WO1990007503A1 - 3-azabicyclo[3.1.1]heptanes substitues, leur production et leur utilisation - Google Patents

3-azabicyclo[3.1.1]heptanes substitues, leur production et leur utilisation Download PDF

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Publication number
WO1990007503A1
WO1990007503A1 PCT/EP1989/001544 EP8901544W WO9007503A1 WO 1990007503 A1 WO1990007503 A1 WO 1990007503A1 EP 8901544 W EP8901544 W EP 8901544W WO 9007503 A1 WO9007503 A1 WO 9007503A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
substituted
phenyl
radical
azabicyclo
Prior art date
Application number
PCT/EP1989/001544
Other languages
German (de)
English (en)
Inventor
Rolf Banholzer
Erich Lehr
Wolf-Dietrich Bechtel
Original Assignee
Boehringer Ingelheim Kg
Boehringer Ingelheim International Gmbh
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 Boehringer Ingelheim Kg, Boehringer Ingelheim International Gmbh filed Critical Boehringer Ingelheim Kg
Priority to KR1019900701871A priority Critical patent/KR910700236A/ko
Publication of WO1990007503A1 publication Critical patent/WO1990007503A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/22—Bridged ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the invention relates to new 3-azabicyclo [3.1.1] heptanes which are substituted in the 1-, 3- and optionally 5-position, their preparation by processes known per se and their use in the treatment of certain diseases.
  • C- A Tomen a C 3 -C 7 -cycloalkyl, saturated or mono-unsaturated and optionally substituted by one or two
  • 1 4 is a phenyl radical which is mono- or polysubstituted by Alike h e or different radicals from the group
  • C-C alkyl may be substituted; or a heteroaromatic or saturated heterocyclic radical which is substituted one or more times by identical or different radicals from the
  • Di- (C, -C 4 alkyl) amino may be substituted; R "also hydrogen;
  • R * hydrogen, one if appropriate
  • NHS0 2 C 1 -C 4 alkyl
  • phenyl can be substituted and their salts with preferably physiologically acceptable acids.
  • halogen means fluorine, chlorine and bromine. Fluorine and chlorine are preferred.
  • the aliphatic groups with several carbon atoms • can be straight-chain or branched. They preferably contain up to 3, especially 1 or 2, carbon atoms. Allyl and propargyl should be emphasized as unsaturated groups, cyclopropyl, cyclopentyl, cyclohexyl and cyclohexenyl as cycloaliphatics.
  • Heteroaromatics are pyridine, pyrazine, pyrimidine, thiophene, pyrrole, furan, imidazole, pyrazole, triazole, tetrazole.
  • Non-aromatic heterocycles in the sense of the invention are the corresponding partially or fully hydrogenated compounds, furthermore five- and six-membered heterocycles with one to three identical or different heteroatoms (N, S, 0) and corresponding substituted compounds.
  • Typical substituents in the sense of the above definitions are CH 3 , OCH 3 , N0 2 , CN, (CH 3 ) 2 , N (C 2 H 5 ) 2 , NH 2 , N (CH 3 ) (C 2 H 5 ), NHC ⁇ , NHCH 3 , HS0 2 CH 3 , NHCOCH 3 , CF 3 , S0 2 NH 2 , CONH 2 , F, Cl, CgH 5 .
  • R "is hydrogen or methyl, R '(optionally substituted in the context of the above definitions) are phenylalkyl and R is phenyl.
  • Acids suitable for salt formation with the compounds of the formula I are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, tartaric acid, citric acid, fumaric acid, methanesulfonic acid. If the compounds of the formula I are to be reacted further, they can of course also be used as salts of any other acids.
  • R, R 'and R are those radicals according to the above definitions, which are among the
  • reaction is carried out in an inert organic solvent, for example toluene, at an elevated temperature, preferably between about 60 ° C. and 120 ° C. or the boiling point of the reaction mixture.
  • a protective gas is expediently used.
  • R ' has the above meaning and X is a leaving group introducing R' into the amino group, e.g. Chlorine, bromine.
  • X is a leaving group introducing R' into the amino group, e.g. Chlorine, bromine.
  • the reductive alkylation method can be used in the customary manner, it being necessary to ensure that side reactions do not occur to a disruptive degree.
  • the benzyl group can be split off from the compound of the formula I obtained by hydrogenol isch according to customary methods.
  • the compounds of formula III thus obtained can then be substituted on nitrogen in the desired manner.
  • the phenyl group in the compounds of the formula III is R and / or R "
  • hydrogenation under suitable conditions can give those compounds of the formula III which contain R / R" in the meaning hexyl.
  • other groups contained in R or R " can optionally also be changed (eg modification of functional groups, reduction of nitro groups).
  • the new compounds are suitable for use as active ingredients in medicinal products, in particular in psychotropic drugs, and can be used therapeutically above all for the treatment of depression.
  • the new compounds show a pronounced antidepressant effect.
  • the effectiveness e.g. compared to the commercial product imipramine, some ascertain multiple superiority.
  • a particular advantage is the lack of side effects even in doses that are significantly higher than that. antidepressant effective dose.
  • the lack of side effects represents a significant therapeutic advance in the field of antidepressants.
  • the new compounds are processed in a manner known per se with customary auxiliaries and / or carriers to give customary galenical preparations, e.g. to tablets, capsules, dragees, solutions, suppositories, syrups.
  • the application is oral or parenteral.
  • the active ingredients can also be used in sustained release forms.
  • Micronized powders, atomizing solutions or suspensions in liquefied propellant gases in containers with a metering valve are used for the likewise possible nasal application.
  • Active ingredient according to the invention 30 parts by weight
  • the ingredients are processed in the usual way into tablets of 600 mg weight. If desired, the active ingredient content can be increased or decreased and the amount of glucose reduced or increased accordingly.
  • Active ingredient according to the invention 80 parts by weight
  • the ingredients are processed in the usual way into suppositories weighing 1.7 g.
  • reaction solution is stirred into a mixture consisting of 500 g of ice and 100 ml of concentrated sodium hydroxide solution while cooling with ice.
  • 500 ml of toluene are added, the water phases are separated off, the toluene phases are dried over sodium sulfate and, after drying, the toluene is distilled off under reduced pressure 11
  • the chromatogram shows a quantitative one for 15 minutes
  • the hydrochloride is produced from the distillation residue in the usual way. 1.51 g (68.2% of theory) of white crystals (ethyl acetate / ether), mp. 138-139 ° C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

On peut produire par des procédés connus en soi de nouveaux 3-azabicyclo[3.1.1]heptanes ayant la formule (I), dont les substituants R, R', et R'' sont définis dans la description de l'invention. Ces composés sont utiles comme médicaments. Des produits intermédiaires sont également décrits.
PCT/EP1989/001544 1988-12-23 1989-12-15 3-azabicyclo[3.1.1]heptanes substitues, leur production et leur utilisation WO1990007503A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
KR1019900701871A KR910700236A (ko) 1988-12-23 1989-12-15 치환된 3-아자비사이클로[3,1,1]헵탄, 이의 제조방법 및 이의 용도

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP3843481.4 1988-12-23
DE3843481A DE3843481A1 (de) 1988-12-23 1988-12-23 Substituierte 3-azabicyclo/3.1.1/heptane, ihre herstellung und ihre verwendung

Publications (1)

Publication Number Publication Date
WO1990007503A1 true WO1990007503A1 (fr) 1990-07-12

Family

ID=6370006

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1989/001544 WO1990007503A1 (fr) 1988-12-23 1989-12-15 3-azabicyclo[3.1.1]heptanes substitues, leur production et leur utilisation

Country Status (4)

Country Link
KR (1) KR910700236A (fr)
AU (1) AU4820990A (fr)
DE (1) DE3843481A1 (fr)
WO (1) WO1990007503A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011054885A1 (fr) 2009-11-04 2011-05-12 Universiteit Gent Dérivés 2-azabicyclo[3.1.1]heptyliques 1-substitués utiles en tant que modulateurs des récepteurs de l'acétylcholine pour le traitement de troubles neurologiques
US8389561B2 (en) 2008-04-30 2013-03-05 Universiteit Gent Substituted 7-azabicyclo[2.2.1]heptyl derivatives useful for making pharmaceutical compositions
US8809365B2 (en) 2009-11-04 2014-08-19 Universiteit Gent 1-substituted 2-azabicyclo [3.1.1] heptyl derivatives useful as nicotinic acetylcholine receptor modulators for treating neurologic disorders

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1195729A (en) * 1966-07-27 1970-06-24 Ciba Ltd Azabicycloaliphatic Compounds
EP0166692A2 (fr) * 1984-06-20 1986-01-02 Ciba-Geigy Ag Azabicycloheptanes substitués, leur utilisation, compositions pharmaceutiques les contenant et procédés pour la préparation des composés
EP0272208A1 (fr) * 1986-11-21 1988-06-22 Ciba-Geigy Ag Acides azacycloalkylalcanediphosphoniques substitués aromatiquement
EP0317505A1 (fr) * 1987-11-13 1989-05-24 Ciba-Geigy Ag Acides azacycloalkylalcanediphosphoniques
EP0317506A2 (fr) * 1987-11-13 1989-05-24 Ciba-Geigy Ag Azabicycloheptanes et procédé pour leur préparation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1195729A (en) * 1966-07-27 1970-06-24 Ciba Ltd Azabicycloaliphatic Compounds
EP0166692A2 (fr) * 1984-06-20 1986-01-02 Ciba-Geigy Ag Azabicycloheptanes substitués, leur utilisation, compositions pharmaceutiques les contenant et procédés pour la préparation des composés
EP0272208A1 (fr) * 1986-11-21 1988-06-22 Ciba-Geigy Ag Acides azacycloalkylalcanediphosphoniques substitués aromatiquement
EP0317505A1 (fr) * 1987-11-13 1989-05-24 Ciba-Geigy Ag Acides azacycloalkylalcanediphosphoniques
EP0317506A2 (fr) * 1987-11-13 1989-05-24 Ciba-Geigy Ag Azabicycloheptanes et procédé pour leur préparation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
J. Am. Chem. Soc., Band. 105, Nr. 22, 1983 Alex Alder et al: "Intramolecular thermal cyclization reactions of diacryloylamines ", siehe Seite 6712- Seite 6714. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8389561B2 (en) 2008-04-30 2013-03-05 Universiteit Gent Substituted 7-azabicyclo[2.2.1]heptyl derivatives useful for making pharmaceutical compositions
WO2011054885A1 (fr) 2009-11-04 2011-05-12 Universiteit Gent Dérivés 2-azabicyclo[3.1.1]heptyliques 1-substitués utiles en tant que modulateurs des récepteurs de l'acétylcholine pour le traitement de troubles neurologiques
US8809365B2 (en) 2009-11-04 2014-08-19 Universiteit Gent 1-substituted 2-azabicyclo [3.1.1] heptyl derivatives useful as nicotinic acetylcholine receptor modulators for treating neurologic disorders

Also Published As

Publication number Publication date
DE3843481A1 (de) 1990-06-28
AU4820990A (en) 1990-08-01
KR910700236A (ko) 1991-03-14

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