DE2707812A1 - L-7-ALPHA-UREIDOACYL-3-CEPHEM-4-CARBONIC ACID COMPOUNDS, METHOD FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS - Google Patents

Description

DIPL-CHEM. DR. VOLKER VOSSIUS PATENT ADVERTISER

MONKS.: E,

2 3

SIEBERTSTRASSE 4 »_ _Λ _ POBOX860767 2707812 PHONE: (O 89) 47 40 75

CABLE ADDRESS: BENZOL PATENT MÖNCHEN TELEX 5-29453 VOPAT D

u.z .: M 098 (Vo / kä) Case: M-764 134-H

CHEMICAL FACTORY VON HEYDEN, G.m.b.H., Volkartstrasse 83, 8000 Munich

¹¹ Lya-ureidoacyl-J-cephem-A-carboxylic acid compounds, process for their preparation and pharmaceuticals "

Priority:

March 8, 1976, V.St.A., No. 664 795 March 8, 1976, V.St.A., No. 664 796 February 2, 1977, V.St.A., No. 764 134

Addendum to patent (patent application P 25 40 804.2)

The invention relates to L-7-a, -ureoacyl-3-cephem-4-carboxylic acid compounds of the general formula I.

R ₁ -CH-CN _n

NH

l C = O

I NH ₂

.N

CH ₂ -SR ₄

(D

COOR-

25 in which R _{1 is} a phenyl, thienyl or furyl group and R is a hydrogen atom, a lower alkyl, phenyl-lower-alkyl or diphenyl-lower-alkyl radical, a tri- (lower-alkyl) silyl or tri - (lower-alkyl) -stannyl group, a salt-forming ion,

7Of 3 7 / C ^r ,

Γ y

a substituted phenyl-lower-alkyl radical or a group of the general formula

denotes, where R is a lower alkyl radical or a given 5

possibly by a calogen atom or a lower alkyl or alkoxy radical substituted phenyl or phenyl-lower alkyl group and R ^ is a group of the general formula

,. N N

10 11 Il i> 11 _ r -ι D

^R 5

I ^R 5

eggs

where Rc is a hydrogen atom or a C ₁ ^ radical.

As lower alkyl or alkoxy radicals, unbranched or branched radicals with 1 to 8, preferably 1 to 4, carbon atoms are possible. Specific examples of these residues are the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy and propoxy groups. Specific examples for Phenyl-lower-alkyl and diphenyl-lower-alkyl radicals are the Benzyl, phenethyl and diphenylmethyl groups.

The kernsuhstituierte by a halogen atom or a lower alkyl or phenyl or phenyl ^D henyl-

^L 7OC 1: 7/0 ': 64 ^Δ

A leather-alkyl group can have one or two of these substituents contain. Chlorine or bromine atoms are preferred as halogen atoms. Specific examples are the 2-, 3- or 4-chlorophenyl, 2-, 3- or 4-bromophenyl, 314-dichlorophenyl, 2-methylphenyl-, 4-xthoxyphenyl-, 2, -, 3- or 4-chlorobenzyl- and 2-, 3- or 4-ethylphenethyl group. They are preferred monosubstituted residues.

The salt-forming ion, R, can be a metal ion, for example an aluminum ion, an alkali metal ion such as a sodium or potassium ion, or an alkaline earth metal ion such as a calcium or Be magnesium ion. Amines can also be used for salt formation, for example phenyl-lower-alkylamines, such as dibenzylamine and Ν, Ν-dibenzylethylenediamine, lower alkylamines, such as Methylamine and triethylamine, and N-lower alkylpiperidines, such as N-ethylpiperidine.

Preference is given to compounds of the general formula I in which R, a hydrogen atom, a sodium or potassium ion and R ^ the group

N N N ΝM

I Il I Ij Il M N

"V ^N ^ UJJ

CH ₃

in particular a 5-methyl-1,3,4-thiadiazol-2-yl or means i-methyl-IH-tetrazol-5-yl group. The connections of the general formula I are prepared according to the invention by either

709

(a) an L-7-α-aminoacyl-3-cephem-4-carboxylic acid of the general formula II

in which R ₁ and R ^ have the above meaning, preferably in the form of their salt with trifluoroacetic acid, with

such as potassium cyanate, an alkali metal or alkaline earth metal cyanate / Ln solution at a pH of about 7 to 8, or

(b) a 7-aminocephalosporanic acid compound of the general Formula III

(III)

in which R, represents a carboxyl protecting group and R ^ the has the above meaning with an L-α-ureidocarboxylic acid of the general formula VI

¹ '(VI)

HN-C-NH ₂

in which R _{1 has} the above meaning, or brings its reactive derivative to reaction and splits off the protective group from the compound obtained and, if appropriate, converts the compound obtained according to (a) or (b) into a salt with a base.

70Γ 37 / CG64

- if-

The compounds of the general formula II can be obtained by acylation the compound of general formula III are prepared in which R, preferably a diphenylmethyl or tert-butyl group or another carboxyl protecting group represents, with an acid chloride of the general formula IV

ο
Ü-ci

NH ₂ -HCl

or an α- (substituted) -amino acid of the general formula V

R ₁ -CH-COOH

NH-Y (V)

in which Y represents an amino protective group, for example a benzyloxycarbonyl, p-methoxybenzyloxycarbonyl or tert-butoxycarbonyl group. The protective group is split off, for example, with trifluoroacetic acid in anisole. The trifluoroacetate of the compound of the general formula II is formed.
20th

The reaction of the compound of the general formula III with the compound of the general formula VI is preferably as follows carried out that first the compound of general formula VI in a mixed carbonic anhydride or a other anhydride is transferred. For this purpose, a solution of the cc-ureido compound in an organic solvent, containing a tri- (lower-alkyl) -amine, with an anhydride-forming reagent, i.e. a lower chloroform

^L 7 0 ^f '/ ' ¹ ^

acid alkyl ester, a chloramelic acid aryl ester or an acyl halide, at temperatures of about 0 to -20 ⁰ C implemented.

The α-ureido compound of the general formula VI can also converted into an activated ester by reaction with a reagent which activates the carboxyl group, such as dicyclohexylcarbodiimide or bisimidazole carbonyl. In some The carboxyl group can be precipitated by conversion into an acid halide, for example the chloride, or into an azide, to be activated.

The compounds of general formula I can also by reacting the compound of general formula VI with 7-Aminocephalosporanic acid, preferably in the presence of dicyclohexylcarbodiimide, to give compounds of the general formula VII L

NH J ^ Nv ^ - ¹ -CH ₂ -OC-CH ₃

I COOK- »

NR ₂

(See. US-PS 3,833,568) and subsequent treatment with a Mercaptan of the general formula VIII

Rr-S-H (VIII)

made in solution at a pH of about 7.8 to 8.0 will.

7 0 C: -. 7 / i. ■ 6 4

-r-

Furthermore, the compounds of the general formula I can be prepared by reacting a compound of the general formula IV or V with an ester of 7-aminocephalosporanic acid, preferably in the presence of dicyclohexylcarbodiimide, and then Be treatment with an acid (HX) preferably trifluoroacetic acid in the presence of anisole, to the salt of the compound of general formula IX

, Q

NH ₂ i ^ ₂ -0-C-CH ₃ (IX)

-HX °

getting produced. The salt of the compound of the general formula IX is then treated with an alkali metal or alkaline earth metal cyanate implemented. The compound obtained is then reacted with a compound of the general formula VIII.

The compounds of general formula I in which R ^ is a lower alkyl, phenyl-lower alkyl, substituted phenyl

lower-alkyl or diphenyl-lower-alkyl radical or an acyl

n oxymethy1gruppe of the general formula -C ^ -OCR can be obtained by reacting the compound of the general formula III or of 7-aminocephalosporanic acid either before or after the acylation of the amino group in the 7-position with a

zv / ei
or / mol of a compound of the general formula X or XI

Halogen-R, or R, = N® = N®

(X) (XI)

in which halogen is preferably a chlorine or bromine atom, in an inert solvent such as dimethylformamide,

7OC> 7 / Ü .84

Acetone, dioxane or benzene, at room temperature or below.

Similarly, the compounds of general formula I in which R, a tri- (lower-alkyl) -stannyl- or Tri- (lower-alkyl) -silyl group means by introducing these groups into the 3-heterothiomethylcephalosporanic acid molecule either before or after acylation.

The salts of the carboxylic acids of the general formula I are obtained by reacting the free carboxylic acid with an inorganic one or organic base of the type mentioned above.

The compounds of general formula I are antibiotics with a broad spectrum of activity against both gram-positive and also gram-negative germs such as Staphylococcus aureus, Salmonella schottmuelleri, Klebsiella pneumoniae, Proteus rettgeri and Escherichia coli. It was found that the L isony

Ren are considerably more active than the corresponding D-isomers or DL-isomer units towards ß-lactamase-forming Germs such as Enterobacter, indole-positive Proteus species, resistant strains of Escherichia coli and Serratia.

The compounds of general formula I are therefore valuable Antibiotics.

The examples illustrate the invention.

70 '. / ' ¹ U

-X-

Example 1 7β- / 77Tmlnocarbonvl) -amlno7 (L-2-thienvl) -acetvl7-amino7-5- / 7 (1-methvl-1H-tetrazole-5-vl) -thio7-methvl7-8-oxo-5-thia -1-azabicvclo / 4 ~. 2.O / oct ^ -en ^ -carboxylic acid (a) Lg - /// (4-Methoxvphenvl) -methoxv7- »carbonvl7-amino7-2- thiophenacetic acid

14.2 g of L- (2-thienyl) -glycine (prepared according to Nishimura et al., Nippon Kagaku Zasshi, Vol. 82, (1961), pp. 1688 to 1691; Chem. Abst., Vol. 58, p 11464 f) are suspended in 142 ml of water and brought into solution by adding 37.9 ml of triethylamine. A solution of 20.6 g of (p-methoxyphenyl) methoxycarbonylazide in 142 ml of dioxane is then added with stirring. The initially cloudy mixture becomes clear after 30 minutes. The mixture is then stirred for an additional hour at room temperature. The dioxane is then distilled off under reduced pressure. Scales form in the aqueous phase and are separated off by extraction with diethyl ether. The aqueous phase is ^{cooled to 0} ° C., covered with a layer of ethyl acetate and acidified to a pH of 2.5 with 2 η hydrochloric acid. The aqueous phase is extracted twice with ethyl acetate. The ethyl acetate extracts are combined, dried over magnesium sulfate and evaporated under reduced pressure. Yield 23.5 g of the title compound (a) with a melting point of 100 to 102 ^° C .; / ä / ^ ° + 68.3 ° (c = 1 in tetrahydrofuran).

7 0 9 3 7/0 for I 6 4

(b) 7ß - ///// (^ - Methoxvphenvl) -methoxv7-carbonvl7-amlno7- (L-2-thienvl) -acetvl7-amino7-5- / 77i-methvl-1H-tetrazole-5-vl) - thio7-methvl7-8.-oxo-5-thia-1-azablcvcloA.2.07oct-2-en-2-

carboxylic acid / phenyl methyl ester
14.9 g of 3 - / (i-methyl-1H-tetrazol-5-yl) -thiq / -7-aminocephalosporanic acid diphenylmethyl ester are dissolved in 300 ml of methylene chloride. 300 ml of anhydrous tetrahydrofuran are then added. 11.62 g of compound (a) are then added, the mixture is ^{cooled to 0} ° C. and a solution of 6.79 g of dicyclohexylcarbodiimide in 100 ml of anhydrous tetrahydrofuran is added dropwise over 30 minutes while stirring. The reaction mixture is stirred for 90 minutes at 0 to 5 ^° C. and for a further 90 minutes at room temperature. The dicyclohexylurea which has crystallized out is then filtered off and the filtrate is evaporated under reduced pressure. The residue is taken up in ethyl acetate, the solution filtered, washed with aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, treated with activated charcoal, filtered and evaporated to a small volume under reduced pressure. The title compound (b) precipitates on stirring in excess petroleum ether and is filtered off. Yield 24 g of F. 11O ⁰ C.

(c) 7β- / 7Ta-Amlno-L-2-thienvl) -acetvl7-amlno7-3 - / "/ '(1-methvl- 1H-tetrazole-5-vl) -thio7-methvl7-B-oxo-5 -thia-1-azabicyclo "

A ^ oZ-oct ^ -en ^ -carboxylic acid trlfluoroacetate

24 g of the compound (b) are stirred in 100 ml of anisole and 300 ml of trifluoroacetic acid are added ^{dropwise at 0 ° C.} After 10 minutes the mixture is under reduced pressure

70S 37 / 0Π64

evaporated. The residue is treated with diethyl ether. The title compound (c) precipitates and is filtered off. Yield 17.8g.

(d) 7β- / 77l-aminocarbonvl) -amino7- (L-2-thienvl) -acetvl7-amino7-3- / 7ii-methvl-1H-tetrazole-5-vl) -thio7-methvl7-8-oxo-5-thia -1-azabicyclo / ^. 2.O7oct-2-en-2-carboxylic acid 12 g of compound (c) are added to a solution of 3.4 g of potassium cyanate in 85 ml of water, and the mixture is stirred at room temperature for 3 hours . The reaction mixture is then filtered and the filtrate is acidified to a pH of 1.5 with 2 η hydrochloric acid while cooling. The resulting precipitate is filtered off. Yield 6.8 g of the title compound

(d) from the ^{mp 149 to 153 0} C (dec.).
15th

An equimolar amount of sodium bicarbonate is added to an aqueous solution of the carboxylic acid and the mixture is freeze-dried. It is the corresponding sodium salt with a temperature of 187 to 188 ° C (Decomp.) Obtained. The potassium salt is produced in a similar way.

Example 2

7ß- / 77 (Amlnocarbonvl) -amino7- (L-3-thienvl) -acetvl7-amino7-3- / 7 (1-methvl-1H-tetrazole-5-vl) -thio7-methvl7-8-oxo-5- thia-1-azablcyclo / fr.2.o7oct-2-en-2-carboxylic acid

(a) La- / 77? 4-methoxyphenyl) -methoxv7-carbonvl7-amino7-3-thiophenesic acid
18 g L- (3-thienyl) -glycine (manufactured according to that of Nishimura

7 0 9 .-- 37/066 A ^J

et al., op. cit., described method) are in 300 ml Suspended water together with 10 g of magnesium oxide. A solution of 32 g of (p-methoxyphenyl) methoxycarbonylazide in 230 ml of dioxane is then added dropwise. The mixture is stirred for 24 hours at room temperature. The dioxane will then turn off distilled. The residue is filtered and the filtrate is extracted with diethyl ether. The aqueous phase is covered with a layer of ethyl acetate and, with cooling, with 2 η hydrochloric acid acidified to a pH of 2.5. The aqueous phase is still Corn extracted with ethyl acetate. The ethyl acetate extracts who the combined, washed with water, dried over sodium sulfate and evaporated. The oily residue is dissolved in toluene dissolved, mixed with cyclohexane and left to stand in the cold. After a while the title compound (a) crystallizes the end. The product is filtered off. Yield 20.8 g of mp 95 to 97 ° C; Z5 / § ⁵ + 76.8 ° (θ, 1 % in methanol).

(b) 7ß- / 7/77 ~ (4-methoxyphenyl) -methoxv7-carbonyl7-amino7- (L- 3-thienvl) -acetvl7-amino7-3 - // "(1-methvl-1H-tetrazole-5- vl) thio7-methvl7-8-oxo-5-thla-1-azabicycloA.2.07oct-2-ene- 2-carboxylic acid-dlphenvlmethvlester

6.5 g of dicyclohexylcarbodiimide are added to a solution of 10 g of compound (a) in 150 ml of tetrahydrofuran at ⁰ ° C. and the mixture is stirred for 15 minutes. Then a solution of Ί4 g 3- / ii-methyl-1H-tetrazol-5-yl) -thio7-7-aminocephaloc; noranoic acid-diphenylmethvlestor in 100 ml tetrahydrofuran was added. After 12 hours of reaction, the reaction mixture becomes filtered, the filtrate treated with activated charcoal and treated under ver

L _

70S: 37 / 0G64

Γ -η

evaporated under reduced pressure. The brown oily residue is dissolved in 20 ml of methylene chloride and in a mixture of diethyl ether and petroleum ether dripped in. The title compound (b) precipitates out as a pale yellow solid. Yield 20g with a temperature of 95 ° C.

(c) 7β- / 7α-amino-L-3-thienvl) -acetvl7-amlno7-3- / 771-methvl-1H-tetrazole-5-vl) -thio7-methvl7-8-oxo-5-thia -1-azabicyclo /^.2.o7-oct-2-en-2-carbonsäure-trifluoracetat 13 g of the compound (b) are dissolved in 200 ml of a mixture of anisole and trifluoroacetic acid (1: 4) at 5 ⁰ C. After stirring for 10 minutes, the mixture is evaporated under reduced pressure. The residue is digested with a mixture of diethyl ether and petroleum ether and filtered. Yield 8.4 g of the title compound (c) in yellow crystals with a melting point of 125 ° C. (decomp.).

(d) 7ß- / 777Aminocarbonvl) -amino7- (L-3-thienvl) -acetvl7- o raino 7- j- / 7 (1- _me thvl-1H-tetrazol-5-vl) -thio7-methvl7-8- oxo-5-thia- 1

A solution of 7.9 g of compound (c) in 50 ml of water is adjusted to a pH of 7.2 with 2 η sodium hydroxide solution. After adding 1.5 g of potassium cyanate, the mixture becomes 3 hours stirred at constant pH. The reaction mixture is then cooled, with 2η hydrochloric acid to a pH of 1.5 adjusted and the resulting precipitate filtered off. The precipitation is dissolved in methanol, the solution with activated charcoal treated and evaporated. The title compound (d) crystallizes

_L siert off. Yield 4.2 g, mp 157 ⁰ C (dec.).

709037/0664

An aqueous solution of the carboxylic acid and an equimolar amount Potassium bicarbonate is freeze-dried. The potassium salt is obtained as a yellow powder; F. 1? 4 ° C (dec.) · When in use the corresponding sodium salt is obtained from sodium bicarbonate.

Example 3

) -amino / - (L-phenvl) -acetyl7-amlno7-3-

/ 7? 1-methvl-1H-tetrazol-5-vl) -thio7-methyl7-8-oxo-5-thia-1- azabicycloA.2.o7oct-2-en-2-carboxylic acid

(a) L-re / 77? 4-Methoxvphenvl) -methoxv7-carbonvl7-amino7-phenylacetic acid

L-phenylglycine (made from DL-phenylglycine according to the method described by Nishimura and Kitarb., loc. cit.) and Magnesium oxide are suspended in water and treated with a solution of (p-methoxyphenyl) methoxycarbonylazide in dioxane according to Example 1 (a) implemented. The title compound (a) is obtained.

(b) 7 ß- / 777714-Hethoxyphenvl) -met, hoxv / -carbonvl7-ami'no7- (L-phenyl) -acetvl7-amlno7-3- / 7? 1-methvl-1H-tetrazol-5 ~ vl) -thio7-methyl / -8-oxo-5-thia-1-azabicyclo / ^. 2.07oct-2-one-2-carboxylic acid dlphenyl methyl ester

7-Amino-3- / Zii-methyl-1H-tetrazol-5-yl) -thio7-ynethyl7-8-oxo-5-thia-1-azabicyclo / ^. 2 .o / oct ^ -en ^ -carboxylic acid diphenylmethyl ester and the compound (a) are reacted in the presence of dicyclohexylcarbodiimide according to Example 1 (b). There is obtained the title compound (b), mp 117 ⁰ C (dec.).

L -J

7 0i::; V / C C 6 4

(c) 7β- / 7Tg-Amino-L-phenvl) -acetvl7-amino7-5- / 7 (1-methvl-1 lite trazol ~ 5-vl) -thio7-methvl7-8-oxo ~ 5-thia ~ 1 -azabicyclo - /Ä^.O/oct^-en^-carbonsäure-trifluoroacetat The compound (b) is reacted with trifluoroacetic acid and anisole according to Example 1 (c). The title compound (c) is obtained.

(d) 7β- / 77lAtninocarbonvl) -amino7-fc-phenvl) -acetvl7-amino7-5- / 7 ~ (1-methvl-1H-tetrazole-5-vl) -thio7-methvl7-8-oxo-5-thia -1-azabicvclo / 4.2.07oct-2-en-2-carboxylic acid The compound (c) is reacted with potassium cyanate according to Example 1 (d). The title compound (d) is obtained with a melting point of 156 ° C. (decomp.).

An aqueous solution of the carboxylic acid in an equimolar amount Potassium bicarbonate is freeze dried. It will be the appropriate one Potassium salt with a melting point of 174 ° C (decomp.) Was obtained.

When using sodium bicarbonate, the corresponding sodium salt is obtained.

Example 4

7β- / 7 / (aminocarbonyl) -amino / - (L-2-furyl) -acetyl7-amino7-3- / 7 "(1-methvl-1H-tetrazol-5-yl) -thio7-methyl7-8-oxo -5-thia-1-azabicycloA ♦ 2.0 / oct-2-en-2-carboxylic acid

(a) Lg- / 7 / (4-Methoxvphenvl) -methoxv7-carbonvl7-amino7-2-

furanesic acid
40 g L- (2-furyl) -glycine (made from D, L- (2-furyl) _r

L glycine after that of Nishimura et al

709037/0664

benen method) are suspended in 455 ml of water and brought into solution by adding 122 ml of triethylamine. A solution of 66 g of (p-methoxyphenyl) methoxycarbonylazide in 455 ml of oxane is then added with stirring. The cloudy mixture becomes clear after 30 minutes. The dioxane is then distilled off under reduced pressure. The aqueous phase is washed with diethyl ether, cooled to ⁰ ° C., covered with ethyl acetate and acidified to a pH of 2.5 with 2 η hydrochloric acid. The aqueous phase is then extracted twice with ethyl acetate. The ethyl acetate extracts are combined, dried over magnesium sulfate and evaporated under reduced pressure. The oily residue solidifies on digestion with petroleum ether. Yield 74 the title compound (a) g, melting at 91 to 95 ⁰ C (dec.). 15th

(b) 7ß- / 777/74-Methoxyphenvl) -methoxv7-carhonyl / -amlno7- (L-2-furvl) -acetvlZ-aminoZ-3 - //? 1-methvl-1H-tetrazole-5-vl) - -e-oxo-5-thia-1-azabicycloA.2.O / oct-2-βη-

Diphenylmethyl 2-carboxylate A solution of 36.4 g (0.074 mol) of 3- / ~ (1-methyl-1H-tetrazol-5-yl) -thio7-7-aminocephalosporan saturate diphenylmethyl ester in 370 ml of methylene chloride is added to a solution of 27 g (0.088 mol) of compound (a) in 450 ml of tetrahydrofuran were added. The mixture is cooled to 0 ⁰ C and treated dropwise with a solution of 16.73 g (0.081 mol) of dicyclohexylcarbodiimide in 150 ml of tetrahydrofuran. The mixture is then ^{stirred for 90 minutes at 0} ° C. and for a further 90 minutes at room temperature. The crystallized dicyclohexyl urine

L J

7 0 «; '.' ■ 7 / V ₁ VQi *

-yf-

¹ substance is filtered off and the filtrate is evaporated. The residue is taken up in ethyl acetate, washed three times with aqueous sodium bicarbonate solution and three times with water, dried and evaporated. The residue solidifies on digestion with diethyl ether. The product is filtered off and slurried in 250 ml of ethyl acetate. The mixture is ^{stirred for 2 hours at 0} ° C. and filtered off. Yield 30.4 g of the title compound (b) with a melting point of 149 to 152 ° C.

(°) 7β-7 / fa-amino-L-2-furvl) -acetvl7-amino7-3- / 7Ti-methvl-1H-tetrazol-5-yl) -thio7-nethvl7-8-oxo-5-thia- 1-azabicvclo- / 4.2.o7oct -? - on-2-carboxylic acid trifluoroacetate 30 g of compound (b) are reacted with 120 ml of anisole and 390 ml of trifluoroacetic acid according to Example 1 (c). Yield 21.9 g of the title compound (c) with a melting point of 133 ° to 135 ° C. (decomp.).

(d) 7ß- / 77TAminocGrl> onvl) -aniino7- (L-2-furvl) -acetvl7-aminc7-3- / 7 (1- _m ethvl-1H-tetrazol-5-vl) -thlo7-methvl7-8- oxo-5-thia-1-azebicvclo / 4.2.0 / oct-2-en-2-carboxylic acid. 8.15 g of potassium cyanate are added to a suspension of 28.2 g of compound (c) in 290 ml of water at room temperature Stirred for 3 hours. The almost clear solution is then cooled to 0 to 5 ° C. and acidified to a pH of 3.5. A flaky precipitate is filtered off. The clear filtrate is acidified to a pH of 1.5 and left to stand at 0 to 5 ° C. The title compound (d) which has crystallized out is filtered off. Yield 19.8 g of mp 142 bis

, ο
145 C (dec.).

L _l

7 o:: ν / r () 4

An aqueous solution of the carboxylic acid with an equimolar amount of sodium bicarbonate is freeze-dried. There is obtained the corresponding Natriurasalz mp 170-174 ⁰ C (dec.).

When using potassium bicarbonate, the corresponding potassium salt is obtained.

Example 5

7ß - /// (Aminocarbonvl) -amino7- (L-3-furyl) -acetyl / -amlno7-3 - //? 1-methvl-1H-tetrazol-5-vl) -thio7-methvl7-8-oxo- 5-t h la -1-azS bicvcloA.2.o7oct-2-en-2-carboxylic acid

Ca) /
According to Example 4Ί, but using L- (3-furyl) -glycine (prepared from D, L- (3-furyl) -glycine according to the process given by Nishimura et al., Loc. Cit.) The title compound and its Sodium and potassium salt made.

Examples 6 to 55

According to Example 1, but using the compounds listed in column A, those listed in column B are listed End products manufactured.

0 9 'J 7 / C ° 6 U

vt-

Sp. A

CH - SR. ²

COOR

Sp. B

O
il
IC-NH—

NH

C = O

COOR.

Ex.

N - N

H il

I.
H

N-N il H

C ₂ H ₅

N -N

7 01; r // I): 'G 4

- aö -

10

20th

25th

Ex.

10

12 13

15th

Cl

-CH.

N N I. N '
j Il
^ N N 4th I.
C ₂ II CH ₃ C ₂ H ₅ I. -N ■ - N N II
-- "1 N Il Λ Jl 4th CH ₃ N N
I. N I. CH ₃ \ CH ₃ U - N N N 4th 4th Il
N N Ji N Ji N- J! N Jl ^ N N
I.
C "H 4th
N Il
N

70 '17 /' -3

¹ At sp.

18th

19th

N N

X. ^ 3 ^U 7

N N

15 21

O Il

- CIl

-CH ₂ -OC ¹ ^ o)

IjI N

CH.

-CH -

70Γ -: Γ // ί) "ίΒ4

N N

- CH.

Ex.

25th

- 22 -

N N

J!

^O'CI1 3

26th

N N

H ι!

27

-CH ₂ -OC-ZoVlIr

N N

A JL

ClI.

N N

O'

29

N II

Ai

30th

-CH

N CH

31

N r - ^CH T

7 0 Γ! . -17 / (ΓΙ 6

Ex

- 2 *

So

10

33

34

N N

Il Il

15th

35

"TT"

20th

36

CH-

37

H ₃ C

38

7 Oi ¹ : J 7 / Oi 6 4

1 ex.

39

40

ΊΑ

"XJ

¹ XT

10

41

IUC

I I

J "

15th

42

43

20th

44

25th

45

-CH -

Λ ο

0 !:) r; / ο ') 6 4

X)

Ψ O

CH,

-25-

1 BQiSP. ^R 3

46 Sn (CH ₃ )

48 ^Sn

Ν — J]

N N

47 ^Si ( ^C 2 ^I1 5 ⁾ 3 Jl

S '

N I.

N N

15 49 Ca / 2 _JI

I CH ₃

50 Mg / 2 V N

- "-. J CII 20 \ s

N N

⁵¹ " ^a \ JJ .. CH ₃

52 Π .. [J »

7Π

Beisj ^ _R R ₄

N N

Il Π

53 Al / 3 ^

54

CH 10 ⁵

55 [(C ₆ H ₅ CII ₂ ) ₂ ΝΗ ₂ ] ^Φ Ν "" Ν

1IJ

¹⁵ Dei using the 7-Amiiiocepha listed in column Λ! Osporanaäurcn in the methods of Beiispiele 2 to 5 other compounds of general formula 1 are prepared.

709837/0664

71). '/ t » ι *

Claims (7)

Claims 1 ji L-y-oc-ureidoacyl-J-cephem-A-carboxylic acid compounds of the general formula I. R ₁ -CH-C-NH- NH Y ~ ^u COOR ₃ NH ₂ in which R _{1 is} a phenyl, thienyl or furyl group and R is a hydrogen atom, a lower alkyl, phenyl-lower-alkyl or diphenyl-lower-alkyl radical, a tri- (lower-alkyl) -siIyI- or l ' ri- (lower-alkyl) -stannyl group, a salt-forming ion, a substituted phenyl-lower-alkyl radical or a ^ 5 group of the general formula O -CH ₂ -OCR denotes, where R is a lower alkyl radical or an optionally by a halogen atom or a lower alkyl or alkoxy radical ring-substituted phenyl- or phenyl-lower- represents alkyl group and R ^ is a group of the general formula N N N N N N ^{25th k} \ XJ. JHir ^R5 . - ^ r> »the XJ-. 709837/0664 where Rc is a hydrogen atom or a C ₁ _ ^ - alkyl radical. 2. Compounds according to claim 1, wherein IW is a hydrogen atom, a c ₁₄ -Mkvlrest, a benzyl, phenethyl, diphenylmethyl, trimethylsilyl or trimethylstannyl group, an aluminum, alkaline earth metal or alkali metal ion or a group of the general formula O
-CH ₂ -OCR and R is a C-j ^ -alkyl radical, a phenyl, benzyl or phenethyl group. 3. Compounds according to claim 2, wherein R _{1 is} a 2-thienyl or 3-thienyl group and R ^ a V / ater to ffa torn, a sodium or Is potassium atom. 4. Compounds according to claim 3, wherein Rc is a methyl group is. 5. Compounds according to claim 4, wherein R ^ is the group N N N N N Il 'I - .. I I I _, " ^H t or ΝN
I, 1 CH is. 6. Compounds according to claim 5 _f wherein Rc is the group ^L - 709 ^ 37/0664 Ν — Ν It is Il. -IUM- «», 7. Compounds according to claim 5, wherein R ^ is the group N N - ^ N ' ^N is. I CH ₃ 8. The compound of claim 7, wherein R _{1 is} a 2-thienyl group. 9 · 7β- / Z ^ (^ ^inocarbon y ^] -) - ^amine o7- (L-2-thienyl) -acetyl7-amino7-3- / Zi ¹ -raethyl-1H-tetrazol-5-yl) -thio7-methyl7 -8-oxo-5-thia-1-azabicyclo ^ .2.0 / oct-2-en-2-carboxylic acid. 10. Sodium salt of the compound according to claim 9 11. Potassium salt of the compound of claim 12. The compound of claim 7, wherein R-j is 3-thienyl group is. 13 7ß- / ZZ (aminocarbonyl) -amino / - (L-3-thienyl) -acetyl7-amino7-3- / ΖΪ1-methyl-1H-tetrazol-5-yl) -thio7-methy lj- 8-oxo- 5-thia-1- azabicyclo ^ ». 2 .O / o et-2-en-2-carboxylic acid. 25th 14. Sodium salt of the compound according to claim 15. Potassium salt of the compound according to claim 709 '"7/0 F, 16. A compound according to claim 3 »wherein R ^ is the group - (, O
is. 17 · Compounds according to claim 2, wherein R _{1 is} a 2-furyl or 3-puryl group and R is a hydrogen, sodium or potassium atom. 18. Compounds according to claim 17, wherein Rc is a methyl group is. 19. Compounds according to claim 17, wherein R ^ is the group N N N N N N Ä [} \ i , J ^ Jj-CH, -HjLcH ^N T ^CH 3 Y ^{S 3} or -J _x ν CH ₃
15th is. 20. A compound according to claim 19 »wherein R ^ is the group N N ~ ^ -c / ~ ^ - ^ 3 is. N N 21. A compound according to claim 19, wherein R ^ is the group - _N ^ - ^N is. CH ₃ 22. The compound of claim 21, wherein R _{1 is} 2-furyl. 23- 7ß- / 7Z (^ ^inocarbon y ¹ ) - ^am i ⁿ o7- (L-2-furyl) -acetyl / -amino / 3-ZZ (1-methyl-1H-tetrazol-5-yl) -thio7- methyl7-8-oxo-5-thia-1- 7 0Γ. , V / Γ '6 4 azabicyclo / 4.2.o7oct-2-en-2-carboxylic acid. 24. The sodium salt of the compound of claim 23.
25 Potassium salt of the compound according to Claim 23 26. The compound of claim 21, wherein R _{1 is} 3-furyl. 27. 7ß- / ZZ ^ ^inocar ^ ^on y ¹ ) - ^amine Q7 - (^ - 3-furyl) -acetyl7-aniino7-3 - // ~ (1 -methyl-1H-tetrazol-5-yl) -thio7- methy 17-8-0X0-5-thia-1-azabicyclo / 4.2.o7oct-2-en-2-carboxylic acid. 28. Sodium salt of the compound according to claim 27.
15th 29. Potassium salt of the compound of claim 27. 30. Compounds according to claim 17, wherein R ^ is the group -C ^ v is. ο 31. Compounds according to claim 2, wherein R _{1 is} a phenyl group and R 1 is a hydrogen, sodium or potassium atom. 32. The compound of claim 31, wherein Re is a methyl group
is. 33. The compound of claim 32, wherein R ^ is the group ^L 7 01 V / V. U4 ^J Ν —N Ν ~ Ν NN _or N, -CH ₁ CH ₃ is.
5 34. The compound of claim 33, wherein Ry _{4 is} the group - ^ ^ -CH ₃ . N N ι Μ 35. The compound of claim 33, wherein Ry, the group ~ ^ _N ^ ^N * 1 is. CH ₃ 36. The compound of claim 35, wherein R-j is phenyl is. 37. 7.beta.-ZZZ ^(amine ocarbonyl) -amino7- (L-phenyl) -acetyl7-aminq7-3- / Z ⁽¹ -n "ethyl-1H-tetrazol-5-yl) methyl7-8-oxo--thio7 5-thia- 1-azabicyclo / 4.2.07oct-2-en-2-carboxylic acid 38. The sodium salt of the compound according to claim 37.20 39. Potassium salt of the compound according to claim 37. 40. Process for the preparation of L-7-a-ureidoacyl-3-cephem- 4-carboxylic acid compounds according to Claim 1, characterized in that they are 25 draws that one either (a) an L-7-α-aminoacyl-3-cephem-4-carboxylic acid of the general Formula II ^L 7 0: V / '0 A NH ₂ H (ID in which R-, and R ^ have the above meaning, with
an alkali metal or alkaline earth metal cyanate, or
(b) a 7-aminocephalosporanic acid compound of the general formula III V] ^{2 4} (HD COOR ₃ in which R, represents a carboxyl protecting group and R ^ the has the above meaning with an L-cc-ureidocarboxylic acid of the general formula VI L. R ₁ -CIl-COOH HN-C-NH ¹ (VI) in which R _{1 has} the above meaning, or brings its reactive derivative to the reaction and splits off the protective group from the compound obtained and optionally the compound obtained according to (a) or (b) with
converted from a base into a salt. 4 * 1. Medicament containing a compound according to claim 1. 7 0