EP0000285B1 - Dérivés des acides 7-acylamino-3-((3-(carboxyméthyl-) thio-1 H-1,2,4-triazol-5-yl) thiométhyl)-3-céphem-4 carboxyliques, procédés pour leur préparation et leurs compositions - Google Patents

Dérivés des acides 7-acylamino-3-((3-(carboxyméthyl-) thio-1 H-1,2,4-triazol-5-yl) thiométhyl)-3-céphem-4 carboxyliques, procédés pour leur préparation et leurs compositions Download PDF

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Publication number
EP0000285B1
EP0000285B1 EP78300103A EP78300103A EP0000285B1 EP 0000285 B1 EP0000285 B1 EP 0000285B1 EP 78300103 A EP78300103 A EP 78300103A EP 78300103 A EP78300103 A EP 78300103A EP 0000285 B1 EP0000285 B1 EP 0000285B1
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Prior art keywords
formula
compound
thio
triazol
carboxylic acid
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EP78300103A
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German (de)
English (en)
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EP0000285A1 (fr
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David Alan Berges
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
    • C07D249/12—Oxygen or sulfur atoms
    • 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, to compositions containing them, and to a process for their preparation.
  • cephem-4-carboxylic acid group, the carboxylic acid group of the -SCH 2 CO 2 H moiety, the group A, when it is -CO 2 H or -OH can form esters. Accordingly herein an ester of a compound of formula (I) means an ester of one or more of these groups.
  • a salt of a compound of formula (I) means a salt of the carboxyl or -S0 3 H group or an acid addition salt as the context requires.
  • an amide derivative of a compound of formula (I) means a pharmaceutically acceptable non-toxic amide derivative of the compounds of formula (1) where R is 7-phenylglycylamino group.
  • salts of compounds of formula (I) include alkali metal salts for example sodium and potassium salts and salts with organic amines, in particular procaine and dibenzylethylenediamine salts.
  • esters of the compounds of formula (I) include simple alkyl and aryl esters and those which are easily cleaved in the body to the parent acid. Examples of these latter esters are indanyl, pivaloyloxymethyl, acetoxymethyl, propionoxymethyl, glyceryloxymethyl, phenylglycyloxymethyl and thienylglycyloxymethyl esters.
  • amide derivatives of the compounds of formula (I) are furyl-, pyranyl-, oxolanyl- and oxiranyl- carbonyl amides (i.e. Belgian Patent No. 835,295).
  • the acyl group R is preferably a group known to be of utility as a substituent on the 7-amino group in the structures of known or prior art cephalosporins or on the 6-amino group in the structures of known or prior art penicillins.
  • Some compounds of formula (I) exist as optical isomers. For example where R is mandelamido or phenylglycylamido. The D-form of these subgeneric groups are preferred.
  • Compounds of formula (I) can be prepared by a process which comprises reacting a compound of formula (11):- where R' is hydrogen or a group R as defined with reference to formula (I) provided that any free amino, carboxy, or sulpho groups are optionally protected and Ac is acetyl, with a compound of formula (III):- or an alkali metal salt thereof and where R' is hydrogen acylating the product so obtained with an acylating agent or active derivative of formula R-OH where R is as defined with reference to formula (I) provided that any free amino, carboxy or sulpho groups are optionally protected, thereafter removing any protecting groups present, and optionally converting the compounds of formula (I) into a salt, ester or non-toxic amide derivative.
  • Esterification of the carboxylic acid groups of compounds of formula (I) can be carried out by known methods.
  • Salts of compounds of formula (I) can be prepared by known methods, for example sodium and potassium salts can be prepared by reacting the acid with sodium or potassium 2-ethyl hexanoate.
  • Non-toxic amide derivatives can be prepared by analogy with known methods for example as described in Belgian Patent No. 835,295.
  • Examples of such groups are t-butyl, for COOH or t-butoxy carbonyl for NH 2 .
  • the protecting groups can be removed by known methods for example t-butyl and t-butoxycarbonyl, can be removed by trifluoracetic acid.
  • the compounds of formula (I) have antibacterial activity against both Gram positive and Gram negative bacteria, and minimum inhibitory concentrations (MIC's) in vitro of from 0.2 to greater than 200 ⁇ g/ml have been observed.
  • Test results for 7-D-mandelamino-3-[[3-(carboxymethyl)thio-lH-1,2,4-triazol-5-yl]thiomethyl]-3-cephem-4-carboxylic acid, disodium salt, hydrate (A) are:
  • Compound A showed an ED 50 in mice of 1.56 against E.coli as well as 1.02 mg/kg against Kleb. pneumo (s.c.).
  • compositions having antibacterial activity which comprise a pharmaceutical carrier containing a compound of formula (I), pharmaceutically acceptable salt, non-toxic amide derivative or ester thereof which is easily cleaved within the body to the parent acid, and their use as antibacterial agents by administering them in a composition in a non-toxic amount sufficient to combat such infections are also within this invention.
  • the administration may be orally or by parenteral injection such as subcutaneously, intramuscularly, or intravenously.
  • the injection of suitably prepared sterile solutions or suspensions containing an effective, non-toxic amount of a cephalosporin compound of the invention is the preferred route of administration.
  • compositions of this invention are preferably formulated and administered in the same manner as other prior art cephalosporins such as cephazolin or cephalothin.
  • the dosage regimen preferably comprises administration, preferably by injection, of an active but non-toxic quantity of a compound of formula (I) from about 250 mg. to 600 mg. with the total daily dosage regimen being from about 750 mg. to 6 g.
  • the precise dosages are dependant upon the age and weight of the subject and on the susceptibility of the infection being treated to each individual. These can be determined by those skilled in the art based on the data disclosed herein compared with that available to the art attained with the known cephalosporins outlined herebefore. The following Examples illustrate the invention. All temperatures are in °C.
  • reaction mixture is purified on an XAD-7 column as described in Example 1 to give a lyophilized product, 7-[ ⁇ (Z)-(methoxyimino)-2-furanacetamido]-3-[(3-(carboxymethyl) thio 1H-1,2,4-triazol-5-yl]thiomethyl]-3-cephem-4-carboxylic acid, disodium salt.
  • This derivative is stirred at 25°C. with 25 ml. of trifluoroacetic acid and 25 ml. of 1,3-dimethoxybenzene for 2 hours. The mixture is evaporated to dryness in vacuo, ethyl acetate is added to the residue and the precipitated salt is collected. This is dissolved in water and treated with Amberlite IR-45 weakly basic ion-exchange resin.
  • the solution is lyophilized to give 7-(D- ⁇ - amino - 4 - hydroxyphenylacetamido) - 3 - [[3- carboxymethyl)thio - 1H- 1,2,4 - triazol - 5 - yl]thiomethyl] - 3 - cephem - 4 - carboxylic acid.
  • 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 into a human patient infected with susceptible bacteria. Other compounds of this invention may be similarly .used.
  • dec used herein means decomposition

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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)

Claims (8)

1. Composé dé formule (i):
Figure imgb0014
dans laquelle R représente
Figure imgb0015
où
X est un groupe thiényle, furyle, phényle ou phényle monosubstitué par un groupe hydroxy, hydroxyméthyle, formamido ou uréido;
A est un groupe NH2, OH, COOH, SO3H, formyloxy ou, lorsque l'a-carbone hydrogène est absent, méthoxyimino;
Y est un groupe cyano, sydnonyle, pyridonyle, thiényle, o-aminométhylphényle, phényle ou tétrazolyle;
Z est un groupe méthyle, trifluorométhyle, trifluoroéthyle, pyridyle ou cyanométhyle;
m varie de zéro à deux;

et ses sels, esters et dérivés amidés non-toxiques.
2. La forme D d'un composé optiquement actif tel que revendiqué dans la revendication 1.
3. Composé de formule (I) tel que revendiqué dans la revendication 1, ses esters qui sont aisément scindés en acide parent dans l'organisme, ses sels pharmaceutiquement acceptables et ses dérivés amidés non-toxiques.
4. Acide 7 - D - mandélamido - 3 - [[3 - (carboxyméthyl)thio - 1H - 1,2,4 - triazol - 5 - yl]thio- méthyl] - 3 - cephème - 4 - carboxylique.
5. Sel disodique de l'acide 7 - [a(Z) - méthoxyimino) - 2 - furanacétamido] - 3 - [[3 - (carboxy- méthyl)thio - 1H - 1,2,4 - triazol - 5 - yl]thiométhyl] - 3 - cephème - 4 - carboxylique.
6. Sel disodique de l'acide 7 - trifluorométhyl(thioacétamido - 3 - [[3 - (carboxyméthyl)thio - 1H,1,2,4 - triazol - 5 - yl]thiométhyl] - 3 - cephème - 4 - carboxylique.
7. Procédé de préparation d'un composé tel que revendiqué dans la revendication 1, caractérisé en ce qu'on fait réagir un composé de formule (II):
Figure imgb0016
dans laquelle R' représente de l'hydrogène ou un groupe R tel que défini pour la formule (I) à condition que tout groupe amino, carboxy ou sulfo libre soit, si on le désire, protégé et Ac représente un groupe acétyle, avec un composé de formule (III):
Figure imgb0017
ou un de ses sels alcalins et, lorsque R' représente de l'hydrogène, on acyle !e produit avec un agent d'acylation ou un dérivé actif de formule ROH dans laquelle R est tel que défini pour la formule (1), à condition que tout groupe amino, carboxy ou sulfo libre soit, si on le désire, protégé, on enlève ensuite tout groupe protecteur et, si on le désire, on transforme le composé de formule (I) en un sel, ester ou dérivé amidé non-toxique.
8. Composition pharmaceutique comprenant un composé tel que revendiqué dans l'une quelconque des revendications 3 à 6 avec un excipient pharmaceutiquement acceptable.
EP78300103A 1977-06-30 1978-06-29 Dérivés des acides 7-acylamino-3-((3-(carboxyméthyl-) thio-1 H-1,2,4-triazol-5-yl) thiométhyl)-3-céphem-4 carboxyliques, procédés pour leur préparation et leurs compositions Expired EP0000285B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US811642 1977-06-30
US05/811,642 US4117124A (en) 1977-06-30 1977-06-30 7-Acylamino-3-[[3-(carboxymethyl)thio-1H-1,2,4-triazol-5-yl]thiomethyl]-3-cephem-4-carboxylic acids

Publications (2)

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EP0000285A1 EP0000285A1 (fr) 1979-01-10
EP0000285B1 true EP0000285B1 (fr) 1982-02-17

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EP80200247A Expired EP0015631B1 (fr) 1977-06-30 1978-06-29 L'acide((4,5-dihydro-5-thioxo-1H-1,2,4-triazol-3-yl)thio)acétique et ses sels
EP78300103A Expired EP0000285B1 (fr) 1977-06-30 1978-06-29 Dérivés des acides 7-acylamino-3-((3-(carboxyméthyl-) thio-1 H-1,2,4-triazol-5-yl) thiométhyl)-3-céphem-4 carboxyliques, procédés pour leur préparation et leurs compositions

Family Applications Before (1)

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EP80200247A Expired EP0015631B1 (fr) 1977-06-30 1978-06-29 L'acide((4,5-dihydro-5-thioxo-1H-1,2,4-triazol-3-yl)thio)acétique et ses sels

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US (1) US4117124A (fr)
EP (2) EP0015631B1 (fr)
JP (1) JPS6054958B2 (fr)
DE (2) DE2861631D1 (fr)

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Publication number Priority date Publication date Assignee Title
JPS57133686A (en) * 1981-02-12 1982-08-18 Sharp Corp Semiconductor light emitting element and manufacture thereof
JPS5834986A (ja) * 1981-08-27 1983-03-01 Sharp Corp 発光素子の製造方法
JPH0783884A (ja) * 1993-09-14 1995-03-31 Kenzo Miya 探傷検査方法、探傷検査装置、及び探傷検査用センサ

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* Cited by examiner, † Cited by third party
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US3641046A (en) * 1969-04-04 1972-02-08 Eastman Kodak Co Derivatives of thiourazoles
US3615618A (en) * 1969-04-04 1971-10-26 Eastman Kodak Co Photographic silver halide compositions comprising thiourazole adducts
JPS5953276B2 (ja) * 1974-04-05 1984-12-24 山之内製薬株式会社 新セフアロスポリン誘導体の製造方法
US4018921A (en) * 1973-08-01 1977-04-19 Smithkline Corporation Substituted phenylglycylcephalosporins
GB1509074A (en) * 1974-04-05 1978-04-26 Yamanouchi Pharma Co Ltd Cephalosporin derivatives
US3989694A (en) * 1974-12-27 1976-11-02 Smithkline Corporation 7-Acyl-3-(substituted triazolyl thiomethyl)cephalosporins
US4045438A (en) * 1975-10-24 1977-08-30 Yeda Research And Development Co. Ltd. Cephalosporin antibiotics
ZA767084B (en) * 1975-12-16 1977-10-26 Erba Carlo Spa Thiadiazolyl derivatives of 7-acylamido 3-cephem-4-carboxylic acid and process for their preparation

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JPS6054958B2 (ja) 1985-12-03
EP0000285A1 (fr) 1979-01-10
US4117124A (en) 1978-09-26
EP0015631A1 (fr) 1980-09-17
DE2862354D1 (en) 1984-01-12
EP0015631B1 (fr) 1983-12-07
DE2861631D1 (en) 1982-03-25
JPS5412396A (en) 1979-01-30

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