Tricyclic compounds
The present invention provides a PPAR γ agonist comprising, as an active ingredient, a tricyclic compound represented by the formula (I) (wherein R 1 represents lower alkyl optionally having substituent(s) or the like, R 2 and R 3 are the same or different and each represents lower alkyl optionally having substituent(s) or the like, R 4 and R 5 are the same or different and each represents a hydrogen atom or the like, Q 1 -Q 2 -Q 3 represents CH═CH—CH═CH or the like, Y represents a single bond or the like, Z 1 -Z 2 represents C═CR 13 (wherein R 13 represents a hydrogen atom or the like), or the like, and A represents —COOH or the like), or a pharmaceutically acceptable salt thereof and the like.
1. A tricyclic compound represented by the formula (IA-C)
wherein
D is CH or N,
R 1X is methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, or propoxy,
R 6X is hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl, or isopropyl,
R 7X is hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl, or isopropyl,
Y X is CH 2 CH 2 or CH 2 O,
R 13X is C 1-6 alkyl, and
A X is formula (b3)
or a pharmaceutically acceptable salt thereof.
2. A pharmaceutical composition comprising the tricyclic compound or the pharmaceutically acceptable salt thereof recited in claim 1 as an active ingredient.
3. A method of activating PPARγ, which comprises administering an effective amount of the tricyclic compound or the pharmaceutically acceptable salt thereof recited in claim 1 to a human in need of activation of PPARγ.
4. A method of activating PPARγ and antagonizing an angiotensin II receptor, which comprises administering an effective amount of the tricyclic compound or the pharmaceutically acceptable salt thereof recited in claim 1 to a human in need of activation of PPARγ and antagonization of an angiotensin II receptor.
5. The method according to claim 3 , wherein the method of activating PPARγ is a method for treating a disease related to PPARγ.
6. The method according to claim 5 , wherein the disease related to PPARγ is a disease further related to an angiotensin II receptor.
7. The method according to claim 5 , wherein the disease related to PPARγ is a disease selected from the group consisting of type 2 diabetes, impaired glucose tolerance, insulin resistance syndrome, hypertension, hyperlipidemia, metabolic syndrome, visceral obesity, obesity and hypertriglyceridemia.
8. A method of antagonizing an angiotensin II receptor, which comprises administering an effective amount of the tricyclic compound or the pharmaceutically acceptable salt thereof recited in claim 1 to a human in need of antagonization of an angiotensin II receptor.
9. The method according to claim 8 , wherein the method of antagonizing an angiotensin II receptor is a method for treating a disease related to an angiotensin II receptor.
10. The method according to claim 9 , wherein the method for treating a disease related to an angiotensin II receptor is a method for treating hypertension.
11. A tricyclic compound selected from the group consisting of
(E)-2-(2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethylidene]-10,11-dihydro-5H-dibenzo[a,d]cycloheptene;
(E)-2-(4-methyl-2-propylbenzimidazol-1-yl)methyl-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethylidene]-10,11-dihydro-5H-dibenzo[a,d]cycloheptene;
(E)-2-(2-ethoxy-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethylidene]-10,11-dihydro-5H-dibenzo[a,d]cycloheptene;
(E)-2-(2-ethoxy-3H-imidazo[4,5-b]pyridin-3-yl)methyl-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethylidene]-10,11-dihydro-5H-dibenzo[a,d]cycloheptene;
(E)-2-(7-chloro-2-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethylidene]-10,11-dihydro-5H-dibenzo[a,d]cycloheptene;
(E)-3-(2-cyclopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-11-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethylidene]-6,11-dihydrodibenzo[b,e]oxepine;
(Z)-8-(7-chloro-2-ethyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-11-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethylidene]-6,11-dihydrodibenzo[b,e]oxepine;
(Z)-8-(7-chloro-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-11-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethylidene]-6,11-dihydrodibenzo[b,e]oxepine;
(Z)-8-(7-chloro-2-ethoxy-3H-imidazo[4,5-b]pyridin-3-yl)methyl-11-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethylidene]-6,11-dihydrodibenzo[b,e]oxepine;
(Z)-8-(7-chloro-2-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-11-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethylidene]-6,11-dihydrodibenzo[b,e]oxepine (Example 139);
(Z)-8-(4-chloro-2-ethoxybenzimidazol-1-yl)methyl-11-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethylidene]-6,11-dihydrodibenzo[b,e]oxepine; and
(Z)-8-(4-chloro-2-cyclopropylbenzimidazol-1-yl)methyl-11-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethylidene]-6,11-dihydrodibenzo[b,e]oxepine,
or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising the tricyclic compound or the pharmaceutically acceptable salt thereof recited in claim 11 as an active ingredient.
13. A method of activating PPARγ, which comprises administering an effective amount of the tricyclic compound or the pharmaceutically acceptable salt thereof recited in claim 11 to a human in need of activation of PPARγ.
14. A method of activating PPARγ and antagonizing an angiotensin II receptor, which comprises administering an effective amount of the tricyclic compound or the pharmaceutically acceptable salt thereof recited in claim 11 to a human in need of activation of PPARγ and antagonization of an angiotensin II receptor.
15. The method according to claim 13 , wherein the method of activating PPARγ is a method for treating a disease related to PPARγ.
16. The method according to claim 15 , wherein the disease related to PPARγ is a disease further related to an angiotensin II receptor.
17. The method according to claim 15 , wherein the disease related to PPARγ is a disease selected from the group consisting of type 2 diabetes, impaired glucose tolerance, insulin resistance syndrome, hypertension, hyperlipidemia, metabolic syndrome, visceral obesity, obesity and hypertriglyceridemia.
18. A method of antagonizing an angiotensin II receptor, which comprises administering an effective amount of the tricyclic compound or the pharmaceutically acceptable salt thereof recited in claim 11 to a human in need of antagonization of an angiotensin II receptor.
19. The method according to claim 18 , wherein the method of antagonizing an angiotensin II receptor is a method for treating a disease related to an angiotensin II receptor.
20. The method according to claim 19 , wherein the method for treating a disease related to an angiotensin II receptor is a method for treating hypertension.