Classifications

• • 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
• • 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

• the present invention relates to new acyl derivatives of the general formula in which R is furyl, thienyl or phenyl which is optionally substituted by halogen, hydroxy, lower alkoxy or lower alkyl, R 1 is lower alkyl or aminocarbonylmethyl and X is a group of the formulas in which one of the two radicals R 2 and R 3 or R 4 and R 5 is hydrogen and the other is lower alkyl, carboxymethyl or sulfomethyl, and salts of these compounds and hydrates of these salts.
• salts of the compounds of formula I are alkali metal salts such as the sodium and potassium salt; the ammonium salt; Alkaline earth metal salts such as the calcium salt; Salts with organic bases, such as salts with amines, e.g. Salts with N-ethyl-piperidine, procaine, dibenzylamine, N, N'-dibenzylethyl-ethylenediamine, alkylamines or dialkylamines, and salts with amino acids, such as e.g. Salts with arginine or lysine.
• the salts can be mono-salts or also disalts.
• the second salt formation takes place on the tautomeric enol form of the triazine residue b, which has an acid character.
• the compounds of formula I also form addition salts with organic or inorganic acids.
• salts are hydrohalides, for example hydrochlorides, hydrobromides, hydroiodides, and also other mineral acid salts, such as sulfates, nitrates, phosphates and the like such as acetates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates and the like.
• the salts of the compounds of formula I can be hydrated.
• the hydration can take place in the course of the production process or can occur gradually as a result of hygroscopic properties of an initially anhydrous salt of a compound of the formula I.
• lower alkyl groups are either straight chain or branched and can contain up to 7 carbon atoms, e.g. Methyl, ethyl, n-propyl, isopropyl, n-pentyl, n-heptyl.
• Lower alkoxy groups have an analogous meaning.
• Halogen represents all four halogens, i.e. Fluorine, chlorine, bromine and iodine; chlorine and bromine are preferred.
• Preferred R groups are furyl, thienyl and phenyl, especially furyl. Methyl is preferred as R 1 .
• Preferred X groups are group (c) and groups (a) and (b), in which one of the two radicals R 2 and R 3 or R 4 and R 5 is hydrogen and the other is methyl. Particularly preferred X groups are the 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl and the 1,4,5,6-tetrahydro-4-methyl -5,6-dioxo-as-triazin-3-yl group.
• Preferred compounds are (7R) -7- [2- (2-furyl) -2- (methoxyimino) acetamido] -3 - / [(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo -as-triazin-3-yl) thio] methyl / -3-cephem-4-carboxylic acid and its salts and the hydrates of these salts.
• the compounds of formula I and their salts or hydrates of the salts can be in the syn-isomeric form or in the anti-isomeric form or as mixtures of these two forms.
• the syn-isomeric form or mixtures in which the syn-isomeric form predominates is preferred.
• the carboxy groups present in the starting compounds of formulas II and IV can optionally be protected, e.g. by esterification to an easily cleavable ester such as a silyl ester, e.g. the trimethylsilyl ester.
• the carboxy group can also be protected by salt formation with an inorganic or tertiary organic base such as triethylamine.
• Suitable reactive functional derivatives of acids of the formula III are e.g. Halides, i.e. Chlorides, bromides and fluorides; Azides; Anhydrides, especially mixed anhydrides with stronger acids; reactive esters, e.g. N-hydroxysuccinimide esters, and amides, e.g. Imidazolides.
• Halogens e.g. Chlorine, bromine or iodine
• acyloxy residues e.g. lower alkanoyl radicals, such as acetoxy, lower.
• Alkyl or arylsulfonyloxy radicals such as mesyloxy or tosyloxy, or the azidorest in question.
• the reaction of a compound of formula II with an acid of formula III or a reactive functional derivative thereof can be carried out in a manner known per se. So you can e.g. condense a free acid of the formula III with one of the esters corresponding to the formula II using a carbodiimide, such as dicyclohexylcarbodiimide, in an inert solvent, such as ethyl acetate, acetonitrile, dioxane, chloroform, methylene chloride, benzene or dimethylformamide and then split off the ester group.
• oxazolium salts e.g. Use N-ethyl-5-phenyl-isoxazolium-3'-sulfonate.
• a salt of an acid of formula II e.g. a trialkylammonium salt
• a reactive functional derivative of an acid of formula III as mentioned above in an inert solvent, e.g. one of the above to.
• an acid halide preferably the chloride of an acid of the formula III
• the amine of the formula II is reacted with the amine of the formula II.
• the reaction takes place - preferably in the presence of an acid-binding agent, for example in the presence of aqueous alkali, preferably sodium hydroxide solution, or also in the presence of an alkali metal carbonate, such as potassium carbonate, or in the presence of a lower alkylated amine, such as triethylamine.
• Water is preferably used as the solvent; but it can also be carried out in an aprotic organic solvent, such as, for example, dimethylformamide, dimethyl sulfoxide or hexamethylphosphoric triamide.
• reaction of a compound of the formula II with a compound of the formula III or a reactive functional derivative thereof can expediently take place at temperatures between about -40 ° C. and room temperature, for example at about 0-10 ° C.
• reaction of a compound of formula IV with a thiol of formula V can be carried out in a manner known per se, e.g. at a temperature between about 40 and 80 ° C, suitably at about 60 ° C, in a polar solvent, for example in an alcohol, e.g. in a lower alkanol such as ethanol, propanol and the like, in dimethylformamide or dimethyl sulfoxide, preferably in water or in a buffer solution with a pH of about 6 to 7, preferably 6.5.
• a polar solvent for example in an alcohol, e.g. in a lower alkanol such as ethanol, propanol and the like, in dimethylformamide or dimethyl sulfoxide, preferably in water or in a buffer solution with a pH of about 6 to 7, preferably 6.5.
• the protective group is a silyl group (silyl ester), this group can be split off particularly easily by treating the reaction product with water. If the carboxyl group of an acid of formula IV is protected by salt formation (e.g. with triethylamine), this salt-forming protective group can be split off by treatment with acid.
• acid e.g. Hydrochloric acid, sulfuric acid, phosphoric acid or citric acid can be used.
• the 7-amino compounds of the formula II used as starting products can be started from a compound of the formula in which Y represents a leaving group and the carboxy group can be in protected form, be prepared with a thiol of formula V.
• the reaction can be carried out under the same conditions as those of the starting compounds IV and V.
• syn / anti mixture of a compound of the formula I obtained can be separated into the corresponding syn and anti forms in a customary manner, for example by recrystallization or by chromatographic methods using a suitable solvent or solvent mixture.
• the compounds of formula I, their salts and the hydrates of these salts are antibiotic, in particular bactericidally active. They have a broad spectrum of activity against Gram-positive and Gram-negative microorganisms, including ⁇ -lactamase-forming staphylococci and various ⁇ -lactamase-forming Gram-negative bacteria, such as e.g. Haemophilus influenzae, - Escherichia coli, Proteus and Klebsiella species.
• the compounds of formula I and the pharmaceutically acceptable salts and hydrated forms thereof can be used for the treatment and prophylaxis of infectious diseases.
• a daily dose of approximately 1 g to approximately 4 g is suitable for the adult.
• the parenteral administration of the compounds according to the invention is particularly preferred.
• mice are infected intraperitoneally with an aqueous suspension of Proteus mirabilis.
• the test substance is applied subcutaneously one hour after the infection.
• the number of surviving animals is determined on the 4th day.
• Different doses are applied and the dose at which 50% of the test animals survived (CD50, mg / kg) is determined by interpolation.
• compositions can contain the compounds of formula I, their salts or hydrated forms of these salts, possibly in a mixture with another therapeutically valuable substance. They are expediently mixed with a pharmaceutical, inorganic or organic inert carrier material which is particularly suitable for parenteral administration, such as, for example, water, gum arabic.
• a pharmaceutical, inorganic or organic inert carrier material which is particularly suitable for parenteral administration, such as, for example, water, gum arabic.
• the pharmaceutical preparations are preferably in liquid form, for example as solutions, suspensions or emulsions. If necessary, they are sterilized and / or contain auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers.
• This compound is prepared analogously to Example 1 from 3.4 g of 2-methoxyimino-2-furyl-acetic acid (syn / anti mixture 80:20) and 7.46 g of (7R) -7-amino-3-deacetoxy-3- [ (1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl) thio] cephalosporanoic acid.
• R f value 0.34 (TLC on silica gel F 254 finished plates in the butanol / glacial acetic acid / water 4: 1: 1 system; visualization with UV light).

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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)
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• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
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• Cephalosporin Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Saccharide Compounds (AREA)

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• 1978
  • 1978-05-25 NL NL7805715A patent/NL7805715A/xx not_active Application Discontinuation
  • 1978-05-25 GB GB22499/78A patent/GB1599232A/en not_active Expired
  • 1978-05-26 MC MC781305A patent/MC1195A1/fr unknown
  • 1978-05-26 NZ NZ187392A patent/NZ187392A/en unknown
  • 1978-05-26 IE IE1056/78A patent/IE46903B1/en unknown
  • 1978-05-29 AU AU36588/78A patent/AU518648B2/en not_active Expired
  • 1978-05-29 IL IL54803A patent/IL54803A/xx unknown
  • 1978-05-31 HU HU78HO2077A patent/HU182498B/hu unknown
  • 1978-06-01 DE DE7878100078T patent/DE2860248D1/de not_active Expired
  • 1978-06-01 EP EP78100078A patent/EP0000005B1/fr not_active Expired
  • 1978-06-01 JP JP6501078A patent/JPS5412394A/ja active Pending
  • 1978-06-01 FR FR7816468A patent/FR2393000A1/fr active Granted
  • 1978-06-01 FI FI781754A patent/FI781754A7/fi not_active Application Discontinuation
  • 1978-06-01 SE SE7806465A patent/SE7806465L/xx unknown
  • 1978-06-01 DE DE19782824065 patent/DE2824065A1/de not_active Withdrawn
  • 1978-06-01 GR GR56409A patent/GR73554B/el unknown
  • 1978-06-02 ES ES470442A patent/ES470442A1/es not_active Expired
  • 1978-06-02 DK DK246878A patent/DK246878A/da not_active Application Discontinuation
  • 1978-06-02 NO NO781934A patent/NO781934L/no unknown
  • 1978-06-02 PH PH21225A patent/PH14653A/en unknown
  • 1978-06-02 PT PT68134A patent/PT68134A/pt unknown
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  • 1978-06-02 CA CA304,644A patent/CA1114808A/fr not_active Expired
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• 1979
  • 1979-02-27 ES ES478115A patent/ES478115A1/es not_active Expired
• 1980
  • 1980-07-02 AT AT0345980A patent/AT365197B/de not_active IP Right Cessation

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