Straightforward entry to 7-azabicyclo[2.2.1]heptane-1-carbonitriles and subsequent synthesis of epibatidine analogues
The present invention relates to a group of substituted-7-azabicyclo-[2.2.1]heptyl derivatives with biological activity. The present invention also relates to synthetic methods for producing said substituted-7-azabicyclo-[2.2.1]heptyl derivatives. The present invention also relates to certain intermediates for producing such substituted-7-azabicyclo-[2.2.1]heptyl derivatives, as well as a synthetic method for producing such intermediates. The present invention also relates to pharmaceutical compositions comprising such substituted-7-azabicyclo-[2.2.1]heptyl derivatives, as well as their use as medicaments for the treatment of diseases mediated by a Nicotinic Acetylcholine Receptor or a receptor being a member of the Neurotransmitter-gated Ion Channel Superfamily, such as pain, Alzheimer's disease, Parkinson's disease, schizophrenia, epilepsy and nicotine addiction.
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 selected from the group consisting of hydrogen, benzyl, naphthylmethyl, 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 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy, dimethylaminoethoxy, dimethylaminopropoxy, morpholinoethoxy, phenoxy, phenoxymethyl, heteroaryl and heteroaryl-methyl;
R 1 is hydrogen and R 2 is hydroxyl, or R 1 in combination with R 2 is oxo or imino;
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 and tert-butylcarboxylate; and
n is 0, 1 or 2; and
Aryl is an arylene or heteroarylene divalent group,
or a pharmaceutically acceptable salt thereof, or a stereochemically isomeric form thereof, or a solvate thereof.
2. The 1-substituted-7-azabicyclo[2.2.1]heptyl derivative according to claim 1 , wherein Aryl is phenylene, or a pharmaceutically acceptable salt thereof, or a stereochemically isomeric form thereof, or a solvate thereof.
3. The 1-substituted-7-azabicyclo[2.2.1]heptyl derivative according to claim 2 , wherein n is 1.
4. The 1-substituted-7-azabicyclo[2.2.1]heptyl derivative according to claim 1 , wherein Aryl is pyrid-3-ylene or pyrid-2-ylene, or a pharmaceutically acceptable salt thereof, or a stereochemically isomeric form thereof, or a solvate thereof.
5. The 1-substituted-7-azabicyclo[2.2.1]heptyl derivative according to claim 4 , wherein n is 1.
6. 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 or aryl bromide represented by the structural formula Y-Aryl-(R 3 ) n wherein Y is iodo or bromo, Aryl, n and R 3 are as defined in claim 1 .
7. The method according to claim 6 , further comprising the step of cleaving off the N-protecting R 0 substituent.
8. 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 or aryl bromide represented by the structural formula Y-Aryl-(R 3 ) n wherein Y is iodo or bromo, Aryl, n and R 3 are as defined in claim 1 .
9. The method according to claim 8 , further comprising the step of cleaving off the N-protecting R 0 substituent.
10. 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 or aryl bromide represented by the structural formula Y-Aryl-(R 3 ) n wherein Y is iodo or bromo, Aryl, n and R 3 are as defined in claim 1 .
11. The method according to claim 10 , wherein said reaction is a Buchwald-Hartwig cross-coupling reaction.
12. The method according to claim 10 , wherein said reaction is performed in the presence of a palladium complex catalyst.
13. The method according to claim 10 , further comprising the step of cleaving off the N-protecting R 0 substituent.
14. A pharmaceutical composition comprising a therapeutically effective amount of a 1-substituted-7-azabicyclo[2.2.1]heptyl derivative according to claim 1 .
15. The pharmaceutical composition according to claim 14 , further comprising one or more pharmaceutically acceptable excipients.
16. 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 selected from the group consisting of hydrogen, benzyl, naphthylmethyl, 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, dimethylaminopropoxy, morpholinoethoxy, phenoxy, phenoxymethyl, heteroaryl and heteroaryl-methyl.
17. 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, naphthylmethyl, 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 heteroaryl-methyl.
18. The 1-substituted-7-azabicyclo[2.2.1]heptyl derivative according to claim 4 , wherein n is 0.
19. The 1-substituted-7-azabicyclo[2.2.1]heptyl derivative according to claim 4 , wherein R 0 is hydrogen.
20. The 1-substituted-7-azabicyclo[2.2.1]heptyl derivative according to claim 4 , wherein n is 0 and R 0 is hydrogen.
21. The 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.
22. The 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, R 2 is hydroxyl and R 0 is hydrogen.
23. The 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, R 2 is hydroxyl, R 0 is hydrogen, and n is 0.
24. The 1-substituted-7-azabicyclo[2.2.1]heptyl derivative according to claim 4 , being represented by the structural formula (I) wherein n is 0 and R 0 is hydrogen.
25. A pharmaceutical composition comprising a therapeutically effective amount of a 1-substituted-7-azabicyclo[2.2.1]heptyl derivative according to claim 4 .
26. A pharmaceutical composition comprising a therapeutically effective amount of a 1-substituted-7-azabicyclo[2.2.1]heptyl derivative according to claim 18 .
27. A pharmaceutical composition comprising a therapeutically effective amount of a 1-substituted-7-azabicyclo[2.2.1]heptyl derivative according to claim 19 .
28. A pharmaceutical composition comprising a therapeutically effective amount of a 1-substituted-7-azabicyclo[2.2.1]heptyl derivative according to claim 20 .
29. A pharmaceutical composition comprising a therapeutically effective amount of a 1-substituted-7-azabicyclo[2.2.1]heptyl derivative according to claim 21 .
30. A pharmaceutical composition comprising a therapeutically effective amount of a 1-substituted-7-azabicyclo[2.2.1]heptyl derivative according to claim 22 .
31. A pharmaceutical composition comprising a therapeutically effective amount of a 1-substituted-7-azabicyclo[2.2.1]heptyl derivative according to claim 23 .
32. A pharmaceutical composition comprising a therapeutically effective amount of a 1-substituted-7-azabicyclo[2.2.1]heptyl derivative according to claim 24 .