EP0000272B1 - Acides 7-acylamino-3-substitués-3-cephem-4-carboxyliques, procédé pour leur préparation, compositions pharmaceutiques les contenant - Google Patents

Acides 7-acylamino-3-substitués-3-cephem-4-carboxyliques, procédé pour leur préparation, compositions pharmaceutiques les contenant Download PDF

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Publication number
EP0000272B1
EP0000272B1 EP78300076A EP78300076A EP0000272B1 EP 0000272 B1 EP0000272 B1 EP 0000272B1 EP 78300076 A EP78300076 A EP 78300076A EP 78300076 A EP78300076 A EP 78300076A EP 0000272 B1 EP0000272 B1 EP 0000272B1
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Prior art keywords
compound
formula
hydrogen
amino
cephem
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EP78300076A
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German (de)
English (en)
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EP0000272A1 (fr
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Davis Alan Berges
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Priority to DE8080200260T priority Critical patent/DE2861899D1/de
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • 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

Definitions

  • This invention relates to cephalosporin derivatives having antibacterial activity their preparation and pharmaceutical compositions containing them.
  • substituent R is asymetric for example when R is mandeloyl or phenylglycyl optical isomers are possible and the D-forms are preferred.
  • cephem-4-carboxlic acid group the carboxylic acid group of the tetrazole substituent and the group A when it is -COOH, can form esters and salts.
  • a pharmaceutical ester or salt of a compound of formula (I) is meant an ester or salt of one or more of these carboxylic acid groups.
  • esters examples include simple alkyl and aryl esters and in particular esters which are easily cleared within the body to the parent acid in particular indanyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl and thienylglycyloxymethyl esters.
  • salts of compounds of formula (I) include alkali metal salts for example the sodium and potassium salts, the ammonium salt and salts with organic amines for example procaine and dibenzylethylene diamine.
  • Hydroxyl groups in the substituent R can form easily split esters or ethers.
  • Amino groups in the substituent R for example when RNH- is 7-phenylglycylamino can be converted into pharmaceutically acceptable amide derivatives for example furanyl-, pyranyl-, oxolanyl-or oxiranylcarbonyl amides (see Belgian Patent No 835, 295).
  • Compounds of formula (I) can be prepared by reacting compound of formula (11):- where AC is acetyl or a derivative thereof where the cephem-4-carboxylic acid group is protected where R 3 is hydrogen or a group R as previously defined provided that any amino, carboxy, sulfo, or hydroxy groups are optionally protected, with a compound of formula (III): ⁇ where R', n and n' are as defined with reference to formula I or an alkali metal salt thereof and where R 3 is hydrogen thereafter reacting the product with an acylating agent or activated derivative of an acid ROH where R is as defined with reference to formula (I) provided that any free amino, carboxy, hydrogen or sulfo groups are optionally protected thereafter where R I is hydrogen optionally acylating the product with an N-acylating agent which supplies lower alkanoyl group thereafter removing any protecting groups and optionally converting the compound of formula (1) so obtained into a salt, ester, easily split ether or amide derivative thereof.
  • the compounds of formula (I) are most conveniently prepared by displacement of acetoxy from a compound of formula (II) above where R 3 is a group R with a compound of formula (III) above.
  • acylation steps referred to in the above process can be carried out by known methods for example as disclosed in Cephalosporins and Penicillins, Flynn, Academic Press, 1972; US Patent Nos. 2,721,196 and 3,953,424; Belgian Patent No. 832,725; German Patent Nos. 2,127,285 and 2,406,165.
  • Protecting groups which can be used during the process described above are known (see “Protective Groups in Organic Chemistry” J.F.W. McOmie, Plenum Press, 1973, Chapters 2 and 3 for use of amino, carboxy, sulfo or hydroxy protecting groups). Examples of such groups include t-butyl for -COOH and t-butoxycarbonyl for -NH 2 . These particular groups can be removed easily using trifluoroacetic acid.
  • salts, esters, easily split ethers and amide derivatives of compounds of formula (I) can be prepared by known methods, in particular sodium or potassium salts can be prepared from sodium or potassium 2-ethylhexanoate.
  • Tetrazole-5-thiones of formula (III) are disclosed and claimed in our co-pending European Patent Application No. 80200260.0.
  • the compounds of formula (1) have antibacterial activity against both Gram positive and Gram negative bacteria with minimum inhibitory concentrations (MIC's) in vitro from 0.2 to 200 pg/ml.
  • Test results for 7 - D - mandel - amido - 3 - [1 - [2 - (carboxymethylamino)ethyl]ethyl]tetrazol - 5 - ylthiomethyl] - 3 - cephem; 4 - carboxylic acid hydrate (A) are:
  • Compound A gave an ED SO in mice of 0.39 mg/kg (s.c.) and 7.2 mg/kg (p.o.) against E. coli, and 0.39 mg/kg against Kleb. pneumo. (s.c.) and 4 mg/kg (p.o.).
  • Cephalexin gives comparable values of 15.7 (s.c.) and 25 (p.o.) against E. Coli and 21.5 mg/kg (s.c.) and 18 mg/kg (p.o.) against Kleb. pneumo.
  • the invention further provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier.
  • compositions of the invention can be formulated so that they can be administered orally or by parenteral injection for example intravenously or intramuscularly.
  • composition is in the form of an injectable sterile solution or suspension.
  • the compounds of the invention can be formulated in the same way as known cephalosporins for example cefazolin or cephalothin.
  • the precise dosages are dependent upon the age and weight of the subject and on the susceptibility of the infection being treated. These can be determined by those skilled in the art based on the data disclosed herein compared with that available in the art attained with known cephalosporins.
  • the filtrate was applied to a Biogel P-2 (100-200 U.S. standard mesh) column, eluting with de-ionized water. Fractions containing product by thin layer chromatography were pooled, concentrated to small volume, and applied to a cellulose column. A mixture of acetonitrile and water (8 to 2) was used as chromatographic solvent. The eluate that contained product was evaporated to dryness. The residue was dissolved in deionized water and solution was lyophilized to give 290 mg.
  • An injectable pharmaceutical composition is formed by adding sterile saline solution (2 ml.) to 500 mg. of the product of Example 1. This material is injected parenterally four times daily to a human patient infected with susceptible bacteria. Other compounds of this invention may be similarly used.
  • reaction mixture is purified on an XAD-2 column as described in Example 4 to give a lyophilized product, 7 - [ ⁇ (Z) - (methoxyimino) - 2 - furanacetamido] - 3 - [1 - [2 - [(carboxymethyl)amino]ethyl] - tetrazole - 5 - ylthiomethyl] - 3 - cephem - 4 - carboxylic acid, disodium salt.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • 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)
  • Plural Heterocyclic Compounds (AREA)

Claims (5)

1. Composé de formule (I)
Figure imgb0011
ainsi que les sels pharmaceutiquement acceptables, les esters et les dérivés éthérés et amidiques aisément clivables de ce composé, dans laquelle R représente:
Figure imgb0012
où X représente un groupe thiényle, furyle, phényle, phényle monosubstitué par un groupe hydroxy, hydroxyméthyle, formamido ou uréido;
A représente un groupe -NH2, -OH, -COOH, -S03H, formyloxy ou méthoxyimino lorsque l'hydrogène sur l'atome de carbone en a est absent;
Y représente un radical cyano, sydnonyle, pyridonyle, thiényle, o-aminométhylphényle, phényle ou tétrazolyle;
Z représente un groupe méthyle, trifluorométhyle, trifluoroéthyle, pyridyle ou cyanométhyle;
R1 représente un atome d'hydrogène ou un groupe alcoyle inférieur ayant de un à quatre atomes de carbone;
R2 représente un atome d'hydrogène ou un groupe méthoxy;
m varie de zero à deux;
n varie de deux à quatre; et n1 varie de un à quatre.
2. Forme D d'un composé tel que revendiqué dans la revendication 1, possédant un substituant R qui est asymétrique.
3. Acide 7 - [α(Z) - (méthoxyimino) - 2 - furanacétamido] - 3 - [1 - [2 - [(carboxy- méthyl)amino]éthyl]tétrazole - 5 - ylthiométhyl] - 3 - céphème - 4 - carboxylique.
4. Procédé de préparation d'un composé suivant la revendication 1 caractérisé en ce qu'on fait réagir un composé de formule (II):
Figure imgb0013
ou un de ses dérivés dans lequel le groupe acide céphème-4-carboxylique est protégé, où Ac représente un groupe acétyle, R3 représente un atome d'hydrogène ou un groupe R tel que défini précédemment, étant entendu que tout groupe amino, carboxy, sulfo ou hydroxy soit éventuellement protégé, avec un composé de formule (III):
Figure imgb0014
ou un sel de métal alcalin de ce composé, où R1, n et n1 sont tels que définis dans la formule (I), et, lorsque R3 représente un atome d'hydrogène, on acyle ensuite le produit ainsi obtenu avec un agent acylant ou un dérivé activé d'un acide ROH où R est tel que défini dans la formule (I) étant entendu que tout groupe amino, carboxy, hydroxy ou sulfo libre soit éventuellement protégé et ensuite, lorsque Rl représente un atome d'hydrogène, on acyle éventuellement le produit à l'aide d'un agent N-acylant qui fournit le groupe alcanoyle inférieur, on élimine ensuite tout groupe protecteur et éventuellement, on transforme ensuite le composé de formule (I) ainsi obtenu en un sel pharmaceutiquement acceptable, ester, dérivé éthéré ou amidique aisément scindable.
5. Composition pharmaceutique caractérisée en ce qu'elle contient un composé suivant l'une quelconque des revendications 1 à 3 en association avec un véhicule pharmaceutiquement acceptable.
EP78300076A 1977-06-24 1978-06-23 Acides 7-acylamino-3-substitués-3-cephem-4-carboxyliques, procédé pour leur préparation, compositions pharmaceutiques les contenant Expired EP0000272B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DE8080200260T DE2861899D1 (en) 1977-06-24 1978-06-23 Tetrazole derivatives and a process for their preparation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US05/809,585 US4117125A (en) 1977-06-24 1977-06-24 7-Acylamino-3-[1-[2-(carboxymethylamino]ethyl) tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acids
US809585 1991-12-17

Related Child Applications (1)

Application Number Title Priority Date Filing Date
EP80200260A Division-Into EP0019308B1 (fr) 1977-06-24 1978-06-23 Dérivés de tétrazole et procédé pour leur préparation

Publications (2)

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EP0000272A1 EP0000272A1 (fr) 1979-01-10
EP0000272B1 true EP0000272B1 (fr) 1982-05-05

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EP80200260A Expired EP0019308B1 (fr) 1977-06-24 1978-06-23 Dérivés de tétrazole et procédé pour leur préparation
EP78300076A Expired EP0000272B1 (fr) 1977-06-24 1978-06-23 Acides 7-acylamino-3-substitués-3-cephem-4-carboxyliques, procédé pour leur préparation, compositions pharmaceutiques les contenant

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EP (2) EP0019308B1 (fr)
JP (1) JPS5412395A (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3070258D1 (en) * 1979-11-30 1985-04-11 Fujisawa Pharmaceutical Co Cephem compounds, processes for their preparation and pharmaceutical compositions containing them
US4420477A (en) * 1979-11-30 1983-12-13 Fujisawa Pharmaceutical Co., Ltd. Cephem compounds
EP0047014B1 (fr) * 1980-09-02 1986-01-15 Asahi Kasei Kogyo Kabushiki Kaisha Thioesters et procédé pour leur préparation
PL2591798T3 (pl) 2011-11-09 2015-04-30 Werner Lubitz Szczepionka do zastosowania w immunoterapii nowotworów
EP3195878A1 (fr) 2016-01-22 2017-07-26 Werner Lubitz Hôtes bactériens pour le traitement du cancer

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB567353A (en) * 1943-08-27 1945-02-09 John David Kendall Improvements in the manufacture of tetrazole compounds
NZ176206A (en) * 1973-12-25 1978-03-06 Takeda Chemical Industries Ltd Cephalosporins
BE832725A (fr) 1974-09-03 1976-02-25 Nouveaux composes meterocycliques et composition pharmaceutique les contenant
US4045438A (en) * 1975-10-24 1977-08-30 Yeda Research And Development Co. Ltd. Cephalosporin antibiotics
US4057631A (en) * 1976-09-02 1977-11-08 Smithkline Corporation 7-(α-Substituted phenylacetamido)-3-(1-carboxymethylthioethyltetrazolyl-5-thiomethyl)-3-cephem-4-carboxylic acids

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JPS5412395A (en) 1979-01-30
EP0019308A1 (fr) 1980-11-26
US4117125A (en) 1978-09-26
JPS617197B2 (fr) 1986-03-04
EP0019308B1 (fr) 1982-06-16
EP0000272A1 (fr) 1979-01-10

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