EP0000285A1 - 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
EP0000285A1
EP0000285A1 EP78300103A EP78300103A EP0000285A1 EP 0000285 A1 EP0000285 A1 EP 0000285A1 EP 78300103 A EP78300103 A EP 78300103A EP 78300103 A EP78300103 A EP 78300103A EP 0000285 A1 EP0000285 A1 EP 0000285A1
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EP
European Patent Office
Prior art keywords
triazol
thio
compound
formula
hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP78300103A
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English (en)
French (fr)
Other versions
EP0000285B1 (de
Inventor
David Alan Berges
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
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SmithKline Corp
SmithKline Beecham Corp
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Classifications

    • 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 compounds having antibacterial activity, to intermediates for preparing them, to compositions containing them, and to processes for their preparation.
  • 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.
  • the 4-carboxylic acid group of the compounds of Formula 1 may be readily esterified by methods well known to the art.
  • esters include, for example, simple alkyl and aryl esters as well as esters which are easily cleaved, within the body, to the parent acid such as indanyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl and thienylglycylbxymethyl esters and others.
  • A is COOH
  • this group may be similarly esterified. All such ester derivatives are included within the scope of this invention.
  • Also covered in this invention are pharmaceutically- acceptable, non-toxic derivatives of the compounds of Formula 1, e.g.salts; as stated above easily split ester or ther derivatives of either a carboxy or hydroxy function; amide derivatives of an amino group in.a 7-phenylglycyl- amino group, for example the furyl-, pyranyl-, oxolanyl or oxiranyl-carbonyl amides (i.e. Belgian Patent No. 835,295); and solvates such as hydrates, glycolates or alcoholates.
  • alkali metal salts such as the sodium or potassium salts (for example using sodium or potassium 2-ethyl hexanoate), ammonium salts, and organic amine salts such as those with procaine or dibenzylethylenediamine.
  • cephalosporin modifications can be made by known synthetic procedures such as introduction of an ⁇ -methoxy group at position 7, preferably at the stage of the 7-aminocephalosporanic acid reactants described below (IV), prior to N-acylation.
  • Optical isomers are also possible, such as with mandeloyl or phenylglycyl substituents at 7. The D-forms of these subgeneric groups are preferred.
  • the compounds of this invention are conveniently prepared by a displacement of the acetoxy group of a known 7-acylaminocephalosporanic acid (II) by [(4,5-dihydro-5-thioxo-lH-1,2,4-triazol-3-yl)thio]acetic acid (III).
  • a similar displacement with the above acetic acid can be effected on 7-aminocephalosporanic acid to give 7-amino-3-((3-(carboxymethyl)thio-1H-1,2,4-triazbl-5-yl]-thiomethyl]-3-cephem-4-carboxylic acid (IV) which may then be N-acylated as known to the art as described above.
  • Suitable protective groups may be used in either method as is known to the art (see “Protective Groups in Organic Chemistry”, J.F.W. McOmie, Plenum Press, 1973, Chapters 2 and 3 for use of amino, carboxy, sulfo or hydroxyl protective groups).
  • t-butyl (for COOH) or t-butoxycarbonyl (for NH 2 ) groups are easily removed by treatment with trifluoroacetic acid.
  • the compound of Formula III which can exist in several tautomeric forms, is a new compound and is part of this invention.
  • This invention also includes the alkali metal and ammonium salts of the compound of Formula III.
  • 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 ug/ml have been observed.
  • MIC's minimum inhibitory concentrations
  • 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 as well as methods of combatting bacterial infections by administering such a composition in a nontoxic amount sufficient to combat such infections are also objects of 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.
  • the compounds of Formula I are preferably formulated adn administered in the same manner as other prior art cephalosporins such as cephazolin of cephalothin.
  • the dosage regimen preferably comprises administration, preferably by injection, of an active but non-toxic quantity of a compound of Formula I selected from the dosage unit range of 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 dependent 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.
  • reaction mixture is purified on an XAD-7 column as described in Example 1 to give a lyophilized product, 7-[ a(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-a-amino-4-hydroxy- phenylacetamido)-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 to a human patient infected with susceptible bacteria. Other compounds of this invention may be similarly used.

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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)
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)

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)

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

Family

ID=25207126

Family Applications (2)

Application Number Title Priority Date Filing Date
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

Family Applications Before (1)

Application Number Title Priority Date Filing Date
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

Country Status (4)

Country Link
US (1) US4117124A (de)
EP (2) EP0015631B1 (de)
JP (1) JPS6054958B2 (de)
DE (2) DE2861631D1 (de)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
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

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2016082A1 (de) * 1969-04-04 1970-10-08 Eastman Kodak Co., Rochester, N.Y. (V.St.A.) Additionsverbindungen aus Thiourazolen und alpha, beta-ungesättigten, organischen Carbony!verbindungen
JPS50131981A (de) * 1974-04-05 1975-10-18
FR2266507A1 (de) * 1974-04-05 1975-10-31 Yamanouchi Pharma Co Ltd
DE2655717A1 (de) * 1975-12-16 1977-06-30 Erba Carlo Spa Thiadiazolylderivate von 7-acylamido-3-cephem-4-carbonsaeure, verfahren zu deren herstellung und dieselben enthaltende pharmazeutische und veterinaermedizinische mittel

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3615618A (en) * 1969-04-04 1971-10-26 Eastman Kodak Co Photographic silver halide compositions comprising thiourazole adducts
US4018921A (en) * 1973-08-01 1977-04-19 Smithkline Corporation Substituted phenylglycylcephalosporins
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

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2016082A1 (de) * 1969-04-04 1970-10-08 Eastman Kodak Co., Rochester, N.Y. (V.St.A.) Additionsverbindungen aus Thiourazolen und alpha, beta-ungesättigten, organischen Carbony!verbindungen
JPS50131981A (de) * 1974-04-05 1975-10-18
FR2266507A1 (de) * 1974-04-05 1975-10-31 Yamanouchi Pharma Co Ltd
DE2655717A1 (de) * 1975-12-16 1977-06-30 Erba Carlo Spa Thiadiazolylderivate von 7-acylamido-3-cephem-4-carbonsaeure, verfahren zu deren herstellung und dieselben enthaltende pharmazeutische und veterinaermedizinische mittel

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS 85 (1976) 21397e. & JP-A-50 131981 (YAMANOUCHI). *

Also Published As

Publication number Publication date
JPS6054958B2 (ja) 1985-12-03
US4117124A (en) 1978-09-26
EP0015631A1 (de) 1980-09-17
DE2862354D1 (en) 1984-01-12
EP0015631B1 (de) 1983-12-07
EP0000285B1 (de) 1982-02-17
DE2861631D1 (en) 1982-03-25
JPS5412396A (en) 1979-01-30

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