Isoquinoline-3-carboxylic acid amides and pharmaceutical uses thereof
The present invention relates to novel isoquinoline-3-carboxylic acid amides having α7 nicotinic acetylcholine receptor agonistic activity, their preparation, their use as pharmaceuticals and pharmaceutical compositions containing them.
1. A compound of formula I
wherein R 1 and R 2 , independently, are hydrogen, (C 1-4 )alkyl, halogen, hydroxy, (C 1-4 )alkoxy, di(C 1-4 )alkylamino, (C 1-4 )alkylthio, cyano or trifluoromethyl, R 3 is hydrogen or (C 1-4 )alkyl and n is 1 or 2, in free base or acid addition salt form,
wherein the compound is selected from the group consisting of:
isoquinoline-3-carboxylic acid{(S)-1-azabicyclo[2.2.2]oct-3-yl}-amide,
isoquinoline-3-carboxylic acid{(R)-1-azabicyclo[2.2.2]oct-3-yl}-amide,
6-fluoro-isoquinoline-3-carboxylic acid{(R)azabicyclo[2.2.2]oct-3-yl}-amide,
8-fluoro-isoquinoline-3-carboxylic acid{(R)-1-azabicyclo[2.2.2]oct-3-yl}amide, and
8-fluoro-isoquinoline-3-carboxylic acid{(S)-1-azabicyclo[2.2.2]oct-3-yl}-amide.
2. A process for the preparation of a compound of formula I
wherein R 1 and R 2 , independently, are hydrogen, (C 1-4 )alkyl, halogen, hydroxy, (C 1-4 )alkoxy, di(C 1-4 )alkylamino, (C 1-4 )alkylthio, cyano or trifluoromethyl, R 3 is hydrogen or (C 1-4 )alkyl and n is 1 or 2, or a salt thereof, which comprises the step of reacting a compound of formula II
wherein R 1 and R 2 are as defined above, with a compound of formula III
wherein R 3 and n are as defined above, and recovering the resulting compound of formula I in free base or acid addition salt form.
3. A pharmaceutical composition comprising a compound of claim 1 in free base or pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent.
4. A compound of claim 1 , wherein the compound is selected from the group consisting of:
isoquinoline-3-carboxylic acid{(S)-1-azabicyclo[2.2.2]oct-3-yl}-amide,
isoquinoline-3-carboxylic acid{(R)-1-azabicyclo[2.2.2]oct-3-yl}-amide,
6-fluoro-isoquinoline-3-carboxylic acid{(R)azabicyclo[2.2.2]oct-3-yl}-amide, and
8-fluoro-isoquinoline-3-carboxylic acid{(R)-1-azabicyclo[2.2.2]oct-3-yl}amide.
5. A compound of claim 1 , wherein the compound is isoquinoline-3-carboxylic acid{(S)-1-azabicyclo[2.2.2]oct-3-yl}-amide.
6. A compound of claim 1 , wherein the compound is isoquinoline-3-carboxylic acid{(R)-1-azabicyclo[2.2.2]oct-3-yl}-amide.
7. A compound of claim 1 , wherein the compound is 6-fluoro-isoquinoline-3-carboxylic acid{(R)-1-azabicyclo[2.2.2]oct-3-yl}amide.
8. A compound of claim 1 , wherein the compound is 8-fluoro-isoquinoline-3-carboxylic acid{(R)-1-azabicyclo[2.2.2]oct-3-yl}amide.
9. A compound of claim 1 , wherein the compound is 8-fluoro-isoquinoline-3-carboxylic acid{(S)-1-azabicyclo[2.2.2]oct-3-yl}-amide.
10. A compound of formula I
wherein
R 1 and R 2 , independently, are hydrogen or fluorine;
R 3 is hydrogen or (C 1-4 )alkyl; and
n is 2;
in free base or acid addition salt form.
11. A process for the preparation of a compound of formula I as defined in claim 10 , or a salt thereof, which comprises the step of reacting a compound of formula II
wherein R 1 and R 2 are as defined in claim 10 , with a compound of formula III
wherein R 3 and n are as defined in claim 10 , and recovering the resulting compound of formula I in free base or acid addition salt form.
12. A pharmaceutical composition comprising a compound of claim 10 in free base or pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent.