CS196382B2 - Method of producing unsaturated derivatives of 7-acylamido-3-cephem-4-carboxylic acid - Google Patents

Description

(54) A method for producing unsaturated 7-acylamido-3-cephem-4-carboxylic acid derivatives

The present invention relates to a process for the preparation of unsaturated 7-acylaimido-3-cephem-4-carboxylic acid derivatives of the general formula I

in which

Z denotes a cyano or carbaithiyl group, A denotes a group trans-CII = CH-, cls-CH = CH- or -CsiC-,

B represents a group of the formula

-O-C-CH 3 or -S-Het,

Wherein Het represents a radical of formula wherein R is hydrogen or methyl, or Het represents wherein R 1 and R 2 are independently selected from the group consisting of hydrogen or methyl and X represents a free carboxyl group or an esterified carboxyl group of the formula - COOM, in which M denotes a group ^! - CH - O - C - R 4

I II

Rs O or —CH — Q — C — O — Rs,

1 'II

R 11 N - N N - N 11, s N) N I

R in which

R3 represents a hydrogen atom or a C ₆ and · apos alkyl, Q / is an oxygen atom or a group - NIH, R 4 is a C ₆ alkyl group or a basic group, in particular C. C _1-6 alkyl or C 1-6 aryl, C 1-6 alkyl, substituent 199382

19B382 is bound by at least one amino group which is optionally substituted, for example R 8 is

C ₁ _ ₆ alkyil-N'H-CH5-Ce-garylCí fialkyl -NH-CH 3,

C 1-6 alkyl

or _-CH2-NH2, R represents C ₆ alkyl, C _6-8 aryil C ₄ _ ₈ cycloalkyl, heteromonocyclic ring, such as pyridyl, heterobicyclic ring like- indanyl, or C _6-8 aryl-C ₆ alkyl such as benzyl.

Also described are pharmaceutically or veterinarily acceptable salts of the compounds of formula I wherein X is a carboxyl group, as well as antibacterially active metabolites and metabolic precursors. compounds of formula I.

The pharmaceutically and veterinarily acceptable salts of the compounds of formula I may be either salts with inorganic bases such as sodium, potassium, calcium or aluminum hydroxide, or alkali and alkaline earth metal carbonates or acid carbonates, or salts with inorganic bases, such as organic amines such as lysinera, triethylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, N, N-dibenzylethylenediamine, dehydroabietylamine, N-ethylpiperidine, dlethanolamine, N-methylglucamine and tris-methylmethylamine.

When X represents an esterified carboxyl group, this is preferably * a group of the formula —COOM, in which M is a radical of the formulas —CH — O — C — R1

R3 O or -CH-Q-C-O-R5,

R @ 3 wherein R @ 3 is hydrogen or C1 -C6 alkyl, Q is --O-- or - NH, R @ 1 is C1 -C6 alkyl or basic, especially C1 -C6 alkyl or a C _6-8 aryl-C _1-6 alkyl group (e.g., a benzyl group) substituted with at least one amino group which may be either unsubstituted or substituted, for example R 1 represents a C 1-6 alkyl-NH-CH 3 group, a C _6-8 arylC _1-6 alkyl-NH-CH 3 group,

-CH 2 NH 2, and R 5 represents a C 1 -C 6 alkyl group, for example methyl, propyl or Isopropyl, a C 6 -C 8 aryl group, in particular phenyl, a C 4 -C 8 cycloalkyl group, particularly cyclopentyl, cyclohexyl or cycloheptyl, heteromonocyclic ring, for example pyridyl, heterobicyclic ring, for example indanyl, and the C ₆ _ ₈ arylC 6alkytovou group, for example benzyl.

Preferably B represents groups of formulas

N — N

-S-C ^ N

N— N ll U r, “S ^-

Kterých in which R, R 1 and R 2 are as defined above, and X represents a free or in the form of salts a carboxyl group.

Particularly preferred are those compounds of formula (I) wherein Z is cyano, A is cis-CH = CH- or C = C-, B is a group of formulas

7, -, 7 7 ~ 7

-S-C 1 -N -S-C 1 N-R 1, wherein R, R 1 and R 2 are as defined above, and X represents a free or salt present carboxyl group; in the latter, substituent A-preferably is cis-CH = CH- and substituent B is preferably i / zN

NH

-S-Cxm

AND

CH,

Preferred compounds of formula I are, for example, the following specific compounds:

1.

7 - [[3-cyanethylene (trans] -thio-acetamido] -3 - [(3-methyl-1,2,3,4-tetrazol-5-yl) -methyl] -3-cephem-4-carboxylic acid,

2.

7- (3-cyanethylene) (trans) -thio198382 acid

acetamido] -3 - ((1,3,4-thiadiazol-2-yl) thiomethyl] -3-cephem-4-carboxylic acid,

3.

7- (3-cyanethylene (cis) - (thiO-acetamido) -3 - ((1-methyl-1,2,3,4-tetrazol-5-yl) thiomethyl) -3-cephem-4 -carboxyl,

4.

7- [3'-Cyanethylene (cis) thioacetamido] -3 - ((1S-thiadiazel-2-yl) thiomethyl] -3-cephem-4-carboxylic acid,

5.

7- (β-cyanethylene (cis) thioacetamido] -cephalosporanic acid,

6.

7- (3-carboxamido-ethyl) (trans] -thio-acetamido] -3 - ((1-methyl-1,2,3,4detrazol-5-yl) -thiomethyl] -3-cephem-4-carboxylic acid ,

7. '7- [β-Carboxamido-ethylene (cis β-thib-acetamido) -3- [1-methyl-1,2,3,4-tetrazal-5-yl] -ethyl] -3-cephem-4-yl acid -carboxyl,

8.

7- (kaFboxanndo-ethynylene-thiO)

- a c e t amide o) c e f a 1 osp o r an o o,

9.

7- (carboxamido-ethynylene-thioacetamido) -3- [(1,3,4-thiadiazol-2-yl) thiomethyl] -3-cephem-4-carboxylic acid,

10.

7-carboxamido-ethynylene-thio-acetamido) -3 - {(1-methyl-1,2,3,4-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid,

11.

7- (cyanethinylene-thio-aeetamidocephalosporanic acid),

12.

7- (cyanethinylene-thioacetamido), -3 - ((1,3,4-thiaidiazol-2-yl) thiomethyl] -3-cefeim-4-carboxylic acid,

13.

7- (cyanethinylpn-thio-aceitaimido) -3 - [(1-methyl-1,2,3,4-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid,

14.

7- (cyanethinylene-thioacetamido) -3 - [(1-methyl-1,3,4-triazol-2-yl) thiomethyl] -3-cephem-4-carboxylic acid,

15 Dec

7-i (cyanethinylene-thioacetamido) -3 - [(5-methyl-1,3,4-triazol-2-yl)]. . thiomethyl-3-cephem-4-carboxylic acid, 16.

7- [β-cyanethylene (cis-thio-acetamido) -3 - [(5-methyl-1,3,4-triazol-2-yl) -thienyl] -3-cyano-4-carboxylic acid,

17.

7- [E-cyanethylene (cis) -thioacetamido] -3 - [(1-methyl-1,3,4-triazol-2-yl) -thiomethyl] -3-cephem-4-carboxylic acid,

18.

7- (1,3-cyanethylene (trans) -thio-aceltamido] -3 - [[(1-methyl-1,3,4-triazol-2-yl) thiomethyl] -3-cephem-4-carboxylic acid as well as pharmaceutically and veterinarily acceptable salts, especially alkali salts, preferably sodium and potassium salts of the above acids.

The structural formulas of the above numbered compounds, listed by increasing order numbers, are shown in the following table.

198382

Combination

TABLE

A X

1 NC— —CH — CH— (trans) —COOH N — N CH, w — w 2. NC— —CH = CH— (trans) —COOH II II S-CH 2 CH N, —N 3 NC— —CH = CH— (cis) —COOH Ψ CH, 4 NC— —CH = CH— (cis) —COOH d n — n -s-ci <Jch 5 NC— —CH = CH— (cis) —COOH —Ococh3 6 H ₂ N —CO— —CH = CH— (trans) —COOH N, —N 11 Ί -S-C \, N IN CH * N — N 7 HžN — CO— -CH = CH- (cis) —COOH - $ - (U 7 CH ₃ 8 H2N-CO— —CsC- —COOH —OCOCH3 9 H2N — CO— _c == c— —COOH Does -S-C _s' CH 10 AND H ₂ N —CO— —C = c— —COOH N - N - s - or _N sN CH, 11 NC— —CšC— —COOH —OCOCH3 12 NC— —CsC— —COOH v, -v -S-CH 2 CH 13 NC— —C = c— —COOH N — N “S-cL _n z'n · ^CH 3 14 NC— —CsC— —COOH N - N - S -, CH - ^CH 3 15 Dec NC— -C = C- -COOH vr * -S-C ^ff & CH, H

Combination Z Z X X

46 NC— -GH CH CH ^ (cis) —COOH 'H 47 NC— —GH = CH— (cis) —COOH -SO-CH ₃ CH N N 18 NC— -CH = OH— (trans) —COOH _{Λ Ί} '1 -S-Gya / _CH3  ppdle of the invention compounds of general interest of formula I can produce in that way; se

the compound of formula VIII

wherein Z, A and X are as defined above, or a salt thereof, is reacted with a compound of formula IX

HB, (IX) wherein B is -S-Het, wherein Heit is as defined above, or a reactive derivative thereof, to give compounds of formula I wherein B is -S-Het, wherein Het is as hereinbefore defined and the compound of formula I obtained is optionally converted to a pharmaceutically or veterinarily acceptable salt, or / and optionally a free compound is prepared from a salt, and / or optionally a compound of formula I is converted or another compound of formula I or a salt thereof.

If, in the compounds of formula (VIII), X represents a free carboxyl group, the carboxyl group may optionally be protected in the usual manner before carrying out the reaction.

Suitable protecting groups are those commonly used in peptide synthesis, for example tert-butyl, benzhydryl, p-methoxybenzyl or p-nitrobenzyl. After completion of the reaction, the protecting groups are removed by known methods, for example by acid hydrolysis under mild reaction conditions.

Compounds of formula I containing protecting groups are also included within the scope of this invention.

The reactive derivatives of the compounds of the general formula (IX) are preferably their salts, for example alkali metal or alkaline earth metal salts.

Reacting a compound of formula VIII, or a salt thereof, with a compound of formula IX, or a reactive thereof; the derivative, for example with an alkali salt, is preferably carried out in an inert organic solvent such as ethanol, dimethylformamide, dioxane, acetone, methylene chloride or chloroform; when a salt of a compound of formula (VIII) is used, for example if in the compound of formula (VIII) X is a carboxyl group converted into a salt, preferably water or a water-miscible solvent or a mixture of water with an organic a solvent such as acetone, ethanol, dioxane or tetrahydrofuran. The reaction temperature may range from about 5 ° C to about 70 ° C, and the pH may range from about 5 to about 7.5. If desired, a buffer such as sodium phosphate or sodium acetate may be used. If, in the compound of formula (VIII), X is a carboxyl group in the form of a salt, an alkali metal or alkaline earth metal hydroxide is preferably used to form the salt.

The optional conversion of a compound of formula I into a salt, as well as the optional conversion of a salt into a free compound, can be carried out by conventional methods, i.e. methods already known in organic chemistry.

As mentioned above, a compound of formula I, or a salt thereof, can be converted to another compound of formula I, e.g.

9 θ 3 8 2 or a salt thereof; these possible conversions can also be carried out by conventional means.

Such conversion may be, for example, esterification of a compound of formula I in which X is a carboxyl group. Said esterification may be carried out by reacting a compound of the formula I in which X represents a carboxyl group, either free or in salt form, for example in the form of sodium, potassium, calcium or triethylammonium salt, in an environment an organic solvent, such as acetone, tetrahydrofuran, chloroform, methylene chloride, dimethylmannanide or dimethylsulfoxide, or in a mixture of water and an organic solvent, such as dioxane or acetone, at a reaction temperature in the range of about -20 ° C to about +80 ° C.

The compound of formula (I) in which X represents an esterified carboxyl group can be saponified further, for example by treatment with an inorganic acid such as hydrochloric acid or by treatment with an inorganic base such as sodium or potassium hydroxide by methods well known in organic chemistry.

A compound of formula VIII can be prepared, for example, by reacting 7-amino-cephalosporanic acid, or a salt thereof, with a compound of formula III, using analogous reaction conditions to those used in the reaction of a compound of formula II with a compound of formula

III.

The compounds of formula (IX) may be prepared readily by known methods using known compounds as starting materials or, if appropriate, compounds already described in the literature.

The compounds of formula I possess high anitibukterial activity in animals and humans, both against Gram-positive and Gram-negative bacteria, and can therefore be used to treat infectious diseases caused by said microorganisms, for example to treat respiratory infections such as bronchitis , bronchopneumonia, pleurisy; for the treatment of liver, bile and abdominal infections such as gall bladder inflammation and peritonitis; for the treatment of blood and cardiovascular infections such as blood poisoning; for the treatment of urinary tract infections such as purulent renal inflammation (pyelonephritis) and urinary inflammation. bladder; for the treatment of obstetric and gynecological infections such as cervical inflammation (cervicitis) and cervical inflammation (endometritis), for the treatment of ear, nose and throat infections such as ear inflammation, sinusitis and mumps.

The following table shows the minimum inhibitory concentrations (MIC) in µg / ml of the compounds of the invention designated by codes K 11 457, K 13 031, K 13 101 and K 13 107 against Gram-positive and Gram-negative bacteria, compared to analogous values of known compounds K 9227 and K 10299 (which are the most potent compounds of sweat compounds of British Patent Specification No. 1478 055), Cefazoline and Cefamandol.

Cefamolin Cefamandol K 9227 K 10 299 K 11 457 - K 13 031 K 13 101 K 13 107

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Chemical names in the table of test compounds listed:

Cephaaolin = 7- [1- (1H) -tetrazolylacetamido) -3- [2- (5-ethyl-1,3,3,4-thiadiazolyl) thiomethyl] -3-cephem-4-carboxylic acid,

Cefamandole = 7-D-mandelamido-3 - {[(1-methyl-1H-tetrazol-5-yl) thlo] -methyl-3-cephem-4-carboxylic acid,

K 9227 = 7 - [(cyanomethylthlo) acetamido] -3- (2- (5-methyl-1,3,4-thiadlazolyl) thiomethyl] -3-cephem-4-carboxylic acid,

K 10 299 = 7- ((cyanomethylthio) acetamido] -3- [5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] -3-cephem-4-carboxylic acid,

K 11457 = 7 - [(4-carboxamido-ethylene trans) -thio-acetamido] -3 - [(1-methyl-1,2,3,4-tetrazol-5-yl) thiomethyl] -3-cephen- 4-carboxylic acid,

Κ 13 031 = 7 - [(1'-carboxamido-β-β1 &lt; 1 &gt; -1'-8) -Ιύ1θΒθβΙαιηΙύ'θ] -3- [(1-methyl-1,2,3,4-tetrazol-5-yl) -thiomethyl] -3 -cephene-4-carboxylic acid,

K = 13101 7- _[8-L kyanethylen; (cis) thio-acetamido] -3 - [{1-methyl-l, 2,3,4-tetrazol-5-yl) thiomethyl] -3-cephem ERN -4-carboxylic acid,

K 13 107 = 7- (3-cyanethylene (C1s) -tlo-acetamido) -3 - [(1,3,4-thiadiazol-2-yl) thiomethyl] -3-cephem-4-carboxylic acid.

As can be seen from the table, the compounds of the invention not only show high activity against Gram positive bacteria, but are also surprisingly effective against graimnegative bacteria; therefore, the compounds of formula I are much more useful than the known compounds in the table, since they also treat infectious diseases caused by gram-negative bacteria, such as urinary and respiratory infections.

In particular, the compound K 13101 is about twice as potent as Cefazoline against streptococci (including diplococci) and about 9.6 kills more potent than Cefazoline against gram-negative bacteria. Compound K13101 was further tested against a series of 60 strains of Gram-negative microorganisms including Klebsiella, Escherichia coli, Proteus mirabilis and Proteus vulgaris compared to Cefazoline, and has always been found to be more potent than Cefazoline. Against Haemophylus influenzae (gram-negative bacteria, tested 7 strains), K 13 101 was about 6 times more potent than Cefazoline.

The compounds of formula I may be administered, either to humans or animals, in various dosage forms, for example orally in the form of tablets, capsules, drops or syrups; rectally in the form of suppositories; parenterally, for example intravenously or intramuscularly, in the form of solutions or suspensions, with intravenous administration being preferable in emergencies; by inhalation in the form of aerosols or solutions for use by inhalers; intravaginally in the form, for example, of cones; or locally in the form of solutions, creams and ointments. Pharmaceutical or veterinary preparations containing the compounds of formula (I) may be prepared by conventional methods using conventional carriers and / or diluents commonly used in formulating known cephalosporins. Suitable carriers and diluents are, for example, water, gelatin, lactose, starches, magnesium siteaate, talc, vegetable oils, cellulose and the like.

The compounds of Formula I may be administered to various species in daily dosages ranging from about 1 to about 100 mg per kg body weight; the exact dose will depend on the age, weight and condition of the patient and the frequency and mode of administration. A preferred method of administering the compounds of formula (I) is by parenteral administration; in this case, the compounds may be administered, for example, to adult humans at a dosage ranging from about 100 mg to about 200 mg per dose, preferably at a dose of about 150 µg per dose, 1 to 4 times daily dissolved in a suitable solvent such as sterile water or in a solution of lidocaine hydrochloride by intramuscular administration, or, by intravenous administration, in sterile water, in physiological saline, in glycose solution or in conventional liquids and electrolytes used for the preparation of intravenous injections.

The compounds of formula (I) may further be used as antibacterials in a prophylactic manner, for example in the form of washing or surface disinfectants, for example at a concentration of about 0.2 to 1% by weight of said compounds mixed, suspended or dissolved in conventional inert anhydrous or aqueous carriers; said preparations are applied by washing or spraying.

The compounds of formula I can also be used as nutritional supplements in animal feed.

Determining the melting points of the compounds has been difficult in some cases since the compounds sometimes have the tendency to retain the crystal solvent. In these cases, the abbreviation "decomposition" is given after the melting point.

The infrared (IR) spectra of the compounds were determined in the solid phase on a spectrophotometer

198382 by Perkin-Elmer 125; ultraviolet spectra were usually measured in a solution of substances in phosphate buffer at pH 7.4 on a Bausch-Lomb instrument. Nuclear magnetic resonance spectra (NMR) were determined on a Varian HA-100 spectrometer, in dimethylsulfoxide (DMSO), using tetramethylsilane as an internal standard.

The process according to the invention is illustrated in more detail by the following non-limiting examples. He did

To a solution of 7 - [(3-cyano-ethyl-cis) -thlo-acetamido] -cep alosporanic acid (4.19 gj in acetone (40 mL) and pH 7 phosphate buffer (200 mL) is added 5-mercapto -1-methyl-1,2,3,4-tetrazole (1.3 g) and sodium bicarbonate (1.84 g) and the mixture was stirred at 60 ° C for 6 hours.

After cooling, the reaction solution was overlaid with ethyl acetate and the mixture was acidified to pH 2 with 10% hydrochloric acid. The two-phase system was filtered, the organic layer was separated and the aqueous portion was adjusted to pH 4.5 with 10% ammonia. The solution was shaken with ethyl acetate, the organic extracts were combined, washed with water, dried and the solvent was distilled off to dryness. 7 - [(3'-Cyan-ethyl) (cis-thlo-acetamido] -3 - [(1-methyl-1,2,3,4-tetrazol-5-yl) thiomethyl] -3-cephem- Elemental analysis, UV spectrum, TLC, IR and NMR spectra of the compound thus obtained are identical to the analogous data described for Example 3.

The following compounds were prepared analogously:

Synthesis of 7 _[g 3-cyano neithylen _l (trans) thio-acetamido] -3- [(l-methyl-l, 2,3,4-tetrazol-5-y 1 j thioriiethyl] -3-cephem-4- Carboxylic acid (5.4 g, 60% yield) M.p. 118-120 ° C (dec.

For C15H15N7O4S3 calculated:

% C, 39.80;% H, 3.33;% N, 21.60;% S, 21.20;

% C, 39.83;% H, 3.42;% N, 21.31;

UV spectrum · (in phosphate buffer pH 7.4):

_{Λ mox} = 267 wt, E / * = 411.

TLC fen (FLC):

R _f = 0.55 (in chloroform: methanol: formic acid = 160: 40: 20).

IC spectrum (KBr tablet :) v (C = N), conjugation, 2200 cm -1 ^] , v (C = O), β-lactam, 1775 cm ^-1 , v (C = O), secondary amide, 1670 cm ^-1 .

Nuclear Magnetic Resonance Spectrum, ppm (DMSO-d6):

1.73 (4H, br-s, -SCH 2 -CO and 2-CH 2),

3.94 (3H, s, CH-N),

4.33 (2H, q, 3-CH 2),.

5.11 (1 H, d, 6-H),

5.64 (1H, d, NC - CH =), ‘

5.7 (1H, dd, 7H), _ _{7H 6H} J = 4.5 Hz, • 7.82 (1H, d, = CH-S), J _CH = CH (trans) = 16 Hz,

9.28 (1H, d, -CON-I), J = _7H _nh 8Hz.

7 - [[3-Cyanethylene (trans) -haloacetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl] -3-cephem-4-carboxylic acid in 68% yield, m.p. 100 ° C (dec.

Calcd for C15H13N5O4S4:

% C, 39.54;% H, 2.87;% N, 15.37;% S, 28.15;

H, 2.91; N, 15.25. S. 28.05.

UV spectrum (in phosphate buffer pH 7.4):

A _max = 267 shots, E = 569.8.

TLC: R _t = 0.54 (in chloroform .: methanol / formic acid = 160: 40: 20).

IR spectrum (KBr): v (C = N), conjugation, 2215 cm ^-1 , v (C = O), β-lactam, 1775 cm ^-1 , v (C = O), secondary amide, 1675 cm ^-1 .

7- [β-cyanethylene (cis-thioacetamido) -3 - [(1,3,4-thiadiazol-2-yl) thiomethyl] -3-cephem-4-carboxylic acid, yield 03%, mp 93-98 95 ° C (dec.).

For C15H13N5O4S1 calculated:

% C, 39.54;% H, 2.87;% N, 15.37;% S, 28.15;

% C, 39.33;% H, 2.94;% N, 16.22.

UV spectrum (in phosphate buffer pH 7.4):

Amax = 2.73 nm, E = 504.

TLC: Rf = 0.56 (chloroform: methanol: formic acid = 160: 40: 20).

IR (KBr): v ^(! C = N), conjugation, 2220 cm ^4, v (C = O) / I-lactam 1775 cm ^-1, v (C = O, secondary amide, 1715 cm ^-1 , in (C — N) + δ (N — H), secondary amide,

1540 cm * ¹ .

7 - [[S-Cyanethylene (cis) -thioacetamide ]cephalosporanic acid, yield 70%, m.p. 132-134 ° C (dec.

188382

For C15H15N3O6S2 calculated:

45.32% C, 3.80 θ / ο H, 10.57% N, 16.13% S, found:

% C, 45.15;% H, 3.93;% N, 10.33.

7- (β-carboxamido-ethylene, (tran; -tlo-acetamido) -3 - ((1-methyl-1,2,3,4-tetrazol-5-yl) thiomethyl) -3-cephem-4-carboxylic acid ( 1.18 g, yield of 50 ° / o), mp 146 to 150 ^q C (dec.).

For C15H17N7O5S3 calculated:

38.20 θ / o C, 3.63 θ / ο H, 20.79 θ / ο N, 20.4% S, found:

38.44 ° C, 3.71% H, 20.68% N, 20.03% S.

UV spectrum (in phosphate buffer opH7,4):

Λ _max = 270 nm, λ = 471.

TLC: Rf = 0.35 (chloroform: methanol: formic acid = 160: 20: 20).

IR (KBr): ν (C = O), β-lactam, 1780 cm ^-1 , v (C = O), acid, 1670 cm ^-1 , υ (C — N), + δ (N — H) ), secondary amide, 1560 cm ^-1 .

7- [β-Carboxamido-ethylene (cis) -thio-acetamido] -3 - ((1-methyl-1,2,3,4-tetrahydro-5-yl) thiomethyl] -3-cephem-4 -carboxylic acid, yield 65%, mp 150 ° C (dec.).

For C 15 H 17 N 7 O 5 S 3 calculated:

38.20% C, 3.63% H, 20.79% N, 20.40% S, found:

% C, 38.36;% H, 3.72;% N, 20.43.

UV spectrum (in phosphate buffer opH7,4):

Λ _max = 277 nm, λ = 409.

TLC: Rf = 0.30 (chloroform: methanol: formic acid = 160: 40: 20).

IR (KBr): v (C = O), β-lactam, 1775 cm ^-1 , v (C = O), conjugated amide, 1650 cm ^-1 , v (C-N) + δ (N-H) , secondary amide,

1540 cm ^-1 .

7- (carboxamido-ethynylene-thio-acetamido) -3 - ((1-methyl-1,2,3,4-tetrazol-5-yl) thiomethyl) -3-cephem-4-carboxylic acid (47% yield) , the structure of said acid was confirmed by IR and NMR spectra, 7- (carboxamido-ethinylene-thio-acetamido) cephalosporanic acid, 7- (carboxamido-ethinylene-thio-acetamido) -3- ((1,3,4-thiadiazole) -2-yl) thlomethyl] -3-cephem-4-carboxylic acid 7- (cyano-ethmylene-thioacetamido) -3 - ({1-methyl-1,2,3,4-tetrazol-5-y) 1) thlomethyl) -3-cephem-4-carboxylic acid structure was confirmed by elemental analysis, IR and NMR spectra, 7- (cyano-ethinylene-thl-acetamido) cephalosporanic acid, 7-cyano-ethinylene-thio-acetamido) -3 - ((1,3,4-phiadiazol-2-yl) thiomethyl] -3-cephem-4-carboxylic acid 7- (cyano-ethynylene-thio-acetamido) -3 - ((1-methyl-1, 2-methyl-2-carboxylic acid) 3 ', 4-triazol-2-yl) thlomethyl] -3-methyl-4-carboxylic acid 7- (cyano-ethynylene-thioacetamido) -3 - [(5-methyl-1,3,4- triazol-2-yl) thiomethyl) -3-cephem-4-carboxyl 7- (18-cyano-ethylene (cis) -thio-acetamido) -3 - ((1-methyl-1,3,4-triazol-2-yl) thiomethyl] -3-cephem-4- carboxylic acid (2.5 g, 55% yield) mp 125-130 ° C (dec.).

Calcd for C16H16N6O4S3:

42.50% C, 3.56% H, 18.60% N, 21.20% S,

TI 31 θ Z 8Π O *

% C, 42.77;% H, 3.96;% N, 16.27;

UV spectrum (in phosphate buffer pH 7.4): _λmax = 267 nm, E = 458.

TLC: Rf = 0.32 (chloroform: methanol: formic acid = 160: 40: 20).

IR spectrum (KBr): v (C =), conjugation, 2215 cm ^-1 , v (C = 0), β-lactam, 1775 cm ^-1 , v (<C = O), secondary amide, 1675 cm -1 ¹ .

7- (O-cyano-ethylene (trans) -thloacetamido] -3 - [(1-methyl-1,3,4-triazol-2-yl) thiomethyl-3-carboxylic acid-4-carboxylic acid, m.p. 127-131 ° C (dec.).

For C1 & H6N6O4S3 calculated:

42.50% C, 3.56% H, 18.60% N, 21.20% S, found:

H, 3.67; N, 18.33; S, 20.73.

198382

UV spectrum (in phosphate buffer pH 7.4): _λmax = 267 nm, E = 444.

TLC: Rf = 0.28 (chloroform: methanol: formic acid = 160: 40: 20).

IC epectrum (KBr): v (CeN), conjugation, 2215 omr ¹ , v (C = O), (Makitam, 1775 cm ^-1 , v) C = O), secondary amide, 1675 cm ^-1 .

N - (β-Cyano-ethylene (cis) -thi-acetamido] -3 - ({5-methyl-1,3,4-triazol-2-yl) thiomethyl] -3-cephem-4-carboxylic acid ové.

For CwHisNeO iSs calculated:

% C, 42.50;% H, 3.56;% N, 18.60;% S, 21.20;

% C, 42.63;% H, 3.73;% N, 18.40.

7- [β-Cyano-ethylene (trans) -thioacetamido] -3 - [(1-methyl-1,2,3,4-tetraazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid (2.3 g) mp 118-120%: (dec.).

The elemental analysis, UV spectrum, TLC and IC and NMR spectra of the compound are identical to those of the compound described in the introduction of the analogously prepared compounds, 7- [[3-, cyano-ethylene (cis) -thio-acetamido] -3- (( 1-methyl: 1,2,3,4-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, mp 113-115% (dec.); elemental analysis, UV spectrum, TLC, and IC and NMR spectra of the compound thus obtained are identical to the analogous data of the compound described previously.

Claims (4)

Process for the preparation of unsaturated 7-acyladimo-3-cephem-4-carboxylic acid derivatives of the general formula I Z-A-S-CH-C-NH & X (I) wherein Z is cyano or carbamoyl, A is trans-CH = CH-, cis-CH = CH- or -G = IC-, B represents a group of the formula —O — C — CH3 or —S — Het, wherein Het represents a group of the formula N — N / ý —- N -c ^ ck-c ^ A » R 'in which R represents a hydrogen atom or methyl or Het represents a group of the formula -COCO in which M represents a group -CH-O-C-Ra Rs O or —CH — Q — C — O — Rs, R O wherein the IRS is hydrogen or C1 «alkyl, Q is an oxygen atom or -NH-, R is Cl.« Alkyl or basic group, in particular C ₆ alkyl or C ₆ · - »arylC ₁ _ ₆ alkyl, substituted with at least one amino group which is optionally substituted, for example R a is C - _O -alkyl-NH-CH3, C KarylCt alkyl-NH-CH, C ₆ -alkyl _ i | Wherein R 1 and R 2 are independently selected from the group consisting of hydrogen or methyl and X represents a free carbonyl group or an esterified carboxyl group or -CH 2 -NH 2, R 5 represents C 1-6 alkyl, C 6-14 aryl C ₄ _ ₈ cycloalkyl, beteromonocyklický ring such as pyrldyl, heterobicyclic ring, such as · indanyl, or C _6-8 aryl-C ₆ alkyl, such as benzyl, and the pharmaceutically or · veterinarily acceptable salts of the compounds of formula I, wherein the substituent X is a free carboxyl group, characterized in that the compound of formula VIII 188382 wherein Z, A and X are as defined above, or a salt thereof, reacts with a compound of formula IX Η — B (IX) wherein B represents a group of the formula —S — Het: wherein Het is as defined above, or with a reactive derivative thereof, to give compounds of formula I wherein B represents a group of the formula —S— Het, in which Het is as defined above, and ^{CW 10} ° ^CW 3 The O (VIII) obtained compound of formula I is optionally converted into a pharmaceutically or veterinarily acceptable salt, and / or optionally a free compound is prepared from a salt, or / and optionally, a compound of formula I or a salt thereof is converted into another compound of formula I or her salt. 2. The process of item 1, for the preparation of unsaturated 7-acylamido-3cephem-4-carboxylic acid derivatives of the above formula I, wherein B is a radical of the formula 7-7 7 “7 -S-C- .- CH, -S-cL.ZV o γ R -S-C '- ^' CR ₁ AND R. wherein R, R 1 and R 2 are as defined above, X is a free or carboxyl group present in the form of a salt and Z and A are as defined above, characterized in that the compound of the above formula VIII wherein A, X and Z are as defined above, or a salt thereof, with a compound of the above formula (IX) wherein B is a radical at this point of the formula, or a reactive derivative thereof, and the resulting compound of formula (I) is optionally converted to a pharmaceutically or veterinarily acceptable salt, and / or optionally forming a free compound from a salt, and / or optionally converting a compound of formula I or a salt thereof into another compound of formula I or a salt thereof. 3. The process according to item 1, for the preparation of unsaturated 7-acylamido-3-cephem-4-carboxylic acid derivatives of the above general formula I, wherein Z is cyano, A is cis-CH = CH- or -C = C- , B is a radical of formula N - N cr ¹ '- - - - w, e, bo N — N II | wherein R, R 1 and R 2 are as defined above, and X is a free or salt present carboxyl group, characterized in that the compound of formula (VIII) above wherein A, X and Z are at this point, or a salt thereof, is reacted with a compound of the above formula (IX), wherein B is as defined herein, or a reactive derivative thereof, and the resulting compound of the above formula (I) is optionally converted to and / or optionally converting a free compound from a salt, and / or optionally converting a compound of Formula I or a salt thereof into another compound of Formula I or a salt thereof. 4. The process of item 1, for the preparation of unsaturated 7-acylamido-3-per-4-carboxylic acid derivatives of the above general formula (I), wherein B is a group of the formula ^{CH 1} and A, Z and X are as defined above, characterized in that the compound of the above general formula (VIII), wherein A, X and Z are as defined above, or a salt thereof, is reacted with a compound of the above of formula (IX) wherein B is a group or a reactive derivative thereof and the compound of formula (I) is optionally converted to a pharmaceutically or veterinarily acceptable salt, and / or optionally a free compound is prepared from a salt, and / or optionally converting a compound of formula I or a salt thereof into another compound of formula I or a salt thereof.