Azaindole derivatives with a combination of partial nicotinic acetyl-choline receptor agonism and dopamine reuptake inhibition
Azaindole derivatives of formula (I): wherein the symbols have the meanings given in the specification, are described. These compounds have a combination of partial nicotinic acetylcholine receptor agonism and dopamine reuptake inhibition. The invention also relates to pharmaceutical compositions containing these compounds, to methods for preparing them, methods for preparing novel intermediates useful for their synthesis, methods for preparing compositions, and uses of such compounds and compositions, for example, their use in administering them to patients to achieve a therapeutic effect in disorders in which nicotinic receptors and/or dopamine transporters are involved, or that can be treated via manipulation of those receptors.
1. A compound of formula (I):
or a tautomer, stereoisomer, or N-oxide thereof, or a pharmacologically acceptable salt of any of the foregoing,
wherein
X is N, and Y and Z are C;
m is 0, and n is chosen from 0 and 1;
R 2 is chosen from a piperidinyl group, a pyrrolidinyl group, a tetrahydropyridinyl group, a morpholinyl group, a azepanyl group, a 1-aza-bicyclo[2.2.2]octanyl group and a 1-aza-bicyclo[2.2.2]-oct-2-enyl group, which group is either unsubstituted or substituted with at least one substituent chosen from a halogen atom, a (C 1-3 )alkyl group, a phenyl group and a benzyl group;
R 3 is hydrogen; and
R 4 , R 5 and R 6 , which are the same or different, are chosen from a hydrogen atom, a halogen atom, a (C 1-3 )alkyl group, a (C 2-3 )alkynyl group, a CF 3 group, a NH(C 1-3 )alkyl group, a hydroxyl group and a (C 1-3 )alkyloxy group with the proviso that when X is N, Y and Z are C, m is 0, n is 1, R 3 , R 4 , R 5 and R 6 are H, R 2 is not pyridin-4-yl.
2. The compound as claimed in claim 1 , wherein R 2 is chosen from a piperidinyl group, a pyrrolidinyl group, a tetrahydropyridinyl group, a morpholinyl group, a azepanyl group, a 1-aza-bicyclo[2.2.2]octanyl group and a 1-aza -bicyclo[2.2.2]oct-2-enyl group, which group is either unsubstituted or substituted with at least one substituent chosen from a halogen atom, a (C 1-3 )alkyl group, a phenyl group and a benzyl group; and R 4 , R 5 and R 6 , which are the same or different, are chosen from a hydrogen atom, a halogen atom, a (C 1-3 )alkyl group, and an alkyl(C 1-3 )oxy group.
3. The compound as claimed to claim 1 , wherein the compound is chosen from:
2-pyrrolidin-3-yl-1H-pyrrolo[3,2-b]pyridine;
2-pyrrolidin-3-yl-1H-pyrrolo[2,3-b]pyridine;
(S)-2-pyrrolidin-3-yl-1H-pyrrolo[2,3-b]pyridine;
(R)-2-pyrrolidin-3-yl-1H-pyrrolo[2,3-b]pyridine;
2-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;
2-piperidin-3-yl-1 H-pyrrolo[2,3-b]pyridine 7-oxide;
(S)-2-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;
(R)-2-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;
3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;
3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine 7-oxide;
4-chloro-2-piperidin-3-yl-1 H-pyrrolo[2,3-b]pyridine;
6-chloro-2-piperidin-3-yl-1 H-pyrrolo[2,3-b]pyridine;
(S)-6-chloro-2-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;
(R)-6-chloro-2-piperidin-3-yl-1 H-pyrrolo[2,3-b]pyridine;
6-chloro-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;
2-(1-methyl-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;
2-(1,2,5,6-tetrahydro-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine;
3-(1H-pyrrolo[2,3-b]pyridine-2-yl)-piperidin-3-ol;
3-(1H-pyrrolo[2,3-b]pyridine-2-yl)-1-aza-bicyclo[2.2.2]octan-3-ol;
3-(1H-pyrrolo[2,3-b]pyridine-2-yl)-1-aza-bicyclo[2.2.2]octane;
3-(1H-pyrrolo[2,3-b]pyridine-3-yl)-piperidin-3-ol;
3-(1H-pyrrolo[2,3-b]pyridine-3-yl)-1-aza-bicyclo[2.2.2]octane;
3-(1H-pyrrolo[2,3-b]pyridine-3-yl)-1-aza-bicyclo[2.2.2]oct-2-ene;
2-pyrrolidin-2-ylmethyl-1 H-pyrrolo[2,3-b]pyridine;
(R)-2-pyrrolidin-2-ylmethyl-1H-pyrrolo[2,3-b]pyridine;
(R)-6-pyrrolidin-2-ylmethyl-7H-pyrrolo[2,3-d]pyrimidine;
(R)-6-fluoro-2-pyrrolidin-2-ylmethyl-1H-pyrrolo[2,3-b]pyridine;
(R)-6-chloro-2-pyrrolidin-2-ylmethyl-1H-pyrrolo[2,3-b]pyridine;
(R)-6-bromo-2-pyrrolidin-2-ylmethyl-1H-pyrrolo[2,3-b]pyridine;
(R)-6-methoxy-2-pyrrolidin-2-ylmethyl-1H-pyrrolo[2,3-b]pyridine;
(R)-5-bromo-2-pyrrolidin-2-ylmethyl-1H-pyrrolo[2,3-b]pyridine;
(R)-5-methyl-2-pyrrolidin-2-ylmethyl-1H-pyrrolo[2,3-b]pyridine;
(R)-5-methoxy-2-pyrrolidin-2-ylmethyl-1H-pyrrolo[3,2-b]pyridine;
(R)-2-pyrrolidin-2-ylmethyl-1H-pyrrolo[3,2-b]pyridine;
(R)-3-pyrrolidin-2-ylmethyl-1H-pyrrolo[3,2-b]pyridine;
(S)-2-pyrrolidin-2-ylmethyl-1H-pyrrolo[3,2-b]pyridine;
(S)-2-pyrrolidin-2-ylmethyl-1H-pyrrolo[2,3-b]pyridine;
(S)-6-fluoro-2-pyrrolidin-2-ylmethyl-1H-pyrrolo[2,3-b]pyridine;
(S)-6-chloro-2-pyrrolidin-2-ylmethyl-1H-pyrrolo[2,3-b]pyridine;
(S)-6-bromo-2-pyrrolidin-2-ylmethyl-1H-pyrrolo[2,3-b]pyridine;
(S)-5-bromo-2-pyrrolidin-2-ylmethyl-1H-pyrrolo[2,3-b]pyridine;
(S)-2-(1-methyl-pyrrolidin-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridine;
(R)-2-(1-methyl-pyrrolidin-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridine;
2-pyrrolidin-3-ylmethyl-1H-pyrrolo[2,3-b]pyridine;
2-(1-methyl-pyrrolidin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine; and
2-(1-benzyl-pyrrolidin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine.
4. The compound as claimed in claim 1 , wherein the compound is an (R)-enantiomer, and wherein R 2 is chosen from a piperidinyl group, a pyrrolidinyl group, a tetrahydropyridinyl group, a morpholinyl, azepanyl group, a 1-aza -bicyclo[2.2.2]octanyl group and a 1-aza-bicyclo[2.2.2]oct-2-enyl group, which group is either unsubstituted or substituted with at least one substituent chosen from a halogen atom, a (C 1-3 )alkyl, phenyl group and a benzyl group, and wherein m and n are 0 and at least one of Y and Z is an asymmetric carbon atom directly linked to the azaindole core.
5. The compound as claimed in claim 1 , wherein the compound is an (R)-enantiomer, and wherein R 2 is chosen from a piperidinyl group, a pyrrolidinyl group, a tetrahydropyridinyl group, a morpholinyl, azepanyl group, a 1-aza -bicyclo[2.2.2]octanyl group, and a 1-aza-bicyclo[2.2.2]oct-2-enyl group, which group is either unsubstituted or substituted with at least one substituent chosen from a halogen atom, a (C 1-3 )alkyl, phenyl group and a benzyl group, and wherein m and n are 1 and at least one of Y and Z is an asymmetric carbon atom linked to the azaindole core via a methylene bridge.
6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and/or at least one pharmaceutically acceptable auxiliary substance and a pharmacologically active amount of at least one compound as claimed in claim 1 , as an active ingredient.
7. A compound of formula (I*):
wherein
Q is a protecting group chosen from:
X is N, wherein the nitrogen atom is substituted with a substituent chosen from a hydrogen atom, a benzyl group, a t-BOC group and a SO 2 -OH group;
Y and Z are C;
m is 0, and n is chosen from 0 and 1;
R 2 is chosen from a piperidinyl group, a pyrrolidinyl group, a tetrahydropyridinyl group, a morpholinyl azepanyl group, a 1-aza-bicyclo[2.2.2]octanyl group and a 1-aza-bicyclo[2.2.2]oct-2-enyl group, which group is either unsubstituted or substituted with at least one substituent chosen from a halogen atom, a (C 1-3 )alkyl group, a phenyl group and a benzyl group;
R 3 is hydrogen; and
R 4 , R 5 and R 6 , which are the same or different, are chosen from a hydrogen atom, a halogen atom, a (C 1-3 )alkyl group, a (C 1-3 )alkynyl group, a CF 3 group, a NH(C 1-3 )alkyl group, a hydroxyl group and an alkyloxy group.