Substituted 7-azabicyclo[2.2.1]heptyl derivatives useful for making pharmaceutical compositions
This invention provides 1-substituted-7-azabicyclo[2.2.1]heptyl derivatives, intermediates and methods for producing them, which are therapeutic agents useful for the prevention and treatment of central nervous system disorders and diseases mediated by a Nicotinic Acetylcholine Receptor such as Alzheimer's disease, Parkinson's disease, schizophrenia, epilepsy, pain, nicotine addiction and dementia.
1. A 1-substituted-7-azabicyclo[2.2.1]heptyl derivative represented by the structural formula (I):
or the structural formula (II):
wherein:
R 0 is hydrogen or a nitrogen-protecting group selected from the group consisting of benzyl, heteroarylmethyl, heteroarylethyl, phenylethyl, naphthylmethyl, naphthylethyl, butoxycarbonyl, C 3-4 alkenyl and C 1-8 alkyl, wherein said benzyl is optionally substituted with one to three substituents is independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy, dimethylaminoethoxy, dimethylaminopropoxy, morpholinoethoxy, phenoxy, phenoxymethyl, heteroaryl and heteroarylmethyl;
R 1 is hydrogen and R 2 is hydroxyl, or R 1 in combination with R 2 is oxo or imino;
each R 3 is a substituent selected from the group consisting of fluoro, chloro, bromo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, cyano, phenyl, trifluoromethyl, trifluoromethoxy, amino, dimethylamino, heteroaryl and tert-butylcarboxylate; and
n is 0, 1, 2 or 3; and
Aryl is an optionally substituted aryl or heteroaryl group,
or a pharmaceutically acceptable salt thereof, or a stereochemically isomeric form thereof, or a solvate thereof.
2. A 1-substituted-7-azabicyclo[2.2.1]heptyl derivative according to claim 1 , or a pharmaceutically acceptable salt thereof, or a stereochemically isomeric form thereof, or a solvate thereof, wherein Aryl is a non-substituted, mono-substituted, di-substituted or tri-substituted phenyl group.
3. A 1-substituted-7-azabicyclo[2.2.1]heptyl derivative according to claim 1 , or a pharmaceutically acceptable salt thereof, or a stereochemically isomeric form thereof, or a solvate thereof, wherein Aryl is an optionally substituted pyrid-3-yl or pyrid-2-yl group.
4. A 1-substituted-7-azabicyclo[2.2.1]heptyl derivative according to claim 3 , wherein n is 0 or 1.
5. A 1-substituted-7-azabicyclo[2.2.1]heptyl derivative according to claim 4 , wherein R 3 is chloro.
6. A 1-substituted-7-azabicyclo[2.2.1]heptyl derivative according to claim 4 , being represented by the structural formula (I).
7. A 1-substituted-7-azabicyclo[2.2.1]heptyl derivative according to claim 6 , wherein R 0 is hydrogen, and n is 0.
8. A 1-substituted-7-azabicyclo[2.2.1]heptyl derivative according to claim 3 , being represented by the structural formula (II) wherein R 1 is hydrogen and R 2 is hydroxyl.
9. A 1-substituted-7-azabicyclo[2.2.1]heptyl derivative according to claim 4 , being represented by the structural formula (II) wherein R 1 is hydrogen and R 2 is hydroxyl.
10. A 1-substituted-7-azabicyclo[2.2.1]heptyl derivative according to claim 9 , wherein R 0 is hydrogen, and n is 0.
11. A 1-substituted-7-azabicyclo[2.2.1]heptyl derivative according to claim 3 , wherein R 0 is benzyl substituted in ortho and/or para positions with one to three methoxy groups.
12. A 1-substituted-7-azabicyclo[2.2.1]heptyl derivative according to claim 4 , wherein R 0 is benzyl substituted in ortho and/or para positions with one to three methoxy groups.
13. A 1-substituted-7-azabicyclo[2.2.1]heptyl derivative according to claim 5 , wherein R 0 is benzyl substituted in ortho and/or para positions with one to three methoxy groups.
14. A method for producing a 1-substituted-7-azabicyclo[2.2.1]heptyl derivative according to claim 1 and being represented by the structural formula (II) wherein R 1 is hydrogen and R 2 is hydroxyl, comprising reacting a 1-formyl-7-R 0 -substituted-7-azabicyclo[2.2.1]-heptane, wherein R 0 is as defined in claim 1 , with an optionally substituted aryl iodide, aryl chloride or aryl bromide represented by the structural formula Y-Aryl-(R 3 ) n wherein Y is iodo, chloro or bromo, and wherein Aryl, n and R 3 are as defined in claim 1 .
15. A method according to claim 14 , wherein R 0 is not hydrogen, further comprising the step of cleaving off the nitrogen-protecting group R 0 .
16. A method for producing a 1-substituted-7-azabicyclo[2.2.1]heptyl derivative according to claim 1 and being represented by the structural formula (II) wherein R 1 in combination with R 2 is oxo, comprising reacting a 1-cyano-7-R 0 -substituted-7-azabicyclo[2.2.1]-heptane, wherein R 0 is as defined in claim 1 , with an optionally substituted aryl iodide, aryl chloride or aryl bromide represented by the structural formula Y-Aryl-(R 3 ) n wherein Y is iodo, chloro or bromo, and wherein Aryl, n and R 3 are as defined in claim 1 .
17. A method according to claim 16 , wherein R 0 is not hydrogen, further comprising the step of cleaving off the nitrogen-protecting group R 0 .
18. A method for producing a 1-substituted-7-azabicyclo[2.2.1]heptyl derivative according to claim 1 and being represented by the structural formula (I) comprising submitting a 1-aminomethyl-7-R 0 -substituted-7-azabicyclo[2.2.1]-heptane, wherein R 0 is as defined in claim 1 , to a reaction step with an optionally substituted aryl iodide, aryl chloride or aryl bromide represented by the structural formula Y-Aryl-(R 3 ) n wherein Y is iodo, chloro or bromo, and wherein Aryl, n and R 3 are as defined in claim 1 .
19. A method according to claim 18 , wherein said reaction is a Buchwald-Hartwig cross-coupling reaction.
20. A method according to claim 18 , wherein said reaction is performed in the presence of a palladium complex catalyst.
21. A method according to claim 18 , wherein R 0 is not hydrogen, further comprising the step of cleaving off the nitrogen-protecting group R 0 .
22. A pharmaceutical composition comprising a therapeutically effective amount of a 1-substituted-7-azabicyclo[2.2.1]heptyl derivative according to claim 1 .
23. A pharmaceutical composition according to claim 22 , wherein R 0 is hydrogen.
24. A pharmaceutical composition according to claim 22 , further comprising one or more pharmaceutically acceptable excipients.
25. A 1-formyl-7-R 0 -substituted-7-azabicyclo[2.2.1]-heptane or 1-cyano-7-R 0 -substituted-7-azabicyclo[2.2.1]-heptane, wherein R 0 is hydrogen or a nitrogen-protecting group selected from the group consisting of benzyl, phenylethyl, naphthylmethyl, naphthylethyl, butoxycarbonyl, C 3-4 alkenyl and C 1-8 alkyl, wherein said benzyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, C 1-8 alkyl, C 1-8 alkoxy, trifluoromethyl, trifluoromethoxy, dimethylaminoethoxy, dimethylamino-propoxy, morpholinoethoxy, phenoxy, phenoxymethyl, heteroaryl and heteroarylmethyl.
26. A method for producing a 1-cyano-7-R 0 -substituted-7-azabicyclo[2.2.1]-heptane comprising reacting 4-methanesulfonyl-cyclohexanone with a molar excess of a primary amine R 0 NH 2 , wherein R 0 is selected from the group consisting of benzyl, phenylethyl, naphthylmethyl, naphthylethyl, butoxy-carbonyl, C 3-4 alkenyl and C 1-8 alkyl, wherein said benzyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy, dimethylaminoethoxy, dimethylaminopropoxy, morpholinoethoxy, phenoxy, phenoxymethyl, heteroaryl and heteroarylmethyl.
27. A method for producing a 1-cyano-7-R 0 -substituted-7-azabicyclo[2.2.1]-heptane according to claim 26 , wherein R 0 is benzyl substituted in ortho position and/or para position with one to three methoxy groups.