Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/20—Hypnotics; Sedatives

Definitions

• the invention relates to new hetaryloxy- ⁇ -carboline derivatives, their production and use in medicaments.
• EP-A-237 467 and EP-A-305 322 describe ⁇ -carbolines which are substituted with a hetaryloxy radical and which influence the central nervous system and are used as psychotropic drugs. According to these patent applications, it was not to be expected that the introduction of the hetaryl substituents according to the invention would result in a shift in the activity profile of the compounds and that the compounds would show an improved side effect profile due to the lack of muscle relaxation.
• the compounds according to the invention have the formula I.
• R C. -Alkyl, C, -Cycloalkyl, C,tician-Bicycloalkyl or a given-
• C is -alkoxy, C 6-alkyl, -CH.-O-C-alkyl, phenyl or benzyl,
• c d R and R each represent hydrogen or together a bond
• R is hydrogen, C -alkyl or C, _ 7 -cycloalkyl
• the substituent R can be in the A ring in the 5-8 position, preferably in the 5-, 6- or 7-position.
• Alkyl contains both straight and branched chain residues such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, tert. Butyl, pentyl, isopentyl and hexyl.
• Halogen is to be understood as fluorine, chlorine, bromine and iodine.
• Cycloalkyl stands for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.
• the benzo-condensed hetaryl radical with 1 - 2 nitrogen atoms has 8-12 ring atoms; for example, quinoline, isoquinoline, quinoxaline, benzimidazole may be mentioned.
• R is a substituted nitrogen-containing hetaryl radical
• pyridine for example, pyrimidine, pyrazine, pyridazine and idazole may be mentioned.
• Phenyl, biphenyl, naphthyl and indenyl called.
• rest R can be in one or two positions in any position.
• R are optionally with halogen
• R is -C0 -C, -alkyl, -CO-R with R in the meaning of a C "- 1-o 3-7
• Cycloalkyl or an optionally substituted phenyl radical, and the isoxazol-3-yl radical are to be regarded as preferred.
• the physiologically tolerated acid addition salts are derived from the known inorganic and organic acids such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid and alkanesulfonic acid such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and others Because of their affinity for benzodiazepine receptors, the compounds of the formula I and their acid addition salts can be used as medicaments and exert partial agonistic activity on the properties known from the benzodiazepines, which is characterized in that the compounds, for example, are anticonvulsant and have an anxiolytic effect and are not atactic / muscle relaxant.
• the compounds are tested in a 4-plate test using the method of Boissier et al Eur. J. Pharmacol. 4, 145-150 (1968).
• the table shows the minimum, lowest dose (MED) that increases the locomotor activity of the punished mice after ip treatment.
• the compounds according to the invention are particularly suitable for the treatment of epilepsy and anxiety.
• a pharmaceutical preparation which, in addition to the active ingredient for enteral or parenteral administration, has suitable pharmaceutical, organic or inorganic inert carrier materials, such as water, gelatin, gum arabic, milk sugar, starch, Contains magnesium stearate, talc, vegetable oils, polyalkylene glycols etc.
• the pharmaceutical preparations can be in solid form, for example as tablets, dragees, suppositories, capsules or in liquid form, for example as solutions, suspensions or emulsions. If necessary, they also contain auxiliaries such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the otic pressure or buffers.
• ection solutions or suspensions in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are particularly suitable.
• Surfactant auxiliaries such as salts of bile acids or animal or vegetable phospholipids, but also mixtures thereof and liposomes or their components can also be used as carrier systems.
• Tablets, coated tablets or capsules with talc and / or hydrocarbon carriers or binders, such as lactose, corn or potato starch, are particularly suitable for oral use. They can also be used in liquid form, for example as juice, to which a sweetener may be added.
• the compounds according to the invention are introduced in a dose unit of 0.05 to 100 mg of active substance in a physiologically compatible carrier.
• the compounds according to the invention are generally used in a dose of 0.1 to 300 mg / day, preferably 0.1 to 30 mg / day, particularly preferably 1-20 mg / day, for example as anxiolytics analogous to diazepam.
• Has meaning and Y is halogen or a reactive group, etherified or
• R has the meaning given above, R is hydrogen or R and Z
• Organic lithium compound optionally after the introduction of a protective group in the 9-position, converts to compounds of the formula I with R ⁇
• R a , R, R c , and R have the above meaning to compounds of
• R is hydrogen or R and R, R a , R c and R have the above meaning with a nitrile oxide of the formula VII
• RA ' is hydrogen or RA and R has the above meaning with a compound of the formula (R 5CO) 0 with R5 in the above meaning
• a 'A K wherein R is hydrogen or R, R has the above meaning and R is OH or a reactive acid derivative, with a compound of
• the reactive compound R -Y where Y is, for example, halogen, tosylate, mesylate or triflate, is in the presence of a base such as alkaline earth metal or alkali metal alcoholate or hydroxide, alkali metal or alkaline earth metal carbonate in polar solvents such as dimethyl sulfoxide, dimethylformamide , Acetonitrile or alcohols at room temperature or elevated temperature, optionally in the presence of phase transfer catalysts.
• a base such as alkaline earth metal or alkali metal alcoholate or hydroxide, alkali metal or alkaline earth metal carbonate in polar solvents such as dimethyl sulfoxide, dimethylformamide , Acetonitrile or alcohols at room temperature or elevated temperature, optionally in the presence of phase transfer catalysts.
• a protective group such as tosyl, mesyl or a trialkylsilyl group can expediently be present in the 9-position of the ⁇ -carboline, which is split off during the workup of the reaction mixture or subsequently in a conventional manner, depending on the type of protective group.
• the cycloaddition of the compounds of the formulas IV and VI by processes c) and d) is carried out by the methods described in EP-A-305 322.
• the addition is carried out at temperatures from 0 ° C. to 40 ° C. in an aprotic solvent such as aliphatic or cyclic ethers, halogenated hydrocarbons, dimethylformamide and others.
• an aprotic solvent such as aliphatic or cyclic ethers, halogenated hydrocarbons, dimethylformamide and others.
• you can Protected ⁇ -carboline derivatives are used in the reaction in the 9-position.
• the protective group is split off in a customary manner when the reaction mixture is worked up or subsequently by treatment with bases or acids, depending on the nature of the protective group.
• the nitrile oxides are prepared, for example, by reacting ⁇ -carboline-3-carbaldehydes to give the corresponding oximes, which are tert-form, for example, with N-halogenosuccinimide.
• Butoxychlorite or Na hypochlorite can be converted into hydroxamic acid halides in the aforementioned aprotic solvents.
• bases such as Na or K alcoholates.
• Trialkylamines, Hünig base, DBU or diazabicyclooctane are split off from the hydroxamic acid halides and hydrogen halide is obtained and the nitrile oxides are obtained which are subjected to cycloaddition without isolation (R. Annunziata et al., 3. Chem. Soc. 1987. 529).
• the ß-carbolin-3-carboxylic acid or its reactive acid derivative such as halide, imidazolide or mixed anhydride or alkyl carboxylate in the presence of alcoholate with an amidoxime
• aprotic solvents such as hydrocarbons such as toluene, ethers or dimethylformamide at room temperature or elevated temperature.
• the methods described in EP-A-237 467 can be used by transesterifying with alkali metal alcoholates or the corresponding alcohol, optionally with the addition of titanium tetra-isopropylate as catalyst, at elevated temperature .
• the introduction of the tert. Butyl ester group takes place for example by reacting the carboxylic acid with tert. Butoxy-bis-dimethylaminomethane.
• the hydrolysis of the ester group can be carried out in the customary acidic or alkaline manner, for example using Na or K hydroxide in protic solvents or by the processes described in EP-A-161 574.
• the isomer mixtures can be separated into the diastereomers or enantiomers by customary methods such as, for example, crystallization, chromatography or salt formation.
• a compound of the formula I is dissolved, for example, in a little alcohol and a concentrated solution of the desired acid is added.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Anesthesiology (AREA)
• Pain & Pain Management (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)

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• 1991
  • 1991-06-05 DE DE4118741A patent/DE4118741A1/de not_active Withdrawn
• 1992
  • 1992-06-02 MX MX9202616A patent/MX9202616A/es not_active IP Right Cessation
  • 1992-06-04 CN CN92105684A patent/CN1039906C/zh not_active Expired - Fee Related
  • 1992-06-04 CZ CS923968A patent/CZ281810B6/cs unknown
  • 1992-06-04 PL PL92297839A patent/PL172481B1/pl unknown
  • 1992-06-04 NZ NZ243014A patent/NZ243014A/en unknown
  • 1992-06-04 WO PCT/DE1992/000465 patent/WO1992021679A1/de not_active Application Discontinuation
  • 1992-06-04 PT PT100565A patent/PT100565A/pt not_active Application Discontinuation
  • 1992-06-04 RU RU93005125A patent/RU2105766C1/ru active
  • 1992-06-04 CA CA002087098A patent/CA2087098A1/en not_active Abandoned
  • 1992-06-04 HU HU9300595A patent/HUT63166A/hu unknown
  • 1992-06-04 JP JP4509774A patent/JPH06500341A/ja active Pending
  • 1992-06-04 KR KR1019930700323A patent/KR930701440A/ko not_active Application Discontinuation
  • 1992-06-04 EP EP92911058A patent/EP0541757A1/de not_active Withdrawn
  • 1992-06-05 ZA ZA924127A patent/ZA924127B/xx unknown
  • 1992-06-05 IL IL10211692A patent/IL102116A/xx not_active IP Right Cessation
  • 1992-06-05 AU AU18074/92A patent/AU658631B2/en not_active Ceased
  • 1992-06-05 US US07/892,819 patent/US5348958A/en not_active Expired - Fee Related
  • 1992-07-01 IE IE182592A patent/IE921825A1/en not_active Application Discontinuation
• 1993
  • 1993-01-25 FI FI930293A patent/FI930293A/fi not_active Application Discontinuation
  • 1993-02-04 NO NO930390A patent/NO300771B1/no unknown
• 1994
  • 1994-07-11 US US08/272,464 patent/US5698555A/en not_active Expired - Fee Related

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