2-heteroarylcarboxylic acid amides
View Patent ↗The invention relates to novel 2-heteroarylcarboxamides, processes for their preparation, and their use for producing medicaments for the treatment and/or prophylaxis of diseases and for improving perception, concentration, learning and/or memory.
1. A process for preparing compounds of formula (I):
in which
R 1 represents 1-azabicyclo[2.2.2]oct-3-yl,
R 2 represents hydrogen or C1-C6-alkyl,
R 3 represents hydrogen, halogen or C 1 -C 6 -alkyl,
A represents oxygen or sulfur,
and
the ring B represents benzo, pyrimido, pyrimidazo or pyridazino which is substituted by a radicals selected from the group consisting of halogen, C 1 -C 6 -alkanoyl, carbamoyl, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C 1 -C 6 -acylamino, C 1 -C 6 -alkyl, C 1 -C 6 -alkyoxy, C 1 -C 6 -alkylthio, C 1 -C 6 -alkylamino, heteroarylcarbonylamino, arylcarbonylamino, C 1 -C 6 -alkylsulfonyl-amino, di(C 1 -C 4 -alkylsulfonyl)amino, arylsulfonylamino, di(arylsulfonyl)amino, C 3 -C 6 -cycloalkylcarbonylmethyl, 1,3-dioxa-propane-1,3-diyl, amino(hydroxyimino)methyl and benzo,
or a salt, a hydrate or a hydrate of a salt thereof,
characterized in that compounds of the formula
R 1 R 2 NH (II),
in which R 1 and R 2 are as defined for formula I are reacted with a compound of the formula
in which
R 3 , A and the ring B are as defined for formula I and
X represents hydroxyl or a suitable leaving group,
in an inert solvent, if appropriate in the presence of a condensing agent and if appropriate in the presence of a base.
2. The process for preparing compounds of formula (I) according to claim 1 , wherein
R 1 represents 1-azabicyclo[2.2.2]oct-3-yl,
R 2 represents hydrogen or C 1 -C 6 -alkyl,
R 3 represents hydrogen, halogen or C 1 -C 6 -alkyl,
A represents oxygen or sulfur, and
the ring B represents benzo, pyrimido, pyridazo or pyridazino which is substituted by a radicals selected from the group consisting of halogen, formyl, carbamoyl, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, formamido, acetamido, (C 1 -C 6 -alkyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkylthio and benzo,
or a salt, a hydrate or a hydrate of a salt thereof.
3. The process for preparing compounds of formula (I) according to claim 2 , wherein
R 1 represents 1-azabicyclo[2.2.2]oct-3-yl,
R 2 represents hydrogen,
R 3 represents hydrogen, chlorine, fluorine or methyl,
A represents oxygen or sulfur,
and the ring B represents benzo which is substituted by 1 to 3 radicals selected from the group consisting of halogen, formyl, carbamoyl, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, formamido, acetamido, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, C 1 -C 4 -alkylamino, furylcarbonylamino, phenylcarbonylamino, methylsulfonylamino, di(phenylsulfonyl)amino, cyclopropylcarbonylmethyl, 1,3-dioxapropane-1,3-diyl, amino(hydroxyiminio)methyl and benzo,
or a salt, a hydrate or a hydrate of a salt thereof.
4. The process for preparing compounds of formula (I) according to claim 1 , wherein
R 1 represents (3R)-1-azabicyclo[2.2.2]oct-3-yl, and
R 2 , R 3 , A and the ring B are as defined in claim 1 .
5. The process for preparing compounds of formula (I) according to claim 1 , wherein
R 1 represents (3R)-1-azabicyclo[2.2.2]oct-3-yl, and
R 2 , and R 3 represent hydrogen,
A represents sulfur,
and
the ring B represents benzo which is substituted by 1 to 3 radicals selected from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, formamido, acetamido and C 1 -C 4 -alkyl,
or a salt, a hydrate or a hydrate of a salt thereof.
6. A process for preparing compounds of formula (Ia):
in which
R 1 represents 1-azabicyclo[2.2.2]oct-3-yl,
R 2 represents hydrogen or C 1 -C 6 -alkyl,
R 3 represents hydrogen, halogen or C 1 -C 6 -alkyl,
A represents oxygen or sulfur,
and
Z represents halogen, formyl, carbamoyl, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, formamido, acetamido, C 1 -C 6 -alkyl, C 1 -C 6 -alkyoxy, C 1 -C 6 -alkylthio, C 1 -C 6 -alkylamino, heteroaryl-carbonylamino, arylcarbonylamino, C 1 -C 4 -alkylsulfonylamino, di(arylsulfonyl)amino, C 3 -C 6 -cycloalkylcarbonylmethyl or amino(hydroxyimino)methyl,
or a salt, a hydrate or a hydrate of a salt thereof,
characterized in that compounds of the formula
R 1 R 2 NH (II),
in which R 1 and R 2 are as defined for formula Ia are reacted with a compound of the formula
in which
R 3 , A and the ring B are as defined for formula I and
X represents hydroxyl or a suitable leaving group,
in an inert solvent, if appropriate in the presence of a condensing agent and if appropriate in the presence of a base.
7. The process for preparing compounds of formula (Ia) according to claim 6 ,
R 1 represents 1-azabicyclo[2.2.2]oct-3-yl,
R 2 represents hydrogen,
R 3 represents hydrogen, chlorine, fluorine or methyl,
A represents oxygen or sulfur,
and
Z represents halogen, formyl, carbamoyl, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, formamido, acetamido, methyl, ethyl, methoxy, ethoxy, C 1 -C 4 -alkylamino, furylcarbonylamino, phenylcarbonylamino, methylsulfonylamino, di(phenyldulfonyl)amino, cyclopropylcarbonylmethyl or amino(hydroxyimino)methyl,
or a salt, a hydrate or a hydrate of a salt thereof.
8. The process for preparing compounds of formula (I) according to claim 6 ,
R 1 represents (3R)-1-azabicyclo[2.2.2]oct-3-yl,
R 2 represents hydrogen,
R 3 represents hydrogen, chlorine, fluorine or methyl,
A represents oxygen or sulfur,
and
Z represents halogen, formyl, carbamoyl, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, formamido, acetamido, methyl, ethyl, methoxy, ethoxy, C 1 -C 4 -alkylamino, furylcarbonylamino, phenylcarbonylamino, methylsulfonylamino, di(phenyldulfonyl)amino, cyclopropylcarbonylmethyl or amino(hydroxyimino)methyl,
or a salt, a hydrate or a hydrate of a salt thereof.
9. The process for preparing compounds of formula (Ia) according to claim 6 , wherein A represents oxygen.
10. The process for preparing compounds of formula (Ia) according to claim 7 , wherein A represents oxygen.
11. The process for preparing compounds of formula (Ia) according to claim 8 , wherein A represents oxygen.
12. The process for preparing compounds of formula (Ia) according to claim 6 , wherein A represents sulfur.
13. The process for preparing compounds of formula (Ia) according to claim 7 , wherein A represents sulfur.
14. The process for preparing compounds of formula (Ia) according to claim 8 , wherein A represents sulfur.
15. The process for preparing compounds of formula (Ia) according to any one of claims 7 - 14 , wherein Z is selected from the group consisting of: halogen, cyano, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, and ethoxy.
16. The process for preparing compounds of formula (I) according to claim 1 , wherein the compound is N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-fluoro-1-benzofuran-2-carboxamide or a salt thereof.
17. The process for preparing compounds of formula (I) according to claim 1 , wherein the compound is N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-fluoro-1-benzothiophene-2-carboxamide or a salt thereof.
18. The process for preparing compounds of formula (I) according to claim 1 , wherein the compound is N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5,7-difluoro-1-benzothiophene-2-carboxamide or a salt thereof.
19. The process for preparing compounds of formula (I) according to claim 1 , wherein the compound is N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-fluoro-1-benzofuran-2-carboxamide or a salt thereof.
20. The process for preparing compounds of formula (I) according to claim 1 , wherein the compound is N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-chloro-1-benzofuran-2-carboxamide or a salt thereof.
21. The process for preparing compounds of formula (I) according to claim 1 , wherein the compound is N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5,7-difluoro-1-benzofuran-2-carboxamide or a salt thereof.
22. The process for preparing compounds of formula (I) according to claim 1 , wherein the compound is N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-fluoro-1-benzothiophene-2-carboxamide or a salt thereof.
23. The process for preparing compounds of formula (I) according to claim 1 , wherein the compound is N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-chloro-1-benzothiophene-2-carboxamide or a salt thereof.
24. The process for preparing compounds of formula (I) according to claim 1 , wherein the compound is N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-cyano-1-benzothiophene-2-carboxamide or a salt thereof.
25. The process for preparing compounds of formula (I) according to claim 1 , wherein the compound is N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-trifluoromethyl-1-benzothiophene-2-carboxamide or a salt thereof.
26. A process for preparing a pharmaceutical composition comprising a compound prepared according to the method of claim 1 comprising combining the compound prepared according to the method of claim 1 with a pharmaceutically acceptable carrier.
27. A process for preparing a pharmaceutical composition comprising a compound prepared according to the method of claim 6 comprising combining the compound prepared according to the method of claim 6 with a pharmaceutically acceptable carrier.
28. The process for preparing a pharmaceutical composition according to claim 26 , wherein the compound is N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-fluoro-1-benzofuran-2-carboxamide or a salt thereof and a pharmaceutically acceptable carrier.
29. The process for preparing a pharmaceutical composition according to claim 26 , wherein the compound is N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-fluoro-1-benzothiophene-2-carboxamide or a salt thereof and a pharmaceutically acceptable carrier.
30. The process for preparing a pharmaceutical composition according to claim 26 , wherein the compound is N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5,7-difluoro-1-benzothiophene-2-carboxamide or a salt thereof and a pharmaceutically acceptable carrier.
31. The process for preparing a pharmaceutical composition according to claim 26 , wherein the compound is N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-fluoro-1-benzofuran-2-carboxamide or a salt thereof and a pharmaceutically acceptable carrier.
32. The process for preparing a pharmaceutical composition according to claim 26 , wherein the compound is N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-chloro-1-benzofuran-2-carboxamide or a salt thereof and a pharmaceutically acceptable carrier.
33. The process for preparing a pharmaceutical composition according to claim 26 , wherein the compound is N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5,7-difluoro-1-benzofuran-2-carboxamide or a salt thereof and a pharmaceutically acceptable carrier.
34. The process for preparing a pharmaceutical composition according to claim 26 , wherein the compound is N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-fluoro-1-benzothiophene-2-carboxamide or a salt thereof and a pharmaceutically acceptable carrier.
35. The process for preparing a pharmaceutical composition according to claim 26 , wherein the compound is N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-chloro-1-benzothiophene-2-carboxamide or a salt thereof and a pharmaceutically acceptable carrier.
36. The process for preparing a pharmaceutical composition according to claim 26 , wherein the compound is N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-cyano-1-benzothiophene-2-carboxamide or a salt thereof and a pharmaceutically acceptable carrier.
37. The process for preparing a pharmaceutical composition according to claim 26 , wherein the compound is N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-trifluoromethyl-1-benzothiophene-2-carboxamide or a salt thereof and a pharmaceutically acceptable carrier.
38. The process for preparing a pharmaceutical composition according to claim 26 , wherein the compound is a hydrate of N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-fluoro-1-benzofuran-2-carboxamide or a salt thereof and a pharmaceutically acceptable carrier.
39. The process for preparing a pharmaceutical composition according to claim 26 , wherein the compound is a hydrate of N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-fluoro-1-benzothiophene-2-carboxamide or a salt thereof and a pharmaceutically acceptable carrier.
40. The process for preparing a pharmaceutical composition according to claim 26 , wherein the compound is a hydrate of N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5,7-difluoro-1-benzothiophene-2-carboxamide or a salt thereof and a pharmaceutically acceptable carrier.
41. The process for preparing a pharmaceutical composition according to claim 26 , wherein the compound is a hydrate of N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-fluoro-1-benzofuran-2-carboxamide or a salt thereof and a pharmaceutically acceptable carrier.
42. The process for preparing a pharmaceutical composition according to claim 26 , wherein the compound is a hydrate of N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-chloro-1-benzofuran-2-carboxamide or a salt thereof and a pharmaceutically acceptable carrier.
43. The process for preparing a pharmaceutical composition according to claim 26 , wherein the compound is a hydrate of N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5,7-difluoro-1-benzofuran-2-carboxamide or a salt thereof and a pharmaceutically acceptable carrier.
44. The process for preparing a pharmaceutical composition according to claim 26 , wherein the compound is a hydrate of N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-fluoro-1-benzothiophene-2-carboxamide or a salt thereof and a pharmaceutically acceptable carrier.
45. The process for preparing a pharmaceutical composition according to claim 26 , wherein the compound is a hydrate of N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-chloro-1-benzothiophene-2-carboxamide or a salt thereof and a pharmaceutically acceptable carrier.
46. The process for preparing a pharmaceutical composition according to claim 26 , wherein the compound is a hydrate of N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-cyano-1-benzothiophene-2-carboxamide or a salt thereof and a pharmaceutically acceptable carrier.
47. The process for preparing a pharmaceutical composition according to claim 26 , wherein the compound is a hydrate of N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-trifluoromethyl-1-benzothiophene-2-carboxamide or a salt thereof and a pharmaceutically acceptable carrier.