WO1992022549A1 - 3-ARYL- OU 3-HETARYL-β-CARBOLINES, LEUR FABRICATION ET LEUR UTILISATION DANS DES MEDICAMENTS - Google Patents

3-ARYL- OU 3-HETARYL-β-CARBOLINES, LEUR FABRICATION ET LEUR UTILISATION DANS DES MEDICAMENTS Download PDF

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Publication number
WO1992022549A1
WO1992022549A1 PCT/DE1992/000497 DE9200497W WO9222549A1 WO 1992022549 A1 WO1992022549 A1 WO 1992022549A1 DE 9200497 W DE9200497 W DE 9200497W WO 9222549 A1 WO9222549 A1 WO 9222549A1
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WO
WIPO (PCT)
Prior art keywords
methoxymethyl
carboline
benzyloxy
alkyl
formula
Prior art date
Application number
PCT/DE1992/000497
Other languages
German (de)
English (en)
Inventor
Andreas Huth
Dieter Seidelmann
Ralph Schmiechen
Herbert Schneider
Lechoslaw Turski
Original Assignee
Schering Aktiengesellschaft Berlin Und Bergkamen
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Schering Aktiengesellschaft Berlin Und Bergkamen filed Critical Schering Aktiengesellschaft Berlin Und Bergkamen
Priority to JP5500741A priority Critical patent/JPH06501956A/ja
Publication of WO1992022549A1 publication Critical patent/WO1992022549A1/fr

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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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine

Definitions

  • the invention relates to new 3-hetaryl and 3-aryl-ß-carbolines, their preparation and use in medicaments.
  • 3-position substituted ⁇ -carbolines according to the invention are bioavailable over a longer period of time and at the same time have a good affinity for the benzodiazepine receptors.
  • the compounds according to the invention have the formula I.
  • R A is halogen, -CHR 1 -R 2 , optionally substituted with halogen, C 1-4 alkoxy or amino, phenyl, hetaryl or OR 5 and can be one to two times and
  • R 1 is hydrogen or C 1-4 alkyl
  • R 2 is hydrogen, C 1-4 alkyl, -OC 1-4 alkyl or an optionally substituted phenyl, benzyl or phenoxy radical and
  • R represents hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl or an optionally substituted phenyl, benzyl, hetaryl or benzo-fused hetaryl radical,
  • Hydrogen, C 1-4 alkyl or C 1-4 alkoxy-C 1-4 alkyl and R 3 is a C 6-12 aryl optionally substituted one or more times with C 1-4 alkyl, C 1-4 cycloalkyl, halogen, C 1-4 alkoxyC 1-4 alkyl, phenyl or amino. or hetaryl radical, and their isomers and acid addition salts.
  • the substituent R A can be in the A-ring in position 5-8, 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 can each represent cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and 2-methylcyclopropyl, 3-5 carbon atoms being preferred.
  • R 5 or R A is a hetaryl radical, this is 5- or 6-membered and contains 1-3 heteroatoms such as nitrogen, oxygen and / or sulfur.
  • the following 5- and 6-ring heteroaromatics may be mentioned: pyridm, pyrimidine, pyrazine, pyridazine. Furan, thiophene, pyrrole, thiazole, imidazole, triazine.
  • R 5 is a benzo-condensed hetaryl radical, this preferably contains 1-2 nitrogen atoms such as quinoline, isoquinoline, quinoxaline or benzimidazole.
  • the substituent of the phenyl, benzyl, hetaryl and benzo-fused hetaryl radical R 5 can be one to three times in any position.
  • Suitable substituents are halogens, nitro, cyano, C 1-4 alkyl, C 1-4 alkoxy, amino, C1-4 alkoxycarbonyl, C 1-4 alkylthio and trifluoromethyl, the mono- and benzyl radicals being the mono- up to two
  • Preferred hetaryl radicals and benzo-fused hetaryl radicals R 5 are nitrogen-containing heterocycles which are substituted one to two times with halogen, C 1-4 -alkyl, C 1-4 -alkoxy or trifluoromethyl, in particular with halogen.
  • Suitable substituents for the phenyl, benzyl and phenoxy radical R 2 are the aromatic substituents mentioned for R 5 , in particular halogen such as chlorine and bromine.
  • the aryl and hetaryl radical R 3 can be present as a mono- or bicyclic and
  • 5-12 ring atoms preferably 5-9 ring atoms, contain such as
  • Heteroatoms such as sulfur, oxygen and / or nitrogen.
  • the substituent of the aryl and hetaryl radical R 3 can be one to three, in particular simple.
  • R A in the meaning of OR 5 , where R 5 is C 1-6 alkyl, or an optionally mono- or disubstituted phenyl or benzyl radical or a five- or six-membered optionally benzo-fused heterocycle with 1 -3 nitrogen atoms, which is optionally mono- or disubstituted, and R 3 is phenyl which is optionally substituted by halogen or C 1-4 -alkoxy or by an optionally substituted five- or six-membered heterocycle with 1-3 heteroatoms such as 1,3,4-oxadiazol-2-yl, thienyl, pyrrolyl, pyridyl, thiazolyl, oxazolyl or a benzo-fused heterocycle such as benzothienyl.
  • C 1-4 alkyl and phenyl are to be regarded as preferred and as a substituent of the 1,3,4-oxadiazolyl radical is C 1-4 alkyl, C 1-4 alkoxy-C 1- 2- alkyl, C 3-7 cyclopropyl and amino preferred.
  • the compounds of the formula I can be in the form of the stereoisomers and mixtures thereof.
  • the physiologically compatible 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 arylsulfonic acids and, for example, such as alkanesulfonic acid and arylsulfonic acids Methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and others
  • the compounds of the formula I and their acid addition salts can be used as medicaments and exert antagonistic, inverse agonistic and agonistic effects on the properties known from benzodiazepines.
  • the compounds according to the invention have an extended duration of action and are distinguished by anxiolytic activity.
  • the affinity for the benzodiazepine receptors is determined by examining the displacement capacity of rakio-labeled flunitrazepam by the benzodiazepine receptors.
  • the compounds are tested in a 4-plate test using the method of Boissier et al Eur. J. Pharmacol. 4, 145-150 (19S8) tested.
  • the minimum, lowest dose (MED) is given, which determines the locomotor activity of the punished mice after i.p. Treatment increased.
  • a decrease in activity in the 4-plate test without punishment indicates sedative properties.
  • the compounds of formula I are particularly suitable for the treatment of anxiety accompanied by depression and sleep disorders.
  • the compounds according to the invention are brought into the form of 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.
  • 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, dragées, suppositories, capsules or in liquid form, for example as solutions, suspensions or emulsions. If necessary, they also contain auxiliary substances such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers.
  • Injection solutions or suspensions in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are particularly suitable for parenteral use.
  • Surface-active 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
  • Example lactose corn or potato starch, suitable. It 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.
  • the compounds according to the invention are prepared by processes known per se.
  • the compounds of the formula I are obtained by a) a compound of the formula II
  • R A and R 4 have the above meaning and Hal is halogen, in the presence of a nickel or palladium catalyst with an organometallic
  • R 3 has the above meaning
  • X is halogen, hydroxy or C 1-4 alkyl
  • n 1 to 3
  • arylated or b) a compound of formula IV
  • R A and R 4 have the above meaning, with orthocarboxylic acid esters cyclized to compounds of formula I with R 3 in the meaning of a
  • R A and R 4 have the meaning given above, Z is halogen and R 9 represents hydrogen or a protective group, cyclized with thiocarboxamides to give compounds of the formula I with R 3 meaning an optionally in
  • R A and R 4 have the above meaning with tosyl methyl isocyanide in the presence of bases cyclized to compounds of the formula I with R 3 in the meaning of an oxazol-5-yl radical and, if desired, subsequently splitting off the benzyl group R 5 or R A in the meaning of Hydroxy etherifies or separates the isomers or forms the acid addition salts.
  • the arylation according to process variant a) takes place in solution or in suspension in inert solvents at temperatures from 0 ° C. to the boiling point of the reaction mixture.
  • Suitable solvents are, for example, cyclic and acyclic ethers such as diethyl ether, tetrahydrofuran and dioxane, hydrocarbons such as toluene and benzene and aprotic, polar solvents such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, etc.
  • cyclic and acyclic ethers such as diethyl ether, tetrahydrofuran and dioxane
  • hydrocarbons such as toluene and benzene and aprotic
  • polar solvents such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, etc.
  • protic solvents such as e.g. Alcohol nothing.
  • bromine and iodine come into consideration as halogen hal.
  • the organometallic compound of the general formula III contain lithium, magnesium, zinc, tin or boron as the metal atom, where the substituent X can in each case be one to three times depending on the valence of the metal atom and X is halogen, in particular chlorine or bromine.
  • Suitable nickel and palladium catalysts are, for example, 1,3-diphenylphosphinopropane-nickel-II-chloride, bis-tri-o-tolylphosphine-palladium-II-chloride, bis-triphenylphosphine-palladium-II-chloride, tetrakis-triphenylphosphine -palladium- (0) and 1,1'-bis-diphenylphosphinoferrocenpal- ladium-II-chloride.
  • 1,3,4-Oxadiazoles are prepared by process variant b) by heating ⁇ -carboline-3-carboxylic acid hydrazides with orthocarboxylic acid esters in solution or in suspension and subsequent cyclization in the presence of a base such as, for example, alkali metal alcoholates such as sodium or potassium ethylate, -ter. butylate.
  • a base such as, for example, alkali metal alcoholates such as sodium or potassium ethylate, -ter. butylate.
  • the corresponding alcohols are suitable as solvents.
  • the reaction takes place at temperatures up to the boiling point of the reaction mixture and is complete after about 2-10 hours.
  • Any protective groups present in the 9-position of the ⁇ -carboline can be treated with the customary methods, such as treatment with bases, for example alkali alcoholate or hydroxide or acids such as dilute mineral acid or with fluorides such as casium fluoride be split off at room temperature or elevated temperature.
  • bases for example alkali alcoholate or hydroxide or acids such as dilute mineral acid or with fluorides such as casium fluoride be split off at room temperature or elevated temperature.
  • fluorides such as casium fluoride be split off at room temperature or elevated temperature.
  • 3-carbaldehyde- ⁇ -carbolines of the formula VI are reacted with tosylmethyl isocyanide in suspension or in solution.
  • the reaction takes place in the presence of bases such as alkali carbonates or alkali alcoholates in protic solvents such as alcohols at temperatures up to the boiling point of the reaction mixture and is complete after about 1-3 hours. If the removal of the radical R 5 is desired, this is done according to the in
  • EP-A-130 140 described methods or by hydrogenolytic
  • the subsequent subsequent etherification of the free hydoxy group is carried out by the process described in EP-A-237 467, in which the reactive compound R A -Y, in which Y is, for example, halogen, tosylate, mesylate or triflate, in the presence of a base such as alkali alcoholate or hydroxide in polar solvents such as dimethyl sulfoxide, dimethylformamide, acetonitrile or alcohols is reacted at room temperature or elevated temperature, if appropriate in the presence of phase transfer catalysts.
  • a base such as alkali alcoholate or hydroxide
  • polar solvents such as dimethyl sulfoxide, dimethylformamide, acetonitrile or alcohols
  • 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 mixed with a concentrated solution of the desired acid.
  • the compounds of the formula IV are prepared by heating the ß-carboline-3-carboxylic acid alkyl ester with hydrazine hydrate.
  • 6-Benzyloxy-4-methoxymethyl-ß-carboline-3-carboxylic acid is prepared according to the process given in EP-A-161 574 from 6-benzyloxy-4-methoxymethyl-ß-carboline-3-carboxylic acid isopropyl ester.

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

Abstract

Il est décrit des composés de formule (I), dans laquelle R3 désigne un reste aryle ou hétaryle en C¿6-12? substitué le cas échéant une ou plusieurs fois par un alkyle en C1-4, un cycloalkyle en C3-7, un halogène, un alkoxy-C1-4-alkyl-C1-2, un phényle ou un amino, le procédé de fabrication de ces composés, ainsi que leur utilisation dans des médicaments.
PCT/DE1992/000497 1991-06-15 1992-06-12 3-ARYL- OU 3-HETARYL-β-CARBOLINES, LEUR FABRICATION ET LEUR UTILISATION DANS DES MEDICAMENTS WO1992022549A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP5500741A JPH06501956A (ja) 1991-06-15 1992-06-12 ３―アリール―または３―ヘテロアリール―β―カルボリン、その製造および薬剤としての使用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE4120109A DE4120109A1 (de) 1991-06-15 1991-06-15 3-aryl- oder 3-hetaryl-(beta)-carboline, deren herstellung und verwendung in arzneimitteln
DEP4120109.4 1991-06-15

Publications (1)

Publication Number Publication Date
WO1992022549A1 true WO1992022549A1 (fr) 1992-12-23

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PCT/DE1992/000497 WO1992022549A1 (fr) 1991-06-15 1992-06-12 3-ARYL- OU 3-HETARYL-β-CARBOLINES, LEUR FABRICATION ET LEUR UTILISATION DANS DES MEDICAMENTS

Country Status (6)

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EP (1) EP0543968A1 (fr)
JP (1) JPH06501956A (fr)
CA (1) CA2089569A1 (fr)
DE (1) DE4120109A1 (fr)
PT (1) PT100593A (fr)
WO (1) WO1992022549A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995006647A1 (fr) * 1993-08-31 1995-03-09 Schering Aktiengesellschaft β-CARBOLINES A SUBSTITUTION ALCOXY AGISSANT SUR LE RECEPTEUR D'AMPA

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1134221A1 (fr) * 2000-03-15 2001-09-19 Aventis Pharma Deutschland GmbH Bêta-carbolines substituées comme inhibiteurs de lkB kinase

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0054507A2 (fr) * 1980-12-17 1982-06-23 Schering Aktiengesellschaft Bêta-carbolines substituées en 3, procédé pour leur préparation et compositions les contenant
EP0110813A2 (fr) * 1982-10-29 1984-06-13 Schering Aktiengesellschaft Procédé pour la préparation de dérivés de la bêta-carboline
EP0130140A2 (fr) * 1983-06-23 1985-01-02 Schering Aktiengesellschaft Bêta-carbolines, procédé pour leur préparation et leur utilisation comme médicaments
EP0161574A2 (fr) * 1984-05-15 1985-11-21 Schering Aktiengesellschaft Dérivés de 3-oxadiazolyl-bêta carboline, méthode pour leur préparation et leur utilisation
EP0234173A2 (fr) * 1985-11-13 1987-09-02 Schering Aktiengesellschaft Dérivés de bêta-carboline substitués par un phénoxy, leur préparation et leur utilisation comme médicaments
EP0237467A2 (fr) * 1986-03-08 1987-09-16 Schering Aktiengesellschaft Dérivés d'hétéroaryl-oxy-bêta-carboline, leur préparation et utilisation comme médicaments
EP0305322A2 (fr) * 1987-08-28 1989-03-01 Schering Aktiengesellschaft Dérivés d'isoxazole-bêta-carboline
WO1990008534A1 (fr) * 1989-02-06 1990-08-09 Schering Aktiengesellschaft Procede de production de solutions micellaires mixtes aqueuses
DE3943225A1 (de) * 1989-12-23 1991-06-27 Schering Ag Neue ss-carboline, verfahren zu deren herstellung und deren verwendung in arzneimitteln

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0054507A2 (fr) * 1980-12-17 1982-06-23 Schering Aktiengesellschaft Bêta-carbolines substituées en 3, procédé pour leur préparation et compositions les contenant
EP0110813A2 (fr) * 1982-10-29 1984-06-13 Schering Aktiengesellschaft Procédé pour la préparation de dérivés de la bêta-carboline
EP0130140A2 (fr) * 1983-06-23 1985-01-02 Schering Aktiengesellschaft Bêta-carbolines, procédé pour leur préparation et leur utilisation comme médicaments
EP0161574A2 (fr) * 1984-05-15 1985-11-21 Schering Aktiengesellschaft Dérivés de 3-oxadiazolyl-bêta carboline, méthode pour leur préparation et leur utilisation
EP0234173A2 (fr) * 1985-11-13 1987-09-02 Schering Aktiengesellschaft Dérivés de bêta-carboline substitués par un phénoxy, leur préparation et leur utilisation comme médicaments
EP0237467A2 (fr) * 1986-03-08 1987-09-16 Schering Aktiengesellschaft Dérivés d'hétéroaryl-oxy-bêta-carboline, leur préparation et utilisation comme médicaments
EP0305322A2 (fr) * 1987-08-28 1989-03-01 Schering Aktiengesellschaft Dérivés d'isoxazole-bêta-carboline
WO1990008534A1 (fr) * 1989-02-06 1990-08-09 Schering Aktiengesellschaft Procede de production de solutions micellaires mixtes aqueuses
DE3943225A1 (de) * 1989-12-23 1991-06-27 Schering Ag Neue ss-carboline, verfahren zu deren herstellung und deren verwendung in arzneimitteln

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LIEBIGS ANNALEN DER CHEMIE, Volume 86, No. 10, October 1986, Weinheim, DE, pages 1749-1764, H. BIERE et al., "Eine neue und besonders einfache Synthese von Zentralaktiven beta-Carbolin-derivaten". *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995006647A1 (fr) * 1993-08-31 1995-03-09 Schering Aktiengesellschaft β-CARBOLINES A SUBSTITUTION ALCOXY AGISSANT SUR LE RECEPTEUR D'AMPA

Also Published As

Publication number Publication date
EP0543968A1 (fr) 1993-06-02
DE4120109A1 (de) 1992-12-17
PT100593A (pt) 1993-08-31
CA2089569A1 (fr) 1992-12-16
JPH06501956A (ja) 1994-03-03

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