PROCEDURE FOR the PRODUCTION OF INSATIATED DERIVATIVES of the 7-ACYLAMIDO-3-CEPHEM-4-CARBONSAEURE.

PATENT CLAIMS NC-CH: CIl-S-CH2 - CO-NHoB 1st procedure for the production of connections of the formula:

. I/s.] (I) LN --CH2 " B C OOH lo where those CH = group of CH cis or trans is and B one of the following groups:

N --N: i' -- N h --N N-- N I H I CH 3 eH 3 (B-I) (B-2) (B-I) (B-4) it represents and their pharmaceutical harmless salts, by the fact characterized that one a connection of the formula:

E1/s BN/CH2-B COOH (II) procedure after one of the requirements 3 and 4, by the fact characterized that one the received connection into an alkali metal salt, preferably ci n Natriumoder Kaliumsa [z, überführt.

6. Procedure for the production of carbonic acid esters of the formula:

T S NC-CH: CH-S-CH2-CO-LHa---- (IA) COOH where represents R the not carboxylischen part of an ester, which - CH=CH-Gruppe cis or trans is meant and B a 1-Methyl-l, a 2,3,4tetrazol-5-ylthio, a 1-Methyl-1,3,4-triazoP2-ylthio, a 5-Methyl1,3,4-triazol-2-ylthiooder 1,3,4-Thiadiazol-2-ylthiogruppe, by the fact characterized that one daselbst in the procedure in accordance with requirement 1 connections given formula I manufactures and these connections accordingly verestert.

7. Procedure according to requirement 6, by the fact characterized that the Veresterung by conversion of the free carbonic acid or a salt the same, for example a sodium, a potassium, a Calciumoder tri ethyl ammonium salt, with an appropriate ester-forming halide in an organic solvent or a mixture from water and an organic solvent accomplished wird.

where B has the above meaning and E a Amino, - NCO or - NCS Grappe represents, or an amine salt the same, if E means an amino group, if necessary under intermediate protection of the group of carboxyls, or a metal salt the same with an acid of the formula: NC-CH=CH-S-CHz-COOH (III) or a reactive functional derivative the same umsetzt.

2. Procedure according to requirement 1, by the fact characterized that the connection of the formula II in form of a Silylesters is intermediately protected, whereby the Silylester itself during the processing of the reaction mixture zersetzt.

3. Procedure according to requirement 1, by the fact characterized that one transfers a received connection of the formula I into a pharmaceutical harmless salt and/or a received salt into a free connection of the formula I überführt.

4. Procedure according to requirement 1, by it characterized that one 7-a-Cyano-äthenylen (trans) - thio acetamido] - 3 [(1-m ethyl1,2,3,4-tetrazol-5-yl) - thiomethyl] - 3-cephem-4-carbonsäure; 7 - - Cyano äthenylen (trans) - thio acetamido] - 3 [(1,3,4-thiadiazol-2-yl) - thiomethyl] - 3-cephem-4-carbonsäure; 7 [Ô-Cyano-äthenylen (ice) - thio acetamido] - 3 [(1-methyl1,2,3,4-tetrazol-5-yl) - thiomethyl] - 3-cephem-4-carbonsäure; 7 [[3-Cyano-äthenylen (cis) - thio acetamido] - 3 (1,3,4-thiadiazol2-yl) - thiomethyl] - 3-cephem-4-carbonsäure; 7-a-Cyano-äthenylen (ice) - thio acetamido] - 3 [(5-methyM, 3,4triazol-2-yl) - thiomethyl] - 3-cephem-4-carbonsäure; 7-a-Cyano-äthenylen (cis) - thio acetamido] - 3 [(1-methyl-1 3,4triazol-2-yl) - thiomethyl] - 3-cephem-4-carbonsäure; or 7 []] - Cyano ethylen (trans) - thio acetamido] - 3 [(1-methyl-1,3,4triazol-2-yl) - thiomethyl] - 3-cephem-4-carbonsäure; as well as the pharmaceutical harmless salts of it, in particular the alkali metal salts, preferably Natriumund of potassium salts, herstellt.

The available invention refers to a procedure for the production of insatiated derivatives of the 7-Acylamido-3cephem-4-carbonsäure. Erhãltlichen the according to invention connections correspond to the formula:

NC-CH: CIl-S-CH2 F " l CO, H LN " B--cH2 'B COOH where die-CH=CH-Gruppe cis or trans is and B one of the following groups:

N --N: i -- N N--N N--N I “I Cri3 CH3 (B-I) (B-2) (B-3) (B) dargestellt.

The subject of the invention is also the production of the pharmaceutical harmless salts of the connection of the formula I.

In accordance with the invention in particular, under the connections of the formula I, the following are manufactured:

7 [[3-Cyano-äthenylen (of trans) - thio acetamido] - 3 [(1-methyl1,2,3,4-tetrazol-5-yl) - thiomethyl] - 3-eephem-4-carbonsäure; 7 [[3-Cyano-äthenylen (of trans) - thio acetamido] - 3 [(1,3,4-thiadiazol-2-yl) - thiomethyl] - 3-cephem-4-carbonsäure, 7 [[3-Cyano-äthenylen (cis) - thio acetamido] - 3 [(1-methyl1,2,3,4-tetrazol-5-yl) - thiomethyl] - 3-cephem-4-carbonsäure:

7 [l%Cyano äthenylen (cis) - thio acetamido] - 3 (1,3,4-thiadiazol2-yl) - thiomethyl] - 3-cephem-4-carbonsäure; 7 [] 3-Cyano-äthenylen (cis) - thio acetamido] - 3 [(5-methyI1,3,4triazol-2-yl) - thiomethyl] - 3-cephem-4-cnrhonsäure 3,634,330 7 [í' Cyano äthenylen (cis) - thio acetamido] - 3 [(1-methyl-l.3, 4triangle-2-yl) - thiomethyl] - 3-cephem-4-carbonsäure; 7 - - Cyano äthenylen (trans) - thio acetamido] - 3 [(1-methyl! .3, 4-triazol-2-yl) - thiomethyl] - 3-cephem-4-carbonsäure; as well as the pharmaceutical harmless salts of it, in particular the alkali metal salts, preferably Natriumund Kaliumsalze.

The structural formulas of the connections enumerated above are in the following table angegeben.

Table 1 connection geometrical of isomers B-group of 1 trans B-I 2 of trans B-3 3 cis B1 4 cis B-3 cis B-2 6 cis B-4 7 of trans B-4 the pharmaceutical harmless salts of the connections of the formula I are salts either with inorganic bases, like e.g. Sodium hydroxide, Kaliumhxdroxyd, calcium hydroxide, aluminum hydroxide and Alkaliund alkaline earth metal carbonates or bicarbonaten, or with organic bases, as for example organic amines, e.g. Lysin, tri ethyl amine, Procain, Dibenzylamin, N-benzyle - phenyläthylamin, N, N' DibenzyIäthylendiamin, Dehydroabietylamin, N-Aethylpiperidin, Diäthanolamin, N-Methylglucamin and trichloroethylene (hydroxymethyl) - aminomethan. The alkali metal salts, in particular Natriumund Kaliumsalze.<br are preferential/> According to invention the connections are manufactured by the fact that one a connection of the formula:

E- - SS BN CIt2 C00tt - B connections which can be manufactured; [gewälflt to 7 (see above). The conversion runs stereospezifiscb. If necessary the group of carboxyls is protected against the reaction in conventional way. Examples of are those, which are usually used with the synthesis by Peptiden, e.g. tert. - Butyl, Benzhydryl, p-Methoxybenzyl únd p-Nitrobenzyl. The groups of protection then removed at the end of the reaction in well-known way, e.g. by mild sour Hydrolyse.

A reaktìonsfähiges derivative of a connection of the formula III lo istz. B. an acyl halide, an anhydride, a mixed anhydride, an amide, an azide, a rcaktionsfähiger ester or a salt, like e.g. the Salze.<br formed with Alkaliund alkaline earth metals, ammonia more oo__der organic bases/> The reaction between the connection of the formula II or one of their derivatives already mentioned and the connection of the formula III or a reaktionsfähígen functional derivative of it can either at ambient temperature or under cooling in a suitable solvent, like e.g. Acetone, Dioxan, tetrahydrofurane, acetonitrile, chloroform, dichloromethane or dimethylformamide, gewünschtenfalls in presence of a base, like e.g. Natriumbicarbonat, Kaliumbicarbonat or a tri alkyl amine, implemented werden.

If the connection of the formula III with a connection of the formula II, where E Amino means, when free acid is converted or as salt, it is desired that the reaction in presence of a condensation means, like e.g. N, N' Dicyclohexylcarbodiimid, implemented wird.

The fakultative Salzbildung from the connection of the formula I as well as the fakultative transfer of a salt into a free connection can in conventional procedures, i.e. in organic chemistry procedures already admitted, implemented werden.

Gegcbenenfalls are verestert the received carbonic acids. The Veresterung can be implemented, by one the connection of the formula I, whose group of carboxyls is present freely or as salt, e.g. in form of a sodium, a potassium, a Calciumoder tri ethyl ammonium salt, with a suitable halide in an organic solvent, like acetone, tetrahydrofurane, chloroform, dichloromethane, dimethylformamide or Dimethylsulfoxyd, or in a mixture from water and an organic solvent, e.g. Dioxan or acetone, converts; the reaction temperatures can within the range of -20 to +80° C liegen.

The connections of the formula II, where E Amino means, can be e.g. manufactured, by one 7-Aminocephalosporansäure or a salt of it with application from the literature of well well-known reaction conditions with a connection of the formula HB (IX), where B one of the initially indicated groups represents, umsetzt.

The connections of the formula IX can be made easily in well-known procedures on the basis of well-known connections and/or already are of the literature bekannt.

The connections of the formula II, where E-NCO or NCS means, can be e.g. manufactured, by one a connection of the formula II, where E Amino means, in presence of a hydrochloric acid acceptor with application bekann ter methods with phosgene or Thiophosgen umsetzt.

The connections of the formula! II can be manufactured after one of the following methods:

1. By conversion of a connection of the formula:

(II) 41) where B meaning-has the above and E a Amino, - NCO or - NCS group represents, or an amine salt the same, if E means an amino group, if necessary under intermediate protection of the group of carboxyls, or a metal salt the same with an acid of the formula:

NC-CH=CH-S-CIt - COOH (fil) or a reactive functional derivative the same umsetzt.

One can transfer a received connection of the formula I of wishing case into a pharmaceutical harmless salt or a received salt into a free connection of the formula I überführen.

The intermediate protection of the group of carboxyls of the connection of the formula II can take place in form of a Silylesters; the Silylester decomposes during the processing of the Reaktionsgemisches.

In the above Verfabren the group becomes B in the formula left and the configuration geometrical isomers in the formula of the III, i.e. the more cisoder trans-CH=CH-Gruppe, as into the Z-CH=CH-Y " (VIIa) where Z Cyano or Carbamoyl represents and Y " halogen, preferably chlorine or bromine, or o-Tosyl or o-Mesyl represents, with a connection of the formula:

HS-CH: - COOR (X) 634,330 4 or by conversion of a connection of the formula V with a connection of the formula:

Y-CH_, - COOR (XI) where Y has the above meaning and R hydrogen or alkyl with I to 6 carbon atoms, preferably ethyl or tert. - Butyl. represents: if R alkyl with 1 to 6 carbon atoms means, the reaction product becomes in well-known procedures verseift.

If Z Carbamoyl means, the connection becomes by tons treatment with a water-splitting off means, e.g. Phosphorus pentachloride, Phosphoroxychlorid or Triphenylphosphin, in an organic solvent, e.g. a mixture from dimethylformamide and diethylether, Tetrakohlenstoff, tri ethyl amine undN, N' Dicyclohexylcarbodiimid, ambient temperature or by warming up to approx. 30 to 120°C in an organic solvent, preferably in hexadecimal methyl phosphoric acid tri amide or Dimethylsulfoxyd, into the desired appropriate Cyanoverbindung iibergeführt.

The reaction of a connection of the formula VIIa with a connection of the formula X or the reaction of a connection of the formula V with a connection of the formula XI preferably becomes in water or in an organic solvent, like tetrahydrofurane, diethylether or benzene, or in a mixture from an organic solvent, e.g. one as above mentioned, with water in presence of approx. 2 to 2.5 equivalents of a base, if R hydrogen meant, bzw.

implemented from approx. 1 to 1.5 equivalents of a base, if R alkyl with 1 to 6 carbon atoms means, at temperatures within the range of approx. -10 to approx. +25° C. A suitable base is e.g. Natrinmhydroxyd, Natriumbicarbonat or Triäthylamin.

In the procedure discussed before is in the formula VIIa the configuration geometrical isomers, i.e. cisoder trans configuration of the Grappe-CH=CH, the same its as in the formula III, there the reaction stereospezifisch verläuft.

2. Conversion of a connection of the formula X with a connection of the formula:

- Z-C=-CH (XII) where Z has the above meaning, whereby, receives a connection of the formula III in the cisoder trans form, depending upon the Reaktionsbedingungên wird.

If the reaction between a connection of the formula X and a connection of the formula XII in per tables a solvent, preferably in wässñgen per tables a solvent, e.g. Water or low aliphatic alcohols, like ethanol, in presence of no more than one equivalent of a base, e.g., tri ethyl amine, a Alkalimetallbicarbonat or an alkali metal hydroxide, and at low temperatures, preferably with approx. 0° C, becomes a connection of the formula III is implemented in cis-CH=CH-Form erhalten.

If the same reaction in the same solvents and in presence of the same bases. but at higher temperatures than ambient temperature, or in a surplus of the Thiolatanions, or using sour catalysts, e.g. Hydrochloric acid is implemented, a connection of the formula III is received, which from a mixture of cis-CH=CHund trans-CH=CHbesteht.

If Z Carbamoyl means, the connection is described again, like already, into the appropriate Cyanoderivat übergeführt.

The separation received isomers can after the usual in which organic chemistry for the separation from geometrical isomers used procedures are ausgefiihrt, for example by fractionated crystallization from solvents, like e.g. Water or low aliphatic Alkoho [EN, z, B. Aethanol, or by chromatographische Trennung.

If Z Carbamoyl means, the connection is described again, like already, into the appropriate Cyanoderivat übergeführt.

In large number halfsynthetic and synthetic connections with antibacterial effect were already manufactured, for example in the French the patent specifications Nr.

2.238.497 and 2.308.369 descriptive connections. Invention in accordance with available connections against it are characterised by another structural formula and a increased antibacterial activity. They prove highly effectively with animals and with humans both against grampositive and against gramnegative bacteria and are useful from there for the treatment of infections caused by these microorganisms, like e.g. Infections of the respiratory system, e.g. Bronchitis, bronchopneumonia and Pleuritis; hepatobiliäre and abdominale infections, e.g. Cholezystitis and Peritonitis; Blutund cardiovascular infections, e.g. Septikämie, infections of the urinary passages, e.g. Pyelonephritis and Zystitis, obstetrische and gynäkologische infections, e.g. Zervizitis and Endometrits, as well as ear, Nasenund neck infections, e.g. Otitis, Sinusitis and Parotitis.

The following table shows the minimum inhibiting concentrations (MIC) in tg/ml the connections 3 and 4 and gramnegative bacteria grampositive of table 1 approximately both in the comparison with the well-known connections K 9227 and K 10299 (with those it around the most effective under the satisfied connections from the British patent specification No. 1478 055 acts) and Cefazolin and Cefamandole.

Table 2 Gram positive bacteria:

Staphylococcus anreus Smith Diplococcns aureus 39/2 Diplococcus pneumoniae ATCC 6301 Streptococcus [3-haemolyticus C203 Gram negative bacteria:

Escherichia coli G Escherichia coli 1507 Klebsiella pneumoniae ATCC 10031 Klebsiella of aero gene 1522E Enterobacter of aero gene ATCC 8308 Enterobacter cloacae 1321E Salmonella typhi Watson Shigella sonnei ATCC 11060 Proteus mirabilis ATCC 9921 Cefazolin Cefamandole K 9227 K 10299 3 4 0 05 0.15 0.05 0.075 0.025 0.025 0.6,1.2,0.2,0.4 0.14 0.14 0.05 0.019 0.4,0.2 0,012 < 0,006 0.05 0.019 0.025 0.037 0.012 < 0,006 1.6 2.35 3.1,0.8 0.14 0.57 1.6,0.8,1.6,0.8,0.1 0.57 0.8 0.15 0.4,0.2,0.1,0.2,1.1,0.4,1.6,0.8,0.1 0.28 1.2,1.6,1.2,0.6,0.2,0.4,3.1,1.6,3.1,1.6 0.56 1.6,1.6,0,6,0.8,0.2 0,07 0.2,1.6 2.35 1.6,1.6,0.8,1.6,6.2,1.6 12.5 6.2,0.4,9,4,634,330 Cefazolin Cefamandole K 9227 K 10299 = 7 [1 (IH) - Tetrazolylacetamido] - 3 [2 (5mcthy [- 1,3,4-thiadiazolyl) - thiomethyl] - 3cêphem-4-carbonsäure; = 7-D-Mandelamido-3 {[(1-methyl1H-tetrazol-5-yl) - thio] - methyl} - 3-cephem-4-carbonsäure; = 7 [(Cyanomethyl thio) - acetamido] - 3 [2 (5methyl-l, 3,4-thiadiazolyl) - thiomethyl] - 3cephem-4-carbonsäure; = 7 [(Cyanomethl thio) - acetamido] - 3 [5 (1methyl1,2,3,4-tetrazolyl) - thiomethyl] - 3cephem-4-carbonsänre.

How is shown by table 2, the connections 3 and 4 show not only a high activity against grampositive bacteria, but have surprisingly also a very high activity against gramnegative bacteria; they are many more useful from there than the well-known connections from the table, for the treatment of infections, as for example infections of the Hamwege caused by gramnegative bacteria and the Atemwege.

In particular the table shows that the connection 3 against staphylococci for instance 2mal more effectively, against Streptokokken (including Diplokokken) about 4.2 times more effectively and against gramnegative bacteria about 9.6 times more effectively than Cefazolin ist.

Furthermore the connection 3 in the comparison with Cefazolin was tested Protens against a set of 60 Stämmcn of gramnegativen microorganisms, including Klebsiella, Escherichia coli, mirabilis and Proteus vulgaris, whereby it was found that she was ever more effective than Cefazolin. Against Haemophylus influenzae (gramnegatives bacterium; 7 trunks tested) was approx. 6 times more effective it than Cefazolin.

The connections can be given humans or animals in the most diverse Darreichungsformen, e.g.

orally in the form of tablets, caps, drops or syrups, rektal in the form of Suppositorien, parenterally, e.g. intravenously or intramuskulär (as solutions or suspensions), whereby the intravenous Vcrabreichung in emergencies one prefers, by inhalation in the form of aerosols or solutions for Zerstäuio more ber, intravaginal in the form of e.g. Candles or topisch in the form of lotions, creams and ointments. The pharmaceutical means, which contain the connections, can be used in conventional way using conventional carriers and/or diluents for the other Cephalosporine, manufactured werden.

Conventional carriers or diluents e.g. are.

Water, gel, lactose, strengths, Magnesinmstearat, talcum powder, vegetable oils, cellulose and such a thing. Daily dosages can be used within the range of approx. 1 to approx. 100mg per kg body weight, with verschiedcnen animal species, whereby the exact dose depends on the age, the weight and the condition of the patient who can be treated and on the 1 Iäufigkeit and the kind of the administration. A preferential kind of the administration of the connections is the parenteraie administration, in this case can the connections ss e.g. to adult humans in a quantity from approx. 100 to ca.

200 mg per dose, preferably approx. 150 mg per dose, once to four times daily to be given, solved in a suitable solvent, like e.g. sterile water or Lidocainhydrochloridlösnng for the intramuskuläre injection and sterile water, physiological saline solution, Dextroselösung or the conventional intravenous liquids or E [ektrolyten for the intravenous Injektion.

Furthermore the connections can be used in prophylaktiseher way as antibacterial means, e.g. with the cleaning or as surface disinfectants, e.g. with a concentration from approx. 0.2 to 1 Gew. - % of the connections in the mixture also, suspends in or solved in conventional inert dry or aqueous carriers for application with washing or Besprühen.

They are also useful as nourishing additives in Tierfuttermitteln.

The regulation of fusion points was in some cases somewhat with difficulty, since the connections are inclined to it, the solvent restrainable. In these cases the word became decomposition zugefügt.

according to the indication of the fusion point The infrarotspektren became in firm phase on a Speklo of trophotometer Perkin Elmer! 25 determines, while usually in a phosphate buffer solution of the pri=7,4 on an Bausch Lomb apparatus determines the ultraviolet spectra wurden.

The magnetic nuclear resonance spectra became in Dimethylsulfoxyd with cinema spectrometer Varian HA-100 under whom! 5 dung of (CH3) 4 SI as internal standard gemessen.

The following examples describe the Erfindung.

Example 1 a solution of 2,88 g [5-Cyano-äthenylen (of trans) - thio acetic acid and 2.8 g tri ethyl amine in 120 ml water-free acetone were shifted with some drops N-Methylmorpholin. The mixture was cooled down auf-10° C, on which under agitating a solution was admitted to water-free acetone of 2,44 valley Pivaloylchlorid in 30 mi. After halfhour agitating bei-10° C an e solution of 6,56 g 7-Ami no-3 [(1-methyl1,2,3,4-tetrazol-5yl) - thiomethyl] became - 3-cephem-4-carbonsäure and 2.8 ml tri ethyl amine in 240m 150% igem acetone, which were cooled for auf-20° C, after 30 minutes zugegeben.

The mixture was then agitated one hour long bei-20° C and afterwards 2 hours long at ambient temperature. The acetone was evaporated in the vacuum. The arrears were taken up with water, subjected with ethyl acetate of the SChichtbildung and the pH value of the mixture with 40% of iger phosphoric acid on 2,5 gebracht.

After filtration ethyl acetate was separated and the organic phase was washed with water, dried over sodium sulfate and evaporated on a small volume. Ethyl ether was added, whereby a fixed substance developed, which was filtered off and agitated with ethyl ether. The fixed substance was again filtered off, whereby one 5,4g (yield 60%) 7 [[5Cyano-äthenylen (of trans) - thio acetamido] - 3 [(1-methyl-l, 2,3,4tetrazol-5-yl) thiomethyl] - 3-cephem-4-carbonsäure of the fusion point 118 to 120°C (decomposition) erhielt.

Analysis for CI5 I-It5 N7 04 83:

Found: C 39,83; H 3,42; N 21,31; S 20,87.

Computed: C 39,80; H 3,33; N 21,60; S 21,20.

Ultraviolet spectrum (phosphate buffer of the pH = 7.4):

max = 267 mg; El£ç = 411.

Dünnschichtchromatographie:

Ri = 0.55 (CHCI3: CH3 OH: HCOOH = 160:40: 20).

Infrarotspektrum (KBr):

v (C--N) conjugates 2200 cm J:

v (C=O) [3-Lactam 1775 cm-i; v (C=O) secondary amide! 670 cm-1.

Magnetic nuclear resonance spectrum, ppm (DMSO dr,):

3,75 (4H, br. s, - S-C__HOE-CO and 2-CH2); 3,94 (3H, s, cìI3 - N); 4,33 (2H, q, 3-CH2); 5,11 (1H, D, 6-H):

5,64 (1H, D, NC-C__H=); 5,7 (IH, D-D, 7-H), J (, H-7 H = 4,5Hz; 7,82 (1H, D, =CH-S), JçH=CH (tran = 16HZ; 9,28 (1H, D, - CONH), J7 H-NH = 8Hz.

As the Ausgangsmatcrial used [5-Cyano-äthenylen (of trans) - thio acetic acid was manufactured in the following procedures:

634,330 6 procedures A for a solution of 2,1 mi 70% iger Thioglycolsäure and 5.6, cooled on +5° C, ml tri ethyl amine in 50 valley water a solution of 1,73 g trans [5-Chloracryl-nitril became course-dripped in 7 mi Tetrahydrofnran. The mixture was agitated 30 minutes long at ambient temperature and acidified with 20% of iger sulfuric acid. The received precipitation was extracted with ethyl acetate: the excerpts were washed with to a satisfied sodium chlorid solution, over sodium sulfate dried, with coal treated and evaporated, whereby one received an oil, lo to 2.5 g (yield 88%) [3-Cyano-äthenylen (of trans) - thio acetic acid of the fusion point 81 to 86° C erstarrte.

Analysis for CsHsNO2 S:

Found: C 41,81; H 3,57; N 9,71; S 22,31.

Computed: C 41,94; H 3,52; N 9,78; S 22,39.

Infrarotspektrum (KBr):

v (C-N) conjugates 2220 cm-l; v (C=O) acid 1720 cm-l; v (C=C) conjugates 1575 cm-l; v (CH): C=C of trans 930 cm-k magnetic nuclear resonance spectrum (DMSO-d6):

5.56 b (D, NC-CH=); 7,78 õ (D, =CH-S), JcH=CH (trans) ---- 16Hz.

Procedure B a solution of 0,5 mi 70% iger Thioglycolsäure and 0,84mg Natriumbicarhonat in 50 ml water was shifted under agitating with 1,03 g 13-Tosyl-acrylnitril. The mixture was agitated and filtered 3 hours long at ambient temperature. The solution was acidified with 20% of iger sulfuric acid and extracted with ethyl acetate. The organic phase was dried over Natñumsulfat and evaporated to dry ones, whereby one p-Cyano-äthenylen 0.65 g (yield 91%) (trans) - thio acetic acid erhielt.

Dureh cleaning by formation of the Dicyclohexylaminsalzes was received a product, that identically to in procedures A manufactured war.

As raw material used [5-Tosylacrylnitril was manufactured, by one the sodium salt of the p-Toluolsulfinsäure and 13-Color-acrylnitril in a well-known procedure in a mixture of Dioxan, water and boric acid umsetzte.

Example 2 if one after example 1 proceeded and [3-Cyano-äthenylen (of trans) - thio acetic acid with 7-Amino-3 [(1,3,4-thiadiazol-2-yl) - thiomethyl] - 3-cephem-4-earbonsäure converted, received one in a yield from 68% 7 [[3-Cyano-äthenylen (of trans) - thioacetamido] - 3 [(1,3,4-thiadiazol-2-yl) - thiomethyl] - 3-cephem-4carbonsäure from the Sehmelzpnnkt 100° C (decomposition).

Analysis for C15 Ht3 NsO “S “:

Found: C 39,66; H 2,91; N 15,25; S 28,05.

Computed: C 39,54; H 2,87; N 15,37; S 28,15.

Ultraviolet spectrum (phosphate buffer of the pH = 7.4):

=1 “= 569,8.

max = 267 m t; 1¢m Dünnschichtehromatographie:

Rf = 0.54 (CHC13: CH3 OH: HCOOH = 160:40: 20).

Infrarotspektrum (KBr):

v (C-N) conjugates 2215 cm-l; v (C=O) - lactam 1775 cm-l; v (C=O) secondary amide 1675 cm-1.

Example 3 a solution of 1,44 g [5-Cyan o-äthenylen (cis) - thio acetic acid and 1 Ami tri ethyl amine in 80mlwasserfreiem acetone were vcrsetzt with some drops N-Methylmorpholin. The solution was cooled down auf0° C and shifted then under agitating with a solution from 1,22 ml Pivaloylchlorid in 20 mi water-free acetone. The Gemsich was agitated 30 minutes long with 0° C. Then a solution of 3,28 g became 7-Amino-3 [(1meth l! , 2,3,4-tetrazol-5-yl) - thio methyl] - 3-cephem-4-carbonsäure and 1.4 ml tri ethyl amine in 160 mi 50% igem acetone added. After the addition the solution was agitated one hour long bëi 0° C and afterwards 2 hours long with Raumtemperatur.

The acetone was evaporated in the vacuum. The arrears were taken up with water and washed with ethyl acetate. After the Abtrennang the aqueous phase with ethyl acetate of the Schichtbildung was subjected and with 20% of iger sulfuric acid on pH = 2 gebracht.

The arrears were filtered off and the organic phase, dried over water-free sodium sulfate and on a small volume was separated eingedampff. The arrears were taken up with ethyl ether, whereby one 2,7g (yield 60%) 7 - [13-Cyano-äthenylen (ice) - thio-aeetamido-3 [(1-methyl-l, 2,3,4tetrazol-5-yl) - thiomethyl] - 3-cephem-4-carbonsäure of the fusion point 113 to 115° C (decomposition) erhielt.

Analysis fûr c1 sH1 sNTO4 S3:

Found: C 39,78; H 3,43; N 21,40; S 20,78.

Computed: C 39,80; H 3,33; N 21,60; S 21,20.

Ultraviolet spectrum (phosphate buffer of the pH = 7.4):

“1% = 463.

ma× = 273 m t; alcm Dünnschichtchromatographie:

Rf = 0.60 (CHCI3: CH3 OH: HCOOH = 160:40: 20).

Infrarotspektrum (KBr):

v (C-N) conjugates 2210 cm-l; v (C=O) [3-Lactam 1775 cm-l; v (C=O) secondary amide 1680 cm-k v (C-N) +õ (N-H) secondary amide 1540-1.

Magnetic nuclear resonance spectrum, ppm (DMSO-d6):

3,68 (2H, q, 1-CH2); 3,73 (2H, s, - S-C_TCO); 3,94 (3H, s, CH3 - N); 4,31 (2H, q, 3-CH2); 5,10 (1H, D, 6-H); 5,63 (1H, D-D, 7-H); 5,72 (1H, D, NC-__CH=); 7,63 (1H, D, =CH-S) m Jcr =cr (cis) = llHZ; 9,2 (1H, D, - CONH).

As the raw material used [3-Cyano-äthenylen (cis) - thio acetic acid was manufactured as follows:

A cooled a solution of 4g [3-Carboxamido-äthenylen (cis), on 0° C - thio acetic acid in 100 mi of a mixture from dimethylformamide and ethyl ether (3: 2) under agitating with 5,2g phosphorus pentachloride one shifted, whereby one the temperature between 8 and 10° Chient. Those then 2 hours long between 0 and 10° C gerührt.

The solution was poured in ice and the ethereal layer was separated. The aqueous layer was extracted four times with for each 50mi ethyl acetate. The united excerpts were dried over sodium sulfate and then at a temperature not over 40° C to dry ones eingedampff, whereby one received a yellowish of oils, which was solved in 10mlMethanol. The resulting solution was washed with the stoichiometric quantity of Dicyclohexylamin shifted, whereby the Dicyclohexylaminsalz of the 13Cyano-äthenylen (cis) was precipitated - thio acetic acid, that after filtration repetitive with ethyl ether (fusion point 180 to 183° C).

“o the salt became with 5° C in 120 mi of a mixture from water and ethyl acetate (5: 7) solved. The solution was acidified by Zutropfen of 10tal 40% of iger phosphoric acid. The resulting solution was extracted three times with ethyl acetate, on which the united organic were washed excerpts with to a satisfied aqueous sodium chlorid solution, dried over Natriumsnlfat and evaporated in the vacuum to dry ones, whereby one 2,76g (yield 77%) [5-Cyano-äthenylen (cis) - thio acetic acid of the fusion point 90 to 92° C erhielt.

7,634,330 analysis for C5 H5 NO2 S:

Found: C 41,70; H 3,63; N 9,64; S 22,25.

Computed: C 41,94; H 3,52; N 9,78; S 22,39.

lnfrarotspektrum (KBr):

v (C-=N) conjugates 2220 cm-i; v (C=O) acid 1720 cm-l; Magnetic nuclear resonance spectrum, (DMSO-d6):

5,4 6 (D, NC-CH=); 7,4 5 (D, =CH-S); JcH=cn () = 10HZ; Example 4 if one after Beispiel3 proceeds and [3-Cyano-äthenylen (cis) - thio acetic acid with 7-Amino-3 [(1,3,4-thiadiazol-2-yl) - thiomethyl] - 3-cephem-4-carbonsäure converts, then one receives in a 1,3,4-triazo! - 2-yl) - thiolpethyl] - 3-cephem-4-carbonsäure of the fusion point 127 to 13! ° C (decomposition).

Analysis for Ct Hv, N “, O, S.:

Found: C 42,82; H 3.67 " N 18,33: S 20,73.

Computed: C 42,50; H 3,5; N 18,60; S 21,20.

Ultraviolet spectrum (phosphate buffer of the pH = 7.4):

Lmax= 267 m t; 1 m: 1 = 444.

Dünnschichtchromatographie:

Ri = 0.28 (CHCI3: CH3 OH: HCOOH = 160:40: 20).

lo Infrarotspektrum (KBr):

v (C-=N) conjugates 2215 cm-z; v (C=O) O-lactam 1775 cm! ; v (C=O) secondary amide 1675 cm-z.

7 [[3-Cyano-äthenylen (cis) - thio acetamido] - 3 [(5-methyl-l, 3,4Ausbeute of 63% 7 [t3-Cyano-äthenylen (cis) - thio acetamido] - 15 triazol-2-yl) - thiomethyl] - 3-cephem-4-carbonsäure.

3 [(1,3,4-thiadiazol-2-yl) - thiomethyl] - 3-cephem-4-carbonsäure analysis for C16 H16 N6 04 S3:

Found: C 42,63; H 3,73; N 18,40; S 20,91.

of the fusion point 93 to 95° C (decomposition).

Analysis for C15 H13 NsO4 S4:

Found: C 39,33; H 2,94; N 15,22; S 27,93.

Computed: C 39,54; H 2,87; N 15,37; S 28,15.

Ultraviolet spectrum (phosphate buffer of the pH = 7.4):

kmax = 273 mbt; l: ç 1 “= 504.

Dünnschichtchromatographie:

R “= 0.56 (CHC13: CH3 OH: HCOOH = 160:40: 20).

infrarotspektrum (KBr):

v (C--N) conjugates 2220 cm-z; v (C=O) [3-Lactam 1775 cm-z; v (C=O) secondary amide 1715 cm-1.

v (C-N) + 8 (N-H) secondary amide 1540 cm example a solution of 1,44g 13-Cyano-äthenylen (cis) - thio acetic acid and 1.4 valley tri ethyl amine in 80tal water-free acetone were shifted with some drops N-Methylmorpholin. After cooling on 0° C under agitating a solution was added to water-free Aeeton of 1,22 valley Pivaloylchlorid in 20 valley. The mixture was agitated 30 minutes long with 0° C and then with a solution of 3,26 g 7-Amino-3 [(1-methyl-1,3,4-triazol-2yl) - thiomethyl] - 3-cephem-4-carbonsäure and 1.4 ml tri ethyl amine in 160 ml 50% igem acetone shift. After the addition the solution became long long with 0° C and then 2 hours one hour at ambient temperature gerührt.

The acetone was evaporated in the vacuum. The arrears were taken up with water and washed with ethyl acetate. After separation of the phases the aqueous phase with ethyl acetate of the Schichtbildung were subjected and brought the pH value with 20% of iger sulfuric acid auf2. The arrears were filtered off and the organic phase over water-free sodium sulfate and evaporated on a small volume was dried. The arrears became with ethyl ether aufgenommen.

By filtration 2.5 g (yield 55%) became 7 [13-Cyanoäthenylen (cis) - thio acetamido] - 3 [(1-methyl-l, 3,4-triazol-2-yl) - thiomethyl] - 3-cephem-4-carbonsäure of the fusion point 125 to 130° C (decomposition) erhalten.

Analysis for CI6 HI6 N6 04 S3:

Found: C 42,77; H 3,96; N 18,27; S 20,87.

Computed: C 42,50; H 3,56; N 18,60; S 21,20.

Ultraviolet spectrum (phosphate buffer of the pH = 7.4):

ß…. = 267 also; Eì m = 458.

Dünnschichtchromatographie:

Ri = 0.32 (CI-ICI: CH3 OH: HCOOH = 160:40: 20).

Infrarotspektrum (KBr):

v (C-=N) conjugates 2215 cm; v (C=O) - lactam 1775 cm-i; v (C=O) secondary amide 1675 cm the following connections were kept similar:

7 [[3-Cyano-äthenylen (of trans) - thio acetamido] - 3 [(1-methylBerechnet: C 42,50; H 3,56; N 18,60; S 21,20.

........ _. ...

Example 6 a auf0° C cooled solution of 3,28 g 7-Amino-3 [(1methyl-l, 2,3,4-tetrazol-5-yl) - thiomethyl] - 3-eephem-4-earbonsäure and 2 g Natriumbicarbonat in 60 mi 50% igem wässfigem acetone became under agitating with a solution of 2,18g [3Cyano-äthenylen (of trans) - thio essigsäureehlorid (received by conversion with Oxalylehlorid to dimethylformamide with 0° C from the acid) in 30ml acetone versetzt.

The mixture was agitated 20 minutes long at a temperature between 0 and 5° C. The Aeeton was evaporated. The resulting aqueous solution was shifted with ethyl acetate and acidified then with 8% of iger hydrochloric acid to pH = 2. The organic phase was washed, dried with water and evaporated in the vacuum. The arrears were treated and filtered with ethyl ether, whereby one 2.3 g 7 [[3-Cyano-äthenylen (of trans) - thio acetamido] - 3 [(1-methyl-l, 2,3,4-tetrazol-5-yl) - thiomethyl] - 3-cephem-4-carbonsäure of the fusion point 118 to 120° C (decomposition) received. The microanalysis as well as the ultraviolet, dünnschichtchromatographie, Infrarotund magnetic nuclear resonance data of this connection were identical to in example the i indicated. By similar procedure also the others became in the preceding examples mentioned connections hergestellt.

Example 7 a solution of 1,44g 13-Cyano-äthenylen (cis) - thio acetic acid in 50 mi wasseffreiem tetrahydrofurane was shifted with 2,1g Dicyclohexylcarbodiimid, on which the mixture was agitated 30 minutes long at ambient temperature. This mixture became with a solution of 3,28 g 7-Amino-3 [(1-methyl1,2,3,4-tetrazol-5-yl) - thiomethyl] - 3-cephem-4-carbonsäure and 0.84 g Natriumbicarbonat in 60tal of a mixture from tetrahydrofurane and water (1: 1) shifted. After 3-stündigem agitating at ambient temperature was evaporated tetrahydrofurane in the vacuum. The arrears were taken up with water and the Dicyclohexylharnstoff was filtered off. The filtrate was acidified the Schichtbildung with ethyl acetate subjected and with 20% of iger sulfuric acid to pH = 2.5. The organic layer was washed separated, with water, evaporated to a small volume and shifted then with ethyl ether, whereby a fixed substance formed, which was filtered off and agitated then with ethyl ether; in this way 7 [[3-Cyano-äthenylen (cis) - thio acetamido] became - 3 [(1-methyl-l, 2,3,4-tetrazol-5-yl) - thiomethyl] - 3-cephem-4-carbonsäure from the fusion point 113 to 115° C (decomposition) receive. The microanalysis as well as the ultraviolet, thin-layer chromatography, Infrarot-und magnetic nuclear resonance data were identically to already in example the 3 angegebenen.

634,330 8 by similar procedure became also the others in the preceding examples mentioned connections erhalten.

Example 8 an aqueous suspension of 4,53 g 7 [[5-Cyano-äthenylen (cis) - thio acet amido] - 3 [(1 - methyl1,2,3,4-tetrazol-5-yl) - thiomethyl] - 3-cephem-4-carbonsäu RH in 80 mi water was shifted with the stoichiometric quantity of Natriumbicarbonat, so that the connection dissolved completely. This solution was then freezingdried, whereby one the sodium salt of 7 [[5Cyano-äthenylen (cis) - thio acetamido] - 3 [(1-methyl-l, 2,3,4tetrazol-5-yl) - thiomethyl] - 3-cephem-4-carbonsäure erhielt.

Analysis for CI “HI4 NTO4 S3 well:

Found: C 37,71; H 2,43; N 20,55; S 20,15; Well 4,75.

Computed: C 37,88; H 2,39; N 20,62; S 20,23; Well 4,83.

Infrarotspektrum (KBr):

v (C=N) conjugates 2210 cmt; v (C=O) 13-Lactam! 775 cm-l; v (C=O) secondary amide 1670 cm-I.

v (C-N) + b [N-H) sec. amide 1540 cm-j.

Example 9 a solution of 1,13 g 7 [[3-Cyano-äthenylen (cis) - thio acetamido] - 3 [(1-methyl1,2,3,4-tetrazol-5-yl) - thiomethyl] - 3cephem-4-earbonsäure shifted in 30 ml ethyl acetate with the stoichiometric quantity 30% igen solution of Natrium-2äthyl-hexanoat in isopropyl alcohol. After halbstündigern agitating at ambient temperature the mixture with PeAnalyse for CIsHI4 N7 became 04 S3 well:

Found: C 37,71; H 2,43: N 20,55; S 20,15; Well 4,75.

Computed: C 37,88; H 2,39; N 20,62: S 20,23; Well 4,83.

Infrarotspektrum (KBr):

v (C C) conjugates 22113 cm-l; v (C=O) - lactam 1775 cm-l; v (C=O) secondary amide 1670 cm v (C-N) + (N-H) sec. amide 1540 cm-I.

lo example a suspension of 2,38 g of the sodium salt of the 7 [[3-Cyanoäthenylen (cis) - thio acetamido] - 3 [(1-methyl1,2,3,4-tetrazol-5yl) - thiomethyl] - 3-cephem -4-carbonsäure in 40 ml acetone became with 0,4ml a 10% igen aqueous sodium iodide solution and 0,72ml of a Chlormethylpivalat versetzt.

The suspension became 3 hours long the return flow erhitzt.

After cooling auf5° C the Festsnbstanz was filtered off and the resulting solution in the vacuum was evaporated. The oily arrears were solved in 50 valley ethyl acetate. The resuttierende zo solution with a 5% igen aqueous Natriumbicarbonatlösung and then with water washed, dried and to dry ones evaporated, whereby the Pivaloyloxymethylester of the 7 - [[5-Cyano-äthenylen (cis) - thio acetamido] - the 3 [(1-methyl-1,2,3,4tetrazol-5-yl) - thiomethyl] - 3-cephem-4-carbonsäure receive wurde.

more troläther diluted and the received precipitation filtered off, example of use a injectable pharmaceutical preparation was manufactured, by one 100 to 500mg Natrium-7 [[3-cyano-äthenylenwobei the sodium salt of the 7 [[3-Cyano-äthenylen (cis) - thio-ace3o (cis) - thio acetamido] - 3 [(1-methyl-l, 2,3,4-tetrazol-5-yl) - thiotamido] - 3 [(1-methyl-1,2,3,4-tetrazol-5-yl) - thiomethyl] - 3methyl] - 3-cephem-4-carboxylat in 1 to 2 ml sterile water or cephem-4-carbonsäure was received, to sterile normal saline solution solved.