DK155329B - 7-AMINOCEPHALOSPORINES USED AS INTERMEDIATES IN THE PREPARATION OF THERAPEUTIC EFFECTIVE 7-ACYLAMINO-CEPHALOSPORINES - Google Patents

Description

in

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The present invention relates to novel 7-amino-cephalosporins for use as intermediates in the preparation of therapeutically active 7-acylamino-cephalosporins. The novel compounds have the general formula I

R1 »S.

h2n-p-i 5 J-CH 2 -s-Y i

COOH

where Y represents hydrogen or methoxy, and Y represents at least one of the lower alkyl, lower alkenyl nitrogen atoms, lower alkoxy substituted lower alkyl, lower alkoxy, amino, mono- or di (lower alkyl) amino substituted and optionally at one or more lower alkyl, halo gene or oxo substituted pyrimidonyl, pyrazonyl, pyridazonyl or triazonyl group atoms, wherein "lower" generally refers to groups having a maximum of 6 carbon atoms.

The above-mentioned 7-amino-cephalosporins of formula I are novel intermediates which, after protecting the carboxy group in the 4-position, can be converted into therapeutically effective 7-acylaminocephalosporins, namely by acylation with an acid with the general formula II

Z-OH II

wherein Z represents an acyl group which can be used as a substituent in the amino group at the 7-position of a cephalosporin, or with a reactive functional derivative thereof, after which the protecting group is cleaved and the reaction product is converted into a salt if desired.

As acids of the formula II in the above reaction, acids of the general formula

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2 R 2 -CH-COOH IIa R 3 wherein R 2 represents cyano, 4-pyridylthio, n-butyl, isobutyl, phenyl, hydroxyphenyl, cyclohexyl, 2-thienyl, 2-furyl, 1-tetrazolyl, 1-triazolyl, 1-pyrazolyl or Represents hydrogen, hydroxy, hydroxymethyl, amino, azido, carboxy or sulfo, wherein a group different from cyano may be substituted with hydroxy, halogen, lower alkyl or lower alkoxy, and if R2 represents a pyridylthio group, is Rg hydrogen.

When acids of formula IIa or their reactive functional derivatives are used, antibiotic-active cephalosporin derivatives 15 are obtained which have the general formula III

R, H

—CH — CONH — r-1 * 3 -Νγ ^ Η2-3-ϊ m

C00H

wherein R 1 represents hydrogen or methoxy and R 2, R 2 and Y are as defined above, and salts thereof.

In this specification, the term "halogen" refers to chlorine, fluorine or bromine, which chlorine is preferred. The term "a lower alkyl group, lower alkoxy group or lower alkenyl group" means a straight or branched alkyl, alkoxy or alkenyl group having up to 6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, pentyl and hexyl, vinyl, propenyl, butenyl, pentenyl and hexenyl, with the alkyl groups having 4 carbon atoms, especially n-butyl and isobutyl being preferred.

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Examples of particularly preferred compounds of formula II or IIa are those in which 1 is 2-thienyl, 2-furyl, 1-tetrazolyl, 1-triazolyl, 1-pyrazolyl, 3-sydnonyl, phenyl, cyclohexyl , 4-pyridylthio or cyano, wherein, if 4-pyridylthio, is hydrogen.

Examples of such compounds are compounds in which Y is a 2-oxopyridin-4-yl group, a 2-oxopyrimidin-4-yl group, e.g., a 1-amino, 1-ethyl or 1-butoxy group. A 1,2-dihydro-2-oxopyrimidin-4-yl group or a 1-butoxy-1,2-dihydro-5-methyl-2-oxopyrimidin-4-yl group, a 4-oxopyrimidin-2-yl group, for example, a 1-ethyl-1,4-dihydro-6-methyl-4-oxopyrimidin-2-yl group or a 1,4-dimethyl-1,6-dihydro-6-oxo-pyrimidin-2-yl group, a 2 , 6-dioxopyrimidin-4-yl group, a 2-oxopyrazin-3-yl group, a 2,3,5-trioxopyrazinyl-6-yl group, a 3-oxopyridazin-6-yl group, a 3-oxopyridazin-4-yl group, a 5,6-dioxo-as-triazin-3-yl group, e.g., a 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 group or a 1,2,5,6,6-tetrahydro-1-ethyl -5,6-dioxo-as-triazin-3-yl group,

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4 a 2-oxotriazin-4-yl group or a 2,4-dioxotriazin-6-yl group.

Further substituents on a ring nitrogen atom may be mentioned lower alkyl or alkenyl, lower alkoxy, amino, mono- or di (lower alkydamino) and as substituent on a ring carbon atom may be mentioned lower alkyl, halogen or oxo, wherein one to a carbon or nitrogen atom bonded lower alkyl group may again be substituted by hydroxy or lower alkoxy.

The lower alkyl, alkenyl or alkoxy groups listed above contain up to 6 carbon atoms. Examples of such alkyl groups are methyl and ethyl. Examples of such alkenyl groups are vinyl and allyl. Examples of such alkoxy groups are methoxy and ethoxy.

Particularly preferred compounds of formula I include: 7-amino-3- {[(1,4,5,6-tetrahydro-4-ethyl I -5,6-dioxo-as-triazin-3-yl) - thio] methyl> -3-cephem-4-carboxylic acid, 7-amino-3 - {[(1,4 <5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl) ) - thio] methyl} -3-cephem-4-carboxylic acid, 7-amino-3 - {[(1,4,5,6-tetrahydro-4-allyl-5,6-dioxo-as-triazine-3- yl) -20 thio] methyl} -3-cephem-4-carboxylic acid, 7-amino-3- {[(1,4,5,6-tetrahydro-4-butyl-5,6-dioxo-ash) triazin-3-yl) -thio] methyl} -3-cephem-4-carboxylic acid, 7-amino-3 - {[(1,4,5 / 6-tetrahydro-4- (2-methoxyethyl) -5,6 dioxo-as-tri-azine-3-yl) thio] methyl} -3-cephem-4-carboxylic acid,

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7-Amino-3 - {[(1,4,5,6-tetrahydro-1,4-dimethyl-5,6-dioxo-az-triazin-3-yl) thio] methyl} -3-cephem-4 -carboxylic acid, 7-amino-3 - {[(1, 4,5,6-tetrahydro-1,4-diethyl-5,6-dioxo-az-triazin-3-yl) thio] methyl} -3 -cephem-4-carboxylic acid, 7-amino-3 - {[(1,2,5,6-tetrahydro-1-ethyl-5,6-dioxo-as-triazin-3-yl) -thio] methyl} 3-Cephem-4-carboxylic acid, 7-amino-7-methoxy-3 - {[(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-tri-azine-3- yl) thio] methyl} -3-cephem-4-carboxylic acid, 7-amino-3 - {[(1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] methyl} -3- Cephem-4-carboxylic acid, 7-amino-3 - {[(1-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] methyl> -3-cephem-4-carboxylic acid, 7 -amino-3- {[(Ί-butoxy-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] methyl} -3-cephem-4-carboxylic acid, 7-amino-3 - {[(1 -butoxy-1,2-dihydro-5-methyl-2-oxo-4-pyrimidinyl) -thio] methyl} -3-cephem-4-carboxylic acid, 7-amino-3 - {[(1,4-dimethyl) -1,6-dihydro-6-oxo-2-pyrimidinyl) thio] methyl} -3-cephem-4-carboxylic acid, 7-3πιίηο-3 - {[(1-6ίΙιγΜ, 4- ^ ϊΙ ^ Γθ -6-ιηβίΙιγΙ-4-οχο-4- ^ ^ ππιι ίη γΙ) ΐΐΉθ] -20 methyl} -3-cephem-4-carboxylic acid and 7-amino-3 - {(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazine-3) -yl) -thiomethyl} -3-cephem-4-carboxylic acid.

Compounds of formula I may exist as optically pure isomers and as isomer mixtures.

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The compounds of formula I and their salts can be prepared by a compound of general formula IV

R1 H S

v-MT \ o - '* - W1

T IV

COOH

where the meaning given above denotes a cleavable moiety and the carboxy group in the 4 position is protected by salt formation with an inorganic or tertiary organic base;

is reacted with a compound of general formula V

H-S-V V

where Y has the meaning given above, and the protecting group is split off if desired.

The protection of the carboxy group in a compound of formula I or IV may be effected by salt formation with an inorganic or tertiary organic base such as triethylamine.

As the leaving group of a compound of formula IV, for example, halogens such as chlorine, bromine or iodine, acyoxy groups such as lower alkanoyl groups, for example acetoxy, lower alkyl or arylsulfonyl oxy groups such as mesyloxy or tosyloxy or an azido group may be used.

The reaction of a compound of formula IV and a compound of formula V can be carried out in a manner known per se, for example at a temperature between ca. 40 and 80 ° C, conveniently at approx. 60 ° C, in water or a buffer solution with a pH of approx. 6-7, preferably 6.5, over a period of 3-8, preferably 6, hours.

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Upon completion of reaction of a compound of formula IV and a compound of formula V, the protecting group is split off as desired. The carboxy group of an acid of formula IV is protected by salt formation (e.g. with triethylamine); the cleavage of this salt-forming protecting group can be effected by treatment with acid at a relatively low temperature, e.g. 0 - approx. 10 ° C. As acid for this purpose can be used, for example, hydrochloric acid, sulfuric acid, phosphoric acid or citric acid.

The compounds of formula V are unknown to some, and to some known. The novel compounds of formula V can be prepared analogously to the preparation of known compounds.

Thus, a 1-substituted 2-oxo-4-mercaptopyridine can be prepared from the corresponding substituted 4-chloro-2-oxopyridine [Chem. Ber.

15 99, 255 (1966)] by nucleophilic replacement, for example, with an alpha potassium hydrogen sulfide.

Similarly, a 1,3-disubstituted 2,6-dioxo-1,2,3,6-tetrahydro-4-mercaptopyrimidine can be prepared from the corresponding 4-chloro-2,6-dioxo-1,2,3, 6-tetrahydropyrimidine.

The 5,6-Dioxo-3-mercapto-as-triazines can be prepared from the corresponding substituted thiosemicarbazides by analogy with the synthesis of 1,4.5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine. , cf. Dissertation by K.H. Ongania (Innsbruck 1972).

A thiol of formula V having a double bond between the carbon atom substituted by the mercapto group and a neighboring nitrogen atom may be in the form of the tautomeric thioketone.

The compounds of formula II and the reactive functional derivatives thereof are known or analogous to known compounds and can be prepared in a manner known per se.

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The compounds of formula III, the salts thereof and the hydrates of these salts are antibiotically active, especially bactericidal. They have broad spectrum of action against Gram-positive and Gram-negative microorganisms, especially against penicillinase-positive staphylococci as well as various cephalo-5 sporinase-positive Gram-negative bacteria, e.g., Escherichia coli, Proteus, Klebsiella, Aerobacter and Serratia species.

The compounds of formula III, as well as the pharmaceutically tolerable salts and hydrated forms thereof, can be used for the treatment and prophylaxis of infectious diseases as well as disinfectants. For adults, a daily dose of approx. 1 - approx. Particular preference is given to parenteral administration of the subject compounds.

The antimicrobial activity of two of the above compounds, namely the sodium salt of (7R) -3-C [(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-asrazine-3) (yl) thio] methyl) -7- [2- (5-oxo-1,2,3-oxadiazolidin-3-yl) acetamido] -3-cephem-4-carboxylic acid (Compound A in the table below) ) and the sodium salt of (7R) -3 - ([(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) thio] methyl) -7- [2 - (1-H-tetrazol-1-yl) acetamido] -3-ceph-20-em-4-carboxylic acid (Compound B in the table below) is shown in the CD 2 values listed below (mg / kg subcutaneously in mouse):

Compound Penicillin Sensitive Penicillin Resistant Escherichia staphylococcer staphylococcer coli 25 A 0.25 5.5 0.38 B 0.60 3.2 3.2 0.90

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The acute toxicity (LD 2) of these substances by intravenous administration in mice is 2000-4000 mg / kg for drug A and 1000-2000 mg / kg for drug B.

Preparation of the intermediates of formula I according to the invention is further elucidated by Examples 1-26 below, and the conversion thereof into antibiotic-active compounds of formula III is illustrated in Examples 27-30: EXAMPLE 1 2.72 g of 7-amino-cephalosporanoic acid are suspended together with 1,4,5,6-10 tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine in 100 ml of water. To this suspension is added 1.85 g of sodium bicarbonate to form a solution of pH 6.4. This solution is stirred for 3 hours at 60 ° C under a nitrogen atmosphere. The solution is cooled to 20 ° C and stirred with the addition of 1 g of activated charcoal under nitrogen atmosphere for an additional 1 hour. After filtration, the filtrate is adjusted to pH 3.8 by the addition of 2N hydrochloric acid solution, cooled to 0 ° C and stirred for 1 hour to crystallize the substance. This is isolated by suction filtration, washed with a small amount of ice water, acetone, ether and petroleum ether in the order indicated and dried in high vacuum 20 at 50 ° C. Yield 2.3 g (60%) of 7-amino-3-desacetoxy-3 - [(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) thio] cephalosporanoic acid in the form of a beige powder, m.p. 230-235 ° C (decomposition).

The 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine used in the process described above can be prepared as follows: 120 g of 4-ethylthiosemicarbazide are reacted in the presence of 23 g of sodium in 1 liter of methanol for 4 hours with 116 g of oxalic acid dimethyl ester at the boiling point of the reaction mixture. The triazine is isolated from the reaction mixture 30 in the form of the sodium salt and then obtained by acidification of an aqueous solution, mp 189-190 ° C.

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EXAMPLE 2 5.1 g of 7-amino-3-azido-3-desacetoxy-cephalosporanoic acid is stirred with 5.16 g of 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-ash. triazine and 4.2 g of sodium bicarbonate in 200 ml of a pH 5 buffer 7.0 for 6 hours at 60 ° C under a nitrogen atmosphere. The reaction solution is cooled to 25 ° C and then adjusted to pH 3.5 by the addition of 2N hydrochloric acid solution. The desired 7-amino-3-desacetoxy-3- [(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) thio] cephalosporanoic acid is crystallized and isolated by suction filtration (2.2 g). Evaporation of the mother liquor yields an additional 1.7 g. Total yield 3.9 g (50%).

EXAMPLE 3 In analogy to Examples 1 or 2, there is obtained: 7-Amino-3-desacetoxy-3 - [(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazine) 3-yl) thio] cephalosporanoic acid in the form of a beige powder, m.p. 240-245 ° C (dec.).

The 1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-3-mercapto-as-triazine used in the above process can be prepared analogously to Example 1 from 176 g of 4-methylthiosemicarbazide and 198 g of oxalic acid dimethyl ester, m.p. 218-220 ° C (dec.).

EXAMPLE 4 In analogy to Examples 1 or 2, 7-Amino-3- [(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazine-3) may also be obtained. -yl) -thio] -3-cephem-4-carboxylic acid in the form of a beige powder, m.p. 245-250 ° C (dec.).

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The 1,2,5,6-tetrahydro-5,6-dioxo-3-mercapto-2-methyl-as-triazine used in the above process can be prepared analogously to Example 1 from 31.5 g of 2-methylthiosemicarbazide and 35.4 g of oxalic acid dimethyl ester, m.p. 260 ° C.

EXAMPLE 5 By analogy with Examples 1 or 2, 7-Amino-3 - {[(1, 4,5,6-tetrahydro-4-allyl-5,6-dioxo-as-triazine-3) can also be obtained. yl) thio] methyl} -3-cephem-4-carboxylic acid.

The 1,4,5,6-tetrahydro-4-allyl-5,6-dioxo-3-mercapto-as-triazine used in the above process can be prepared analogously to Example 1 from 26.2 g of 4- allylthiosemicarbazide and 23.6 g of oxalic acid dimethyl ester, mp 138-140 ° C.

EXAMPLE 6 By analogy to Examples 1 or 2, 7-Amino-3- {[(1,4,5,6-tetrahydro-4-butyl-5,6-dioxo-as-triazine-3) can also be obtained. yl) - thio] methyl} -3-cephem-4-carboxylic acid.

The 1,4,5,6-tetrahydro-4-butyl-5,6-dioxo-as-triazine used in the above process can be prepared analogously to Example 1 from 14.7 g of 4-butylthiosemicarbazide and 11.8 g of oxalic acid dimethyl ester, m.p. 180-181 ° C.

EXAMPLE 7 By analogy to Examples 1 or 2, 7-Amino-3 - {[n, 4,5,6-tetrahydro-4- (2-methoxyethyl) -5,6-dioxo-asa] can also be obtained. (triazin-3-yl) thio] methyl} -3-cephem-4-carboxylic acid.

The 1,4,5,6-tetrahydro-4- (2-methoxyethyl) -5,6-dioxo-3-mercapto-as-triazine used in the above process can be prepared analogously to Example 1 from 14, 9 g of 4- (2-methoxyethyl) thiosemic carbazide and 11.8 g of oxalic acid dimethyl ester, mp 158-160 ° C.

EXAMPLE 8 10 By analogy to Examples 1 or 2, 7-Amino-3 - {[(1,4,5,6-tetrahydro-1,4-dimethyl-5,6-dioxo-as-triazine) is also obtained. 3-yl) thio] methyl} -3-cephem-4-carboxylic acid.

The 1,4,5,6-tetrahydro-1,4-dimethyl-5,6-dioxo-3-mercapto-as-triazine used in the above process can be prepared analogously to Example 1 from 11, 9 g of 1,4-dimethylthio-semicarbazide and 11.8 g of oxalic acid dimethyl ester, mp 231-233 ° C (dec.).

EXAMPLE 9 By analogy with Examples 1 or 2, 7-Amino-3 - {[(1,4,5,6-tetrahydro-1,4-diethyl-5,6-dioxo-as-triazine-20) can also be obtained. 3-yl) thio] methyl} -3-cephem-4-carboxylic acid.

The 1,4,5,6-tetrahydro-1,4-diethyl-5,6-dioxo-3-mercapto-as-triazine used in the above process can be prepared analogously to Example 1 from 14.7 g of 1 , 4-diethylcarbazide and 11.8 g of oxalic acid dimethyl ester, mp 177-179 ° C.

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EXAMPLE 10 By analogy to Examples 1 or 2, 13 7-Amino-3 - {[(1,2,5,6-tetrahydro-1-ethyl-5,6-dioxo-as-triazine-3 yl) -thio] methyl} -3-cephem-4-carboxylic acid.

The 1,2,5,6-tetrahydro-1-ethyl-5,6-dioxo-3-mercapto-as-triazine used in the process described above can be prepared as follows: 46.5 g of 1-ethylthiosemicarbazide react in 700 ml of acetone at 40 ° C with 48 g of oxalic acid monomethyl ester chloride. To 34.3 g of the product obtained is added 9.2 g of sodium methylate in 300 ml of methanol. The triazine is isolated from the reaction mixture in the form of the sodium salt and then obtained by acidification in an aqueous solution, mp 213-214 ° C (dec.).

EXAMPLE 11 In analogy to Examples 1 or 2, 7-Amino-3 - {[(1-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] methyl} -3-cephem can also be obtained. -4-carboxylic acid.

EXAMPLE 12 By analogy to Examples 1 or 2, 7-Amino-3- {[(1-butoxy-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] methyl} 3-cephem-4-ca rboxylic acid.

The 1-butoxy-1,2-dihydro-4-mercapto-2-oxo-pyrimidine used in the above process can be prepared from 2 g of 1-butoxy-uracil and 4 g of phosphorus pentasulfide, mp 99-100 ° C.

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EXAMPLE 13 By analogy to Examples 1 or 2, there are also available: 14 7-Amino-3- {[(1-butoxy-1,2-dihydro-5-methyl-2-oxo-4-pyrimidinyl) -thiolmethyl} - 3-cephem-4-carboxylic acid.

The 1-butoxy-1,2-dihydro-4-mercapto-5-methyl-2-oxo-pyrimidine used in the above process can be prepared analogously to Example 12 by reacting 25 g of 1-butoxy-5-methyl -uracil and 50 g of phosphorus pentasulfide. 7-Butoxy-5-methyl-uracil can be prepared by reacting 110 g of butoxyurea with 184 g of β, β-diethoxy-α-methyl-propionic acid ester.

EXAMPLE 14 By analogy to Examples 1 or 2, 7-Amino-3 - {[(1,4-dimethyl-1,6-dihydro-6-oxo-2-pyrimidinyl) thio] methyl} -3- cephem-4-carboxylic acid.

EXAMPLE 15 By analogy to Examples 1 or 2, 7-Amino-3 - {[(1-ethyl-1,4-dihydro-6-methyl-4-oxo-2-pyrimidinyl) thio] methyl can also be prepared. I} -3 -cep h em -4- ca r boxy In his re.

The 1-ethyl-1,4-dihydro-2-mercapto-6-methyl-4-oxopyrimidine used in the above process can be prepared as follows: 18 g of N-ethylthiourea is dissolved in 50 ml of acetic acid, boiled under reflux and 17.2 g of the diket is added dropwise. Then, reflux for 20 minutes, then evaporate to 50 ml.

While cooling and stirring, add 50 ml of water. The yellow crystals

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15 precipitates. They are isolated by weekly titration and recrystallized from tetrahydrofuran, mp 190 ° C.

EXAMPLE 16 By analogy to Examples 1 or 2, there is also obtained: 5 7-Amino-3 - {[O-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] methyl} -3-cephem 4-carboxylic acid.

EXAMPLE 17 By analogy to Examples 1 or 2, 7-Amino-3 - {[(1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] methyl} -10 3-cephem can also be obtained. -4-carboxylic acid.

The 1-amino-1,2-dihydro-4-mercapto-2-oxo-pyrimidine used in the above process can be prepared from 8.6 g of 1-benzylidene-amino-uracil [mp 220-223 ° C; Lit .: Monatshefte fur Chemie 96, 1735 (1965)] and 12 g of phosphorus pentasulfide in pyridine followed by hydrolysis with hydrochloric acid.

EXAMPLE 18 By analogy to Examples 1 or 2, 7-Amino-3- {[(1,2-dihydro-1-methyl-2-oxo-4-pyrimidmyl) thio] methyl) -3- cephem-4-carboxylic acid.

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EXAMPLE 19 In analogy to Examples 1 or 2, there is also obtained: 16 7-Amino-3 - {[(1,2-dihydro-1-methoxy-2-oxo-4-pyrimidinyl) thio] methyl} -3 -cephem-4-carboxylic acid.

The 1,2-dihydro-4-mercaptomethoxy-2-oxo-pyrimidine used in the above process can be prepared from 6 g of 1-methoxyuracil and 18 g of phosphorus pentasulfide, mp 177 ° C.

EXAMPLE 20 In analogy to Examples 1 or 2, 7-Amino-3- {[(1-ethoxy-2,2-di hydro-2-oxo-4-pyrimidinyl) thio] methyl} can also be obtained. -3-cephem-4-carboxylic acid.

The 1-ethoxy-2,2-dihydro-4-mercapto-2-oxo-pyrimidine used in the above process can be prepared from 6.4 g of 1-ethoxy-oxyuracil and 18 g of phosphorus pentasulfide, m.p. 119-120 °. C.

EXAMPLE 21 By analogy to Examples 1 or 2, 7-Amino-3 - {[(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl) thio] methyl} -3 can also be obtained. -cephem-4-carboxylic acid.

The 1,6-dihydro-3-mercap-20 to-1-methyl-6-oxo-pyridazine used in the above process can be prepared from 2.88 g of 3-chloro-1,6-dihydro-1-methyl 6-oxo-pyridazine [m.p. 91-92 ° C, Lit .: Monatshefir Chemie 99, 33 (1968)] and 5.88 g of sodium hydrogen sulfide in ethanol at 130 ° C and 5-7 atm, m.p. 115 ° C .

By analogy to Examples 1 or 2, one can also obtain: EXAMPLE 22

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17 7-Amino-3 - {[(1,2,3,6-tetrahydro-2,6-dioxo-1-methyl-s-triazin-4-yl) -thiomethyl}] - 3-cephem-4-carboxy !acid.

The 1,2,3,6-tetrahydro-2,6-dioxo-4-mercapto-1-methyl-s-triazine used in the above process can be prepared as follows:

To a solution of 14.8 g of sodium in 1000 ml of methanol is added 39.9 g of 5-methyl-2-thio-biuret and 72 g of diethyl carbonate and reflux for 24 hours. The reaction solution is evaporated in vacuo to a volume of 200 ml. The crystallized substance thus obtained is isolated by suction filtration, then dissolved in 200 ml of water and acidified with 2N hydrochloric acid. The precipitated compound is isolated by suction filtration and recrystallized from 350 ml of ethanol. Yield 11.2 g (23%) of colorless substance, m.p. 275 ° C.

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

To a solution of 76 g of thiourea in 1000 ml of dimethylformamide is added 65.4 ml of methyl isocyanate and then stirred for 72 hours at 50-20 55 ° C. The reaction solution is evaporated in vacuo and the residue is recrystallized from water. Yield 79.4 g (60%) of colorless substance, mp 209-210 ° C.

EXAMPLE 23 In analogy to Examples 1 or 2, 7-Amino-3 - {[(1-ethyl-5-chloro-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] methyl can also be obtained. ) -3-cephem-4-carboxylic acid.

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The 1-ethyl-5-chloro-1,2-dihydro-4-mercapto-2-oxo-pyrimidine used in the above process can be prepared as follows: 1.74 g of 1-ethyl-5-chloro-uracil is first mixed with 4.44 g of phosphorus pentasulfide and 0.1 ml of water, then 30 ml of pyridine is added and refluxed for 5.75 hours. The reaction mixture is evaporated in vacuo at 40 ° C and the residue is suspended in 30 ml of water and 30 ml of 2N hydrochloric acid is added. The crystalline substance is isolated by suction filtration, washed with water and recrystallized from ethanol. Yield 1.3 g (68%) of yellow substance, mp 217-220 ° C.

The 1-ethyl-5-chloro-uracil used in the above process can be prepared as follows:

Into a solution of 9.9 g of 1-ethyl-uracil in 150 ml of glacial acetic acid, chlorine is passed for so long (about 1/2 hour) that iodine potassium starch paper reacts positively and no longer can be detected by thin layer chromatography. ethyl-uracil. The reaction mixture is evaporated in vacuo at 40 ° C and the crystalline residue is recrystallized from ethanol (300 ml). Yield 10.0 g (81%) of colorless fine needles, mp 244-247 ° C.

The 1-ethyl-uracil used in the above process can be prepared as follows: 1 2 3 4 5 6 7 8 9 10 11

To a solution of 15.0 g of sodium in 700 ml of ethanol is added 44 g of N-2 ethyl urea and 105 g of β, β-diethoxypropionic acid ethyl ester. Then, the yellow reaction solution is kept for 3 hours at 25 ° C and 4 is refluxed for 15 hours. The reaction solution is evaporated in vacuo, the above residue is dissolved in 300 ml of water, cooled 6 to 0 ° C and acidified with 100 ml of concentrated hydrochloric acid to precipitate a crude 7 stallin intermediate (43 g). The latter is isolated by 8 suction filtration, washed with 100 ml of ice water and then heated to 9 80-100 ° C in 250 ml of water until the conversion to the desired water-soluble 10-ethyl-uracil is completed. The solution is evaporated in 11 vacuum at 40 ° C and the residue is recrystallized from ethanol-ether. Yield 14.0 g (20%) of colorless substance, mp 150 ° C.

By analogy to Examples 1 or 2, one can also obtain: EXAMPLE 24 19

DK 1553.29 B

7-Amino-3 - {[(1- (dimethylamino) -1,2-dihydro-2-oxo-4-pyrimidinyl) -thio] methyl} -3-cephem-4-carboxylic acid.

EXAMPLE 25 In analogy to Examples 1 or 2, 7-Amino-3- {[(3-chloro-1,6-dihydro-1-methyl-6-oxo-4-pyridazinyl) thio] can also be obtained. -methyl} -3-cephem-4-carboxylic acid.

The 3-chloro-1,6-dihydro-4-mercapto-1-methyl-6-oxo-pyridazine used in the above process can be prepared as follows:

To a solution of 17.9 g of 3,4-dichloro-1,6-dihydro-1-methyl-6-oxo-pyridazine in 200 ml of methanol is added a solution of 14.8 g of sodium hydrogen sulfide monohydrate in 200 ml of methanol. . The reaction mixture is then stirred for 1 1/2 hours at 25 ° C under nitrogen atmosphere.

Then, some undissolved substance is filtered off and the filtrate is evaporated in vacuo. The residue is suspended in 150 ml of water, adjusted to acidic reaction with 1N hydrochloric acid and extracted three times with ethyl acetate. The combined ethyl acetate extracts are washed with water, dried over sodium sulfate and evaporated in vacuo. The residue thus obtained is recrystallized from ethanol. Yield 9 g of yellow needles, mp 163 ° C.

The 3,4-dichloro-1,6-dihydro-1-methyl-6-oxo-pyridazine used in the above process can be prepared as follows: 67.75 g of 3,4-dichloro-6-hydroxy-pyridazine dissolve in 205 ml of 2N sodium hydroxide solution and add 36 ml of dimethyl sulfate. Then, the reaction mixture is heated to 70 ° C for 1/2 hour, then cooled and extracted twice with chloroform. The combined chloroform extracts are washed with water, dried over sodium sulfate and concentrated by evaporation.

DK 155329 B

20 is evaporated in vacuo. The crystal lysis residue is made from high boiling petro-leum ether. Yield 54 g (73%), mp 97 ° C.

EXAMPLE 26 By analogy to Examples 1 or 2, there is also obtained: 5 7-Amino-3 - {[(1,2-dihydro-1,6-dimethyl-2-oxo-4-pyridyl) thio] methyl} -3-cephem-4-carboxylic acid.

EXAMPLE 27 By analogy to Examples 1 or 2, 7-Amino-3- {[(1-ethyl-1,2-dihydro-2-oxo-3-pyrazinyl) thio] methyl} -3-10 cephem can also be obtained. -4-carboxylic acid.

The 1-ethyl-1,2-dihydro-3-mercapto-2-oxo-pyrazine used in the above process can be prepared as follows:

To a solution of 22.2 g of sodium hydrogen sulfide monohydrate in 1000 ml of methanol is added 23.7 g of 1-ethyl-3-chloro-1,2-dihydro-2-oxo-pyrazine and stirred for 3 hours at 25 ° C. The precipitated sodium chloride is then filtered off and the yellow filtrate is evaporated in vacuo at 40 ° C. The evaporation residue is recrystallized from ethanol. Yield 8.0 g (34%) of yellow crude. For purification, 5.0 g in 50 ml of 0.5N hydrochloric acid is suspended, then vigorously acidified by the addition of 10 ml of 2N hydrochloric acid, the mixture is stirred for 10 minutes at 25 ° C and then stored overnight in a refrigerator. The orange-yellow crystals thus formed (3.65 g) are isolated by suction filtration, washed with a little ice water and dried in vacuo at 50 ° C. Melting point 204-206 ° C (dec.).

EXAMPLE 28

DK 155329 B

21

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 - (1-H-tetrazol-1-yl) acetamido] -3-cephem-4-carboxylic acid.

Dissolve 1.28 g of tetrazole-1-acetic acid in a mixture of 50 ml of tetrahydrofuran and 5 ml of dimethylformamide. To this solution is added at -20 ° C 1.18 ml of N-methylmorpholine and 1.4 ml of chloroformic acid isobutyl ester in the order given, then stirred for 20 minutes at a temperature between -10 and -20 ° C. Then an ice-cold solution of it is added from 3.85 g of 7-amino-3-desacetoxy-3 - [(1,4,5 (, 6-tetrahydro-4-ethyl-5,6-dioxo-ash) -Triazin-3-yl) thio] cephalosporanoic acid and 1.4 ml of triethylamine obtained salt in 50 ml of water, then the reaction mixture is stirred for 30 minutes at 0 ° C and for 1 hour at 20 ° C. The reaction mixture is evaporated in vacuo The acid is isolated by suction filtration, washed with a lot of ethyl acetate and dissolved in dimethylformamide. ethyl acetate and then diluted with ethanol and ether to precipitate the desired crude sodium salt (3.3 g). To purify, the thus obtained substance is dissolved in 20 ml of water and 60 ml of ethanol are added to give a dark resin, The filtrate is evaporated in vacuo and the residue is treated with ethanol and ether to give 2.3 g (44.5%) of pure fabric in the form of a light beige color? n 25 powder with melting point 210 ° C (dec.) and [a] + = + 23 ° (c = 0.824 in water).

EXAMPLE 29

DK 155329 B

22

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) -2-hydroxyhexanamido] -3-cephem-4-carboxylic acid.

4.4 g of 7-amino-3-desacetoxy-3 - [(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxoaz-triazin-3-yl) thio] cephalosporanoic acid is dissolved by 0 ° C with stirring in a mixture of 44 ml of water and 44 ml of acetone by the addition of 2.5 g of potassium hydrogen carbonate. Then, at 0 ° C, with stirring, a solution of 3 g of (R) -2-dichloroacetoxy-n-capric acid chloride (boiling point "c at 0 ° C and for 1 hour at 20 ° C. Of the filtered solution, the acetone is distilled off under reduced pressure at 30 ° C. The aqueous solution is added to potassium carbonate and stirred for 45 minutes at a pH of 9.5, then extracted twice with ethyl acetate and adjusted to 15 at 0 ° C at a pH of 1.5-2.0 by the addition of 3N sulfuric acid solution. Extract with ethyl acetate with the addition of dimethylformamide. The ethyl acetate solution is washed several times with 10% sodium chloride solution, dried with magnesium sulfate and evaporated under reduced pressure at 25 ° C. The residue is dissolved in 100 ml of isoprop-20 anol and 12 ml of a 2N solution of the sodium salt of 2-ethyl-capric acid in isopropanol is added. The crude sodium salt is suctioned off, precipitated by water isopropanol and dried under reduced pressure. A beige colored powder is obtained having a melting point of 183 ° C (decomposition); [α] D = + 8.2 ° (c = 1.00 in water). Yield 56%.

EXAMPLE 30

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- (1H-tetrazole-ly) acetamido] -3-cephem-4-carboxylic acid.

This compound is prepared analogously to the procedure described in Example 28 from 2.95 g of tetrazole-1-acetic acid and 8.55 g of 7-amino-3 - [(1,2,5,6-tetrahydro-2 methyl-5,6-dioxo-as-triazin-3-y |) thio] CE

Claims (19)

Cephalosporin derivatives according to Claim 1, 5, characterized in that Y is a non-aromatic, at least one of the nitrogen atoms and optionally substituted 2-oxo-pyrimidin-4-yl, 4-oxo-pyrimidine at least one or more carbon atoms. 2-yl, 2,6-dioxopyrimidin-4-yl, 2-oxopyrazin-3-yl, 2,3,5-trioxopyrazin-6-yl, 3-oxopyridazin-6-yl, 3-oxopyridazin-4-yl, 5,6-dioxo-as-triazin-3-yl, 2-oxotriazin-4-yl or 2,4-dioxo-triazin-6-yl, wherein as a substituent at a ring nitrogen atom or a ring carbon atom, they may be present in claim 1 defined groups. Cephalosporin derivatives according to claim 1 or 2, characterized in that Y represents 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-3-mercapto-as-triazinyl. Cephalosporin derivatives according to claim 1 or 2, characterized in that Y is 1,2,5,6-tetrahydro-ethyl-5,6-dioxo-3-mercapto-as-triazinyl. Cephalosporin derivatives according to any one of claims 1-3, characterized in that Y represents 1-amino, 1-ethyl or 1-butoxy-1,2-dihydro-4-mercapto-2-oxopyrimidinyl, 1- butoxy-1,2-di-hydro-4-mercapto-5-methyl-2-oxopyrimidinyl, 1,4-dimethyl-1,6-dihydro-2-mercapto-6-oxopyrimidinyl or 1-ethyl-1, 4-dihydro-2-mercap-to-6-methyl-4-oxopyrimidinyl. 1 2 3 4 Cephalosporin derivative according to claim 1,2 characterized in that it is 7-amino-3- {[(1,4,5,6-tetrahydro-3-hydro-4-ethyl-5,6-dioxo) as-triazin-3-yl) thio] methyl} -3-cephem-4-carbo-4 oxylic acid or a salt thereof. DK 155329 B 25 The cephalosporin derivative according to claim 1, characterized in that it is 7-amino-3 - {[(- i - 5e-tetanahydro-4-methyl-5,6-dioxo-as-triazine-3) -yl) thio] methyl} -3-cephem-4-carboxylic acid or a salt thereof. Cephalosporin derivative according to claim 1, characterized in that it is 7-amino-3 - {[(1H-4a5Ae-tetrahydro-4-allyl-5,6-dioxo-as-triazin-3-yl) thio] methyl} -3-cephem-4-carboxylic acid or a salt thereof. Cephalosporin derivative according to Claim 1, 10, characterized in that it is T-amino-Sf (1 S) G-tetrahydro-4-butyl-5,6-dioxo-as-triazin-3-yl) thio] methyl} -3-cephem-4-carboxylic acid or a salt thereof. Cephalosporin derivative according to claim 1, characterized in that it is T-amino-5-phenyl-tetrahydro-4- (2-methoxyethyl) -5,6-dioxo-as-triazin-3-yl ) thio] methyl} -3-ce-phem-4-carboxylic acid or a salt thereof. Cephalosporin derivative according to claim 1, characterized in that it is 7-amino-3- {[(1,4,5,6-tetrahydro-1,4-dimethyl-5,6-dioxo-as-triazine) 3-yl) thio] methyl} -3-cephem-4-20 carboxylic acid or a salt thereof. Cephalosporin derivative according to claim 1, characterized in that it is 7-amino-3- {[(1,4,5,6-tetrahydro-1,4-diethyl-5,6-dioxo-as-triazine) 3-yl) thio] methyl} -3-cephem-4-carboxylic acid or a salt thereof. 1 Cephalosporin derivative according to claim 1, characterized in that it is 7-amino-3- {[(1,2,5,6-tetrahydro-1-ethyl-5, G-dioxo-as-triazine-3 yl) thio] methyl} -3-cephem-4-ca rb-oxylic acid or a salt thereof. DK 155329B 26 Cephalosporin derivative according to claim 1, characterized in that it is 7-amino-7-methoxy-3 - {[(1,4, - 5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazine) 3-yl) thio] methyl} -3-ce-phem-4-carboxylic acid or a salt thereof. Cephalosporin derivative according to claim 1, characterized in that it is 7-amino-3 - {[(1-amino-1,2-di-hydro-2-oxo-4-pyrimidinyl) thio] methyl} -3-cephem -4-carboxylic acid or a salt thereof. Cephalosporin derivative according to claim 1, characterized in that it is 7-amino-3 - {[(1-ethyl-1,2-di-hydro-2-oxo-4-pyrimidinyl) thio] methyl} -3- cephem-4-carboxylic acid or a salt thereof. Cephalosporin derivative according to claim 1, characterized in that it is 7-amino-3 - {[(1-butoxy-1,2-di-hydro-2-oxo-4-pyrimidinyl) thio] methyl> -3- cephem-4-carboxylic acid or a salt thereof. Cephalosporin derivative according to claim 1, characterized in that it is 7-amino-3 - {[(1-butoxy-1,2-di-hydro-5-methyl-2-oxo-4-pyrimidinyl) thiomethyl} -3 -cephem-4-carb-oxylic acid or a salt thereof. Cephalosporin derivative according to claim 1, characterized in that it is 7-amino-3 - {[(1,4-dimethyl-1,6-dihydro-6-oxo-2-pyrimidinyl) thio] methyl} -3-cephem-4 -carboxylic acid or a salt thereof. 1 Cephalosporin derivative according to claim 1, characterized in that it is 7-amino-3 - {[(1-ethyl-1,4-di-hydro-6-methyl-4-oxo-2-pyrimidinyl) thio] methyl} -3-cephem-4-carboxylic acid or a salt thereof. DK 155329 B 27 21. Cephalosporin derivative according to claim 1, characterized in that it is 7-amino-3- {[0,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazine -3-yl) thio] methyl} -3-cephem-4-earboxylic acid or a salt thereof.