DE2527291C2 - - Google Patents

Description

The invention relates to cephalosporins of the general formula

wherein
R 2-amino-2- (p-hydroxyphenyl) acetyl, 2-thienyl acetyl, α -hydroxyphenylacetyl or α- aminophenylacetyl and
Y represents a non-aromatic pyrimidonyl, pyridazonyl or triazonyl radical which is substituted on at least one of the nitrogen atoms and optionally on a carbon atom, lower alkyl, lower alkenyl, lower alkoxy, lower alkoxy-lower alkyl, amino or di- as substituent of a ring nitrogen atom. lower alkylamino and lower alkyl can be considered as a substituent of a ring carbon atom,
and salts of these compounds and hydrates of these salts.

Examples of salts of the compounds of formula I are Alkali metal salts such as the sodium and potassium salt; the Ammonium salt; Alkaline earth metal salts such as the calcium salt; Salts with organic bases, such as amines, e.g. B. N-ethyl piperidine, Procaine, dibenzylamine, N, N′-dibenzylethyl-ethylenediamine, Alkylamines or dialkylamines, and salts with amino acids, such as B. arginine or lysine.

Which is a free basic group, e.g. B. an amino group, containing compounds of formula I form addition salts with organic or inorganic acids. Examples of such Salts are hydrohalides, for example hydrochlorides, Hydrobromides, hydroiodides and other mineral acid salts, such as Sulfates, nitrates, phosphates and the like, alkyl and mono-aryl sulfonates, such as ethanesulfonates, toluenesulfonates, benzenesulfonates and the like. and also other organic acid salts, such as Acetates, tartrates, maleates, citrates, benzoates, salicylates, Ascorbates and the like

The salts of the compounds of formula I can be hydrated be. The hydration can take place during the manufacturing process occur or gradually as a result of hygroscopic Properties of an initially anhydrous salt of a compound Formula I occur.

Compounds of formula I are those in which the radical Y is a non-aromatic, N-substituted and optionally on one or more Carbon atoms substituted pyrimidonyl, pyridazonyl or triazonyl radical.

As examples of such compounds, those in which Y
a 2-oxopyrimidin-4-yl residue, e.g. B. the 1-amino, 1-ethyl or 1-butoxy-1,2-dihydro-2-oxopyrimidin-4-yl radical or the 1-butoxy-1,2-dihydro-5-methyl-2-oxopyrimidin-4 -yl residue;
a 4-oxopyrimidin-2-yl residue, e.g. B. the 1-ethyl-1,4-dihydro-6-methyl-4-oxopyrimidin-2-yl radical or the 1,4-dimethyl-1,6-dihydro-6-oxopyrimidin-2-yl radical;
a 2,6-dioxopyrimidin-4-yl radical;
a 3-oxopyridazin-6-yl radical;
a 3-oxopyridazin-4-yl radical;
a 5,6-dioxo-as-triazin-3-yl residue, e.g. B. the 4-ethyl, 4-methyl, 4-allyl, 4-butyl, 4- (2-methoxyethyl) -, 1,4-dimethyl or 1,4-diethyl-1,4,5 , 6-tetrahydro-5,6-dioxo-as-triazin-3-yl residue or the 1,2,5,6-tetrahydro-1-ethyl-5,6-dioxo-as-triazin-3-yl residue;
a 2-oxotriazin-4-yl radical; or
a 2,4-dioxotriazin-6-yl residue
represents.

Come as a substituent of a ring nitrogen atom lower alkyl, lower alkenyl, lower alkoxy-lower alkyl, lower alkoxy, amino, di-lower alkylamino, in question, and as a substituent of a ring carbon atom is coming lower alkyl in question.  

The abovementioned lower alkyl, alkenyl and alkoxy radicals contain up to 6 carbon atoms.
Examples of such alkyl radicals are methyl, ethyl.
Examples of such alkylene radicals are vinyl, allyl.
Examples of such alkoxy radicals are methoxy, ethoxy.

The following can be mentioned as particularly preferred compounds of the formula I:
(7R) -3 - / <(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) thio <methyl / -7- <2- (2nd -thienyl) -acetamido <3-cephem-4-carboxylic acid,
(7R) -3 - / <(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl) -thio <methyl / -7- <2- (2nd -thienyl) -acetamido <-3-cephem-4-carboxylic acid,
(7R) -3 - / <(1,4,5,6-tetrahydro-4-allyl-5,6-dioxo-as-triazin-3-yl) -thio <methyl / -7- <2- (2nd -thienyl) -acetamido <-3-cephem-4-carboxylic acid,
(7R) -3 - / <(1,4,5,6-tetrahydro-4-butyl-5,6-dioxo-as-triazin-3-yl) thio <methyl / -7- <2- (2nd -thienyl) -acetamido <-3-cephem-4-carboxylic acid,
(7R) -3 - / <(1,4,5,6-tetrahydro-4- (2-methoxyethyl) -5,6-dioxo-as-triazin-3-yl) thio <methyl / -7- < 2- (2-thienyl) acetamido <- 3-cephem-4-carboxylic acid,
(7R) -3 - / <(1,4,5,6-tetrahydro-1,4-dimethyl-5,6-dioxo-as-triazin-3-yl) -thio <methyl / -7- <2- (2-thienyl) acetamido <-3-cephem-4-carboxylic acid,
(7R) -3 - / <(1,4,5,6-tetrahydro-1,4-diethyl-5,6-dioxo-as-triazin-3-yl) -thio <methyl / -7- <2- (2-thienyl) acetamido <-3-cephem-4-carboxylic acid,
(7R) -3 - / <(1,2,5,6-tetrahydro-1-ethyl-5,6-dioxo-as-triazin-3-yl) thio <methyl / -7- <2- (2nd -thienyl) -acetamido <-3-cephem-4-carboxylic acid,
(7R) -3 - / <(1-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl) - thio <methyl / -7- <2- (2-thienyl) acetamido <-3-cephem -4-carboxylic acid,
(7R) -3 - / <(1-butoxy-1,2-dihydro-2-oxo-4-pyrimidinyl) thio <methyl / -7- <2- (2-thienyl) acetamido <-3-cephem -4-carboxylic acid,
(7R) -3 - / <(1-butoxy-1,2-dihydro-5-methyl-2-oxo-4-pyrimidinyl) thio <methyl / -7- <2- (2-thienyl) acetamido < -3-cephem-4-carboxylic acid,
(7R) -3 - / <(1,4-dimethyl-1,6-dihydro-6-oxopyrimidinyl) - thio <methyl / -7- <2- (2-thienyl) acetamido <-3-cephem -4-carboxylic acid,
(7R) -3 - / <(1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl) -thio <-methyl / -7- <2- (2-thienyl) -acetamido <-3- cephem-4-carboxylic acid,
(7R) -3 - / <(1-ethyl-1,4-dihydro-6-methyl-4-oxo-2-pyrimidinyl) - thio <methyl / -7- <2- (2-thienyl) acetamido < -3-cephem-4-carboxylic acid,
(7R) -3 - / <(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) -thio <methyl / -7 - <(R) - mandelamido <-3-cephem-4-carboxylic acid,
(7R) -7 - <(R) -2-amino-2-phenylacetamido <-3 - / <(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazine-3 -yl) -thio <methyl / -3-cephem-4-carboxylic acid,
and their salts.

The compounds of formula I can be optically pure Isomers and are present as mixtures of isomers.

The compounds of formula I and their salts can in are produced in a manner known per se by

• a) a compound of the general formula X'-W ₁ (II) wherein
  X 'one of the compound I corresponding deacetoxy-cephalosporinylrest, the carboxyl radical in position 4 is protected by salt formation with an inorganic or tertiary organic base and
  W _{1 represents} a common leaving group,
  with a compound of the general formula H-SY (III) wherein
  Y has the above meaning, implements and splits off the protective group, or
• b) a compound of the general formula X ′ ′ - SY (IV) wherein
  Y has the above meaning and
  X '' represents a compound I corresponding 7-amino-desacetoxy-cephalosporanylrest, the carboxyl radical of which is present in position 4 in protected form
  with an acid of the formula R-OH (V) wherein
  R has the above meaning or reacts with a reactive functional derivative thereof, splits off the protective group and, if desired, converts the reaction product into a salt.

Protection of the carboxyl radical in the radical X ′ ′ a compound of formula IV can e.g. B. by Conversion into an easily removable ester, for example the benzyl ester or a silylester, e.g. B. the trimethylsilyl ester, or by salt formation with an inorganic or tertiary organic base such as triethylamine.  

As leaving groups W₁ a compound of formula II come, for example, halogens, e.g. B. chlorine, bromine or iodine, Acyloxy radicals, e.g. B. lower alkanoyloxy radicals, such as acetoxy, lower alkyl or arylsulfonyloxy, such as mesyloxy or Tosyloxy or the Azidorest in question.

The reaction of a compound of formula II with a Compound of the formula III can be prepared in a manner known per se, e.g. B. at a temperature between about 40 and 80 ° C, appropriate at about 60 ° C, in a polar solvent, for example an alcohol such as B. a lower alkanol, such as ethanol, Propanol and the like, dimethylformamide, dimethyl sulfoxide, preferably in water or a buffer solution with a pH of about 6 to 7, preferably 6.5, for a period of about 3 to 8, preferably 6 hours.

As reactive functional derivatives of acids the formula V come z. B. Halide, d. H. Chlorides, bromides and Fluorides; Azides; Anhydrides, especially mixed anhydrides with stronger acids; reactive esters, e.g. B. N-hydroxy-succinimide ester, and amides, e.g. B. imidazolides.

The reaction of a compound of formula IV with a Acid of formula V or a reactive functional Derivative thereof can be carried out in a manner known per se will. So you can z. B. with a free acid of formula V. one of the mentioned esters of formula IV using a carbodiimide, such as dicyclohexylcarbodiimide, in an inert solvent, such as ethyl acetate, acetonitrile, dioxane, chloroform, Condense methylene chloride, benzene or dimethylformamide and then split off the ester group. Instead of carbodiimides Oxazolium salts can also be used as condensing agents, e.g. B. Use N-ethyl-5-phenyl-isooxazolium-3'-sulfonate.  

In another embodiment, a salt is used Acid of formula IV, e.g. B. a trialkylammonium salt with a reactive functional derivative of an acid of formula V as mentioned above in an inert, e.g. B. one of the above Solvent to.

The reaction of a compound of formula IV with a Compound of formula V or a reactive functional Derivative thereof can be useful at temperatures between about + 5 ° C and -40 ° C, for example at about 0 ° C, take place.

After the implementation of a compound of formula II or IV with a compound of formula III or V is the Protective group split off. If the protecting group is a benzyl group represents (benzyl ester), this can be catalytic Hydrogenation are split off, e.g. B. by means of a noble metal catalyst, e.g. B. Palladium-carbon. If the protecting group is one Represents silyl group (silylester), this group can in particular easily split off by treating the reaction product with water will. Finally, when the carboxyl group is one Acid of formula IV by salt formation (e.g. with triethylamine) is protected, the elimination of these salt-forming Protection group by treatment with acid at a relatively low level Temperature, e.g. B. at about 0 ° C to about 10 ° C. As Acid can z. B. hydrochloric acid, sulfuric acid, phosphoric acid or citric acid can be used.

The compounds of formula II are known and can in a manner known per se, starting from the corresponding Cephalosporins, i.e. H. of compounds of the general formula

X'-O-CO-CH₃

where X ′ has the above meaning getting produced.

As examples of compounds of formula II, the Alkali metal salts, e.g. B. the sodium salt of cephalothin, Cephacetril, (7R) -mandelamido-cephalosporanic acid and 7- (3-sydnonacetamido) cephalosporanic acid and the zwitterion is called cephaloglycin.

Some of the compounds of the formula III are new, partly known. The new compounds of formula III can in an analogous manner to the preparation of the known compounds getting produced.

In the same way, a 1,3-disubstituted 2,6- Dioxo-1,2,3,6-tetrahydro-4-mercaptopyrimidine starting from that corresponding 4-chloro-2,6-dioxo-1,2,3,6-tetrahydropyrimidine getting produced.

The 5,6-dioxo-3-mercapto-as-triazines can be obtained from the correspondingly substituted thiosemicarbazides in analogy for the synthesis of 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3- mercapto-as-triazins, cf. PhD thesis by K. H. Ongania (Innsbruck 1972).  

A thiol of formula III, which has a double bond between the carbon atom substituted by the mercapto residue and contains an adjacent nitrogen atom are in the form of the tautomeric thioketone.

A compound of formula IV can by reacting a Compound of the general formula

X ′ ′ - W₁

where X '' and W₁ have the above meaning, be prepared with a compound of formula III. The Implementation can be done under the same conditions as that a compound of formula II with a compound of Formula III are made.

The compounds of formula V and the reactive Functional derivatives thereof are known or analogs too known compounds and can in a conventional manner getting produced.

The compounds of formula V which have an asymmetric carbon atom are normally obtained in the form of racemic mixtures. Such racemates can be separated into the optically active isomers by known methods. For example, diastereomers can be formed from the racemic mixture with an optically active cleaving agent, such as an optically active base, such as. B. α , α - (1-naphthyl) ethylamine or α- methylbenzylamine, which can react with the carboxyl group. The diastereomers formed are separated by selective crystallization and then converted into the corresponding optical isomers.

A compound of formula I in D-form can be made that either connect the Formula I, which is in the form of a mixture of isomers, in in a known manner, for example by fractional Crystallization of a salt, such as. B. the calcium salt and isolate the desired D-form or that one Compound of formula III or IV with a D-form present compound of formula II or V or one reactive functional derivative of such a compound of formula V, the latter method is preferred.

The compounds of formula I, their salts and the Hydrates of these salts are antibiotic, especially bactericidal effective. They have a broad spectrum of activity against gram-positive and gram-negative microorganisms, in particular against penicillinase-positive staphylococci as well as various Cephalosporinase-positive gram-negative bacteria, such as. B. Escherichia coli, Proteus, Klebsiella, Aerobacter and Serratia species.

The compounds of formula I and those pharmaceutical usable salts and hydrated forms thereof can be used for Treatment and prophylaxis of infectious diseases as well can be used as a disinfectant. For the Adults receive a daily dose of approx. 1 g to approx. 4 g into consideration. The parenteral administration of the invention Connections is particularly preferred.

Pharmaceutical preparations, preferably dry ampoules, can the compounds of formula I, their salts or hydrated Form these salts, possibly in a mixture with one contain other therapeutically valuable substance.  

example 1 Preparation of the sodium salt of (7R) -3 - / <(1,4,5,6- Tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) -thio <methyl / -7- <2- (2-thienyl) acetamido <-3-cephem-4-carboxylic acid

4.4 g cephalothin sodium salt

are in 100 ml of water with 2.25 g of 1,4,5,6-tetrahydro 4-ethyl-5,6-dioxo-3-mercapto-as-triazine and 1.05 g sodium hydrogen carbonate 6 hours at 60 ° C and pH about 6.5 with nitrogen fumigation touched. The reaction mixture is then at 10 ° C. cooled and adjusted to pH 2 with 2N hydrochloric acid. The one there Any substance that has been noticed is filtered off with suction and 25 ml of ice water washed. Then this is dissolved in acetone and the solution evaporated in vacuo. The remaining residue is in Dimethylformamide dissolved and the solution with 7.5 ml of a 2N Solution of the sodium salt of 2-ethyl-caproic acid in ethyl acetate transferred. When diluted with ethyl acetate, the desired one crystallizes Substance out. This is sucked off, one after the other washed with ethyl acetate, ether and petroleum ether and in Vacuum dried, yield 4.5 g (80%). Mp <170 ° C (dec.).

The 1,4,5,6-tetrahydro- 4-ethyl-5,6-dioxo-3-mercapto-as-triazine can be prepared as follows will:

120 g of 4-ethylthiosemicarbazide are in the presence of 23 g of sodium in 1 liter of methanol for 4 hours with 116 g of dimethyl oxalate implemented at the boiling point of the reaction mixture. The triazine is in the form of the sodium salt from the reaction mixture isolated and then by acidifying an aqueous Solution obtained, mp. 189-190 ° C.  

Example 2 Preparation of the sodium salt of (7R) -3 - / <(1,4,5,6- Tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl) -thio <methyl / -7- <2- (2-thienyl) acetamido <-3-cephem-4-carboxylic acid

This compound is analogous to Example 1 from 4.18 g Cephalothin sodium salt and 1.91 g 1,4,5,6-tetrahydro-4-methyl 5,6-dioxo-3-mercapto-as-triazine produced, yield 2.8 g (54.1%). Mp 200-205 ° C (dec.).

The triazine used in the above process becomes analog Example 1 from 176 g of 4-methylthiosemicarbazide and 198 g Oxalic acid dimethyl ester produced. M.p. 218-220 ° C (dec.).

Example 3 Preparation of the sodium salt of (7R) -3 - / <(1,4,5,6- Tetrahydro-4-allyl-5,6-dioxo-as-triazin-3-yl) -thio <methyl / -7- <2- (2-thienyl) acetamido <-3-cephem-4-carboxylic acid

This compound is analogous to Example 1 from 6.27 g Cephalothin sodium salt and 3.33 g 1,4,5,6-tetrahydro-4-allyl- 5,6-dioxo-3-mercapto-as-triazine. Yield 3.0 g (36.8%). Mp <180 ° C (dec.).

The triazine used in the above process becomes analog Example 1 starting from 26.2 g of 4-allylthiosemicarbazid and 23.6 g of dimethyl oxalate prepared. M.p. 138-140 ° C.  

Example 4 Preparation of the sodium salt of (7R) -3 - / <(1,4,5,6- Tetrahydro-4-butyl-5,6-dioxo-as-triazin-3-yl) -thio <methyl / -7- <2- (2-thienyl) acetamido <-3-cephem-4-carboxylic acid

This compound is analogous to Example 1 from 6.27 g Cephalothin sodium salt and 3.62 g 1,4,5,6-tetrahydro-4-butyl 5,6-dioxo-3-mercapto-as-triazine. Yield 3.0 g (35.7%). Mp <160 ° C (dec.).

The triazine used in the above process becomes analog Example 1 from 14.7 g of 4-butylthiosemicarbazide and 11.8 g Oxalic acid dimethyl ester produced. Mp 180-181 ° C.

Example 5 Preparation of the sodium salt of (7R) -3 - / <(1,4,5,6- Tetrahydro-4- (2-methoxyethyl) -5,6-dioxo-as-triazin-3-yl) -thio <- methyl / -7- <2- (2-thienyl) acetamido <-3-cephem-4-carboxylic acid

This compound is analogous to Example 1 from 6.27 g Cephalothin sodium salt and 3.65 g 1,4,5,6-tetrahydro-4- (2- methoxyethyl-5,6-dioxo-3-mercapto-as-triazine. Yield 2.0 g (23.8%).

The triazine used in the above process becomes analog Example 1 from 14.9 g of 4- (2-methoxyethyl) thiosemicarbicide and 11.8 g of dimethyl oxalate prepared. M.p. 158-160 ° C.  

Example 6 Preparation of the sodium salt of (7R) -3 - / <(1,4,5,6- Tetrahydro-1,4-dimethyl-5,6-dioxo-as-triazin-3-yl) -thio <methyl / - 7- <2- (2-thienyl) acetamido <-3-cephem-4-carboxylic acid

This compound is analogous to Example 1 from 6.27 g Cephalothin sodium salt and 2.6 g 1,4,5,6-tetrahydro-1,4- Dimethyl-5,6-dioxo-3-mercapto-as-triazine prepared, yield 4.6 g (58.0%).

The triazine used in the above process becomes analog Example 1 from 11.9 g of 1,4-dimethylthiosemicarbazide and 11.8 g Oxalic acid dimethyl ester produced. Mp 231-233 ° C (dec.).

Example 7 Preparation of the sodium salt of (7R) -3 - / <(1,4,5,6- Tetrahydro-1,4-diethyl-5,6-dioxo-as-triazin-3-yl) -thio <methyl / - 7- <2- (2-thienyl) acetamido <-3-cephem-4-carboxylic acid

This compound is analogous to Example 1 from 6.27 g Cephalothin sodium salt and 2.01 g 1,4,5,6-tetrahydro-1,4- diethyl-5,6-dioxo-3-mercapto-as-triazine prepared, yield 5.5 g (65.7%). Mp <175 ° C (dec.).

The triazine used in the above process becomes analog Example 1 from 14.7 g of 1,4-diethylthiosemicarbazide and 11.8 g Oxalic acid dimethyl ester produced. Mp 177-179 ° C.  

Example 8 Preparation of the sodium salt of (7R) -3 - / <(1,2,5,6- Tetrahydro-1-ethyl-5,6-dioxo-as-triazin-3-yl) -thio <methyl / -7- <2- (2-thienyl) acetamido <-3-cephem-4-carboxylic acid

This compound is analogous to Example 1 from 10.45 g Cephalothin sodium salt and 4.8 g 1,2,5,6-tetrahydro-1-ethyl 5,6-dioxo-3-mercapto-as-triazine prepared, yield 7.0 g (52.6%). Mp 210-215 ° C (dec.).

The triazine used in the above process can be as are produced as follows:

46.5 g of 1-ethylthiosemicarbazide are dissolved in 700 ml of acetone reacted at 40 ° C with 48 g of monomethyl oxalate. 34.3 g of the product obtained are mixed with 9.2 g of sodium methylate added in 300 ml of methanol. The triazine comes in the form of the sodium salt isolated from the reaction mixture and then by Acidify an aqueous solution obtained, mp. 213-214 ° C (dec.).  

Example 9 Preparation of the sodium salt of (7R) -3 - / <(1-ethyl-1,2- dihydro-2-oxo-4-pyrimidinyl) thio <methyl / -7- <2- (2-thienyl) - acetamido <-3-cephem-4-carboxylic acid

This compound is analogous to Example 1 from 4.18 g Cephalothin sodium salt and 1.8 g of 1-ethyl-1,2-dihydro-4- Mercapto-2-oxopyrimidine prepared, yield 3.2 g (65.3%). Mp <190 ° C (dec.).

Example 10 Preparation of the sodium salt of (7R) -3 - / <(1-butoxy-1,2- dihydro-2-oxo-4-pyrimidinyl) thio <methyl / -7- <2- (2-thienyl) - acetamido <-3-cephem-4-carboxylic acid

This compound is analogous to Example 1 from 4.18 g Cephalothin sodium salt and 2.2 g 1-butoxy-1,2-dihydro-4- Mercapto-2-oxopyrimidine prepared, yield 3.8 g (70%).

The triazine used in the above process is made from 2 g of 1-butoxyuracil and 4 g of phosphorus pentasulfide were prepared. Mp 99-100 ° C.

Example 11 Preparation of the sodium salt of (7R) -3 - / <(1-butoxy- 1,2-dihydro-5-methyl-2-oxo-4-pyrimidinyl) thio <methyl / -7- <2- (2- thienyl) acetamido <-3-cephem-4-carboxylic acid

This compound is analogous to Example 1 from 6.0 g Cephalothin sodium salt and 3.36 g of 1-butoxy-1,2-dihydro-4-  mercapto-5-methyl-2-oxopyrimidine. Yield 0.8 g (9.7%). Mp <170 ° C (dec.).

The triazine used in the above process can be prepared analogously to Example 11 by reacting 25 g of 1-butoxy-5-methyl-uracil with 50 g of phosphorus pentasulfide. The 1-butoxy-5-methyl-uracil is prepared by reacting 110 g of butoxyurea with 184 g of β , b -diethoxy- α- methylpropionic acid ester.

Example 12 Preparation of the sodium salt of (7R) -3 - / <(1,4-dimethyl- 1,6-dihydro-6-oxo-2-pyrimidinyl) thio <methyl / -7- <2- (2-thienyl) - acetamido <-3-cephem-4-carboxylic acid

This compound is analogous to Example 1 from 4.18 g Cephalothin sodium salt and 1.8 g 1,4-dimethyl-1,6-dihydro-2- mercapto-6-oxo-pyrimidine. Yield 1.35 g (26.3%). Mp 200-210 ° C (dec.).

Example 13 Preparation of the sodium salt of (7R) -3 - / <(1-ethyl-1,4- dihydro-6-methyl-4-oxo-2-pyrimidinyl) thio <methyl / -7- <2- (2- thienyl) acetamido <-3-cephem-4-carboxylic acid

This compound is analogous to Example 1 from 6.27 g Cephalothin sodium salt and 2.98 g of 1-ethyl-1,4-dihydro-2- mercapto-6-methyl-4-oxopyrimidine. Yield 3.2 g (40.4%). Mp <170 ° C (dec.).

The pyrimidine used in the above process can be as are produced as follows:  

18 g of N-ethylthiourea are dissolved in 50 ml of acetic acid dissolved, boiled at reflux and dropwise with 17.2 g of diketene transferred. Then it is refluxed for 20 minutes and then evaporated to 50 ml. With cooling and stirring is mixed with 50 ml of water. The yellowish crystals are cancelled. They are sucked off and made of tetrahydrofuran recrystallized. Mp 190 ° C.

Example 14 Preparation of the sodium salt of (7R) -3 - / <(1,4,5,6- Tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) -thio <methyl / -7- <(R) -mandelamido <-3-cephem-4-carboxylic acid

This compound is analogous to Example 1 from 8.0 g of the sodium salt of (7R) -mandelamido-cephalosporanic acid and 3.72 g of 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-mercapto-as- triazine. Yield 1.7 g (16.8%).

Example 15 Preparation of (7R) -7 - <(R) -2-amino-2-phenylacetamido <-3- / <1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) -thio <- methyl / -3-cephem-4-carboxylic acid

This compound is made from 8.1 g analogously to Example 1 Cephaloglycine and 3.78 g 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo- 3-mercapto-as-triazine produced and isolated as a zwitterion. Yield 4.19 g (40.5%) mp. <180 ° C (dec.).

Example 16 Preparation of the sodium salt of (7R) -3 - / <(1-amino-1,2- dihydro-2-oxo-4-pyrimidinyl) -thio <methyl / -7- <2- (2-thienyl) -acetamido - <- 3-cephem-4-carboxylic acid

This compound is analogous to Example 1 from 8.36 g Cephalothin sodium salt and 3.0 g of 1-amino-1,2-dihydro-4-mercapto 2-oxo-pyrimidine produced. Yield 4.1 g (40.2%). Mp <185 ° C (Dec.).

The triazine used in the above experiment is made from 8.6 g of 1-benzylideneamino-uracil [mp. 220-223 ° C; Lit .: monthly issues for Chemistry 96, 1735 (1965)] and 12 g of phosphorus pentasulfide in pyridine, followed by hydrolysis with hydrochloric acid.

Example 17 Preparation of the sodium salt of (7R) -3 - / <(1,2,5,6-tetrahydro- 2-methyl-5,6-dioxo-as-triazin-3-yl) thio <methyl / -7- <2- (2-thienyl) acetamido-3-cephem-4-carboxylic acid

This compound is analogous to Example 1 from 8.36 g Cephalothin sodium salt and 3.34 g 1,2,5,6-tetrahydro-5,6- dioxo-3-mercapto-2-methyl-as-triazine. yield 5.8 g (56%) mp 185 ° C (dec.).

The triazine used in the above process becomes analog Example 1 from 31.5 g of 2-methylthiosemicarbiazide and 35.4 g of dimethyl oxalate produced. Mp 260 ° C.

Example 18 Preparation of the sodium salt of (7R) -3 - / <(1,2-dihydro- 1-methyl-2-oxo-4-pyrimidinyl) thio <methyl / -7- <2- (2-thienyl) - acetamido <-3-cephem-4-carboxylic acid

This compound is analogous to Example 1 from 8.36 g of cephalothin sodium salt and 2.98 g of 1,2-dihydro-4-mercapto-1-methyl 2-oxo-pyrimidine produced. Yield 6.3 g (62.4%). Mp 180 ° C (Dec.).

Example 19 Preparation of the sodium salt of (7R) -3 - / <(1,2-dihydro- 1-methoxy-2-oxo-4-pyrimininyl) thio <-methyl / -7- <2- (2-thienyl) - acetamido <-3-cephem-4-carboxylic acid

This compound is analogous to Example 1 from 8.36 g Cephalothin sodium salt and 3.32 g 1,2-dihydro-4-mercapto-1- methoxy-2-oxopyrimidine. Yield 6.3 g (61.2%). Mp 175-180 ° C (dec.).

The triazine used in the above process becomes analog Example 11 from 6 g of 1-methoxyuracil and 18 g of phosphorus pentasulfide produced. Mp 177 ° C.

Example 20 Preparation of the sodium salt of (7R) -3 - / <(1-ethoxy- 1,2-dihydro-2-oxo-4-pyrimidinyl) thio <methyl / -7- <2- (2-thienyl) - acetamido <-3-cephem-4-carboxylic acid

This compound is analogous to Example 1 from 6.27 g Cephalothin sodium salt and 2.75 g of 1-ethoxy-1,2-dihydro-4- mercapto-2-oxo-pyrimidine. Yield 3.5 g (44%). Mp <180 ° C (dec.).

The triazine used in the above process becomes analogously to Example 11 from 6.4 g of 1-ethoxyuracil and 18 g of phosphorus pentasulfide produced. Mp 119-120 ° C.

Example 21 Preparation of the sodium salt of (7R) -3 - / <(1,6-dihydro- 1-methyl-6-oxo-3-pyridazinyl) thio <methyl / -7- <2- (2-thienyl) - acetamido <-3-cephem-4-carboxylic acid

This compound is analogous to Example 1 from 1.25 g Cephalothin sodium salt and 0.470 g 1,6-dihydro-3-mercapto-1- methyl-6-oxopyridazine. Yield 1.0 g (66.7%). M.p. <215 ° C (dec.).

The triazine used in the above process is made from 2.88 g of 3-chloro-1,6-dihydro-1-methyl-6-oxopyridazine [m.p. 91-92 ° C, Lit .: Monthly magazines for chemistry 99, 33 (1968)] and 5.88 g Sodium hydrogen sulfide in ethanol at 130 ° C and 5-7 atü produced. Mp 115 ° C.  

Example 22 Preparation of (7R) -7 - <(R) -2-amino-2- (p-hydroxyphenyl) - acetamido <-3 - / <(4-ethyl-1,4,5,6-tetrahydro-5,6-dioxo-as-triazine 3-yl) thio <methyl / -3-cephem-4-carboxylic acid

This compound is analogous to Example 1 by reaction of 24.5 g of D-p-hydroxy-N-t-butyl-oxycarbonyl-cephaloglycine 8.66 g of 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine and then removing the t-butyloxycarbonyl protecting group made with formic acid. Yield 5.7 g (23%). M.p. 200 ° C (dec.).

Example 23 Preparation of the sodium salt of (7R) -3 - / <(1,2,3,6- Tetrahydro-2,6-dioxo-1-methyl-s-triazin-4-yl) -thio <methyl / -7- <2- (2-thienyl) acetamido <-3-cephem-4-carboxylic acid

This compound is analogous to Example 1 from 8.36 g Cephalothin sodium salt and 3.34 g 1,2,3,6-tetrahydro-2,6-dioxo- 4-mercapto-1-methyl-s-triazine. Yield 5.5 g (53%). Mp from 200 ° C (decomp.).

The 1,2,3,6-tetrahydro- 2,6-dioxo-4-mercapto-1-methyl-s-triazine can be prepared as follows will.

A solution of 14.8 g sodium in 1000 ml methanol is 39.9 g 5-methyl-2-thio-biuret and 72 g of diethyl carbonate and Boiled at reflux for 24 hours. The reaction solution is in a vacuum concentrated to a volume of 200 ml. The crystallized out  The substance is sucked off and then dissolved in 200 ml of water and acidified with 2N hydrochloric acid. The failed connection is filtered off and recrystallized from 350 ml of ethanol. Yield 11.2 g (23%) colorless substance with mp. 275 ° C.

The 5-methyl-2-thio-biuret used in the above procedure can be made as follows:

A solution of 76 g thiourea in 1000 ml dimethylformamide is mixed with 65.4 ml of methyl isocyanate and then Stirred at 50-55 ° C for 72 hours. The reaction solution is in a vacuum evaporated and the residue recrystallized from water. Yield 79.4 g (60%) of colorless substance, mp. 209-210 ° C.  

Example 24 Preparation of the sodium salt of (7R) -7- (R) -mandelamido- 3 - / <(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl) thio < methyl / -3-cephem-4-carboxylic acid

This compound becomes analog from 9.25 g D-0-dichloroacetyl-mandelic acid chloride and 11.1 g of 7-amino-3- deacetoxy-3 - [(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazine 3-yl) thio] cephalosporanic acid. Yield 4.3 g (27%). Mp 200-210 ° C (dec.).

Example 25 Preparation of the sodium salt of (7R) -3 - / [<1- (dimethylamino) - 1,2-dihydro-2-oxo-4-pyrimidinyl <thio] methyl / -7- <2- (2-thienyl) acetamido <-3-cephem-4-carboxylic acid

This compound is analogous to Example 1 from 3.34 g of cephalothin sodium salt and 1.42 g of 1,2-dihydro-1-dimethylamino 4-mercapto-2-oxopyrimidine. Yield 2.4 h (57%). Mp from 165 ° C (decomp.)

Example 26 Preparation of the sodium salt of (7R) -3 - <(1,4,5,6- Tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) thio <methyl / -7- <2- (2-thienyl) acetamido <-3-cephem-4-carboxylic acid (variant of Procedure of Example 1)

4.0 g (7R) -3- (azidomethyl) -7- <2 - (- thienyl) -acetamido <-3- cephem-4-carboxylic acid sodium salt

are in 100 ml of pH 7.0 buffer with 2.07 g 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as- triazine and 1.01 g sodium hydrogen carbonate for 24 hours at 50-55 ° C stirred under nitrogen gas. The reaction mixture is thereupon cooled to 25 ° C and adjusted to pH 2 with 2N hydrochloric acid. The precipitated, raw acid is filtered off for cleaning washed with water and then in 100 ml of ethyl acetate stirred for 10 minutes. The acid purified in this way is filtered off with suction (1.3 g), suspended in 25 ml of methanol and 2.5 ml a 2N solution of 2-ethyl caproic acid sodium salt in ethyl acetate offset, creating a solution. When diluting with 100 ml of ethyl acetate precipitates the desired sodium salt. yield 1.25 g (24%). The substance thus obtained has all properties identical to the substance prepared according to Example 1.

Example 27 Comparative tests

A variety of cephalosporins that are different are already known. With regard to the invention Establishable connections are similar connections e.g. B. in German Offenlegungsschriften No. 22 25 694 and 23 56 704 and U.S. Patent Nos. 37 96 801 and 38 67 380 have been described. All in these publications the compounds mentioned are 3- (heterocyclic thiomethyl) cephalosporin compounds against which the new, according to the invention producible cephalosporins by particularly advantageous properties, e.g. B. by lower CD₅₀ values, award.  

The results in the following table are more comparative in vivo tests on penicillin-resistant S. aureus strains infected mice from which the obtained technical progress emerges.

The compounds used for comparison are involved the following:

A = 3- (1-methyltetrazol-5-ylthiomethyl) -7-D-mandelamido. 3-cephem-4-carboxylic acid (cefamandol) B = 7- (D- α- amino-p-hydroxyphenylacetamido) -3- (1,2,3-triazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid ( Cefazitrin) C = 7- (D- α- amino-p-hydroxyphenylacetamido) -3- (pyrimidin-4-ylthiomethyl) -3-cephem-4-carboxylic acid. D = cefalotin

The new compounds are identified in Table I by the number of the example describing their preparation in the present application.
Compound CD₅₀ (mg / kg), mouse, sc S. aureus penicillin resistant A15 B19 C15 D 7.4 5 5.5 6 3.8 7 8.8 8 7.3 9 5.8 13 5.8 14 5.6 15 7.0 21 6.4 23 8.3

Checking activity against Escherichia coli

The compounds were in a physiological saline solution (0.95%) solved. A group of 5 mice with one Weights of 18 to 19 g were given for each dose of the compounds and used for the untreated control groups. The animals became 8 times interperitoneal minimal lethal infection dose of an overnight culture infected. The compounds were administered subcutaneously 3 times, d. H. an hour, 2½ hours and 4 hours after infection.

The survival-to-death ratios were recorded daily for 8 days. The CD₅₀ values were determined after 4 days.
Compounds of CD₅₀ (mg / kg), sc, Example No. Escherichia coli 10.4 20.5 30.9 50.4 63.2 81.1 91.2 101.9 122.9 130.6 140.5 150, 6 161.2 170.5 180.9 191.0 201.5 220.2 231.2 240.2 251.1 Cephacetril 5.8 Cefamandol 0.36

Claims (5)

1. Cephalosporins of the general formula wherein
R 2-amino-2- (p-hydroxyphenyl) acetyl, 2-thienyl acetyl, α -hydroxyphenylacetyl or α- aminophenylacetyl and
Y represents a non-aromatic pyrimidonyl, pyridazonyl or triazonyl radical which is substituted on at least one of the nitrogen atoms and optionally on a carbon atom, lower alkyl, lower alkenyl, lower alkoxy, lower alkoxy-lower alkyl, amino or di- as substituent of a ring nitrogen atom. lower alkylamino and lower alkyl as a substituent of a ring carbon atom,
and salts of these compounds and hydrates of these salts. 2. (7R) -7- (R) -2-amino-2- (p-hydroxyphenyl) acetamido-3- [(4-ethyl-1,4,5,6-tetrahydro-5,6-dioxo-as-triazin-3-yl) - thiomethyl)] - 3-cephem-4-carboxylic acid and its salts. 3. (7R) -7- (R) -Mandelamido-3 - [(1,2,5,6-tetrahydro-2-methyl- 5,6-dioxo-as-triazin-3-yl) thiomethyl] -3-cephem-4-carboxylic acid and their salts.   4. A process for the preparation of the cephalosporins according to any one of claims 1-3 and the salts of these compounds and the hydrates of these salts, characterized in that either in a manner known per se

• a) a compound of the general formula X'-W ₁ (II) wherein
  X 'one of the compound I corresponding deacetoxy-cephalosporinrest, the carboxyl radical in position 4 is protected by salt formation with an inorganic or tertiary organic base and
  W _{1 represents} a common leaving group,
  with a compound of the general formula H-SY (III) wherein
  Y has the meaning given in claim 1, in a polar solvent, preferably in water or a buffer solution with a pH of about 6 to 7, preferably 6.5, and the protective group is split off or
• b) a compound of the general formula
  X ′ ′ - SY (IV) in which
  Y has the meaning given in claim 1 and
  X '' represents a 7-amino-desacetoxy-cephalosporanyl radical corresponding to the compound I, the carboxyl radical of which is in the protected position in position 4,
  with an acid of the formula R-OH (V) wherein
  R has the meaning given in claim 1, or reacts with a reactive functional derivative thereof, cleaves the protective group and, if desired, converts the reaction product into a salt.

5. Pharmaceutical preparations, characterized by a Content of a compound according to one of the claims 1-3.