IE41888B1 - Substituted desacetoxy-7-acylamino-cephalosporanic acids - Google Patents

Substituted desacetoxy-7-acylamino-cephalosporanic acids

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Publication number
IE41888B1
IE41888B1 IE1366/75A IE136675A IE41888B1 IE 41888 B1 IE41888 B1 IE 41888B1 IE 1366/75 A IE1366/75 A IE 1366/75A IE 136675 A IE136675 A IE 136675A IE 41888 B1 IE41888 B1 IE 41888B1
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group
dioxo
tetrahydro
formula
amino
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Hoffmann La Roche
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/56—One oxygen atom and one sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
    • C07D253/06—1,2,4-Triazines
    • C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
    • C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D253/075—Two hetero atoms, in positions 3 and 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/36—Methylene radicals, substituted by sulfur atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Cephalosporin Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Acyl derivatives of the general formula X-S-Y in which X denotes a 3-acetoxymethylcephalosporinyl radical decreased by the acetoxy group and -S-Y denotes the thio group standing instead of the acetoxy group, in which Y represents a 6-membered, optionally substituted, heterocyclic radical having 1 to 3 nitrogen atoms, which is not heteroaromatic and cannot be enolised to give a heteroaromatic radical, where at least one of these nitrogen atoms is substituted and at least one of these nitrogen atoms forms an amide group with an adjacent carbonyl group, or salts of these compounds or hydrates of these salts are antibiotically active products. These products can be prepared by reacting a cephalosporin derivative which carries an easily removable group on the 3-methyl group instead of the acetoxy substituent and whose carboxyl group in position 4 is present in protected form, with a mercapto compound Y-SH and removing the protective group.

Description

The present invention is concerned with acyl derivatives, a process for the manufacture thereof and pharmaceutical preparations containing same.
The acyl derivatives provided by the present invention 5 are compounds of the general formula X—S—Y (I) wherein X represents a desacetoxy-cephalosporinyl group and ϊ represents a 6-membered heterocyclic group which contains 1, 2 or nitrogen atoms but which is not aromatic and is not enolisable to an aromatic group; at least one of said nitrogen atoms being substituted and at least one of said IS nitrogen atoms forming an amide group with an adjacent carbonyl group and a carbon atom(s) being optionally substituted and salts thereof and hydrates of said salts.
Examples of salts of the compounds of formula I are alkali metal salts Such as the sodium and potassium salts, the ammonium salts, alkaline earth metal salts such as the calcium salts, salts with organic bases such as amines (e.g. N-ethyl-piperidine, procaine, dibenzylamine, Ν, N *-dibenzylethy1-ethylenediamine, alkylamines or dialkylamines) and salts with amino acids (e.g. arginine or lysine).
The compounds of formula I containing a free basic group (e.g. an amino group) form addition salts with organic and inorganic acids. Examples of such salts are hydrohalides (e.g. hydrochlorides, hydrobromides and hydroiodides), other mineral acid salts (e.g. sulphates, nitrates and phosphates), alkylsulphonates and monoarylsulphonates (e.g. ethanesulphonates, toluenesulphonates and be'nzenesulphonates) and other organic acid salts (e.g. acetates, tartrates, maleates, citrates, benzoates, salicylates and ascorbates).
The salts of the compounds of formula I can be hydrated.
The hydration can be carried out during the manufacturing process or can occur gradually as a result of the hygroscopic properties of an Initially anhydrous salt of a compound of formula I.
Preferred compounds of formula I are those in which X represents a group of the general formula wherein R^ represents a hydrogen atom or a methoxy group, R2 represents a cyano or pyridylthio group or an aliphatic, alicyclic, aromatic or heteroaromatic group and R3 represents a hydrogen atom or a hydroxy, hydroxymethyl, amino, azido, carboxy or sulpho group; a group other - 3 41888 than cyano denoted by R2 being optionally substituted by hydroxy, halogen, lower alkyl or lower alkoxy and, when R2 represents a pyridylthio group R^ represents a hydrogen atom.
As used in this specification, the term halogen denotes chlorine, fluorine or bromine with chlorine being preferred.
The term aliphatic group includes both straight-chain and branched-chain alkyl and alkenyl groups containing up to .6 carbon atoms such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, pentyl, and hexyl, vinyl, propenyl, butenyl, pentenyl, and hexenyl; the alkyl groups containing 4 carbon atoms, particularly n-butyl and isobutyl, being preferred. The term alicyclic group denotes a saturated or unsaturated, non-aromatic group containing from 3 to 6 carbon atoms such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl and cyclohexadienyl; the groups containing 6 carbon atoms, particularly cyclohexyl and cyclohexadienyl, being preferred. The term aromatic group relates to phenyl, phenyl-(C1_3~alkyl) and phenoxy-(C^_3-alkyl), wherein the phenyl and/or the alkyl moiety may carry one or more substituents from the series hydroxy, halogen, lower alkyl or lower alkoxy; phenyl and p-hydroxyphenyl being preferred. The term heteroaromatic group relates to 5- or 6-membered aromatic groups containing 1-4 nitrogen atoms and/or one oxygen or sulphur atom such as for example, sydnonyl, tetrazolyl, triazolyl, furyl, thienyl, pyrazolyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl and isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and! triazinyl; the 5-membered groups, particularly thienyl, furyl, tetrazolyl, triazolyl, pyrazolyl and sydnonyl, being preferred.
Most preferred compounds of formula I are those in which 5 R2 represents a 2-thienyl, 2-furyl, 1-tetrazolyl, 1-triazolyl, 1-pyrazolyl, 3-sydnonyl, phenyl, cyclohexyl, 4-pyridylthio or cyano group, with the proviso that when R2 represents a 1-tetrazolyl, 1-triazolyl, 1-pyrazolyl, 3-sydnonyl or 4-pyridylthio group, Rg represents a hydrogen atom.
Preferred compounds of formula I are, furthermore, those in which Y represents a non-aromatic N-substituted pyridonyl group which is optionally substituted on one or more carbon atoms or represents a non-aromatic pyrimidonyl, pyrazonyl, pyridazonyl or triazonyl group which is substituted on at least one of the nitrogen atoms and optionally substituted on one or more carbon atoms.
Examples of such compounds are those in which Y represent a 2-oxopyridin-4-yl group? a 2-oxopyrimidin-4-yl group such as the Ι-amino-, 120 -ethyl- or l-butoxy-l,2-dihydro~2-oxopyrimidin-4-yl group or the l-butoxy-l,2-dihydro-5-methyl-2-oxopyrimidin-4-yl group; a 4-oxopyrimidin-2-yl group such as the 1-ethyl-l,4-dihydro-6-methyl-4-oxopyrimidin-2-yl group or the 1,4-dimethyl1 -1,6-dihydro-6-oxopyrimidin-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 such as the 4-ethyl-, 4-methyl-, 4-allyl-, 4-butyl-, 4-(2-methoxyethyl)-, 1,4-dimethyl- or l,4-diethyl-l,4,5,6-tetrahydro-5,6-dioxo-as-triazln-3-yl group or the l,2,5,6-tetrahydro-l-ethyl-5,6-dioxo-as-triazin-3-yl group; a 2-oxotriasin-4-yl group; or a 2,4-dioxotriazin-6-yl group.
As substituents on a cyclic nitrogen atom there may be mentioned lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, hydroxy, lower alkoxy, amino, mono(lower alkyl)amino, di(lower alkyl)amino, formyl, lower alkanoyl, lower alkanoylamino, carbamoyl, mono(lower-alkyl)aminocarbonyl ahd di(lower alkyl)aminocarbonyl, and as substituents on a cyclic carbon atom there may be 20 mentioned lower alkyl, lower alkoxy, amino, mono(lower alkyl)amino, di(lower alkyl)amino, lower alkanoylamino, carboxy, lower alkoxycarbonyl, carbamoyl, mono(lower alkyl)aminocarbonyl, di(lower alkyl)aminocarbonyl, cyano and halogen; a lower alkyl group bonded to a carbon or nitrogen atom being, in turn, optionally substituted by hydroxy, lower alkoxy, amino, mono(lower alkyl)amino, di(lower alkyl)amino, formyl, lower alkanoyl, lower alkanoylamino, carboxy, lower alkoxycarbonyl, carbamoyl, mono(lower alkyl)aminocarbonyl, di(lower alkyl)30 aminocarbonyl, cyano, halogen or epoxy.. - 6 41888 The aforementioned lower alkyl, lower alkenyl, lower alkynyl and lower alkoxy groups contain up to 6 carbon atoms and the lower alkanoyl groups contain up to 7 carbon atoms. Examples of such lower alkyl groups are methyl and ethyl.
Examples of such lower alkenyl groups are vinyl and allyl. Examples of such lower alkynyl groups are ethynyl and propynyl. Examples of such lower alkoxygroups are methoxy and ethoxy. Examples of such lower alkanoyl groups are acetyl and propionyl. The term cycloalkyl denotes a cyclic hydrocarbon group containing from 3 to 7 carbon atoms such as cyclopropyl, and cyelohexyl.
Especially preferred acyl derivatives provided by this invention are the following compounds of formula I and their salts: (7R)-3-/ [(1,4,5,5-tetrahydro-4-ethyl-5,6-dioxo-as-triaz in -3-yl)-thio]methy1_T~7- [2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid, (7R)-3-/”[ (1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as20 -triazin-3-yl)-thio]methyl_7-7-[2-(2-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_7-7-[2-(2-thienyl)-acetamido]-3 -cephem-4-carboxylic acid, - 7 418 8© (7R)-3-/ [(l,4,5,6-tetrahydro-4-butyl-5,6-dioxo-as-triazin-3-yl)-thio]mathyl_/-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid. (7R)-3-/ [(l,4,5,6-tetrahydro-4-(2-raethoxye.thyl)-5,65 -dioxo-as-triazin-3-yl)-thio]methyl_7-7- [2- (2-thienyl)-acetamido]-3-cephem-4-carboxylie acid, (7R)-3-/ [(1,4,5,6-tetrahydro-l,4-dimethyi-5,6-dioxo-as-triazin-3-yl)-thio]methyl_7-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic aoid, (7R)-3-/- [(1,4,5,6-tetrahydro-l,4-diethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl_7-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid, (7RJ-3-/-[(l,2,5,6-tetrahydro-l-ethyl-5,6-dioxo-as-triasin-3-yl)-thio]methyl_7-7-[2-(2-thienyl)-acetamido]-315 -cephem-4-carboxylic acid, (7S)-7-methoxy-3-/— [(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl)-thio]methyij-Ί-[2-(thienyl)-acetamido]-3-cephem-4-carboxylic acid, (7R)-3-/- [(l-amino-l,2-dihydro-2-oxo-4-pyrimidinyl)-thio]20 methyl_7-7-[2-(2-thienyl)-acetamido]-3-oephem-4-carboxylic acid, (7R)-3-/- [ (l-ethyl-l,2-dihydro-2-oxo-4-pyrimidinyl)-thio]methyl_7-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid, (7R)-3-/-[ (l-butoxy-l,2-dihydro-2-oxo-4-pyrimidinyl)25 -thio]methyl_7-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid, - 8 41888 (7R)-3-/ [(1-butoxy-l,2-dihydro-5-methyl-2-oxo-4-pyrimidinyl)-thio]methyl_/-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid, (7R)-3-/ [(l,4-dimethyl-l,6-dihydro-6-oxo-2-pyrimidinyl)5 -thio]methyl_7-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid, (7R)-3-/ [(l-ethyl-l,4-dihydro-6-methyl-4-oxo-2-pyrimidinyl)-thio]methyl_/-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid, (7R)-7-(2-cyanoacetamido)-3-/—[ (1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl_7-3-cephem-4-carboxylic acid, (7R)-3-//1 (l,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl_7-7-[(R)-mandelaniido]-3-cephem-415 -carboxylic acid, (7R)-7-[(R)-2-amino-2-phenylacetamido]-3-/- [(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methy1_7“ -3-cephem-4-carboxylic acid, (7R)-3-/ [(1,4,5,6-tetrahydro-4-ethy1-5,6-dioxo-as20 -triazin-3-yl)-thio]methyl_T-7-[2-(5-oxo-l,2,3-oxadiazolidin-3-yl)-acetamido]-3-cephem-4-carboxylic acid, (7R)-3-/-[ (l-ethyl-l,2-dihydro-2-oxo-4-pyrimidinyl)-thio]-methyl_7_7-[2-(5-oxo-l,2,3-oxadiazolidin-3-yl)-acetamido]-3-cephem-4-carboxylic acid, (7R)-3-//( (l-amino-l,2-dihydro-2-oxo-4-pyrimidinyl)-thio]methyl_7-7-[2-(3-sydnonyl)-acetamido]-3-cephem-4-carboxylic acid. - 9 (7R)-3-/-[l-amino-l,2-dihydro-2-oxo-4-pyriinidinyl) -thio] methyl_7-7-[2-(1-tetrazolyl)-acetamido]-3-cephem-4-carboxylic acid, (7R)-3-/ [(l,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as5 -triazin-3-yl)-thio]methyl_7-7-[2-(1-H-tetrazol-l-yl)-acetamido] -3-cephem-4-carboxylic acid, (7R)-3-/ [(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl_7-7-[(R)-2-hydroxyhexanamido]-3-cephem-4-carboxylic acid, (7R)-3-/- [(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl_7-7-[(R)-2-hydroxy-4-methylvaleramido]-3-cephem-4-carboxylic acid, (7R)-3-/-[ (1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl_7-7-[(R)-2-hydroxy-2-(cyclohexyl15 acetamido]-3-cephem-4-carboxylic acid, and (7R)-3-/- [ (l,4,5,6-tetrahydro-4-ethyl-5,5-dioxo-as-triazin-3-yl)-thio]methyl_7-7-[2-(2-furyl)-acetamido]-3-cephem-4-carboxylic acid.
The compounds of formula I can be present as optically 20 pure isomers and as isomer mixtures.
According to the process provided by the present invention the compounds of formula I and their salts are manufactured by a) reacting a compound of the general formula X'—W± (II) , wherein X' represents a desacetoxy-cephalosporinyl group which corresponds to - 10 41888 the group X but in which the carboxyl group in the 4-position is prooant in- protected by salt formation with an inorganic or tertiary organic bast form and W1 represents a leaving atom or group, with a compound of the general formula H—S—Y (III) , wherein Y has the significance given earlier, in the presence of water and cleaving off the protecting group, or b) reacting a compound of the general formula X—S—Y (IV) wherein Y has the significance given earlier and X'' represents a desacetoxy- 7-amino-eephalosporanyl group which corresponds to the group X but in which the carboxyl group in the 4-position is present in protected form, with an acid of the general formula Z—OH (V) , wherein Z represents an acyl group which comes into consideration as a substituent on the amino group in the 7-position of a cephalosporin, or with a reactive functional derivative thereof, and cleaving off the protecting group and, in either case if desired, converting the product obtained into a salt.
The carboxyl group in the group-Χ*—eae-X'of a compound of formula -51-or IV can be protected, for example, by conversion into a readily cleavable ester (e.g. the benzyl ester or a silyl ester such as the trimethylsilyl ester) or by salt formation with an inorganic or tertiary organic base such as triethylamine. In the case of the carboxyl group in the group x*of a compound of Formula II a suitable tertiary organic base is tri-ethylamine.
As the leaving atom or group denoted by in a compound of formula II there may be mentioned, for example, a halogen atom (e.g. chlorine, bromine or iodine), an acyloxy group (e.g. a lov;er alkanoyloxy group such as acetoxy), a lower alkylsulphonyloxy group such as mesyloxy, an arylsulphonyloxy group such as tosyloxy and the azido group.
The reaction of a compound of formula II with a compound of formula III according to embodiment a) of the process can be carried out in a manner known per se; for example, at a temperature between 4O°C and 8O°C, expediently at about ,6O°C, in- a polag-solvent·;·--for—examgl-e—an-aieefeei—eueh-as—alower-- alkanol ~(e. g. ethanol· -and -propanol·)-,· -dimethylformamide or-dlmethyl-sulphoxide,- preferably in water or a buffer solution having a pH of 5 to 7, preferably 6.5, over a period of 3 to 8, preferably 6, hours.
As reactive·functional derivatives of acids of formula V there may be mentioned, for example, halides (i.e. chlorides, bromides and fluorides), azides, anhydrides, especially mixed anhydrides with strong acids, reactive esters (e.g. N-hydroxysuccinimide esters) and amides (e.g. imidazolides).
The reaction of a compound of formula IV with an acid of formula V or a reactive functional derivative thereof according to embodiment b) of the process can be carried out in a manner known per se. Thus, for example, a free acid of formula V can be reacted with one of the aforementioned esters of formula IV in the presence of a carbodiimide such as dicyclohexylcarbodi5 imide in an inert solvent such as ethyl acetate, acetonitrile, dioxane, chloroform, methylene chloride, benzene or dimethylformamide and the ester group subsequently cleaved off. In place of carbodiimides, the reaction can also he carried out in the presence of oxazolium salts (e.g. N-ethyl-5-phenyl10 -isoxazolium-3'-sulphonate).
In another embodiment, a salt of an acid of formula IV (e.g. a trialkylammonium salt) can be reacted with a reactive functional derivative of an acid of formula V in an inert solvent (e.g. one of the aforementioned solvents,.
The reaction of a compound of formula IV with an acid of formula V or a reactive functional derivative thereof can expediently be carried out at a temperature between +5°C and -40°C, for example at about 0°C.
After the reaction of a compound of formula II with a compound of formula III or a compound of formula IV with an acid of formula V or a reactive functional derivative thereof has been effected, the protecting group is cleaved off. Where the protecting group is a benzyl group (benzyl ester), this can be cleaved off by catalytic hydrogenation (e.g. in the presence of a noble metal catalyst such as palladium/carbon.
Where the protecting group is a silyl ftroup (silyl ester), this group can be cleaved off especially readily by treatment of the reaction product with water. Finally, where the carboxyl group of an acid of formula IV is protected by salt formation (e.g. with triethylamine), then the cleavage of this protecting group can be carried out by treatment with acid at a proportion ately lower temperature (e.g. at 0°C to 10°C).
Examples of acids which can be used are hydrochloric acid, sulphuric acid, phosphoric acid and citric acid.
The compounds of formula II are known and can be prepared in a manner known per se starting from the corresponding cephalosporins, i.e. compounds of the general formula X—o—CO—ch3 wherein X has the significance given earlier.
Examples of compounds of formula II are the alkali metal 15 ' salts (e.g. the sodium salt) of cephalothin, 7-a-methoxy-cephalothin, cephacetrile, (7R)-mandelsmido-cephalosporanic acid and 7-(3-sydnonacetamido)-cephalosporanic acid and the zwitter-ion cephaloglycine.
Certain of the compounds of formula III are novel and 20 certain of them are known. The novel compounds of formula III can be prepared in a manner analogous to the preparation of the known compounds.
Thus, a 1-substituted 2-oxo-4-mercaptopyridine can be prepared from a correspondingly-substituted 4-chloro-2-oxo25 pyridine [chem. Ber. 99, 255 (1966)] by nucleophilic exchange (e.g. with an alkali metal hydrogen sulphide). - 14 i In a similar manner, a l,3-disubstituted-2,6-dioxo-l,2,3,6-tetrahydro-4-mercaptopyrimidine can be prepared from a corresponding 4-chloro-2,6-dioxo-1,2,3,6-tetrahydropyrimidine.
The 5,6-dioxo-3-mercapto-as-triazines can be prepared from 5 the correspondingly-substituted thiosemicarbazides in an analogous manner to the synthesis of l,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine - see the dissertation of K. H. Ongania (Innsbruck 1972).
A thiol of formula III which contains a double-bond 10 between the carbon atom substituted by the mercapto group and an adjacent nitrogen atom can be present in the form of a tautomeric thioketone.
A compound of formula IV can be prepared by reacting a compound of the general formula X—Wx , wherein X'' and have the significance given earlier, with a compound of formula III. The reaction can be carried out under the same conditions as those described earlier in connection with the reaction of a compound of formula II with a compound of formula III.
The acids of formula V and reactive functional derivatives thereof are known or are analogues of known compounds and can be prepared in a manner known per se. —β 4 1 8 8 δ The acids of formula V which contain an asymmetric carbon atom normally occur in the form of racemic mixtures. The separation of such racemates into the optically active isomers can be carried out according to known procedures. Thus, for example, diastereomers can be formed from a racemic mixture using an optically active resolving agent such as an optically active base, for example a,a-(1-naphthyl)-ethylamine or ‘ The diastereomers formed can be separated by selective 10 crystallisation and subsequently converted into the corresponding optical isomers.
A compound of formula I in the D-form can be manufactured either by separating a compound of formula I which is present in the form of an isomer mixture in a manner known per se (e.g. by fractional crystallisation of a salt such as the calcium salt) and isolating the desired D-form, or by reacting a compound of formula XII with a D-compound of formula II or a compound of formula IV with a D-acid of formula V or a reactive functional derivative thereof. The latter method is preferred.
The compounds of formula I, their salts and hydrates of these salts possess antibiotic, especially bactericidal, activity. They possess a wide spectrum of activity against gram-positive and gram-negative microorganisms, especially against penicillinase-positive Staphylococci as well as various cephalosporinase-positive gram-negative bacteria such as, for example, Escherichia coli, Proteus, Klebsiella, Aerobacter and Serratia types. - 16 41888 The compounds of formula I, their pharmaceutically acceptable salts and hydrates of said salts can be used for the treatment and prophylaxis of infectious diseases and as disinfectants. For adults, a daily dose of 1 g to> 4 g come irrto consider5 ation. Parenteral administration is especially preferred.
The antimicrobial activity of two of the acyl derivatives provided by the present invention, namely the sodium salt of (7R)-3-/—[(l,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) -thio] methy lJ-Ί- [2- (5-oxo-l,2,310 -oxadlazolidin-3-yl)-acetamido] -3-cephem~4-carboxylie acid (substance A in the following Table) and the sodium salt of (7R)-3-/-£(l,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio] methylJ-7-[2-(1-H-tetrazol-l-yl)-acetamido] -3-cephem-4-carboxylic acid (substance B in the following Table) will be seen from the following CD5Q values (mg/kg subcutaneously in the mouse): Table Substance Penicillin- -sensitive Staphylococci Penicillin- -resistent Staphylococci Escherichia coli A 0.25 5.5 0.38 B 0.60 3.2 0.90 The acute toxicity (LDj-θ) of these substances on intravenous administration to mice amounts to 2000-4000 mg/kg 4S1888 in the case of substance A and to 1000-2000 mg/kg in the case of substance B.
Pharmaceutical preparations, preferably dry ampoules, can contain the compounds of formula I, their pharmaceutically acceptable salts or hydrates of said salts, optionally in association with other therapeutically valuable substances.
Applicants are aware of the specification of Patent Application Ho. 1693/75.
The following Examples Illustrate the process provided by the present invention: Example 1 Manufacture of the sodium salt of (7R)-3-/~[(1,4,5,65 -tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio] methy1_/-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid. 4.4 g of cephalcthin sodium salt /~[α]θ° = +130° (c = 1 in water)_/ are stirred 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 of sodium bicarbonate for 6 hours at 60°C and pH ca 6.5 while gassing with nitrogen. The mixture is then cooled to 10°C and adjusted to pH 2 with 2-N hydrochloric acid. The substance thereby precipitated is filtered off under suction and washed with 25 ml of ice-water. It is then dissolved in acetone and the solution evaporated in vacuo. The residue remaining is dissolved in dimethylformamide and the solution treated with 7.5 ml of a 2-N solution of the sodium salt of 2-ethyl-caproic acid in ethyl acetate. By dilution with ethyl acetate, the desired product crystallises out. This is filtered off under suction, washed successively with ethyl acetate, ether and petroleum ether and dried in vacuo; yield 4.5 g (80%); melting point >170°C (decomposition); [α]θθ = +13.1° (c ~ 0.800 in water).
The 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as25 -triazine used as the starting material can be prepared as follows: 120 g of 4-ethyl-thiosemicarbazide are reacted in the presence of 23 g of sodium in 1 litre of methanol for 4 hours with 116 g of oxalic acid dimethyl ester at the boiling point of the mixture. The triazine is isolated from the mixture in the form of the sodium salt and then an aqueous solution is obtained by acidification; melting point 189°-19O°C.
Example 2 Manufacture of £he sodium salt of (TR}-3~£~[(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl)-thio]methy1_/10 -7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid.
This salt is manufactured in a manner analogous to that described in Example 1 from 4.18 g of cephalothin sodium salt and 1.91 g of l,4,5,6-tetrahydro-4-methyl-5,6-dioxo-3-mercapto-as-triazine; yield 2.8 g (54.1%); melting point 2QO°-2O5°C (decomposition); = “2.7° (c = 0.592 in water).
The triazine used as the starting material is prepared in a manner analogous to that described in Example 1 from 176 g of 4-methyl-thiosemicarbazide and 198 g of oxalic acid dimethyl ester; melting point 218°-22O°C (decomposition).
Example 3 Manufacture of the sodium salt of (7R)-3-/~[(l,4,5,6-tetrahydro-4-allyl-5,6-dioxo-as-triazin-3-yl)-thic] methy!_/-7-Jj2-(2-thienyl)-acetamido] -3-cephem-4-carboxylic acid.
This salt is manufactured in a manner analogous to that described in Example 1 from 6.27 g of cephalothin sodium salt and 3.33 g of l,4,5,6-tetrahydro-4-allyl-5,6-dioxo-3-mercapto -as-triazine; yield 3.0 g (36.8%); melting point >180°C (decomposition); £α]θ° = +19.7° (c = 0.376 in water).
The triazine used as the starting material is prepared in a manner analogous to that described in Example 1 Starting from 26.2 g of 4-allyl-thiosemicarbazide and 23.6 g of oxalic acid dimethyl ester; melting point 138°-14O°C.
Example 4 Manufacture 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 salt is manufactured in a manner analogous to that 15 described in Example 1 from 6.27 g of cephalothin sodium salt and 3.62 g of l,4,5,6-tetrahydro-4-butyl-5,6-dioxo-3-mercapto-as-triazine; yield 3.0 g (35.7%); melting point >160°C (decomposition); D*3q° ” +17.6° (c = 0.640 in water).
I The triazine used as the starting material is prepared 20 in a manner analogous to that described in Example 1 from 14.7 g of 4-butyl-thiosemicarbazide and 11.8 g of oxalic acid dimethyl ester; melting point 18O°-181°C.
Example 5 Manufacture of the sodium salt of (7R)-3-/~£(1,4,5,6- 21 -tetrahydro-4-(2-methoxyethyl)-5,6-dioxo-as-triazin-3-yl)-thiojmethyl_/-7- [2-(2-thienyl)-acetamido]-3-cephem-4-carfcoxylic acid.
This salt is manufactured in a manner analogous to that 5 described in Example 1 from 6.27 g of cephalothin sodium salt and 3.65 g of 1,4,5,6-tetrahydro-4-(2-methoxyethyl)-5,6-dioxo-3-mercapto-as-triazine; yield 2.0 g (23.8%); Q/J^0 = +io° (c = 0.280 in water) .
The triazine used as the starting material is prepared in 10 a manner analogous to that described in Example 1 from 14.9 g of 4-(2-methoxyethyl)-thiosemicarbazide and 11.8 g of oxalic acid dimethyl ester; melting point 158°-rl6O°C.
, Example 6 Manufacture of the sodium salt of (7I0-3-/-£(1,4,5,615 -tetrahydro-1,4-dimethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl_7-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid.
This salt is manufactured in a manner analogous to that described in Example 1 from 6.27 g of cephalothin sodium salt and 2.6 g of l,4,5,6-tetrahydro-l,4-dimethyl-5,6-dioxo-320 -mercapto-as-triazine; yield 4.6 g (58.0%); £α]θ° = -9.55° (c = 0.461 in water).
The triazine used as the starting material is prepared in a manner analogous to that described in Example 1 from 11.9 g of 1,4-dimethy1-thiosemicarbazide and. 11.8 g of oxalic acid dimethyl ester; melting point 231°-233°C (decomposition).
Example 7 Manufacture of the sodium salt of (7R)-3-/— [(1,4,5,6-tetrahydro-1,4-diethy1-5,6-dioxo-as-triazin-3-yl)-thio]methyl_/ -7- [2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid.
This salt is manufactured in a manner analogous to that described in Example 1 from 6.27 g of cephalothin sodium salt and 2.01 g of l,4,5,6-tetrahydro-l,4-diethyl-5,6-dioxo-3-mercapto-as-triazine; yield 5.5 g (65.7%); melting point >175°C (decomposition); Ηρθ = +1θ·2° (c = 0.547 in water).
The triazine used as the starting material is prepared in a manner analogous to that described in Example 1 from 14.7 g of 1,4-diethyl-thiosemicarbazide and 11.8 g of oxalic acid dimethyl ester; melting point 177°-179°C.
Example 8 Manufacture of the sodium salt of (7R)-3-/-[(1,2,5,6-tetrahydro-l-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methy1_7-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid.
This salt is manufactured in a manner analogous to that described in Example 1 from 10.45 g of cephalothin sodium salt and 4.8 g of l,2,5,6-tetrahydro-l-ethyl-5,6-dioxo-3-mercapto-as-triazine; yield 7.0 g (52.6%); melting point 21O°-215°C (decomposition); [α]θ° = +8.85° (c = 0.181 in water).
The triazine used as the starting material can be prepared as follows: 46.5 g of 1-ethyl-thiosemicarbazide are reacted in 700 ml of acetone at 40°C with 48 g of oxalic acid monomethyl ester chloride. 34.3 g of the product obtained are treated with 9.2 g of sodium methylate in 300 ml of methanol. The triazine is isolated from the mixture in the form of the sodium salt and then an aqueous solution is obtained by acidification; melting point 213°-214°C (decomposition).
Example 9 Manufacture of the sodium salt of (7S)-7-methoxy-310 Q(l,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 salt is manufactured in a manner analogous to that described in Example 1 from 5.16 g of 7-a-methoxy-cephalothin sodium salt [_ [α]^° = +194.5° (c = 0.308 in water)_/ and 1.82 g of 1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-3-mercapto-as-triazine; yield 1.0 g (15.9%); [ρί]ρ° = +54.6° (c = 0.308 in water).
Example 10 Manufacture of the sodium salt of (7R)-3-/ [(1-ethyl20 -l,2-dihydro-2-oxo-4-pyrimidinyl)-thio]methyl_7-7-[2-(2-thienyl)-acetamido]-3-eephem-4-carboxylic acid.
This salt is- manufactured In a manner analogous to that described in Example 1 from 4.18 g of cephalothin sodium salt and 1.8 g of 1-ethyl-l,2-dihydro-4-mercapto-2-oxo-pyrimidine; I I yield 3.2 g (65.3%); melting point >190°C (decomposition); £α]ρθ = -58° (c = 0.570 in water).
Example 11 Manufacture of the sodium salt of (7R)-3-/_[(l-butoxy5 -l,2-dihydro-2-oxo-4-pyrimidinyl)-thio]methyl_7-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid.
This salt is manufactured in a manner analogous to that described in Example 1 from 4.18 g of cephalothin sodium salt and 2.2 g of l-butoxyl,2-dihydro-4-mercapto-2-oxo-pyrimidine; yield 3.8 g (70%); £α]θ° = -83.6° (c = 0.850 in water).
The pyrimidine used as the starting material is prepared from 2 g of 1-butoxyuracil and 4 g of phosphorus pentasulphide; melting point 99°-100°C.
Example 12 Manufacture of the sodium salt of (7R)-3-/~£(l-butoxy-1,2-dihydro-5-methyl-2-oxo-4-pyrimidinyl)-thio]methyl_/-7-£2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid.
This salt is manufactured in a manner analogous to that described in Example 1 from 6.0 g of cephalothin sodium salt and 3.36 g of l-butoxy-l,2-dihydro-4-mercapto-5-methyl-2-oxo-pyrimidine; yield 0.8 g (9.7%); melting point >170°C (decomposition).
The pyrimidine used as the starting material is prepared in a manner analogous to that described in Example 11 by the reaction of 25 g of'l-butoxy-5-methyl-uracil., with 50 g of phosphorus pentasulphide. The l-butoxy-5-methyl-uracil is prepared by the reaction of 110 g of butoxyurea with 184 g of 8, β-diethoxy-α-methylpropionic acid ester.
Example 13 Manufacture of the sodium salt of (7R)-3-/— [(1,4-dimethyl-1,6-dihydro-6-oxo-2-pyrimidinyl)-thio]methyl_/-710 - [2-(2-thienyl)-acetamido]-3-cephem-4-carboxylie acid.
This salt is manufactured in a manner analogous to that described in Example 1 from 4.18 g of cephalothin sodium salt and 1.8 g of l,4-dimethyl-l,6-dihydro-2-mercapto-6-oxo-pyrimidine yield 1.35 g (25.3%); melting point 2OO°-21O°C (decomposition); Wd° = +9-5° (° = 0-348 in water).
Example 14 Manufacture of the sodium salt of (7R)-3-/ [(1-ethy1-1,4-dihydro-6-methyl-4-oxo-2-pyrimidinyl)-thio]methyl_/-7-p-(2-thienyl)-acetamido]-3-cephem-4-oarboxylic acid.
This salt is manufactured in a manner analogous to that described in Example 1 from 6.27 g of cephalothin sodium salt and 2.98 g of 1-ethyl-l,4-dihydro-2-mercapto-6-methy1-4-oxo-pyrimidine; yield 3.2 g (40.4%); melting point >170°C (decomposition); Ηρθ ~ (c = 0.333 in methanol).
The pyrimidine used as the starting material can be prepared as follows: g of U-ethyl-thiourea are dissolved in 50 ml of glacial acetic acid, boiled to reflux and treated dropwise with 17.2 g of diketene. The mixture is then boiled at reflux for 20 minutes and subsequently evaporated to 50 ml. While cooling and stirring, the residue is treated with 50 ml of water. Yellowish crystals precipitate, which are filtered off under suction and recrystallised from tetrahydrofuran; melting point 190°C.
Example 15 Manufacture of the sodium salt of (7R) -7-(2-cyanoacetamido) -3-// [(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl__/-3-cephem-4-carboxylic acid.
This salt is manufactured in a manner analogous to that described in Example 1 from 9.5 g of cephacetrile sodium salt and 5.46 g of l,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine; yield 3.3 g (26.8%); [a]^0 = +7.85° (c = 0.1785 in water).
Example 16 Manufacture of the sodium salt of (7R)-3-/( [(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio] methy1_/-7-[(R)-mandelamido]-3-cephem-4-carboxylic acid. - 27 43.88 This salt is manufactured, in a manner analogous to that described in 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-3-mercapto-as-triazine; yield 1.7 g (16.8%); [a]20 = -19.6° (c = 0.500 in water).
Example 17 Manufacture of (7R)-7-[(R)-2-amino-2-phenylacetamido]-3-/-[(1,4,5,6-tetrahyaro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl_/-3-cephem-4-carboxylic acid.
This compound is manufactured in a manner analogous to that described in Example 1 from 8.1 g of= cephaloglycine and 3.78 g of l,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine and isolated as a Zwitter ion; > yipld 4.19 g (40.5%); melting point >180°C (decomposition); [ίχ]2θ = -56.3° (c = 0.276 in dimethylformamide).
Example 18 Manufacture of the sodium salt of (7R)-3-/ [(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methy1_7-7-[2-(5-oxo-l,2,3-oxadiazolidin-3-yl)-acetamido] -3-cephem-420 -carboxylic acid.
This salt is manufactured' in a manner analogous to that described in Example 1 from 7.7 g of the sodium salt of 7-(3-sydnonacetamido)-cephalosporanic acid and 3.46 g of 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine; yield - 28 41888 3.3 g (31%); melting point >210°C (decomposition); [a] = r +17.9° (c = 0.380 in water).
Example 19 Manufacture of the sodium salt of (7R)-3-/-[(l-ethyl-1,25 -dihydro-2-oxo-4-pyrimidinyl)-thio]methyl_/-7- [2-(5-oxo-l,2,3-oxadiazolidin-3-yl)-acetamido]-3-cephem-4-carboxylic acid.
This salt is manufactured in a manner analogous to that described in Example 1 from 11.6 g of the sodium salt of 7-(3-sydnonacetamido)-cephalosporanic acid and 4.7 g of 1-ethyl10 -l,2-dihydro-4-mercapto-2-oxo-pyrimidine; yield 3.6 g (23.2%); [a]p° = -43.7° (c = 0.600 in water).
Example 20 Manufacture of the sodium salt of (7Η)-3-/“[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methy1_7~ -7-[2-(1 H-tetrasol-l-yl)-acetamido]-3-cephem-4-carboxylic acid. 1.28 g of tetrazole-l-acetic acid are dissolved in a mixture of 50 ml of tetrahydrofuran and 5 ml of dimethylformamide The solution is treated at -20°C successively with 1.18 ml of N-methyl-morpholine and 1.4 ml of chloroformic acid isobutyl ester and subsequently stirred for 20 minutes between -10°C and -20°C. There is then added an ice-cold solution in 50 ml of water of the salt obtained starting from 3.85 g of 7-amino-3-desacetoxy-3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]-cephalosporanic acid and 1.4 ml of triethylamine. The mixture is then stirred for 30 minutes at 4J.SS8 0°C and for 1 hour at 20°C. Subsequently, the mixture is concentrated in vacuo and the aqueous phase acidified with 5 ml of 2-N hydrochloric acid, whereby the desired product precipitates out as a crude acid. The latter is filtered off under suction, washed with plenty of ethyl acetate and then dissolved in dimethylformamide. The solution is treated with a 2-N solution of the sodium salt of 2-ethyl-caproic acid in ethyl acetate and subsequently diluted with ethanol and ether, whereby the desired crude sodium salt (3.3 g) precipitates out. For purification, the crude sodium salt is dissolved in 20 ml of water and treated with 60 ml of ethanol, after which a dark resin precipitates and is rejected. The filtrate is evaporated in vacuo and the residue treated with ethanol and ether to yield 2.3 g (44.5%) of desired pure sodium salt as a light-beige powder of melting point 210°C (decomposition); £u]q° = +23° (c = 0.824 in water).
The 7-amino-3-desacetoxy-3- £(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]-cephalosporanic acid used as the starting material can be prepared as follows; 2.72 g of 7-amino-cephalosporanic acid are suspended in 20 100 ml of water together with l,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine. The suspension is treated with 1.85 g of sodium bicarbonate, a solution of pH 6.4 resulting.
The latter is stirred for 3 hours at 60°C while gassing with nitrogen, then cooled to 20°C and stirred under nitrogen for a further 1 hour with addition of 1 g of active carbon. After •filtration, the filtrate is adjusted to pH 3.8 with 2-N hydrochloric acid, cooled to 0°C and stirred for 1 hour. The crystals which separate are filtered off under suction, washed successively with a small amount of ice-water, acetone, ether and petroleum ether and dried at 50°C in a high vacuum; yield 2.3 g (60%) of beige powder of melting point 23O°-235°C (decomposition).
The 7-amino-3-desacetoxy-3- [(1,4,5,6-tetrahydro-4-ethy1-5,6-dioxo-as-triazin-3-yl)-thio]-cephaiosporanic acid can also be prepared as follows: .1 g of 7-amino-3-azido-3-desacetoxy-cephalosporanic acid are stirred for 6 hours at 60°C while gassing with nitrogen, together with 5.16 g of l,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine and 4.2 g of sodium bicarbonate in 200 ml of a buffer of pH 7.0. The solution is cooled to 25°C and adjusted to pH 3.5 with 2-N hydrochloric acid. The crystals which separate are filtered off under suction (2.2 g). Concentration of the mother liquor yields a further 1.7 g; total yield 3.9 g (50%).
Example 21 Manufacture of the sodium salt of (7R)-3-/~[(l,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methylj-Ί-[(R)-2-hydroxyhexanamido] -3-cephem-4-carboxylic acid. 4.4 g of 7-amino-3-desacetoxy-3-£(l,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]-cephaiosporanic acid are dissolved at 0°C in a mixture of 44 ml of water and 44 ml of acetone by the addition of 2.5 g of potassium bicarbonate and stirring. There is then added dropwise at 0°C while stirring, a solution of 3 g of (R)-2-dichloroacetoxy-n-caproic - 31 418 8 8 acid chloride (boiling pointQ 5 = 75°-76°C) in 30 ml of acetone. The mixture is then stirred for 2 hours at 0°C and for 1 hour at 20°C. The acetone is distilled off from the filtered solution at 30°C under reduced pressure. The aqueous solution is stirred for 45 minutes at pH 9.5 by the addition of potassium carbonate, then extracted twice with ethyl acetate and adjusted to a pH of 1.5-2.0 with 3-N sulphuric acid. After extraction with ethyl acetate with addition of dimethylformamide, the ethyl acetate solution is washed several times with a 10% sodium chloride solution, dried over magnesium sulphate and evaporated under reduced pressure at 25°C. The residue is dissolved in 100 ml of isopropanol and treated with 12 ml of a 2-N solution of the sodium salt of 2-ethyl-caproic acid in isopropanol. The desired crude sodium salt is filtered off under suction, re-precipitated from water/isopropanol and dried under reduced pressure. The pure sodium salt is obtained as a beige powder; o 25 yield 56%; melting point from 183 C (decomposition); [a]D = +8.2° (c = 1.00 in water).
Example 22 Manufacture of the sodium salt of (7R)-3-/ [(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methy1_/-7- [(R)-2-hydroxy-4-methylvaleramido] -3-cephem-4-carboxylic acid.
This salt is manufactured in a manner analogous to that described in Example 21 from 3.5 g of 7-amino-3-desacetoxy-3- L(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio] -cephalosporanic acid and 2.4 g of (R)-2-dichloroacetoxy32 -isocaproic acid chloride (boiling pointQ= S3°-64°C); yield 51%; melting point from 180°C (decomposition); [α]θ5 = +6.0° (c = 1.09 in water).
Example 23 Manufacture of the sodium salt of (7R)-3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl_7-7- [(?,;“2-hydroxy-2-cyclohexyl-acetamido]-3-cephem-4-carboxylic acid.
This salt is manufactured in a manner analogous to that described in Example 21 from 3.9 g of 7-amino-3-desacetoxy-3- [(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]-cephalosporanic acid and 2.9 g of (R)-2-dichloroacetoxy-2-cyciohexyl-acetyl chloride (boiling pointQ $ = 1O5°-1O7°C); yield 37%; melting point from 190°C (decomposition); [α]θ5 = +2.8° (c = 0.50 in water).
Example 24 Manufacture of the sodium salt of (7r)-3-1/ [(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methy1_/-7-[2--(2-furyl)-acetamido]-3-cephem-4-carhoxylic acid. 3.85 g of 7-amino-3-desacetoxy-3-[(l,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]-cephalosporanic acid are dissolved at 0°C in a mixture of 40 ml of water and 40 ml of acetone by the addition of 2.4 g of potassium bicarbonate and stirring. To this solution there is added dropwise at -5°C, a solution of 1.45 g of 2-(2-furyl)-acetyl chloride in 15 ml of acetone and the mixture stirred for 3 hours at -5°C and for 1.5 hours at 20°C. The solution is extracted twice with ethyl acetate and the aqueous phase acidified at 0°C with 3-N sulphuric acid to a pH value of 2. After extraction with ethyl acetate with addition of dimethylformamide, the ethyl acetate solution is washed three times with a 10% sodium chloride solution, dried over magnesium sulphate and evaporated under reduced pressure at 25°C. The residue is dissolved in methanol and treated with 8 ml of a 2-N solution of the sodium salt of 2-ethyl-caproic acid in isopropanol. The desired crude sodium salt is precipitated with diethyl ether, filtered off under suction, washed with diethyl ether and then recrystallised from water with addition of acetone. There is obtained a beige powder; yield 43%; melting point from 180°C (decomposition); [α]θ5 = +18.4° (c = 1.0 in water).
Example 25 Manufacture of the sodium salt of (7R)-3-/-£(l-amino-l,2-dihydro-2-oxo-4-pyrimidlnyl)-thio]methyl_7~7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid.
This salt is manufactured in a manner analogous to that described in Example 1 from 8.36 g of cephalothin sodium salt and 3.0 g of l-amino-l,2-dihydro-4-mercapto-2-oxo-pyrimidine; yield 4.1 g (40.2%); melting point >185°C (decomposition); Hd° =78·5° (c = °·439 in water).
The pyrimidine used as the starting material is prepared from 8.6 g of 1-benzylideneamino-uracil [melting point 22O°-223°C; - 34 41888 Literature: Monatshefte flir Chemie 9(5, 1735 (1965)] and 12 g of phosphorus pentasulphide in pyridine, followed by hydrolysis with hydrochloric acid.
Example 26 Manufacture of the sodium salt of (7R)-3-/~[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)-thio]methy1_7-7- [2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid.
This salt is manufactured in a manner analogous to that described in Example 1 from 8.36 g of cephalothin sodium salt and 3.34 g of l,2,5,6-tetrahydro-5,6-dioxo-3-mercapto-2-methyl-as-triazine; yield 5.8 g (56%); melting point 185°C (decomposition); [a]^ = -49.3 (c = 0.450 in water).
The triazine used as the starting material is prepared in a manner analogous to that described in Example 1 from 31.5 g of 2-methyl-thiosemicarbazide and 35.4 g of oxalic acid dimethyl ester; melting point 26O°C.
Example 27 Manufacture of the sodium salt of (711)-3-/ [(1,2-dihydro-l-methyl-2-oxo-4-pyrimidinyl)-thio]methyl_7-7- [2-(2-thienyl)20 -acetamido]-3-cephem-4-carboxylic acid.
This salt is manufactured in a manner analogous to that described in Example 1 from 8.36 g of cephalothin sodium salt and 2.98 g of l,2-dihydro-4-mercapto-l-methyl-2-oxo-pyrimidine; yield 6.3 g (62.4%); melting point 180°C (decomposition); L°0p° = -67.7° (c = 0.6O4 in water).
Example 28 Manufacture of the sodium salt of (7R)-3-/—£(l,2-dihydro5 -l-methoxy-2-oxo-4-pyrimidinyl)-thio]methyl_/-7~p-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid.
This salt is manufactured in a manner analogous to that described in Example 1 from 8.36 g of cephalothin sodium salt and 3.32 g of l,2-dihydro-4-mercapto-l-methoxy-2-oxo-pyrimidine; yield 6.3 g (61.2%); melting point 175°-18O°C (decomposition); Md° = “9θ·6° (c - 0.338 in water).
The pyrimidine used as the starting material is prepared in a manner analogous to that described in Example 11 from 6 g of 1-methoxyuracil and 18 g of phosphorus pentasulphide; melting point 177°C.
Example 29 Manufacture of the sodium salt of (7R)-3-/ pl-ethoxy-l,2-dihydro-2-oxo-4-pyrimidinyl)-thio]methyl_/-7-[2-(2-thienyl)-acetamido]-3-cephem-4-oarboxylio acid.
This salt is manufactured in a manner analogous to that described in Example 1 from 6.27 g of cephalothin sodium salt and 2.75 g of l-ethoxy-l,2-dihydro-4-mercapto-2-oxo-pyrimidine; yield 3.5 g (44%); melting point >180°C (decomposition); [a] 2° = -74.2° (c = b.525 in water). - 36 41888 The pyrimidine used as the starting material is prepared in a manner analogous to that described in Example 11 from 6.4 g of 1-ethoxyuracil and 18 g of phosphorus pentasulphide; melting point 119°-120°C.
Example 30 Manufacture of the sodium salt of (7R)-3-/- [(1,6-dihydro-l-methyl-6-oxo-3-pyridazinyl)-thio]methyl_7-7- [2-(2-thienyl)-acetamidoJ-3-cephem-4-earboxylic acid.
This salt is manufactured in a manner analogous to that 10 described in Example 1 from 1.25 g of cephalothin sodium salt and 0.470 g of 1,6-dihydro-3-mercapto-l-methyl-6-oxo-pyridazine; yield 1.0 g (66.7%); melting point >215°C (decomposition); Γ7]20 = -49.7° (c = 0.332 in water).
The pyridazine used as the starting material is prepared 15 from 2.88 g of 3-chloro-l,6-dihydro-l-methyl-6-oxo-pyridazine (melting point 91°-92°C; Literature: Monatshefte fur Chemie 99, 33 (1968)] and 5.88 g of sodium hydrosulphide in ethanol at 130°C and 5-7 atmospheres; melting point 115°C.
Example 31 Manufacture of the sodium salt of (7R)-3-/-[(l-amino-1,2-dihydro-2-oxo-4-pyrimidinyl)-thio]methyl_7-7- [2-(3-sydnonyl)-acetamido]-3-cephem-4-carboxylic acid.
This salt is manufactured in a manner analogous to that described in Example 20 from 9.5 g of sydnone-3-acetic acid and 4188» 21.4 g of 7-amino-3-desacetoxy-3- £(l-,amino-l,2-dihydro-2-oxo-pyrimidin-4-yl)-thio]cephalosporanic acid; yield 9.7 g (32%); melting point from 200QG (decomposition);' E“]q°= -61.3° (c = 0.5 in water).
Example 32 Manufacture of (7R)-7- [(R)-2-amino-2-(p-hydroxyphenyl)-acetamido]-3-/- Q( 4-ethyl-l,4,5,6-tetrahydro-5,6-dioxo-as-triazin-3-yl)-thio]methyl_7~3-cephem-4-carboxylic acid.
This compound is manufactured in a manner analogous to 10 that described in Example 1 by the reaction of 24.5 g of D-p-hydroxy-N-tert.butyl-oxycarbonyl-cephaloglycine with 8,66 g of 1.4.5.6- tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine and subsequent removal of the tert.butyloxycarbonyl protecting group with formic acid; yield 5.7 g (23%); melting point from 200°C (decomposition); E°Od° “ -79.8° (c = 0.3 in dimethylformamide) Example 33 Manufacture of the sodium salt of (7R)-3-/ £(4-ethyl- . -1,4,5,6-tetrahydro-5,6-dioxo-as-triazin-3-yl)-thio]methy1_7-7-(2-(4-pyridyl-thio)-acetamido]-3-cephem-4-carboxylic acid.
This salt is manufactured in a manner analogous to that described in Example 1 from 6.0 g of cephapirin and 2.56 g of 1.4.5.6- tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine; yield 1.9 g (26%); melting point from 2O5°C (decomposition); = +36.2° (c = 0.5 in water). - 38 41888 Example 34 Manufacture of the sodium salt of (7R)-3-/~[(4-ethyl-1,4,5,6-tetrahydro-5,6-dioxo-as-triazin-3-yl)-thio]methy1_7“ -7-(2-pyrazol-l-yl-acetamido)-3-cephem-4-carboxylic acid.
This salt is manufactured in a manner analogous to that described in Example 1 from 6 g of (pyrazol-l-yl-methyl)-cephalosporin sodium salt and 3.12 g of 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine; yield 4.0 g (51%); melting point from 190°C (decomposition).
Example 35 Manufacture of the sodium salt of (7R)-3-/~[(l,2,3,6-tetrahydro-2,6-dioxo-l-methyl-s-triazin-4-yl)-thio]methy1_7-7-[2-(2-thienyl)-acetamido] -3-cephem-4-carboxylic acid.
This salt is manufactured in a manner analogous to that 15 described in Example 1 from 8.36 g of cephalothin sodium salt and 3.34 g of l,2,3,6-tetrahydro-2,6-dioxo-4-mercapto-l-methyl -s-triazine; yield 5.5 g (53%); melting point from 200°C (decomposition); = -43° (c = 0.1 in water).
The 1,2,3,6-tetrahydro-2,6-dioxo-4-mercapto-l-methyl-s20 -triazlne used as the starting material can be prepared as follows: A solution obtained by treating 14«8 g of sodium with 1000 ml of methanol is treated with 39.9 g of 5-methy1-2thio-biuret and 72 g of - 39 41888 diethyIcarbonate and boiled at reflux for 24 hours. The solution is concentrated to a volume of 200 ml in vacuo. The substance which crystallises out is filtered off under suction, dissolved in 200 ml of water and acidified with 2-N hydrochloric acid. The precipitated compound is filtered off under suction and recrystallised from 350 ml of ethanol; yield 11.2 g (23%) of a colourless substance; melting point 275°C.
The 5-methyl-2-thio-biuret used in the foregoing can be prepared as follows; A solution of 76 g of thiourea in 1000 ml of dimethylformamide is treated with 65.4 ml of methyl isocyanate and then stirred for 72 hours at 50°-55°C. The solution is then evaporated in vacuo and the residue recrystallised from water; yield 79.4 g (60%) of colourless substance; melting point 209°-210°C.
Example 36 Manufacture of the sodium salt of (7R)-3-/ £(l-ethyl-5-chloro-1,2-dihydro-2-oxo-4-pyrimidinyl)-thio] methyl_7~7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid.
This salt is manufactured in a manner analogous to that described in Example 1 from 6.27 g of cepholothin sodium salt and 3.04 g of l-ethyl-5-chloro-l,2-dihydro-4-mercapto-2-oxo-pyrimidine; yield 3.5 g (42%); melting point from 185°C (decomposition); £α]βθ = -95.2° (c = 0.394 in water).
The l-ethyl-5-chloro-l,2-dihydro-4-mercapto-2-oxo-pyrimidine used as the starting material can be prepared as follows: 1.74 g of l-ethyl-5-chlorouracil are first mixed with 4.44 g of phosphorus pentasulphide and 0.1 ml of water, then treated with 30 ml of pyridine and boiled at reflux for 3.75 hours.
The mixture is evaporated in vacuo at 40°C, the residue suspended in 30 ml of water and treated with 30 ml of 2-N hydrochloric acid. The crystals obtained are filtered off under suction, washed with water and recrystallised from ethanol; yield 1.3 g (68%) of yellow substance; melting point 217°-22O°C. t The l-ethyl-5-chlorouracil used in the foregoing can be prepared as follows: Chlorine is led into a solution of 9.9 g of 1-ethyluracil in 150 ml of glacial acetic acid until potassium iodide -starch paper reacts positively and 1-ethyl-uracil is no longer detectable by thin-layer chromatography (ca 0.5 hours). The mixture is evaporated in vacuo at 40°C and the crystalline residue recrystallised from 300 ml of ethanol; yield 10.0 g (81%) of colourless, fine needles; melting point 244°-247°C.
The 1-ethyl-uracil used in the foregoing can be prepared as follows: g of N-ethylurea and 105 g of β,β-diethoxypropionic acid ethyl ester are added to a solution of 15.0 g of sodium in 700 ml of ethanol. The yellow solution is then heated for hours at 25°C and subsequently boiled under reflux for 15 41883 hours. The mixture is evaporated in vacuo and the residue dissolved in 300 mi of water, cooled to 0°C and acidified with 100 ml of concentrated hydrochloric acid. A crystalline intermediate precipitates out (43 g) and is filtered off under vacuum, washed with 100 ml of ice-water and subsequently heated to'80°-100°C in 250 ml of water until conversion into the desired water-soluble 1-ethyl-uracil is complete. The solution is evaporated in vacuo at 40°C and the remaining residue recrystallised fpom ethanol/ether; yield 14.0 g (20%) of colourless substance; melting point 15p°C.
Example 37 Manufacture 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-(1 H-tetrazol-l-yl)-acetamido]-3-cephem-4-carboxylic acid.
This salt is manufactured in a manner analogous to that described in Example 20 from 2.95 g of tetrazole-l-acetic acid and 8.55 g of 7-amino-3-[(l,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)-thio]-cephalosporanic acid; yield 4.65 g (40%); melting point 220°-230°C (decomposition); DGd° = 53·6θ (° = 0.321 in water).
Example 38 Manufacture of the sodium salt of (7R)-7-(R)-mandelamido-3-/-[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl) 25 -thio]methyl_7-3-cephem-4-carboxylic acid.
This salt is manufactured in a manner analogous to that described in Example 21 from 9.25 g of D-O-dichloroacetyl-mandelic acid chloride and 11.1 g of 7-amino-3-desacetoxy-3- £(l,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)5 -thio]-cephalosporanic acid; yield 4.3 g (27%); melting point 2OO°-21O°C (decomposition); [α]θ° = 66.8° (c = 0.296 in water) Example 39 Manufacture of the sodium salt of (7R)-7-[2-(3-sydnonyl)-acetamido]-3-/- £{ 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as10 -triazin-3-yl)-thio]methyl_7-3-cephem-4-carboxylic acid.
This salt is manufactured in a manner analogous to that described in Example 20 from 5.76 g of sydnone-3-acetic acid and 14.95 g of 7-amino-3-desacetoxy-3-£(l,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)-thio]-cephalosporanic acid; yield 7.0 g (33%); melting point from 200°C (decomposition); £α]2θ = -25.5° (c = 0.227%).
Example 40 Manufacture of the sodium salt of (7R)-3-/ [(1-dimethylamino-l,2-dihydro-2-oxo-4-pyrimidinyl)-thio] methy1_7~7-[220 -(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid.
This salt is manufactured in a manner analogous to that described in Example 1 from 3.34 g of cephalothin sodium salt and 1.42 g of l,2-dihydro-l-dimethylamino-4-mercapto-2-oxo-pyrimidine; yield 2.4 g (57%); melting point from 165°C (decomposition); = -65.2° (c = 0.557 in water).
Example 41 Manufacture of the sodium salt of (7R).-3-/~[(3-chloro-1,6-dihydro-l-methyl-6-oxo-4-pyridazinyl)-thio]methyl_T-7-(2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid.
This salt is manufactured in a manner analogous to that described in Example 1 from 8.36 g of cephalothin sodium salt and 3.7 g of 3-chloro-l,6-dihydro-4-mercapto-l-methyl-6-oxo-pyrida2ine; yield 4.7 g (44%); melting point 225°-23O°C (decomposition); Ηρθ = +5-35° (c = 0.522 in water).
The 3-chloro-l,6-dihydro-4-mercapto-l-methyl-6-oxo-pyridazine used as the starting material can be prepared as follows; A solution of 17.9 g of 3,4-dichloro-l,6-dihydro-l-methyl-6-oxo-pyridazine in 200 ml of methanol is treated with a solution of 14.8 g of sodium hydrosulphide monohydrate in 200 ml of methanol. The mixture is then stirred for 1.5 hours at 25°C while gassing with nitrogen. Undissolved material is then filtered off and the filtrate concentrated in vacuo. The residue is suspended in 150 ml of water, made acidic with 1-N hydrochloric acid and extracted three times with ethyl acetate. The combined ethyl acetate extracts are washed with water, dried over sodium sulphate and evaporated in vacuo. The residue obtained is recrystallised from ethanol; yield 9 g of yellowish needles; melting point 163°C.
The 3,4-dichloro-l,6-dihydro-l-methyl-6-oxo-pyridazine used in the foregoing can be prepared as follows: - 44 41888 67.75 g of 3,4-dichloro-6-hydroxy-pyridazine are dissolved in 205 ml of a 2-N sodium hydroxide solution and treated dropwise with 36 ml of dimethylsulphate. The mixture is then heated at 70°C for 0.5 hour, subsequently cooled and extracted twice with chloroform. The combined chloroform extracts are washed with water, dried over sodium sulphate and evaporated in vacuo. The residue is recrystallised from high boiling petroleum ether? yield 54 g (73%); melting point 97°C.
Example 42 Manufacture of the sodium salt of (7R)-3-/-[(1,2-dihydro-l,S-dimethyl-2“OXO-4-pyridyl)-thio]methyl_77-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid.
This salt is manufactured in a manner analogous to that described in Example 1 from 7.55 g of cephalothin sodium salt and 2.95 g of l,2-dihydro-l,6-dlmethyl-4-mercapto-2-oxo-pyridine? yield 3.0g (31%)? melting point 178°-185°C (decomposition)? [a]p° +46.2° (c = 0.353 in water).
Example 43 Manufacture of the sodium salt of (TR}-3-/ [(4-ethyl20 -1,4,5,6-tetrahydro-5,6-dioxo-as-triazin-3-yl)-thio]methy!_/-7-(2-phenylacetamido)-3-cephem-4-carboxylic acid.
This salt is manufactured in a manner analogous to that described in Example 1 from 8.24 g of cephaloram sodium salt and 3.63 g of l,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto45 £3.883 -as-triazine; yield 2.2 g (21%); melting point 19O°-2OO°C (decomposition); [α]20 = +19.8° (c = 0.339 in water).
Example 44 Manufacture of the disodium salt of (7R)-7-[(RS)-2-sulpho-2-phenylacetamido]-3-/-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]-methyl_7-3-cephem-4-carboxylic acid. 9.07 g of (7R)-7-[(RS)-2-bromo-2-phenylacetamido]-3-/ [(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-y1) -thio]methyl_7-3-cephem-4-carboxylic acid sodium salt are dissolved in 10O ml of water and treated with 2.8 g of sodium sulphite. The solution is stirred at 25°C for 4.5 hours and then acidified to pH 2 with 2-N hydrochloric acid. The substance precipitated is filtered off and rejected. The filtrate is subsequently extracted twice with 100 ml of ethyl acetate each time. The ethyl acetate extracts are likewise rejected. The aqueous phase, which contains the desired product, is then concentrated in vacuo at 40°C to a volume of ca 30 ml and chromatographed on a column of 400 g of Amberlite XAD-2 (particle size: 300-1000 μ); yield 1.0 g (10.6%); melting point from 23O°C (decomposition); =-5.0° (c = 0.1 in water).
The (7R)-7-[(RS)-2-bromo-2-phenylacetamido]-3-/ £(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio] methy1_/-3-cephem-4-carboxylic acid sodium salt used as the starting material is prepared in a manner analogous to that described in Example 21 from 23.1 g of 7-amino-3-desacetoxy-3- [(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]-cephalosporanic acid and 14.0 g of DL-a-bromophenylacetic acid chloride; yield 10 g (28%); melting point from 190°C (decomposition).
Example 45 Manufacture of the sodium salt of (7R)-3-/ [(1-ethyl-l,2-dihydro-2-oxo-3-pyrazinyl)-thio]methyl_/-7- [2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid.
This salt is manufactured in a manner analogous to that 10 described in Example 1 from 6.27 g of cephalothin sodium salt and 2.50 g of l-ethyl-l,2-dihydro-3-mercapto-2-oxo-pyrazine; yield 5.0 g (65%); melting point from 175°C (decomposition); [α]θ° = +12.2° (c = 0.5 in water).
The 1-ethyl-1,2-dihydro-3-mercapto-2-oxo-pyrazine used 15 as the starting material can be prepared as follows; 23.7 g of l-ethyl-3-chloro-l,2-dihydro-2-oxo-pyrazine are added to a solution of 22.2 g of sodium hydrosulphide monohydrate in 1000 ml of methanol and the mixture stirred for 3 hours at 25°C. The .precipitated sodium chloride is then filtered off and the yellow filtrate evaporated in vacuo at 40°G. The residue is recrystallised from ethanol; yield 8.0 g (34%) of a crude yellow substance. For purification, .0 g of the latter are suspended in 50 ml of 0.5-N hydrochloric acid and then strongly acidified with addition of 10 ml of 2-N hydrochloric acid. The mixture is stirred for 10 minutes at 25°C and subsequently stored overnight in a refrigerator. - 47 41883 The resulting orange-yellow crystals (3.65 g) are filtered off under vacuum, washed with a small amount of ice-water and dried in vacuo at 50°C; melting point 2O4°-2O6°C (decomposition).
Example 46 Manufacture of the sodium salt of (7R)-3-/-£(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl_7-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid (a variation of the process of Example 1). 4.0 g of (7R)-3-azidomethyl-7-£2-(2-thienyl)-acetamido]10 -3-cephem-4-carboxylic acid sodium salt /melting point from 170°C (decomposition); £α]ρθ = +134.4° (c = 0.5 in water)_/ in 100 ml of a buffer of pH 7.0 are stirred for 24 hours at 5O°-55°C while gassing with nitrogen, together with 2.07 g of 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine and 1.01 g of sodium bicarbonate. The mixture is then cooled to °C and adjusted to pH 2 with 2-N hydrochloric acid. The crude acid which precipitates is filtered off under suction, washed with water and (then stirred for 10 minutes in 100 ml of ethyl acetate. The now pure acid is filtered off under suction (1.3 g), suspended in 25 ml of methanol and treated with 2.5 ml of a 2-N solution of 2-ethyl-caproic acid sodium salt in ethyl acetate, a solution resulting. By dilution with 100 ml of ethyl acetate, the desired sodium salt precipitates out; yield 1.25 g (24%); identical in all characteristics with the product manufactured according to Example 1.
Example 47 Manufacture of the sodium salt of (7R)-3-/~[(1-amino-l,2-dihydro-2“OXo-4-pyrimidinyl)-thio]methyl_7-7-[2-(1-tetrazolyl)-acetamido]-3-cephem-4-carboxylic acid.
This salt is manufactured in a manner analogous to that described in Example 20 from 6.4 g of (1-tetrazolyl)-acetic acid and 17.75 g of 7-amino-3-desacetoxy-3-[(1-amino-l,2-dihydro-2-oxopyrimidin-4-yl)-thio]-cephalosporanic acid; yield 8.0 g (33%); melting point from 190°C (decomposition).
The following Examples illustrate pharmaceutical preparations containing the acyl derivatives provided by the invention: Example A Manufacture of dry ampoules for intramuscular administration : A lyophilisate of 1 g of the sodium salt of (7R)-3-/ [(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl_7-7-[2-(1 Ή-tetrazol-l-yl)-acetamido]-3-cephem-4-carboxylic acid is manufactured in the normal manner and filled into an ampoule. The latter is treated with 2.5 ml of a 2% lidocaine hydrochloride solution before administration.
Example B Manufacture of dry ampoules for intramuscular administration : A lyophilisate of 1 g of the sodium salt of (7R)-325 -/[ (l,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methy1-/-7-[2-(5-oxo-l,2,3-oxadiazolidin-3-yl)-acetamido]-3-cephem-4-carboxylic acid is manufactured in a manner analogous to that described in Example A and filled into an ampoule.

Claims (25)

1. ) Compounds of the general formula X—S—Y (I) , wherein X represents a desacetoxy5 -cephalosporinyl group and Y represents a G-membered heterocyclic group which contains 1, 2 or 3 nitrogen atoms but which is not aromatic and is not enolisable to an aromatic groupj
2. 9) (7R)-3-/ - £(1,4,5,6-Tetrahydro-4-ethyl-5,6-dioxo-as20 -trlazin-3-yl)-thio]methyl_7-7-£2-(1-H-tetrazol-l-yl)-acetamido] -3-cephem-4-carboxylic acid and salts thereof. 30) (7R)-3-/ - £( 1,4,5,6-Tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl_7-7-£(R)-2-hydroxyhexanamido] -3-cephem-4-carboxylic acid and salts thereof. - 55 4ΙίΒ8 31) (7R)-3- ££(l,4,5,6-Tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio] methyl]-7- [(R)-2-hydroxy-4-methylvaleramido]-3“cephem-4-carboxylic acid and salts thereof. 32) (7R)-3~ ££(l,4,5,6-Tetrahydro-4-ethyl-5,6-dioxo-as5 -triazin-3-yl)-thio]methyl]-7- £(R)-7-hydroxy-2-(cyclohexyl)-acetamido]-3-cephem-4-carboxylic acid and salts thereof. 33) (7R)-3- ££(l,4,5,6-Tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)thiq]methyI]-7-[2-(2-furyl)-acetamidqt-3-cephem-4-carboxylic acid and salts thereof. IO 34) (7R)-3-Q£(l-Amino-l,2-dihydro-2-oxo-4-pyrimidinyl)-thiolmethyl}-7-[2-(3-sydnonyl)-acetamido]-3-cephem-4-carboxylic acid and salts thereof. 35) (7R)-3- £Ql-Amino-l,2-dihydro-2-oxo-4-pyrimidinyl)thio]methyl]-7-[2-(1-tetrazolyl)-acetamido][-3-cephem-4-carboxylic 2- thienyl, 2-furyl, 1-rtetrazolyl, 1-triazolyl, 1-pyrazolyl,
3. -3-cephem-4-carboxylxc acid and salts thereof. 3- sydnonyl, phenyl, cyclohexyl, 4-pyridylthio or cyano group and Rg has the significance given in claim 2, with the proviso that when Rg represents a 1-tetrazolyl, 1-triazolyl,' 1-pyrazolyl, 3-sydnonyl or pyridylthio group, Rg represents a hydrogen atom. 3) Acyl derivatives according to claim 1 or claim 2, wherein X represents a group of formula X^ in which Rg represents a
4. ) Acyl derivatives according to any one of claims 1 to 3 inclusive, wherein Y represents a non-aromatic, N-substituted pyridonyl group which is optionally substituted on one or more carbon atoms, or represents a non-aromatic pyrimidonyl, pyrazonyl, pyridazonyl or triazonyl group which is substituted on at least one of the nitrogen atoms and optionally substituted on one or more carbon atoms.
5. Reacted with tetrazole-l-acetic acid or a reactive functional derivative thereof. 73) A process according to any one of claims 37 to 41 Inclusive, claim 49 and claim 51 , wherein a compound of formula IV derived from 7-amino-3-desacetoxy-3- [(1,4,5,6-tetrahydro10 -4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]-cephalosporanic acid is reacted with α-hydroxycaproic acid or a reactive functional derivative thereof. 74) . A process according to any one of claims 37 to 41 inclusive, claim 49 and claim 51, wherein a compound of formula 5 cephalothin is reacted with l,4,5,6-tetrahydro-4-methyl-5,6 -dioxo~3-mercapto-as-tria2ine. 54) Ά process according to any one of claims 37 to 43 inclusive, wherein a compound of formula II derived from cephalothin is reacted with l,4,5,6-tetrahydro-4-allyl-5,610 -dioxo-3-mercapto-as-triazine. 55) a process according to any one of claims 37 to 43 inclusive, wherein a compound of formula II derived from cephalothin is reacted with 1,4,5,6-tetrahydro-4-buty1-5,6-dioxo-3-mercapto-as-trlazine. 15 56) a process according to any one of claims 37 to 43 inclusive, wherein a compound of formula II derived from oephalothin is reacted with l,4,5,6-tetrahydro-4-(2-methoxy ethyl)-5,6-dioxo-3-mercapto-as-triazine. 57) A process according to any one of claims 37 to 43 5 ? 41388 or di(lower alkyl)aminocarbonyl and the substituent on a cyclic carbon atom being lower alkyl, lower alkoxy, amino, mono(lower alkyl)amino, di(lower alkyl)amino, lower alkanoylamino, carboxy, lower alkoxycarbonyl, carbamoyl, mono(lower alkyl)aminocarbonyl, di(lower alkyl)aminocarbonyl, cyano or halogen; and a lower alkyl group bonded to a cyclic nitrogen or cyclic carbon atom being optionally substituted by hydroxy, lower alkoxy, amino, mono(lower alkyl)amino, dl(lower alkyl)amino, formyl, lower alkanoyl, lower alkanoylamino, carboxy, lower alkoxycarbonyl, carbamoyl, mono(lower alkyl)aminocarbonyl, di(lower alkyl)aminocarbonyl, cyano, halogen or epoxy. 42) A process according to any one of claims 37 to 41 inclusive, wherein there is used as the starting material of formula XI a compound derived from cephalothin, 7-a-methoxy-cephalothin, cephacetrile, (7R)-mandelamido-cephalosporanic acid, cephaloglycine or 7-(3-sydnonacetamido)-cephalosporanic acid. 43) A process according to any one of claims 37 to 42 inclusive, wherein 4-ethyl-, 4-methyl-, 4-allyl-, 4-(2-methoxyethyl)-, 1,4-dimethyl- or l,4-diethyl-l,4,5,6-tetrahydro-5,6-dioxo-3-mercapto-as-triazine is used as the starting material of formula III. 1 44) A process according to any one of claims 37 -to 42 inclusive, wherein l,2,5,6-tetrahydro-l-ethyl-5,6-dioxo-3-mercapto-as-triasine is used as the starting material of formula III. 45) a process according to any one of claims 37 to 42 inclusive, wherein 1-amino, 1-ethyl- or 1-butoxy-l,2-dihydro-4-mercapto-2-oxopyrimidine is used as the starting material of formula III, 46) A process according to any one of claims 37 to 42 inclusive, wherein 1-butoxy-l,2-dihydro-4-mercapto-5-methyl-2-oxopyrimidine is used as the starting material of formula III. 47) a process according to any one of claims 37 to 42 inclusive, wherein 1,4-dimethy1-1,6-dihydro-2-mercapto-6-oxo-pyrimidine is used as the starting material of formula III. 48) a process according to any one of claims 37 to 42 inclusive, wherein l-ethyl-l,4-dihydro-2-mercapto-6-methyl-4-oxopyrimidine is used as the starting material of formula III. 49) A process according to any one of claims 37 to 41 inclusive, wherein a compound derived from 7-amino-3-desacetoxy-3-((1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-y1)-thio]-cephaiosporanic acid is used as the starting material of formula IV. 50) A process according to any one of claims 37 to 41 inclusive, wherein a compound derived from 7-amino-3-desacetoxy-3-[(l-amino-l,2-dihydro-2-oxopyrimidin-4-yl)-thio]-cephaiosporanic acid is used as the starting material of formula IV. 51) A process according to any one of claims 37 to 41 inclusive and claims 49 an d 50 , wherein tetrazole-l-acetic acid, α-hydroxycaproic acid, α-hydroxyisocaproic acid, cyclohexyl-a-hydroxyacetic acid, sydnonyl-3-acetic acid or furyl-2-acetic acid or a reactive functional derivative thereof is used as the starting material of formula V. 52) a process according to any one of claims 37 to 43 inclusive, wherein a compound of formula II derived from ¢, 1 41388 cephalothin is reacted with l,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine. 53} A process according to any one of claims 37 to 43 inclusive, wherein a compound of formula XI derived from 5 3 the group X* or Z has the formula Χ' 3 or Z 1 respectively, wherein R 2 represents a 2-thienyl, 2-furyl, 1-tetrazolyl, 1-triazolyl, 1-pyrazolyl, 3-sydnonyl, phenyl, cyclohexyl, 4-pyridylthio or cyano group and R^ has the significance given in claim 38, with the proviso that when R 2 represents a 1-tetrazolyl, 1-triazolyl, 1-pyrazolyl, 3-sydnonyl or 4-pyridylthio group, R 3 represents a hydrogen atom. 40) A process according to any one of claims 37 to 39 inclusive, wherein there is used a starting material of formula III or IV in which Y represents a non-aromatic, N-substituted pyridonyl residue which is optionally substituted on one or more carbon atoms or represents a non-aromatic pyrimidonyl, pyrazonyl, pyridazonyl or triazonyl group which is substituted on at least one of the nitrogen atom and optionally substituted on one or more carbon atoms. 41) A process according to any one of claims 37 to 40 inclusive, wherein there is used a starting material of formula III or IV in which Y represents a non-aromatic, N-substituted 2-oxopyridin-4-yl group which is optionally substituted on one or more carbon atoms, or represents a non-aromatic 2-oxopyrimidin-4-yl, 4-oxopyrimidin-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-dioxotriazin-6-yl group which is substituted on at least one nitrogen atom and optionally substituted on one or more carbon atoms; the substituent on a cyclic nitrogen atom being lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, hydroxy, lower alkoxy, amino, mono(lower alkyl)amino, di(lower alkyl)amino, formyl, lower alkanoyl, lower alkanoylamino, carbamoyl, mono(lower alkyl)aminocarbonyl 5) Acyl derivatives according to any one of claims 1 to 4 inclusive, wherein Y represents a non-aromatic, N-substituted 2-oxo-pyridin-4-yl group which is optionally substituted on one or more carbon atoms, or represents a non-aromatic 2-oxopyrimidin-4-yl, 4-oxopyrimidin-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 group which is substituted on at least one nitrogen atom and optionally substituted on one or more carbon atoms; the substituent on a cyclic nitrogen atom being lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, hydroxy, lower alkoxy, amino, mono(lower alkyl)amino, di(lower alkyl)amino, formyl, lower alkanoyl, lower alkanoylamino, carbamoyl, mono(lower alkyl)aminocarbonyl or di(lower alkyl)aminocarbonyl and the substituent on a cyclic carbon atom being lower alkyl, lower alkoxy, amino, mono(lower alkyl)amino, di(lower alkyl)amino, lower alkanoylamino, carboxy, lower alkoxyearbonyl, carbamoyl, mono(lower alkyl)aminocarbonyl, di(lower alkyl)aroinocarbonyl, cyano or halogen; and a lower alkyl group bonded to a cyclic nitrogen atom or cyclic carbon atom being optionally substituted by hydroxy, lower alkoxy, amino, mono(lower alkyl)amino, di(lower alkyl)amino, formyl, lower alkanoyl, lower alkanoylamino, carboxy, lower alkoxycarbonyl, carbamoyl, mono(lower alkyl)aminocarbonyl, di(lower alkyl)aminocarbonyl, cyano, halogen or epoxy.
6. ) Acyl derivatives according to any one of claims 1 to 5 inclusive, wherein X represents a group of formula X^ in which R 2 represents a 2-thienyl, cyano, phenyl, cyclohexyl, 3-sydnonyl, 1-tetrazolyl, 2-furyl, n-butyl or isobutyl group, R 1 represents a hydrogen atom and, when R 2 represents a 2-thienyl group, represents a hydrogen atom or a methoxy group and R^ represents a hydrogen atom or, when R 2 represents a phenyl group, R^ represents a hydroxy or amino group, or, when R 2 represents a cyclohexyl, n-butyl of isobutyl group, R 3 represents a hydroxy group.
7. ) Acyl derivatives according to any one of claims 1 to 6 inclusive, wherein Y represents the 4-ethyl-, 4-methyl-, 4- 52 41888 -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 group or the l,2,5,6-tetrahydro-l-ethyl-5,6-dioxo-3-mercapto-as-triazinyl group.
8. ) Acyl derivatives according to any one of claims 1 to 6 inclusive, wherein Y represents the 1-amino, 1-ethyl- or 1-butoxy-1,2-dihydro-4-mercapto-2-oxopyrimidinyl group, the 1-butoxy-1,2-dihydro-4-mercapto-5-methyl-2-oxopyrimidinyl group, the l,4-dimethyl-l,6-dihydro-2-mercapto-6-oxopyrimidinyl group or the l-ethyl-l,4-dihydro-2-mercapto-6-methyl-4-oxopvrimidinyl group.
9. ) (7R)-3-/ - [(l,4,5,6-Tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio] methyl_7”7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid and salts thereof.
10. Inclusive, wherein a compound of formula II derived from cephalothin is reacted with l-ethyl-1,2-dihydro· -4-mercapto-2-oxo-pyrimidine. 62) a process according to any one of claims-37 to 42 inclusive, wherein a compound of formula II derived 10) (7R)-3-/ - [(1,4,5,6-Tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl)-thio] methyl_7-7- [2-(2-thienyl)-acetamido] -3-oephem-4-carboxylic acid and salts thereof. 10 at least one of said nitrogen atoms being substituted and at least one of said nitrogen atoms forming an amide group with an adjacent carbonyl group and a carbon atom(s) being optionally substituted and salts thereof and hydrates of said salts.
11. ) (7R)-3-/ - [(1,4,5,6-Tetrahydro-4-allyl-5,6-dioxo-as-triazin-3-yl)-thio] methyl_7-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid and salts thereof.
12. ) (7R)-3-/ - [(1,4,5,6-Tetrahydro-4-butyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl_7-7-[2-(2-thienyl,-acetamido] -3-cephem-4-carboxylic acid and salts thereof.
13. ) (7R)-3-/ - [(l,4,5,6-Tetrahydro-4-(2-methoxyethyl)-5,6-dioxo-as-triazin-3-yl)-thio]methylJ7-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid and salts thereof. 53 41888
14. ) (7R)-3-/-[(l,4,5,6-Tetrahydro-l,4-dimethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl_7-7-[2-(2-thienyl)-acetamido]-3-cephem-3-carboxylic acid and salts thereof. t .
15. IV derived from 7-amino-3-desacetoxy-3-[(l,4,5,6-tetrahydro-4-ethy1-5,6-dioxo-as-triazin-3-yl)-thio]-cephalosporanic acid is reacted with α-hydroxyisocaproic acid or a reactive functional derivative thereof. 75) a process according to an^ one of claims 37 to 41 > 15 from cephalothin is reacted with l-butoxy-l,2-dihydro-4-mercapto-2-oxo-pyrimidine. 63) a process according to any one of claims 37 to 42 inclusive, wherein a compound of formula II derived from cephalothin is reacted with l-butoxy-l,2-dihydro-420 -mercapto-5-methyl-2-oxo-pyrimidine. 64) a process according to any one of claims 37 to 42 inclusive, wherein a compound of formula II derived from cephalothin is reacted with l,4-dimethyl-l,6-dihydro-2-mercapto-6-oxo-pyrimidine. - 63 41888 65) A process according to any one of claims 37 to 42 inclusive and claim 48 , wherein a compound of formula II derived from cephalothin is reacted with 1-ethyl-l,4-dihydro-2-mercapto-6-methyl-4-'oxo-pyrimidine. 5 66) A process according to any one of claims 37 to 42 inclusive and claim 45 , wherein a compdund of formula II derived from cephalothin is reacted with l-amino-l,2-dihydro-4-mercapto-2-oxo-pyrimidine. 67) A process according to any one of claims 37 to 43 10 inclusive, wherein a compound of formula II derived from cephacetrile is reacted with l,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine. 68) A process according to any one of claims 37 to 43 inclusive, wherein a compound of formula II derived from (7R)15 -mandelamido-cephalosporanic acid is reacted with 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine. 69) A process according to any one of claims 37 to 43 inclusive, wherein a compound of formula II derived from cephaloglycine is reacted with 1,4,5,6-tetrahydro-4-ethyl20 -5,6-dioxo-3-mercapto-as-triazine. · 70) A process according to any one of claims 37 to 43 inclusive, wherein a compound of formula II derived from 7-(3-sydnonacetamido)-cephalosporanic acid is reacted with 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine. 25 71) A process according to any one of claims 37 to 42 inclusive and claim 45, wherein a compound of formula II derived from 7-(3-sydnonacetamido)-cephalosporanic acid is reacted with 1-ethyl-l,2-dihydro-4-mercapto-2-oxo-pyrimidine, 72) A process according to any one of claims 37 to 41 inclusive, claim 49 and claim 51 , wherein a compound of formula IV derived from 7-amino-3-desacetoxy-3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thioJ-cephalosporanic acid is 15 , wherein R and Rg have the significance given earlier in this claim, is reacted with an acid of formula V given in claim 36 in which the group Z has the general formula Rg—CH—CO(Zg) . wherein Rg and Rg have the significance given earlier in this claim. 39) A process according to claim 37 or claim 38 , wherein there is used a starting material of formula II or V in which 15 acid and salts thereof. 36) (7R)-7-(R)-Manaelamido-3-££(1,2,5,6-tetrahydro-2-methyl5,6-dioxo-as-triazin-3-yl)-thio]-methyl]-3-cephem-4-carboxylic acid and salts thereof. 37) A process for the manufacture of the acyl derivatives 15 and salts thereof. 15) (7R)-3-/ i(l,4,5,6-Tetrahydro-l,4-diethyl-5,6-dioxo-as5 -triazin-3-yl)-thio]methyl_7-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid and salts thereof. 15 2) Acyl derivatives according to claim 1, wherein the group X has the general formula wherein R^ represents a hydrogen atom or a methoxy group, R 2 represents a cyano or pyridylthio group or an aliphatic, alicyclic, aromatic or heteroaromatic group and R 3 represents a hydrogen atom or a hydroxy, hydroxymethyl, amino, azido, carboxy or 50 41888 sulpho group; a group other than cyano denoted by Rg being optionally substituted by hydroxy .,halogen, lower alkyl or lower alkoxy and, when Rg represents a pyridylthio group, Rg represents a hydrogen atom.
16. ) (7R)-3~/—[(1,2,5,6-Tetrahydro-l-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl_7-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid and salts thereof. 10
17. ) (7S)-7-Methoxy-3-/— [ (1,4,5,6-tetrahydro-4-methy1-5,6-dioxo-as-triazin-3-yl)-thio]methyl_7-7-[2-(thienyl)-acetamido]t
18. ) (7R)-3-// [ (l-Amino-l,2-dihydro-2-oxo-4-pyrimidinyl)-thio]methyl_7-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid
19. ) (7R)-3-// [ (1-Ethyl-l,2-dihydro-2-oxo-4-pyrimidinyl)-thio]methyl_7-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid and salts thereof.
20. Inclusive, claim 49 and claim 51, wherein a compound of formula IV derived from 7-amino-3-desacetoxy-3-[(l,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio] -cephalosporanic acid is reacted with cyclohexyl-a-hydroxyacetic acid or a reactive functional derivative thereof. 25 76) a process according to any one of claims 37 to 41 inclusive, claim 49 and claim 51, wherein a compound of formula IV derived from 7-amino-3-desacetoxy-3-[(l,4,5,6-tetrahydro41888 — -4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]-cephalosporanic acid is reacted with furyl-2-acetic acid or t a reactive functional derivative thereof. 77) A process according to any one of claims 37 to 41 5 inclusive, claim 50 and claim 51, wherein a Compound of formula IV derived from 7-amino-3-desacetoxy-3- [(l-amino-l,2-dihydro-2-oxopyrimidin-4-yl)-thicQ-cephalosporanic acid is reacted with sydnonyl-3-acetic acid or a reactive functional derivative thereof. 10 78) A process according to any one of claims 37 to 41 inclusive, claim 50 and claim 51, wherein a compound of formula IV derived from 7-amino-3-desacetoxy-3- [(l-amino-l,2-dihydro-2-oxopyrimidin-4-yl)-thio]-cephalosporanic acid is reacted with tetrazolyl-1-acetic acid. 15 79) A process according to any one of claims 37 to 41, wherein a compound of formula IV derived from 7-amino-3-desacetoxy-3[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)thio]Cephalosporanic acid is reacted with D-mandelic acid or a reactive functional derivative thereof. 20 80) A process for the manufacture of the acyl derivatives set forth in claim 1, substantially as hereinbefore described with reference to any one of Examples 1 to 47. 81) Acyl derivatives as set forth in claim 1, when manufactured by the process claimed in any one of claims 37 to 80 inclusive. 20 inclusive, wherein a compound of formula II derived from cephalothin is reacted with 1,4,5,6-tetrahydro-l,4-dimethyl· -5,6-dioxo-3-mercapto-as-triazine. 58) A process according to any one of claims 37 to 43 inclusive, wherein a compound of formula II derived from 25 cephalothin is reacted with 1,4,5,6-tetrahydro-l,4-diethyl-5,6-dioxo-3-mercapto-as-triazine. 418 59) A process according to any one of claims 37 to 42 inclusive, wherein a compound of formula II derived from cephalothin is reacted with 1,2,5,6-tetrahydro-l-ethyl-5,6-dioxo-3-mercapto-as-triazine. 5 60) A process according to any one of claims 37 to 43 inclusive, wherein a compound of formula II derived from 7-a -methoxy-cephalothin is reacted with 1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-3-mercapto-as-triazine. 61) A process according to any one of claims 37 to 42 20 claimed in claim 1, which process comprises a) reacting a compound of the general formula X'-(ΪΙ) , wherein X' represents a desacetoxy-cephalosporinyl group which corresponds 25 to the group X in claim 1 but in which the carboxyl group in the 4-position is pToaeftt by salt formation with an inorganic or tertiary organic base in- protected/form-and represents a leaving atom or group, with a compound of the general formula 30 H-S-Y (III) , wherein Y has the significance given 56 41888 in claim 1, in the presence of water and cleaving off the protecting group, or b) reacting a compound of the general formula (IV) , wherein Y has the significance given in claim 1 and X'’ represents a desacetoxy-7-amino-cephalosporanyl group which corresponds to the group X in claim 1 but in which the carboxyl group in the 4-position is present in protected form, with an acid of the general formula Z—OH (V) , wherein Z represents an acyl group which comes into consideration as a substituent on the amino residue in the 7-position of a cephalosporin, or with a reactive functional derivative thereof, and cleaving off the protecting group and, in either case if desired, converting the product obtained into a salt. 38) A process according to claim 37 wherein there is used a starting material of formula II in which the group X' has the general formula R, H 11 1 R. N· , wherein R represents a protected carboxy group, R^ represents a hydrogen atom or a '3 0 : methoxy group, Rg represents a cyano or pyridylthio group or an aliphatic, alicyclic, aromatic or heteroaromatic group and Rg represents a hydrogen atom or a hydroxy, hydroxymethyl, amino, azido, carboxy or sulpho group; a group other than cyano denoted by Rg being optionally substituted by hydroxy, halogen, ‘lower alkyl or lower alkoxy and, wheri Rg represents a pyridylthio group, Rg represents a hydrogen atom, or wherein a compound of formula IV in which the group X'* has the general formula (X”l) 20) (7R)-3-/- [ (l-Butoxy-l,2-dihydro-2-oxo-4-pyrimidinyl)20 thio]methyl_7-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid and salts thereof.
21. ) (7R)-3-/~[(l-Butoxy-l,2-dihydro-5-methyl-2-oxo-4-pyrimidinyl)-thio]methy 3.//-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid and salts thereof. 25
22. ) (7R)-3-/“[(l,4-Dimethyl-l,6-dihydro-6-oxo-2-pyrimidinyl)-thio]methyl__7 - 7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid and salts thereof. 54 41888
23. ) (7R)-3-/ £(l-Ethyl-l,4-dihydro-6-methyl-4-oxo-2-pyrimidinyl)-thio]methyl_/-7-£2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid and salts thereof.
24. ) (7R)-7-(2-Cyanoacetamido)-3-/ - £(1,4,5,6-tetrahydro-45 -ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl_7 - 3-cephem-4-carboxylic acid and salts thereof. 25) (7R)-3-/ - £( 1,4,5,6-Tetrahydro-4-ethyl-5,6-dioxo-as-trlazin-3-yl)-thio]methy1_7“7- £(R)-mandelamido]-3-cephem-4-carboxylic acid and salts thereof. 10 26) (7R)-7-£(R)-2-Amino-r2-phenylacetamido]-3-/ — £(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methy1_7 -3-cephem-4-carboxylic acid and salts thereof. 27) (7R)-3-/ - £(1,4,5,6-Tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio] methyl_/-7-£2-(5-oxo-l,2-oxadiazolidin15 -3-yl)-acetamido]-3-cephem-4-carboxylic acid and salts thereof. 28) (7R)-3-/ - £(l-Ethyl-l,2-dihydro-2-oxo-4-pyrimidinyl)-thio] methy l_/-7-£2-(5-oxo-l,2,3-oxadiazolidin-3-yl)-acetamido]· -3-cephem-4-carboxylic acid and salts thereof.
25. 82) A pharmaceutical preparation containing a compound of formula I given in claim 1 or a pharmaceutically acceptable salt thereof or a hydrate of such a salt in association with a compatible pharmaceutical carrier material.
IE1366/75A 1974-06-21 1975-06-18 Substituted desacetoxy-7-acylamino-cephalosporanic acids IE41888B1 (en)

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NL7805715A (en) * 1977-06-03 1978-12-05 Hoffmann La Roche METHOD FOR PREPARING ACYL DERIVATIVES.
JPS5419990A (en) * 1977-07-14 1979-02-15 Shionogi & Co Ltd Dihydrotriazinylthioxacephalosporin
MC1259A1 (en) * 1978-05-30 1980-01-14 Hoffmann La Roche ACYL DERIVATIVES
FR2474030A1 (en) * 1980-01-17 1981-07-24 Rhone Poulenc Ind 2-Mercapto-1,2,4-triazine, 1,3,4-triazole or tetrazole derivs. - useful as intermediates for antibacterial cephalosporin(s)
FR2494278A1 (en) * 1980-11-20 1982-05-21 Rhone Poulenc Ind NEW DERIVATIVES OF CEPHALOSPORIN, THEIR PREPARATIONS AND THE MEDICINAL PRODUCTS CONTAINING THEM
EP1379531A2 (en) * 2001-04-19 2004-01-14 Bioferma Murcia, S.A. Enzymatic process for preparing cephalosporanic acid derivatives using alpha-ketoacid derivatives
CA2717753C (en) 2008-03-05 2016-09-13 Merck Patent Gmbh Pyrazinone derivatives as insulin secretion stimulators, methods for obtaining them and use thereof for the treatment of diabetes

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US3868369A (en) * 1972-11-14 1975-02-25 Smithkline Corp 3-heterocyclicthiomethylcephalosporins

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SE7506908L (en) 1975-12-22
NZ177508A (en) 1978-04-03
DK153155B (en) 1988-06-20
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DK155329B (en) 1989-03-28
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FR2275215A1 (en) 1976-01-16
IL47299A0 (en) 1976-10-31
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CU34293A (en) 1979-01-16
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FR2275215B1 (en) 1980-05-16

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