THIENO[2,3-B]PYRIDINE DERIVATIVES AS EPAC INHIBITORS AND THEIR PHARMACEUTICAL USES
The present invention relates to thieno[2,3-b]pyridine derivatives for use in the treatment and/or the prevention of a disease selected from the group consisting of inflammation, cancer, vascular diseases, kidney diseases, cognitive disorders, pain, infections, obesity, and cardiac diseases. Indeed, the inventors found that thieno[2,3-b]pyridine derivatives of the invention are inhibitors of the Epac protein and can thus be useful for the prevention and/or treatment of diseases wherein the Epac protein is involved. Particularly, the inventors showed that thieno[2,3-b]pyridine derivatives of the invention are potent and non-competitive inhibitors of Epac and demonstrated that they also inhibit the activation of Epac downstream effectors such as Rap1 in cells.
1 . A method for treating and/or preventing a disease wherein the Epac protein is involved, wherein said disease is 5 a cardiac disease selected from the group consisting of: cardiac hypertrophy, cardiac arrhythmias, valvulopathies, diastolic dysfunction, chronic heart failure, ischemic heart failure, myocardial ischemia, reperfusion injury, myocarditis, hypertrophic and dilated cardiomyopathies, said method comprising administering to a patient in need thereof a pharmaceutical acceptable amount of a compound of formula (I), said compound having the following formula (I):
wherein:
R 1 is selected from the group consisting of:
H;
(C 2 -C 20 )alkyl;
(C 3 -C 10 )cycloalkyl;
3-10 membered heterocycloalkyl;
(C 6 -C 10 )aryl; and
5-10 membered heteroaryl;
wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted;
R 2 is selected from the group consisting of:
H;
(C 1 -C 20 )alkyl;
(C 3 -C 10 )cycloalkyl;
3-10 membered heterocycloalkyl;
(C 6 -C 10 )aryl; and
5-10 membered heteroaryl;
or R 2 and R 4 together with the carbon atoms carrying them form a (C 3 -C 10 )cycloalkyl group;
wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted;
R 3 is selected from the group consisting of:
H;
(C 3 -C 10 )cycloalkyl;
3-10 membered heterocycloalkyl;
(C 6 -C 10 )aryl; and
5-10 membered heteroaryl;
wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted; and
R 4 is selected from the group consisting of: H, —OH, —NRxRy and —C(O)ORz, Rx, Ry and Rz being independently of each other H or a (C 1 -C 10 )alkyl;
or R 2 and R 4 together with the carbon atoms carrying them form a (C 3 -C 10 )cycloalkyl group;
or its pharmaceutically acceptable salt, hydrate or hydrated salt or its polymorphic crystalline structure, racemate, diastereomer or enantiomer.
2 . The method according to claim 1 , wherein in formula (I) R 3 is selected from the group consisting of:
(C 3 -C 10 )cycloalkyl;
3-10 membered heterocycloalkyl;
(C 6 -C 10 )aryl; and
5-10 membered heteroaryl;
wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted.
3 . The method according to claim 1 , wherein in formula (I) R 1 is selected from the group consisting of:
H;
(C 6 -C 10 )aryl; and
5-10 membered heteroaryl;
wherein said aryl and heteroaryl groups are optionally substituted by one or more substituent(s) selected from the group consisting of —NR 7 R 8 , (C 1 -C 10 )alkyl and halogen atom; wherein R 7 and R 8 are independently of each other selected from (C 1 -C 10 )alkyl or H.
4 . The method according to claim 1 , wherein in formula (I) R 2 is selected from the group consisting of:
H;
(C 1 -C 20 )alkyl;
(C 6 -C 10 )aryl; and
5-10 membered heteroaryl;
or R 2 and R 4 together with the carbon atoms carrying them form a (C 3 -C 10 )cycloalkyl group;
wherein said alkyl, cycloalkyl, aryl and heteroaryl groups are optionally substituted by one or more substituent(s) selected from the group consisting of: (C 1 -C 10 )alkyl and halogen atom.
5 . The method according to claim 1 , wherein in formula (I) R 3 is a (C 6 -C 10 )aryl optionally substituted by one or more substituent(s) selected from the group consisting of: (C 1 -C 10 )alkyl and halogen atom.
6 . The method according to claim 1 , wherein R 4 is H or R 2 and R 4 together with the carbon atoms carrying them form a (C 5 -C 6 )cycloalkyl group.
7 . The method according to claim 1 , wherein in formula (I) R 1 is a phenyl group and/or R 2 is a thienyl group, said phenyl and thienyl groups being optionally substituted.
8 . The method according to claim 1 , wherein in formula (I):
R 1 is selected from the group consisting of:
(C 2 -C 20 )alkyl;
(C 3 -C 10 )cycloalkyl;
3-10 membered heterocycloalkyl;
(C 6 -C 10 )aryl; and
5-10 membered heteroaryl;
wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted; and
R 2 is selected from the group consisting of:
H;
(C 1 -C 20 )alkyl;
(C 3 -C 10 )cycloalkyl;
(C 6 -C 10 )aryl; and
5-10 membered heteroaryl;
or R 2 and R 4 together with the carbon atoms carrying them form a (C 3 -C 10 )cycloalkyl group;
wherein said alkyl, cycloalkyl, aryl and heteroaryl groups are optionally substituted.
9 . The method according to claim 1 , comprising administering a pharmaceutical acceptable amount of a compound having the following formula (II):
wherein Ra, Rb, Rc, Rd, Re, Rx, Ry and Rz are selected among the group consisting of: H, —OH, halogen atom, —C(O)OH, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, and —NR 5 R 6 ,
wherein R 5 and R 6 are independently of each other selected from (C 1 -C 10 )alkyl or H;
R 4 is selected from the group consisting of H, —OH, —NH 2 and —C(O)OH; and
R 3 is as defined in claim 1 .
10 . The method according to claim 1 , wherein the compound has one of the following formulae:
11 . The method according to claim 1 , wherein the compound has the following formula:
12 . A pharmaceutical composition comprising a compound having formula (I) as defined in claim 1 , in association with at least one pharmaceutically acceptable excipient.
13 . (canceled)