EP0000100B1 - 7-Acylamino-3-(1-(2-Sulfamoylaminoäthyl)-tetrazol-5-ylthiomethyl)-3-cephem-4-carbonsäuren, ein Verfahren zu ihrer Herstellung und pharmazeutische Präparate - Google Patents

7-Acylamino-3-(1-(2-Sulfamoylaminoäthyl)-tetrazol-5-ylthiomethyl)-3-cephem-4-carbonsäuren, ein Verfahren zu ihrer Herstellung und pharmazeutische Präparate Download PDF

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Publication number
EP0000100B1
EP0000100B1 EP78300031A EP78300031A EP0000100B1 EP 0000100 B1 EP0000100 B1 EP 0000100B1 EP 78300031 A EP78300031 A EP 78300031A EP 78300031 A EP78300031 A EP 78300031A EP 0000100 B1 EP0000100 B1 EP 0000100B1
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Prior art keywords
formula
compound
pharmaceutically acceptable
sulfamoylaminoethyl
cephem
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EP0000100A1 (de
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David Alan Berges
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SmithKline Beecham Corp
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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
    • 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

Definitions

  • This invention relates to cephalosporin compounds having antibacterial activity, processes for their preparation, pharmaceutical compositions containing them for use as antibacterial agents.
  • Cephalosporin derivatives having specific tetrazolylthiomethyl substituents at position 3 of the cephem nucleus are known.
  • West German Offenlegungsschrift No. 2649545 discloses cephalosporin derivatives of general formula: where W is hydrogen or a methoxy group and R 1 is where X is thienyl, dihydrophenyl, phenyl or phenyl monosubstituted with hydroxy, hydroxymethyl, formamido or ureido; A is NH 2 , OH, COOH, S0 3 H or when X is a phenyl group a formyloxy group; Y is thienyl, tetrazolyl, sydnonyl, cyano or o-aminomethylphenyl; Z is a methyl, trifluoromethyl, trifluoroethyl, cyanomethyl or pyridyl group; M is 0, 1 or 2 and N is 2, 3, 4
  • the compounds of this invention differ from previously known cephalosporins in general and those of the above Offenlegungsschrift in particular principally because they have a 1-(2-sulfamoylaminoethyl)tetrazolyl-5-thiomethyl substituent at position 3 of the cephem nucleus.
  • esters of the carboxylic acid group include simple alkyl and aryl esters as well as esters which are cleaved within the body to the parent acid such as indanyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl and thienylglycyloxymethyl esters and others. Accordingly, by an ester of a compound of formula (I) we mean esters of one or more of these groups. All such ester derivatives are included within the scope of this invention.
  • amide derivatives of the compounds of formula (I) are also covered in this invention.
  • a pharmaceutically acceptable amide derivative we mean an amide derivative at an amino group contained in a 7-phenylglycylamino group, for example the furyl-, pyranyl-, oxolanyl- or oxiranyl- carbonyl amides (i.e., Belgian Patent No. 835,295).
  • pharmaceutically acceptable salts of compounds of formula (I) are alkali metal salts such as the sodium or potassium salts, ammonium salts and organic amine salts such as those with procaine or dibenzylethylenediamine.
  • the compounds of the invention can exist in the form of solvates for example hydrates, glycolates and alcoholates. It will be understood that such forms are within the scope of invention.
  • Optical isomers are also possible such as with the mandeloyl or phenylglycyl substituents at position 7.
  • the D-forms of these subgeneric groups are preferred.
  • the compounds of the invention are most conveniently prepared by displacement of the acetoxy group of a known 7-acylamino-cephalosporanic acid of formula (II):- where R 1 is hydrogen or a group R as defined with reference to formula (I) in which any amino, carboxy, sulfo or hydroxy groups are optionally protected, with 1-(2-sulfamoylaminoethyl)-1,4-dihydro-5H-tetrazole-5-thione of formula (III):- and when R 1 is hydrogen, acylating the product with an acylating agent or active derivative of an acid ROH where R is as defined with reference to formula (I) thereafter removing any protecting groups and optionally thereafter converting the compound of formula (I) so obtained into an ester or a pharmaceutically acceptable salt or amide derivative.
  • the acylation step can be carried out by known methods. N-acylation procedures may be found in Cephalosporins and Penicillins, Flynn, Academic Press, 1972; U.S. Patent Nos. 2,721,196 and 3,953,424; Belgian Patent No. 832,725; German Patent Nos. 2,127,285 and 2,406,165.
  • Suitable protecting groups are 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-butoxy-carbonyl (for NH 2 ) groups are easily removed by treatment with trifluoroacetic acid.
  • Certain compounds for formula (I) have shown antibacterial activity against both Gram positive and Gram negative bacteria with minimum inhibitory concentrations (MIC's) in vitro from 0.4 to 200 ⁇ g/ml.
  • Test results for 7-D-(-)mandelamido-3-[1-(2-sulfamoylaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid, sodium salt, dihydrate (A) and 7-[ ⁇ (Z)-(methoxyimino)-2-furanacetamido]-3-[1-(2-sulfamoylaminoethyl)tetrazolyl-5-ylthiomethyl]-3-cephem-4-carboxylic acid sodium salt (B) are:
  • Compound A gave an ED 50 in mice of 0.26 against E. coli as well as 0.195 mg/kg against Kleb. pneumo. (s.c.).
  • compositions having antibacterial activity which comprise a pharmaceutical carrier containing an active quanitity of a compound of formula (I) or a pharmaceutically acceptable salt or amide derivative thereof which is easily cleaved within the body, as well as their use in combating bacterial infections by administering such a composition to an infected animal, or human host in a non-toxic amount sufficient to combat such infections are also within this invention.
  • the administration which, of course, should be of a non-toxic quantity of a compound of formula (1) may be oral or by parenteral injection for example subcutaneous, intramuscular or intravenous.
  • the injection of suitably prepared sterile solutions or suspensions containing an effective non-toxic amount of the new cephalosporin compound is the preferred route of administration.
  • the compounds of the invention used in this way 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) selected from the dosage unit range of from about 250 mg to 60C 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 in 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.
  • Example 2 illustrates the preparation of an intermediate for preparing the compounds. Temperatures are in degrees Centigrade (°C) unless otherwise stated.
  • Triethylamine (1.0 g., 0.01 mol) was added to a suspension of 1.73 g. (0.005 mol) of the above tetrazole hydrochloride in 50 ml. of dry tetrahydrofuran. The suspension was cooled to 0°C. At that . temperature 0.885 g. (0.005 mol) of N-tert-butylsulfamoyl chloride in 40 ml. of dry tetrahydrofuran was added. After 30 minutes of stirring, the triethylamine hydrochloride was separated by filtration. The filtrate was evaporated to dryness.
  • the tert-butyl compound (51.5 g.) was added to 500 mi. of trifluoroacetic acid and 250 ml. of m-dimethoxybenzene. The mixture was stirred at room temperature for 3 hours then stripped of the trifluoroacetic acid in vacuo. The dimethoxybenzene solution was diluted with 1.5 I. of ether to give a yellow precipitate. The solid was chromatographed on silica using 50:50 acetone/chloroform as eluant. The product-containing eluate was stripped. The residue was triturated with 100 ml.
  • the sulfamoylamino intermediate (25.55 g., 0.065 mol) was suspended in 300 ml. of dry methanol and treated with 17 ml. of 25% sodium methoxide in methanol at room temperature with stirring. The methanol was stripped off in vacuo and the residue dissolved in 300 ml. of water. After filtering, the aqueous solution (pH 9.0) was extracted with ethyl acetate and then adjusted to pH 7.5 with dilute hydrochloric acid and again extracted with ethyl acetate.
  • the aqueous layer was applied to an XAD-4 column (a nonionic resin which is a crosslinked copolymer of styrenedivinylbenzene) and eluted first with water and then 50% aqueous methanol.
  • the methanol was stripped in vacuo from the pooled product-containing fractions.
  • the remaining aqueous solution was treated with dilute hydrochloric acid to a pH of 1.5 and then extracted with ethyl acetate. After drying (MgS0 4 ) the extracts, the ethyl acetate was removed in vacuo to give a residue which was dissolved in dry methanol and adjusted to pH of 7.0 with 12.5% sodium methoxide in methanol.
  • the product-containing effluent is evaporated to dryness to give a residue which is dissolved in a small amount of water and lyophilized to give 7-trifluoromethylthioacetamido-3-[1-(2-sulfamoylaminoethyl)tetrazole-5-ylthiomethyl]-3-cephem-4-carboxylic acid sodium salt.
  • 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)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (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)
  • Plural Heterocyclic Compounds (AREA)

Claims (6)

1. Verbindungen der Formel (1)
Figure imgb0017
ihre Ester, pharmazeutisch verträgliche Salze und Amidderivate, wobei R die Reste
Figure imgb0018
bedeutet, in denen
X eine Thienyl- oder Furylgruppe oder einen gegebenenfalls mit einer Hydroxy-, Hydroxymethyl-, Formamido- oder Ureidogruppe einfach substituierte Phenylgruppe ist;
A NH2, OH, COOH, S03H, eine Formyloxyl- oder Methoxyiminogruppe ist, wobei das α-Kohlenstoffatom kein Wasserstoffatom aufweist;
Y eine Cyano-, Sydnonyl-, Pyridonyl-, Thienyl-, o-Aminomethylphenyl-, Phenyl- oder Tetrazolylgruppe ist;
Z eine Methyl-, Trifluormethyl-, Trifluoräthyl-, Pyridyl- oder Cyanomethylgruppe ist;
m den Wert 0 bis 2 hat.
2. Die D-Form einer Verbindung nach Anspruch 1, die optische Isomere aufweist.
3. Eine Verbindung der Formel 1 nach Anspruch 1 oder 2, ihre pharmazeutisch verträglichen Salze, Amidderivate und Ester, die im Körper gespalten werden.
4. 7 - [a(Z) - (Methoxyimino) - 2 - furanacetamido] - 3 - [1 - (2 - sulfamoylaminoäthyl) - tetrazol - 5 - ylthiomethyl] - 3 - cephem - 4 - carbonsäure.
5. Verfahren zur Herstellung einer Verbindung nach Anspruch 1, dadurch gekennzeichnet, daß eine Verbindung der Formel II
Figure imgb0019
in der R1 ein Wasserstoffatom ist oder den Rest R bedeutet, wie er im Anspruch 1 definiert ist, wobei etwaige Amino-, Carboxy-, Sulfo- oder Hydroxygruppen gegebenenfalls geschützt sind, mit einer Verbindung der allgemeinen Formel III
Figure imgb0020
umgesetzt wird und falls R1 ein Wasserstoffatom ist, die Verbindung mit einem Acylierungsmittel oder einem aktivierten Derivat der Formel ROH, wobei R die in Anspruch 1 angegebene Bedeutung hat, acyliert wird, anschließend die Schutzgruppen entfernt werden und gegebenenfalls die so erhaltene Verbindung der Formel I in einen Ester, ein pharmazeutisch verträgliches Salz oder ein Amidderivat umgewandelt wird.
6. Arzneimittel, enthaltend eine Verbindung nach Anspruch 3 oder 4 und einen pharmazeutisch verträglichen Träger.
EP78300031A 1977-06-09 1978-06-09 7-Acylamino-3-(1-(2-Sulfamoylaminoäthyl)-tetrazol-5-ylthiomethyl)-3-cephem-4-carbonsäuren, ein Verfahren zu ihrer Herstellung und pharmazeutische Präparate Expired EP0000100B1 (de)

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DE8080200252T DE2861732D1 (en) 1977-06-09 1978-06-09 1-(2-sulfamoylaminoethyl)-1,4-dihydro-5h-tetrazole-5-thione and its salts

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US05/805,197 US4117123A (en) 1977-06-09 1977-06-09 7-Acylamino-3-[1-(2-sulfamidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acids
US805197 1977-06-09

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EP80200252A Expired EP0018669B1 (de) 1977-06-09 1978-06-09 1-(2-Sulfamoylaminoäthyl)-1,4-dihydro-5H-tetrazol-5-thion und seine Salze

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Publication number Priority date Publication date Assignee Title
US4171433A (en) * 1975-10-30 1979-10-16 Smithkline Corporation 7-Amino-3-(sulfaminoalkyl substituted tetrazolylthiomethyl)cephalosporin intermediates for preparing 7-acylamino cephalosporins
US4171362A (en) * 1975-10-30 1979-10-16 Smithkline Corporation 7-Acylamino-3-(sulfaminoalkyl substituted tetrazolylthiomethyl)cephalosporins antibacterial compositions containing them and methods of treating bacterial infections with them
US4171368A (en) * 1975-10-30 1979-10-16 Smithkline Corporation 7-Acylamino-3-(sulfaminoalkyl substituted tetrazolylthiomethyl)cephalosporins, antibacterial compositions containing them and methods of treating bacterial infections with them

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AR207752A1 (es) * 1973-03-30 1976-10-29 Fujisawa Pharmaceutical Co Procedimiento para obtener acidos 7-amino-sustituido-3-tiometilsustituido-3-cefem-4-carboxilicos
US4045438A (en) * 1975-10-24 1977-08-30 Yeda Research And Development Co. Ltd. Cephalosporin antibiotics
IL50546A (en) * 1975-10-30 1980-07-31 Smithkline Corp 7-acyl-3-(1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid derivatives and pharmaceutical compositions containing them
US4025626A (en) * 1975-12-09 1977-05-24 Smithkline Corporation 7-Acyl-3-(ureidoalkyl substituted tetrazolylthiomethyl)-cephalosporins
US4101656A (en) * 1976-07-12 1978-07-18 Smithkline Corporation 7β-Acylamino-3-(alkanesulfonamidoalkyl substituted tetrazolylthiomethyl) cephalosporins, antibacterial compositions containing them and methods of treating bacterial infections with them
US4066762A (en) * 1976-07-12 1978-01-03 Smithkline Corporation Derivatives of 7-(2-substituted-2-hydroxyiminoacetamido)-3-(1-substituted tetrazol-5-ylthiomethyl-3-cephem-4-carboxylic acid

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EP0000100A1 (de) 1978-12-20
EP0018669A1 (de) 1980-11-12
DE2861592D1 (en) 1982-03-11
US4117123A (en) 1978-09-26
JPS6053028B2 (ja) 1985-11-22
JPS545994A (en) 1979-01-17
EP0018669B1 (de) 1982-04-14

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