Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• • 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 invention relates to new substituted 2-oxoalkanoic acid [2- (indol-3-yl) ethyl] amides, processes for their preparation and antibacterial agents containing them.
• the present invention relates to
• R 1 represents optionally branched Cj-C 8 alkyl or C 4 -C 8 cycloalkyl
• R 2 is independently of R 3 is hydrogen, -CC alkyl, C j -C 4 alkoxy, C j -C thioalkyl, phenyl or halogen,
• R 3 represents hydrogen, -CC alkyl or halogen
• R 4 for optionally branched C j -Cg alkyl, C 4 -Cg cycloalkyl, optionally one to three times by C] -C 3 alkyl, C
• Cj-C 3 -thioalkyl halogen, nitro or amino-substituted phenyl or optionally mono- to trisubstituted by Cj-C 3 -alkyl, Ct-C 3 -alkoxy, -C-C 3 -thioalkyl, halogen, nitro or amino-substituted benzyl .
• the compounds of the general formula (I) can be present in the form of their racemates or as enantiomerically pure compounds and in the form of their pharmaceutically usable hydrates and acid addition salts.
• R 1 represents optionally branched Ci-Cg-alkyl or C 4 -C 8 cycloalkyl, - 3 -
• R 2 independently of R 3 represents hydrogen, Cj-C alkyl, C r C alkoxy, C j -C 4 thioalkyl, phenyl or halogen,
• R 3 represents hydrogen, C ] -C 4 alkyl or halogen
• R 4 for optionally branched Ci-Cg-alkyl, C -C 6 cycloalkyl, optionally one to three times by Ct-C 3 alkyl, C j -C 3 alkoxy,
• C 1 -C 3 -thioalkyl C 1 -C 3 -thioalkyl, halogen, nitro or amino-substituted phenyl or optionally mono- to trisubstituted by C ] -C 3 -alkyl, C 1 -C 3 -alkoxy, C] -C 3 -thioalkyl, halogen, nitro or amino
• R 2 , R 3 , R 4 have the meaning given above,
• Y represents OH or halogen
• R 1 has the meaning given above, if appropriate in the presence of an acid binding agent and if appropriate in the presence of a diluent.
• the compounds of the general formula (I) according to the invention surprisingly have a significantly higher antibacterial action than the known representatives of this type of structure. They are therefore suitable as antibacterial agents for human and veterinary medicine.
• R 1 represents optionally branched C 1 -C 4 -alkyl or C 4 -C 6 cycloalkyl
• R 2 independently of R 3 represents hydrogen, C r C 2 alkyl, C r C 2 alkoxy, C r C 2 thioalkyl, phenyl, fluorine, chlorine or bromine,
• R 3 represents hydrogen, C j -C 2 alkyl, fluorine, chlorine or bromine and
• R 4 for optionally branched C j -C 4 alkyl, C 4 -C 6 cycloalkyl, optionally mono- to triple by -CC 2 alkyl, -C-C 2 alkoxy, fluorine, chlorine, bromine, nitro or amino substituted phenyl or optionally mono- to trisubstituted by C 1 -C 2 alkyl, C 1 -C 2 alkoxy, fluorine, chlorine, bromine, nitro or amino,
• R ' represents optionally branched C 1 -C 6 -alkyl 1 or C 4 -C 6 -cycloalky 1,
• R 2 independently of R 3 for hydrogen, -C 2 alkyl, -C 2 alkoxy, fluorine or
• Chlorine stands, R 3 represents hydrogen, -CC 2 alkyl, fluorine or chlorine and
• R 4 for optionally branched C j -C 4 alkyl, C 4 -Cg cycloalkyl, optionally once or twice by Cj-C 2 alkyl, -C-C 2 alkoxy, fluorine, chlorine,
• R 1 represents branched alkyl having up to 4 carbon atoms
• R 2 and R 3 represent hydrogen
• R 4 for C ! -C 4 - alkyl, phenyl or benzyl.
• the compounds of formula (III) are also known and in some cases. commercially available.
• Compounds of formula (III) where Y is halogen, e.g. Chlorine can be obtained from the compounds of formula (III) with Y equal to OH by known methods by reaction with halogenating agents such as e.g. be prepared with thionyl chloride or oxalyl chloride.
• halogenating agents such as e.g. be prepared with thionyl chloride or oxalyl chloride.
• Examples of compounds (III) where Y is OH are:
• the compounds of the formula (I) are prepared in an inert solvent in the presence of an acid scavenger.
• Halogenated hydrocarbons e.g. Methylene chloride, chloroform, carbon tetrachloride, aliphatic or aromatic
• Hydrocarbons e.g. Toluene
• polar inert solvents such as e.g. Dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide or sulfolane can be used. Mixtures of these solvents can also be used.
• Conventional acid binding agents such as e.g. Alkali or alkaline earth carbonates, trimethylamine, triethylamine, tributylamine, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or pyridine can be used .
• DABCO 1,4-diazabicyclo [2.2.2] octane
• DBU 1,8-diazabicyclo [5.4.0] undec-7-ene
• pyridine pyridine
• the acid scavengers used are generally used in an amount of 80 to
• the compounds of the formula (II) and (III) are generally used in an approximately equimolar ratio.
• reaction temperatures can be varied between -20 and 80 ° C with this procedure. It is preferred to work between -10 ° C and 25 ° C.
• the reaction can be carried out at normal pressure, but also at elevated pressure. Generally one works at pressures between 1 bar and 100 bar, preferably between 1 and 10 bar. If compounds of the formula (III) where Y is OH are used as starting compounds, the reaction is carried out in an inert solvent in the presence of an auxiliary which is customary for the formation of amide bonds.
• the solvents mentioned above such as methylene chloride, chloroform, dimethylformamide or N-methylpyrrolidone, can be used as solvents. Mixtures of these solvents can also be used.
• N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide (EDC) or dicyclohexylcarbodiimide (DCC) are used as auxiliaries.
• Hydroxybenzotriazole in the presence of an organic base such as triethylamine, tributylamine or N-methylmorpholine, for example, can be used as an auxiliary to form the amide bond.
• organic base such as triethylamine, tributylamine or N-methylmorpholine, for example.
• Starting compounds of the formula (II) and (III) are used in an approximately equimolar ratio to one another.
• the auxiliaries are used in approximately equimolar amounts based on the compound of the formula (III).
• reaction temperatures can be varied between -20 and 80 ° C with this procedure. It is preferred to work between -10 ° C and 25 ° C.
• the reaction can be carried out at normal pressure, but also at elevated pressure. Generally one works at pressures between 1 bar and 100 bar, preferably between 1 and 10 bar.
• the compounds of formula (I) obtained are purified by conventional organic chemistry methods, e.g. by crystallization or chromatography.
• the acid addition salts of the compounds according to the invention are prepared in the customary manner, for example by dissolving them in a sufficient amount of aqueous acid and precipitating the salt with a water-miscible organic solution. - 9 -
• the compounds according to the invention have a strong antibiotic action and are distinguished by a very good action against gram-positive germs, especially staphylococci.
• gram-positive bacteria in particular staphylococci, and bacteria-like microorganisms can be combated and the diseases caused by these pathogens can be prevented, improved and / or cured.
• the compounds according to the invention also show surprising increases in activity against bacteria which are classified as less sensitive to other antibacterial agents, in particular resistant Staphylococcus aureus.
• the compounds according to the invention are particularly effective against bacteria and bacteria-like microorganisms. They are therefore particularly well suited for the prophylaxis and chemotherapy of local and systemic infections in human and veterinary medicine, which are caused by these pathogens.
• the compounds are also suitable for combating protozoonoses and
• the compounds according to the invention can be used in various pharmaceutical preparations.
• Preferred pharmaceutical preparations are tablets, dragees, capsules, pills, granules, suppositories, injection and orally administrable solutions, suspensions and emulsions, as well as pastes, ointments,
• the active ingredients are preferably suitable for combating bacterial diseases which occur in animal husbandry and animal breeding in farm animals, breeding, zoo, laboratory, experimental and hobby animals. They are effective against all or individual stages of development as well as against resistant and normally sensitive strains. By combating bacterial diseases, illness, deaths and reduced performance (e.g. in the production of meat, milk, wool, skins, eggs, honey, etc.) are to be reduced, so that the use of the active ingredients enables more economical and easier animal husbandry.
• the livestock and breeding animals include mammals such as Cattle, horses, sheep, pigs, goats, camels, water buffalos, donkeys, rabbits, fallow deer, reindeer, fur animals such as Mink, chinchilla, raccoon, birds such as Chickens, geese, turkeys, ducks, pigeons, bird species for home or zoo keeping. It also includes
• Laboratory and experimental animals include mice, rats, guinea pigs, golden hamsters, dogs and cats.
• the active ingredients can also be administered together with the animal's feed or drinking water. - 11 -
• Feed and food contain 0.01 to 100 ppm, preferably 0.5 to 50 ppm of the active ingredient in combination with a suitable edible material.
• Such feed and food can be used for medicinal purposes as well as for prophylactic purposes.
• Such a feed or foodstuff is produced by mixing a concentrate or a premix containing 0.5 to 30%, preferably 1 to 20% by weight, of an active ingredient in a mixture with an edible organic or inorganic carrier with conventional feedstuffs.
• Edible carriers are e.g. Corn meal or corn and soybean meal or mineral salts, which preferably contain a small amount of an edible dust control oil, e.g. Corn oil or soybean oil.
• the premix obtained in this way can then be added to the complete feed before it is fed to the animals.
• the minimum inhibitory concentrations (MIC) of the compounds according to the invention were determined by serial dilution on Iso-Sensitest Agar (Oxoid). A series of agar plates were prepared for each test substance, which contained decreasing concentrations of the active ingredient at twice the dilution.
• Agar plates were inoculated with a multipoint inoculator (Denley). Overnight cultures of the pathogens were used for inoculation, which were previously diluted so that each inoculation point contained approximately 10 4 colony-forming particles. The inoculated agar plates were incubated at 37 ° C and the germ growth was read after about 20 hours. The MIC value ( ⁇ g / ml) indicates the lowest active substance concentration at which no growth could be seen with the naked eye.
• 0.5 g of product in the form of a thick oil is prepared from 0.91 g of 4-methyl-2-oxovaleric acid and 1.43 g of 1-isopropyl-tryptamine.

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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)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Indole Compounds (AREA)

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• 1998
  • 1998-04-16 DE DE19816780A patent/DE19816780A1/de not_active Withdrawn
• 1999
  • 1999-03-03 US US09/673,155 patent/US6255335B1/en not_active Expired - Fee Related
  • 1999-04-03 WO PCT/EP1999/002302 patent/WO1999054301A1/de not_active Application Discontinuation
  • 1999-04-03 CN CN99805078A patent/CN1297437A/zh active Pending
  • 1999-04-03 HU HU0102099A patent/HUP0102099A3/hu unknown
  • 1999-04-03 KR KR1020007011057A patent/KR20010052236A/ko not_active Application Discontinuation
  • 1999-04-03 JP JP2000544642A patent/JP2002512226A/ja active Pending
  • 1999-04-03 CA CA002328875A patent/CA2328875A1/en not_active Abandoned
  • 1999-04-03 EP EP99917958A patent/EP1071664A1/de not_active Withdrawn
  • 1999-04-03 BR BR9909692-7A patent/BR9909692A/pt not_active IP Right Cessation
  • 1999-04-03 AU AU36050/99A patent/AU752273B2/en not_active Ceased

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