3-phenyl-propionamido, 3-phenyl-acrylamido and 3-phenyl-propynamido derivatives
View Patent ↗The invention relates to 3-phenyl-propionamido, 3-phenyl-acrylamido and 3-phenyl-propynamido derivatives, for example, deriviatives of the formula wherein A is selected from R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 21 , R 22 , R 23 , R 24 , and n are as defined herein or pharmaceutically acceptable salts thereof. The invention also relates to processes for preparation of such compounds, compositions containing them, and the use of such derivatives as MAO-B inhibitors. The invention further relates to methods for treating or preventing Alzheimer's disease and senile dementia by administering compounds of the invention.
1. A compound of formula I
wherein
R 1 is (C 1 -C 3 )-alkyl, halogen, halogen-(C 1 -C 6 )-alkyl, cyano, (C 1 -C 6 )-alkoxy or halogen-(C 1 -C 6 )-alkoxy;
R 21 , R 22 , R 23 and R 24 are each independently selected from the group consisting of hydrogen and fluoro;
R 3 is hydrogen or (C 1 -C 3 )-alkyl;
A is selected from
R 4 is hydrogen or (C 1 -C 3 )-alkyl;
R 5 , R 6 and R 7 are each independently hydrogen or (C 1 -C 6 )-alkyl; and
n is 1, 2 or 3;
wherein when n is 2 or 3, each R 1 is the same or different;
or a pharmaceutically acceptable salt thereof.
2. A compound of according to claim 1 , wherein n is 1.
3. A compound according to claim 1 , wherein R 1 is halogen or halogen-(C 1 -C 6 )-alkyl.
4. A compound according to claim 3 , wherein R 1 is fluoro or trifluoromethyl.
5. The compound according to claim 1 , wherein R 21 , R 22 , R 23 and R 24 are hydrogen.
6. A compound according to claim 1 , wherein R 3 is hydrogen.
7. A compound according to claim 1 , wherein R 3 is methyl.
8. A compound of formula I-a
wherein
R 1 is (C 1 -C 3 )-alkyl, halogen, halogen-(C 1 -C 6 )-alkyl, cyano, (C 1 -C 6 )-alkoxy or halogen-(C 1 -C 6 )-alkoxy;
R 21 , R 22 , R 23 and R 24 are each independently selected from the group consisting of hydrogen and fluoro;
R 3 is hydrogen or (C 1 -C 3 )-alkyl;
R 4 and R 5 are each independently hydrogen or (C 1 -C 3 )-alkyl; and
n is 1, 2 or 3;
wherein when n is 2 or 3, each R 1 is the same or different; or a pharmaceutically acceptable salt thereof.
9. A compound according to claim 8 , wherein R 3 is methyl.
10. A compound according to claim 9 , wherein R 1 is fluoro or trifluoromethyl.
11. A compound according to claim 9 , wherein R 1 is (C 1 -C 3 )-alkyl or (C 1 -C 6 )-alkoxy.
12. A compound selected from the group consisting of
N-methyl-3-[4-(4-methyl-benzyloxy)-phenyl]-acrylamide and
3-[4-(3-methoxy-benzyloxy)-phenyl]-N-methyl-acrylamide.
13. A compound selected from the group consisting of
3-[4-(3-fluoro-benzyloxy)-phenyl]-2,N-dimethyl-acrylamide,
3-[4-(3-fluoro-benzyloxy)-phenyl]-N-methyl-acrylamide,
N-methyl-3-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-acrylamide,
3-[4-(3,4-difluoro-benzyloxy)-phenyl]-N-methyl-acrylamide, and
3-[4-(4-fluoro-benzyloxy)-phenyl]-N-methyl-acrylamide.
14. A compound selected from the group consisting of
3-[4-(3-fluoro-benzyloxy)-phenyl]-2,N-dimethyl-propionamide,
3-[4-(3,4-difluoro-benzyloxy)-phenyl]-propionamide, and
3-[4-(3-fluoro-benzyloxy)-phenyl]-N-methyl-butyramide.
15. A compound of formula I-c
wherein
R 1 is (C 1 -C 3 )-alkyl, halogen, halogen-(C 1 -C 6 )-alkyl, cyano, (C 1 -C 6 )-alkoxy or halogen-(C 1 -C 6 )-alkoxy;
R 21 , R 22 , R 23 and R 24 are each independently selected from the group consisting of hydrogen and fluoro;
R 3 is hydrogen or (C 1 -C 3 )-alkyl; and
n is 1, 2 or 3;
wherein when n is 2 or 3, each R 1 is the same or different;
or a pharmaceutically acceptable salt thereof.
16. The compound 3-[4-(3-fluoro-benzyloxy)-phenyl]-propynoic acid methylamide.
17. A composition comprising a compound of formula I
wherein
R 1 is (C 1 -C 3 )-alkyl, halogen, halogen-(C 1 -C 6 )-alkyl, cyano, (C 1 -C 6 )-alkoxy or halogen-(C 1 -C 6 )-alkoxy;
R 21 , R 22 , R 23 and R 24 are each independently selected from the group consisting of hydrogen and fluoro;
R 3 is hydrogen or (C 1 -C 3 )-alkyl;
A is selected from
R 4 is hydrogen or (C 1 -C 3 )-alkyl;
R 5 , R 6 and R 7 are each independently hydrogen or (C 1 -C 6 )-alkyl; and
n is 1, 2 or 3; wherein when n is 2 or 3, each R 1 is the same or different;
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
18. A composition according to claim 17 , wherein the compound of formula I is a compound of formula I-a
wherein
R 1 is (C 1 -C 3 )-alkyl, halogen, halogen-(C 1 -C 6 )-alkyl, cyano, (C 1 -C 6 )-alkoxy or halogen-(C 1 -C 6 )-alkoxy;
R 21 , R 22 , R 23 and R 24 are each independently selected from the group consisting of hydrogen and fluoro;
R 3 is hydrogen or (C 1 -C 3 )-alkyl;
R 4 and R 5 are each independently hydrogen or (C 1 -C 3 )-alkyl; and
n is 1, 2 or 3;
wherein when n is 2 or 3, each R 1 is the same or different;
or a pharmaceutically acceptable salt thereof.
19. A composition according to claim 17 , wherein the compound of formula I is a compound of formula I-c
wherein
R 1 is (C 1 -C 3 )-alkyl, halogen, halogen-(C 1 -C 6 )-alkyl, cyano, (C 1 -C 6 )-alkoxy or halogen-(C 1 -C 6 )-alkoxy;
R 21 , R 22 , R 23 and R 24 are each independently selected from the group consisting of hydrogen and fluoro;
R 3 is hydrogen or (C 1 -C 3 )-alkyl; and
n is 1, 2 or 3;
wherein when n is 2 or 3, each R 1 is the same or different;
or a pharmaceutically acceptable salt thereof.
20. A process for the manufacture of a compound of formula I according to claim 1 , which process comprises
a) reacting a compound of formula II
wherein R 1 and n are as defined in claim 1 and Y is a leaving group, with a compound of formula III
wherein R 3 , R 21 , R 22 , R 23 , R 24 and A are as defined in claim 1 .
21. A process for the manufacture of a compound of formula I according to claim 1 , which process comprises
reacting a compound of formula IV
wherein R 1 , R 21 , R 22 , R 23 , R 24 and n are as defined in claim 1 and R 8 is hydrogen or (C 1 -C 6 )-alkyl,
with an amine of formula V
H 2 NR 3 (V)
wherein R 3 is as defined in claim 1 .