was crystallized from hot acetone to give 7.1 g of N-methylsulfonylimidazolid-2-one. The percentage elemental composition of the product was determined by microanalysis.

A solution of 4.1 g of the product described above in dioxane is treated with 7 g of trimethylchlorosilane and 5 g of triethylamine.

The solution is heated to reflux using a reflux condenser for about 2.5 days and then cooled to room temperature. The triethylamine hydrochloride precipitate is filtered and the filtrate is treated with 3 ml of phosgene. The filtrate was allowed to stand at room temperature for 2 days and evaporated to dryness in vacuo. The residue was crystallized from hot acetone and the product was further dried under vacuum to give 2.8 g of the title compound melting at about 178 ° C.

To a solution of 200 mg of 7- [α-amino-α- (2-thienyl) acetamido] -3- (1-methyl-1H-tetrazol-4-ylmethyl) -4-cephem-1-carboxylic acid in 25 mL of dichloromethane was added 2 molar equivalents The mixture was filtered and 100 mg of 3-methylsulfonylimidazolidin-2-one-1-ylcarbonyl chloride was added to the filtrate, the reaction mixture was stirred on a water bath for 3 hours, then the dichloromethane was evaporated. The extract was washed with water and water was removed The anhydrous extract was evaporated in vacuo and the residue was recrystallized twice from acetone diethyl ether: petroleum ether to give 109 mg of product.

NMR (DMSO d6):

3.45 (S, 3H, CH 3 SO 2 -),

3.65 [AB, 2H, C (2) -H 2],

3.8 (broad, 4H, CH 2 CH 2),

3.95 (S, 3H, tetrazole CH3),

4,6 [AB, 2H, C (3 °) - H2],

5.05 [d, J = 5, 1H, C (6) - H],

5.75 [dd, J = 8, J 2 = 5, 1H, C (7) -H],

5.88 (d, J = 7.5, 1H, sidechain CH),

6.94 to 7.15 (m, 2H, aromatic thiophene), 7.4 to 7.5 (dd, 1H, aromatic thiophene),

8.72 (d, J = 7, 1H, NH) and

9.51 (d, J = 8.5, 1H, NH) .delta.

According to the methods described in the above examples, 7- [α- (3-methylcarbamoyl-3-methyl-11-ureido) -α- (4-hydroxyphenyl) acetamido] -3- (1-methyl-1,2- 3-triazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid and 7- [D - N - (imidazolidin-2-one-1-ylcarbonylamino) -α-phenylacetamido] -3- (1- methyl-1,2,3-triazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid.

Claims (2)

OBJECT OF THE INVENTION A process for the manufacture of 1-ureidosubstituted 3-thlomethylcephalosporin compounds of formula I wherein R is as defined above, and A represents a chlorine atom or a group wherein Ř is a 3-substituted ureido group of formula a H o <I II R - N - C - N -, where R ^u is hydrogen, methyl, phenyl, benzyl or furfuryl, R ‘is hydrogen or methyl, R 1 is phenyl, hydroxyphenyl or thienyl, R2 is acetoxy, groups of formulas, and optionally converting the acid thus obtained to a non-toxic salt. 2. The process of item 1, for the preparation of 1-ureidosubstituted 3-thiomethylcephalosporin compounds of formula I wherein: R is a 3-substituted ureido group of the formula HIM N — C — N—, N - N -SO ° ^b where Z is C 1 -C 4 alkyl, as well as pharmaceutically acceptable non-toxic salts of these compounds, characterized in that a compound of formula (II) is reacted in the reaction: R 'is methyl, R ⁽ is hydrogen or methyl, R 1 is phenyl, hydroxyphenyl or thienyl, R2 is acetoxy, > N-Nm-z COOH wherein Z is C 1 -C 4 alkyl, as well as pharmaceutically acceptable non-toxic salts of these compounds, characterized in that the compound of formula II (II) is reacted wherein: R 1 and R 2 are as defined above, with a compound of formula O II R — C — A, 19В261 kde R 1 and R 2 are as defined above, with a compound of formula O II R - C - Cl, where R is as defined above, and optionally converting the acid so obtained into a non-toxic salt.