Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1994-12-16
1996-05-28
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
514408, 514414, 5462767, 548452, 548466, A61K 3140, C07D20952
Patent
active
055212093
DESCRIPTION:
BRIEF SUMMARY
This application is the national phase of PCT/EP93/01440 filed on Jun. 8, 1993.
The present invention relates to novel N-substituted azabicycloheptane derivatives, the preparation and use thereof for the preparation of drugs.
It is known that benzamide and butyrophenone derivatives with basic substituents have cerebroprotective and neuroleptic effects respectively (U.S. Pat. No. 4,605,655, EP 410 114, DE 1 289 845, EP 400 661, DE 2 941 880, EP 190 472).
In these cases it appears that the observed affinities for .sigma. receptors are, besides the dopamine and serotonin affinities, particularly important.
We have now found that N-substituted 3-aza-bicyclo[3.2.0]heptane derivatives of the formula I ##STR2## where R.sup.1 is a phenyl, pyridyl, thienyl or pyrrolyl group which is unsubstituted or mono- or disubstituted by halogen atoms, C.sub.1 -C.sub.4 -alkyl, trifluoromethyl, hydroxyl, C.sub.1 -C.sub.4 -alkoxy, amino, monomethylamino, dimethylamino, cyano or nitro groups, substituted by halogen, methoxy, hydroxyl or amino, ##STR3## R.sup.3 is a hydrogen atom, a hydroxyl radical or a phenyl radical which is unsubstituted or substituted by a fluorine, chlorine or bromine atom, nitro, C.sub.1 -C.sub.4 -alkyl or methoxy group, and physiologically tolerated acids have valuable pharmacological properties.
The substituents R.sup.1 to R.sup.7, and n, in the formula I preferably have the following meanings: methoxy, trifluoromethyl, nitro, hydroxyl or amino
The following compounds are particularly preferred:
1-(4-fluorophenyl)-4-[exo-6-phenyl-3-azabicyclo-[3.2.0] heptan-3-yl]butane-1-one,
1-(4-fluorophenyl)-4-[exo-6-p-fluorophenyl-3-aza-bicyclo[3.2.0]heptan-3-yl] butan-1-ol,
1-phenyl-4-[exo-6-phenyl-3-azabicyclo[3.2.0]- heptan-3-yl]-butan-1-one,
1-phenyl-4-[exo-6-p-fluorophenyl-3-azabicyclo-[3.2.0]heptan-3-yl]-butan-1-o ne,
1-(4-fluorophenyl)-4-[exo-6-phenyl-3-azabicyclo-[3.2.0]heptan-3-yl]butan-1- ol,
1-(4-fluorophenyl)-4-[exo-6-p-fluorophenyl-3-aza-bicyclo[3.2.0]heptan-3-yl] butan-1-ol,
1-phenyl-4-[exo-6-phenyl-3-azabicyclo[3.2.0]-heptan-3-yl]-butan-1-ol,
1-phenyl-4-[exo-6-p-fluorophenyl-3-azabicyclo[3.2.0]heptan-3-yl]-butan-1-ol
1,1 -bis(4-fluorophenyl)-4-[exo-6-phenyl-3azabicyclo
N-(3-[exo-6-phenyl-3-azabicyclo[3.2.0]heptan-3-yl]propyl)-4-fluorobenzamide
N-(2-[exo-6-phenyl-3-azabicyclo[3.2.0]heptan-3-yl]ethyl)-4-fluorobenzamide,
N-(2-[exo-6-phenyl-3-azabicyclo[3.2.0]heptan-3-yl]ethyl)-N-methyl-4-fluorob enzamide,
N-(2-[exo-6-phenyl-3-azabicyclo[3.2.0]hetan-3-yl]ethyl)-N-methylbenzamide,
N-(3-[exo-6-p-fluorophenyl-3-azabicyclo[3.2.0]-heptan-3-yl]propyl)-4-fluoro benzamide,
N-(2-[exo-6-p-fluorophenyl-3-azabicyclo[3.2.0]-heptan-3-yl]ethyl)-benzamide and
N-(2-[exo-6-p-fluorophenyl-3-azabicyclo[3.2.0]-heptan-3-yl]ethyl)-N-methylb enzamide.
The compounds of the formula I according to the invention can be prepared by reacting a compound of the formula II group, with a 3-azabicyclo[3.2.0]heptane derivative of the formula III ##STR4## where R.sup.1 is a phenyl, pyridyl, thienyl or pyrrolyl group which is unsubstituted or mono- or disubstituted by halogen atoms, C.sub.1 -C.sub.4 -alkyl, trifluoromethyl, hydroxyl, C.sub.1 -C.sub.4 -alkoxy, amino, monomethylamino, dimethylamino, cyano or nitro groups, substituted by halogen, methoxy, hydroxyl or amino, addition salts with physiologically tolerated acids.
Suitable and preferred nucleofugic leaving groups for Nu are halogen atoms, in particular bromine or chlorine.
The reaction is expediently carried out in the presence of an inert base such as triethylamine or potassium carbonate to trap the acid and in an inert solvent such as a cyclic saturated ether, especially tetrahydrofuran or dioxane, or in an aromatic hydrocarbon such as toluene or xylene.
The reaction is, as a rule, carried out at from 20.degree. to 150.degree. C. and is generally complete within 1 to 10 hours.
The compounds of the formula I according to the invention can be purified either by recrystallization from conventional organic solvents, preferably from a lower alcohol such as ethanol, or by column chromatogra
REFERENCES:
patent: 3328390 (1967-06-01), Grogan
patent: 4605655 (1986-08-01), Yevich et al.
Oppolzer W., Achini R., Pfenninger E., Weber H. P. (1976). Helv. Chim. Acta 58(4) 1186-1202.
107 -Azabicyclic Butyrophenones, Grogan et al., Jul. (1967) J. Med. Chem. pp. 621-623.
Behl Berthold
Steiner Gerd
Teschendorf Hans-Juergen
Unger Liliane
BASF - Aktiengesellschaft
Huang Evelyn
Ivy C. Warren
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