Morpholine and 1,4-oxazepane amides as somatostatin receptor subtype 4 (SSTR4) agonists
The invention relates to morpholine and 1,4-oxazepane amide derivatives of general formula (I), which are agonists of somatostatin receptor subtype 4 (SSTR4), useful for preventing or treating medical disorders related to SSTR4. In addition, the invention relates to processes for preparing pharmaceutical compositions as well as processes for manufacture of the compounds according to the invention.
1. A compound of formula (I)
wherein
m=0, p=1, q=1 or;
m=1, p=1, q=1 or;
m=0, p=2, q=1 or;
m=0, p=1, q=2;
A is selected from the group consisting of
H and C 1-6 -alkyl;
R 1 and R 2 are independently selected from the group consisting of C 1-6 -alkyl and C 3-6 -cycloalkyl, or wherein R 1 and R 2 together form a 2- to 5-membered alkylene-bridge incorporating 0 to 2 heteroatoms independently selected from the group consisting of N, O and S
wherein the C 1-6 -alkyl, the C 3-6 -cycloalkyl or the alkylene-bridge is optionally substituted with halogens;
W is selected from the group consisting of a
bicyclic aryl, bicyclic heteroaryl, bicyclic heterocyclyl and bicyclic cycloalkyl,
wherein each of these ring systems are optionally substituted with one or more R 3 , and wherein the heteroaryl comprises up to 4 heteroatoms and one or two 5- or 6-membered ring(s);
R 3 is independently selected from the group consisting of
C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-6 -alkyl-O—, benzyl, halogen, HO—, NC—, mono- or bicyclic heteroaryl, and 5- or 6-membered monocyclic heterocyclyl containing one heteroatom selected from the group consisting of N, O and S(O) r , wherein the heteroaryl contains up to 4 heteroatoms and one or two 5- or 6-membered ring(s), and r is 0, 1 or 2,
wherein the C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-6 -alkyl-O—, benzyl, heteroaryl and the heterocyclyl are optionally substituted with halogens, HO—, acetyl, C 1-6 -alkyl-O—, oxo, R 4 —S(O) 2 —, with R 4 being aryl, C 3-6 -cycloalkyl and/or C 1-6 -alkyl;
Y is selected from the group consisting of a bond and —CH 2 O—;
or a salt of any of the above compounds.
2. The compound according to claim 1 , wherein
A is H.
3. The compound according to claim 1 , wherein
W is selected from the group consisting of a
bicyclic aryl, a bicyclic heteroaryl and a bicyclic heterocyclyl,
wherein each of these ring systems are optionally substituted with one or more R 3 , and wherein the heteroaryl comprises up to 4 heteroatoms and one or two 5- or 6-membered ring(s).
4. The compound according to claim 1 , wherein
W is selected from the group consisting of
wherein each of these ring systems are optionally substituted with one or more R 3 .
5. The compound according to claim 1 , wherein
W is selected from the group consisting of
wherein each of these ring systems are optionally substituted with one to three R 3 .
6. The compound according to claim 1 , wherein
m is 0, p is 1 and q is 1 or
m is 1, p is 1 and q is 1.
7. The compound according to claim 1 , wherein
R 3 is selected from the group consisting of
C 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-3 -alkyl-O—, halogen, and NC—,
wherein, in case R 3 is connected to N-atoms of W, R 3 is selected from the group consisting of C 1-3 -alkyl and C 3-6 -cycloalkyl,
wherein the C 1-3 -alkyl, C 3-6 -cycloalkyl, and the C 1-3 -alkyl-O-substituents are optionally substituted with halogens.
8. The compound according to claim 1 , wherein
R 3 is selected from the group consisting of
H 3 C—, F— and F 3 C—,
wherein, in case R 3 is connected to N-atoms of W, R 3 is H 3 C—.
9. The compound according to claim 1 , wherein
R 1 and R 2 are both H 3 C—.
10. The compound according to claim 1 , wherein Y is a bond.
11. A compound according to claim 1 , wherein the compound is selected from the group consisting of:
or a salt of any of the above compounds.
12. A compound selected from the group consisting of:
or a salt thereof.
13. A compound according to claim 12 , wherein the compound is
or a salt thereof.
14. A compound according to claim 12 , wherein the compound is
or a salt thereof.
15. A compound according to claim 12 , wherein the compound is
or a salt thereof.
16. A compound according to claim 12 , wherein the compound is
or a salt thereof.
17. A compound according to claim 12 , wherein the compound is
or a salt thereof.
18. A compound according to claim 12 , wherein the compound is
or a salt thereof.
19. A compound according to claim 12 , wherein the compound is
or a salt thereof.
20. A compound according to claim 12 , wherein the compound is
or a salt thereof.
21. A compound according to claim 12 , wherein the compound is
or a salt thereof.
22. A compound according to claim 12 , wherein the compound is
or a salt thereof.
23. A compound according to claim 12 , wherein the compound is
or a salt thereof.
24. Pharmaceutical compositions containing at least one compound according to claim 1 or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers.
25. A method for the treatment of pain, selected from acute pain, neuropathic peripheral pain, chronic pain or osteoarthritis, which comprises administering to a human a therapeutically effective amount of a compound according to claim 1 , a pharmaceutical salt thereof or a pharmaceutical composition thereof.