Pyrazole compound and pharmaceutical use thereof
View Patent ↗The present invention provides a pyrazole compound of the following general Formula [Ib] having SGLT1 inhibitory activity, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the same, and its pharmaceutical use: wherein each symbol is the same as defined in the description.
1. A compound or a pharmaceutically acceptable salt thereof represented by the general formula [Ib]:
wherein
Ring Cy is
(1) C 6-10 aryl,
(2) C 3-8 cycloalkyl or
(3) C 3-8 cycloalkenyl,
n1 is 0, 1, 2, 3 or 4,
R 1a is
(1) a halogen atom,
(2) hydroxy,
(3) carboxy,
(4) a C 1-6 alkyl group,
(5) a C 2-8 alkenyl group,
(6) a C 2-8 alkynyl group,
(7) a C 1-6 alkoxy group,
(8) a C 3-6 cycloalkyl group,
(9) a halo C 1-6 alkyl group,
(10) a hydroxy C 1-6 alkyl group,
(11) a C 1-6 alkoxy C 1-6 alkyl group,
(12) a halo C 1-6 alkoxy C 1-6 alkyl group,
(13) a C 1-6 alkylsulfonyl C 1-6 alkyl group,
(14) a halo C 1-6 alkylsulfonyl C 1-6 alkyl group,
(15) a halo C 1-6 alkylamino C 1-6 alkyl group,
(16) a C 3-6 cycloalkyl C 2-6 alkynyl group,
(17) a halo C 1-6 alkoxy group,
(18) a carboxy C 1-6 alkoxy group,
(19) a C 1-6 alkylsulfanyl group,
(20) a C 1-6 alkylsulfonyl group,
(21) a halo C 1-6 alkylsulfonyl group,
(22) a C 1-8 alkylcarbonyl group,
(23) a C 1-6 alkyloxycarbonyl group,
(24) a group represented by the Formula:
wherein
R 5 is
(a) a hydrogen atom or
(b) a C 1-6 alkyl group, and
R 6 is
(a) a C 1-6 alkyl group, or
(b) a halo C 1-6 alkyl group,
(25) a saturated heterocyclo C 1-6 alkyl group, wherein the saturated heterocycle is a 4-membered to 6-membered saturated heterocycle having 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur, or
(26) a saturated heterocyclo oxy C 1-6 alkyl group, wherein the saturated heterocycle is a 4-membered to 6-membered saturated heterocycle having 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur,
provided that when n1 is 2, 3 or 4, each R 1a is the same or different,
R 2a is
(1) a C 1-8 alkyl group,
(2) a C 3-8 cycloalkyl C 1-6 alkyl group,
(3) a C 6-10 aryl C 1-6 alkyl group,
(4) a saturated heterocyclo C 1-6 alkyl group, wherein the saturated heterocycle is a 4-membered to 6-membered saturated heterocycle having 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur,
(5) a C 3-8 cycloalkyl group,
(6) a halo C 1-6 alkyl group,
(7) a C 1-6 alkoxy C 1-6 alkyl group,
(8) a halo C 3-8 cycloalkyl group,
(9) a C 6-10 aryl group, wherein the C 6-10 aryl group is optionally substituted by 1 to 4 substituents selected from the group consisting of:
(a) a halogen atom,
(b) hydroxy,
(c) a C 1-6 alkyl group,
(d) a C 2-8 alkenyl group,
(e) a C 2-6 alkynyl group,
(f) a C 1-6 alkoxy group,
(g) a halo C 1-6 alkyl group,
(h) a C 1-6 alkoxy C 1-6 alkyl group,
(i) a halo C 1-6 alkoxy group,
(j) a hydroxy C 1-6 alkoxy group,
(k) a C 1-6 alkoxy C 1-6 alkoxy group,
(l) a carboxy C 1-6 alkoxy group,
(m) a C 6-10 aryl C 1-6 alkoxy group,
(n) a C 1-6 alkylsulfanyl C 1-6 alkoxy group,
(o) a C 1-6 alkylsulfonyl C 1-6 alkoxy group,
(p) a C 6-10 aryl C 1-6 alkoxy C 1-6 alkoxy group,
(q) a saturated heterocyclo C 1-6 alkoxy group, wherein the saturated heterocycle is a 4-membered to 6-membered saturated heterocycle having 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur, and is optionally substituted by 1 to 2 C 1-6 alkyl groups,
(r) a saturated heterocyclo oxy group, wherein the saturated heterocycle is a 4-membered to 6-membered saturated heterocycle having 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur,
(s) a C 3-8 cycloalkyloxy group,
(t) a C 1-6 alkoxycarbonyloxy group and
(u) a C 1-6 alkylsulfonyl group, or
(10) a saturated heterocycle group, wherein the saturated heterocycle is a 4-membered to 6-membered saturated heterocycle having 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur, and is optionally substituted by 1 to 4 C 1-6 alkyl groups, and
Ring Cy a is a group selected from the group consisting of:
(1) a group represented by the Formula:
wherein
m2 is 1, 2 or 3,
m3 is 1, 2 or 3,
n3 is 1 or 2,
(2) a group represented by the Formula:
wherein
m4 is 0, 1, 2 or 3,
m5 is 0, 1 or 2,
provided that the sum of m4 and m5 is 1 or more,
(3) a group represented by the Formula:
wherein
m4 is 0, 1, 2 or 3,
m5 is 0, 1 or 2,
provided that the sum of m4 and m5 is 1 or more,
(4) a group represented by the Formula:
wherein
m6 is 0, 1 or 2,
m7 is 0, 1 or 2,
provided that the sum of m6 and m7 is 1 or more,
(5) a group represented by the Formula:
wherein
m6 is 0, 1 or 2,
m7 is 0, 1 or 2,
provided that the sum of m6 and m7 is 1 or more,
(6) a group represented by the Formula:
wherein
m8 is 1 or 2,
m9 is 1 or 2, and
(7) a group represented by the Formula:
wherein
m8 is 1 or 2,
m9 is 1 or 2,
n2 is 0, 1, 2, 3 or 4,
R 3a is
(1) hydroxy,
(2) a C 1-6 alkyl group or
(3) a hydroxy C 1-6 alkyl group,
provided that when n2 is 2, 3 or 4, each R 3a is the same or different,
R 3b is
(1) hydroxy,
(2) a C 1-6 alkyl group, which optionally forms a C 3-6 cycloalkyl group together with the carbon to which it is attached and the carbon adjacent thereto,
(3) a hydroxy C 1-6 alkyl group, or
(4) when two R 3b are attached to the same carbon, they optionally form a C 3-6 cycloalkyl group together with the carbon to which they are attached,
provided that when n2 is 2, 3 or 4, each R 3b is the same or different, and
R 4b is
(1) a hydrogen atom,
(2) a C 1-6 alkyl group,
(3) a carboxy C 1-6 alkyl group,
(4) a halo C 1-6 alkyl group or
(5) a C 1-6 alkoxy C 1-6 alkyl group.
2. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein
Ring Cy a is selected from the group consisting of:
(1) a group represented by the Formula:
wherein
m4 is 0, 1, 2 or 3,
m5 is 0, 1 or 2,
provided that the sum of m4 and m5 is 1 or more,
(2) a group represented by the Formula:
wherein
m6 is 0, 1 or 2,
m7 is 0, 1 or 2,
provided that the sum of m6 and m7 is 1 or more,
(3) a group represented by the Formula:
wherein
m6 is 0, 1 or 2,
m7 is 0, 1 or 2,
provided that the sum of m6 and m7 is 1 or more,
(4) a group represented by the Formula:
wherein
m8 is 1 or 2,
m9 is 1 or 2, and
(5) a group represented by the Formula:
wherein
m8 is 1 or 2,
m9 is 1 or 2,
n2 is 0, 1, 2, 3 or 4,
R 3a is
(1) hydroxy,
(2) a C 1-6 alkyl group or
(3) a hydroxy C 1-6 alkyl group,
provided that when n2 is 2, 3 or 4, each R 3a is the same or different,
R 3b is
(1) hydroxy,
(2) a C 1-6 alkyl group, which optionally forms a C 3-6 cycloalkyl group together with the carbon to which it is attached and the carbon adjacent thereto,
(3) a hydroxy C 1-6 alkyl group, or
(4) when two R 3b are attached to the same carbon, they optionally form a C 3-6 cycloalkyl group together with the carbon to which they are attached,
provided that when n2 is 2, 3 or 4, each R 3b is the same or different, and
R 4b is
(1) a hydrogen atom,
(2) a C 1-6 alkyl group,
(3) a carboxy C 1-6 alkyl group,
(4) a halo C 1-6 alkyl group or
(5) a C 1-6 alkoxy C 1-6 alkyl group.
3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein
Ring Cy a is selected from the group consisting of:
(1) a group represented by the Formula:
wherein,
m4 is 0, 1, 2 or 3,
m5 is 0, 1 or 2,
provided that the sum of m4 and m5 is 1 or more, and
(2) a group represented by the Formula:
wherein
m6 is 0, 1 or 2,
m7 is 0, 1 or 2,
provided that the sum of m6 and m7 is 1 or more,
n2 is 0, 1, 2, 3 or 4,
R 3a is
(1) hydroxy,
(2) a C 1-6 alkyl group or
(3) a hydroxy C 1-6 alkyl group,
provided that when n2 is 2, 3 or 4, each R 3a is the same or different,
R 3b is
(1) hydroxy,
(2) a C 1-6 alkyl group, which optionally forms a C 3-6 cycloalkyl group together with the carbon to which it is attached and the carbon adjacent thereto,
(3) a hydroxy C 1-6 alkyl group, or
(4) when two R 3b are attached to the same carbon, they optionally form a C 3-6 cycloalkyl group together with the carbon to which they are attached,
provided that when n2 is 2, 3 or 4, each R 3b is the same or different, and
R 4b is
(1) a hydrogen atom,
(2) a C 1-6 alkyl group,
(3) a carboxy C 1-6 alkyl group,
(4) a halo C 1-6 alkyl group or
(5) a C 1-6 alkoxy C 1-6 alkyl group.
4. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein
Ring Cy a is selected from the group consisting of:
(1) a group represented by the Formula:
wherein
n2 is 0, 1, 2, 3 or 4, and
(2) a group represented by the Formula:
wherein
n2 is 0 or 1,
R 3a is
(1) hydroxy,
(2) a C 1-6 alkyl group or
(3) a hydroxy C 1-6 alkyl group, and
R 3b is
(1) hydroxy,
(2) a C 1-6 alkyl group, which optionally forms a C 3-6 cycloalkyl group together with the carbon to which it is attached and the carbon adjacent thereto) or,
(3) a hydroxy C 1-6 alkyl group, or
(4) when two R 3b are attached to the same carbon, they optionally form a C 3-6 cycloalkyl group together with the carbon to which they are attached,
provided that when n2 is 2, 3 or 4, each R 3b is the same or different, and
R 4b is
(1) a hydrogen atom,
(2) a C 1-6 alkyl group,
(3) a carboxy C 1-6 alkyl group,
(4) a halo C 1-6 alkyl group or
(5) a C 1-6 alkoxy C 1-6 alkyl group.
5. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the ring Cy is C 6-10 aryl.
6. The compound or a pharmaceutically acceptable salt thereof according to claim 5 , wherein the ring Cy is phenyl.
7. The compound or a pharmaceutically acceptable salt thereof according to claim 1 wherein R 1a is
(1) a halogen atom,
(2) a C 1-6 alkyl group,
(3) a C 1-6 alkoxy group,
(4) a halo C 1-6 alkyl group,
(5) a C 1-6 alkoxy C 1-6 alkyl group,
(6) a halo C 1-6 alkoxy C 1-6 alkyl group or
(7) a halo C 1-6 alkoxy group,
provided that when n1 is 2, 3, or 4, each R 1a is the same or different.
8. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 2a is a C 6-10 aryl group and
wherein the C 6-10 aryl group is optionally substituted by 1 to 4 substituents selected from the group consisting of:
(a) a halogen atom,
(b) a C 1-6 alkyl group,
(c) a C 1-6 alkoxy group and
(d) a carboxy C 1-6 alkoxy group.
9. The compound or a pharmaceutically acceptable salt thereof according to claim 8 , wherein R 2a is a phenyl group and
wherein the phenyl group is optionally substituted by 1 to 4 substituents selected from the group consisting of:
(a) a halogen atom,
(b) a C 1-6 alkyl group,
(c) a C 1-6 alkoxy group and
(d) a carboxy C 1-6 alkoxy group.
10. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is selected from the following Formulae:
11. A pharmaceutical composition which comprises a compound or a pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable carrier.
12. A SGLT1 inhibitor which comprises a compound or a pharmaceutically acceptable salt thereof according to claim 1 .
13. A method for inhibiting SGLT1 comprising administering to a mammal a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to claim 1 .
14. A method for treating or preventing diabetes comprising administering to a mammal a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to claim 1 .
15. The method according to claim 14 , wherein the diabetes is type II diabetes mellitus.
16. The compound or pharmaceutically acceptable salt thereof of claim 1 represented by the following Formula:
17. The compound or pharmaceutically acceptable salt thereof of claim 1 represented by the following Formula:
18. The compound or pharmaceutically acceptable salt thereof of claim 1 represented by the following Formula:
19. The compound or pharmaceutically acceptable salt thereof of claim 1 represented by the following Formula:
20. The compound or pharmaceutically acceptable salt thereof of claim 1 represented by the following Formula:
21. The compound or pharmaceutically acceptable salt thereof of claim 1 represented by the following Formula:
22. The compound or pharmaceutically acceptable salt thereof of claim 1 , represented by the following Formula:
23. The compound of claim 1 represented by the following Formula:
24. The compound of claim 1 represented by the following Formula:
25. The compound of claim 1 represented by the following Formula:
26. The compound of claim 1 represented by the following Formula:
27. The compound of claim 1 represented by the following Formula:
28. The compound of claim 1 represented by the following Formula:
29. The compound of claim 1 represented by the following Formula:
30. A pharmaceutical composition which comprises a compound or a pharmaceutically acceptable salt thereof according to any one of claims 16 to 29 and a pharmaceutically acceptable carrier.
31. A method for inhibiting SGLT1 comprising administering to a mammal a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 16 to 29 .
32. A method for treating or preventing diabetes comprising administering to a mammal a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 16 to 29 .
33. The method according to claim 32 , wherein the mammal is a human.
34. The method according to claim 32 , wherein the method is for treating diabetes.
35. The method according to claim 34 , wherein the mammal is a human.
36. The method according to claim 14 , wherein the mammal is a human.
37. The method according to claim 14 , wherein the method is for treating diabetes.
38. The method according to claim 37 , wherein the mammal is a human.