EP0000285B1 - 7-Acylamino-3-((3-(carboxymethyl) thio-1 H-1,2,4-triazol-5-yl) thiomethyl)-3-cephem-4-carbon-Säurederivaten, Verfahren zu ihrer Herstellung und ihre Präparate - Google Patents

7-Acylamino-3-((3-(carboxymethyl) thio-1 H-1,2,4-triazol-5-yl) thiomethyl)-3-cephem-4-carbon-Säurederivaten, Verfahren zu ihrer Herstellung und ihre Präparate 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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English (en)
French (fr)
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EP0000285A1 (de
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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)
  • 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)
  • Oncology (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. Eine Verbindung der Formel I
Figure imgb0010
in der R die Gruppen
Figure imgb0011
in denen X eine Thienyl- oder Furylgruppe oder eine gegebenenfalls mit einer Hydroxy-, Hydroxymethyl-, Formamido- oder Ureidogruppe einfach substituierte Phenylgruppe ist;
A NH2, OH, COOH, S03H, eine Formyloxygruppe oder bei Abwesenheit von Wasserstoff ein α-Kohlenstoffatom eine Methoxyiminogruppe ist;
Y eine Cyano-, Sydnonyl-, Pyridonyl-, Thienyl-, o-Aminomethylphenyl-, Phenyl- oder Tetrazolylgruppe ist;
Z eine Methyl-, Trifluoromethyl-, Trifluoräthyl-, Pyridyl- oder Cyanomethylgruppe ist;
m den Wert 0 bis 2 hat;

und ihre Salze, Ester und nicht toxischen Amidderivate.
2. Die D-Form einer optisch aktiven Verbindung nach Anspruch 1.
3. Eine Verbindung der Formel nach Anspruch 1 und ihre Ester, die sich im Körper leicht in ihre Säure und pharmazeutisch verträglichen Salze spalten läßt und ihre nichttoxischen Amidderivate.
4. 7 - D - mandelamido - 3 - [[3 - (carboxymethyl) - thio - 1 H - 1,2,4 - triazol - 5 - yl] - thiomethyl] - 3 - cephem - 4 - carbonsäure.
5. 7 - [a(Z) - (methoxyimino) - 2 - furanacetamido] - 3 - [[3 - (carboxymethyl) - thio - 1 H - 1,2,4 - triazol - 5 - yl]thiomethyl] - 3 - cephem - 4 - carbonsäure-dinatriumsalz.
6. 7 - Trifluormethyl - (thioacetamido - 3 - [[3 - (carboxymethyl) - thio - 1 H - 1,2,4 - triazol - 5 - yl] - thiomethyl] - 3 - cephem - 4 - carbonsäure-dinatriumsalz.
7. Ein Verfahren zur Herstellung einer Verbindung nach Anspruch 1, gekennzeichnet durch Umsetzung einer Verbindung der Formel II
Figure imgb0012
in der R' ein Wasserstoffatom oder einen Rest R, wie er für die Formel I definiert ist, bedeutet, mit der Maßgabe, daß etwaige freie Amino-, Carboxy- oder Sulfogruppen gegebenenfalls geschützt sind, und Ac eine Acetylgruppe ist, mit einer Verbindung der Formel III
Figure imgb0013
oder ihrem Alkalimetallsalz, wobei, falls R' ein Wasserstoffatom ist, die Verbindung mit einem Acylierungsmittel oder einem aktiven Derivat der Formel ROH, in der R dieselbe Bedeutung wie in der Formel I hat, acyliert wird, mit der Maßgabe, daß etwaige freie Amino-, Carboxy- oder Sulfogruppen gegebenenfalls geschützt werden, anschließend etwaige Schutzgruppen entfernt werden und gegebenenfalls die Verbindung der Formel I in ein Salz, einen Ester oder ein nicht-toxisches Amidderivat überführt wird.
8. Eine pharmazeutische Zusammensetzung, enthaltend eine Verbindung nach einem der Ansprüche 3 bis 6 und einen pharmazeutisch verträglichen Träger.
EP78300103A 1977-06-30 1978-06-29 7-Acylamino-3-((3-(carboxymethyl) thio-1 H-1,2,4-triazol-5-yl) thiomethyl)-3-cephem-4-carbon-Säurederivaten, Verfahren zu ihrer Herstellung und ihre Präparate Expired EP0000285B1 (de)

Applications Claiming Priority (2)

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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

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

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EP80200247A Expired EP0015631B1 (de) 1977-06-30 1978-06-29 ((4,5-Dihydro-5-thioxo-1H-1,2,4-triazol-3-yl)thio)Essigsäure und ihre Salze
EP78300103A Expired EP0000285B1 (de) 1977-06-30 1978-06-29 7-Acylamino-3-((3-(carboxymethyl) thio-1 H-1,2,4-triazol-5-yl) thiomethyl)-3-cephem-4-carbon-Säurederivaten, Verfahren zu ihrer Herstellung und ihre Präparate

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EP (2) EP0015631B1 (de)
JP (1) JPS6054958B2 (de)
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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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US3615618A (en) * 1969-04-04 1971-10-26 Eastman Kodak Co Photographic silver halide compositions comprising thiourazole adducts
US3641046A (en) * 1969-04-04 1972-02-08 Eastman Kodak Co Derivatives of thiourazoles
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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EP0015631A1 (de) 1980-09-17
DE2862354D1 (en) 1984-01-12
EP0015631B1 (de) 1983-12-07
JPS6054958B2 (ja) 1985-12-03
EP0000285A1 (de) 1979-01-10
US4117124A (en) 1978-09-26
DE2861631D1 (en) 1982-03-25
JPS5412396A (en) 1979-01-30

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