التفاصيل البيبلوغرافية
| العنوان: |
THIENO-PYRIDINE DERIVATIVES AS MEK INHIBITORS |
| Document Number: |
20110021558 |
| تاريخ النشر: |
January 27, 2011 |
| Appl. No: |
12/839752 |
| Application Filed: |
July 20, 2010 |
| مستخلص: |
A series of thieno[2,3-b]pyridine derivatives which are substituted in the 2-position by a substituted anilino moiety, being selective inhibitors of human MEK (MAPKK) enzymes, are accordingly of benefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, proliferative (including oncological) and nociceptive conditions. |
| Inventors: |
Brookings, Daniel Christopher (Slough, GB); Hutchings, Martin Clive (Slough, GB); Langham, Barry John (Slough, GB) |
| Assignees: |
UCB Pharma S.A. (Brussels, BE) |
| Claim: |
1. A compound of formula (I), or a pharmaceutically acceptable salt, solvate or N-oxide thereof: [chemical expression included] wherein Y is C(O) or S(O)2; R1 is hydrogen, halogen, cyano, nitro, C1-6 alkyl, trifluoromethyl, C1-6 alkoxy, trifluoromethoxy, C1-6 alkylthio, C1-6 alkylsulphinyl or C1-6 alkylsulphonyl; R2 is halogen, nitro, cyano, C1-6 alkyl, C2-6 alkynyl, hydroxy(C1-6)alkyl or formyl; and R3 is selected from the group consisting of formulas (a), (b), (c), (d) and (e): [chemical expression included] wherein the asterisk (*) identifies the point of attachment of R3 to the remainder of the compound of formula I; R4 and R5 are each independently hydrogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino(C1-6)alkoxy, C1-6 alkoxy(C1-6)alkyl, C1-6 alkylthio, C1-6 alkylsulphonyl, hydroxy, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, nitro(C1-6)alkyl, cyano, trifluoromethyl, C2-6 alkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, azido, amino, C1-6 alkylamino, di(C1-6)alkylamino, bis[hydroxy(C1-6)alkyl]amino, C1-6 alkylamino(C1-6)alkylamino, arylamino, heteroarylamino, C2-6 alkylcarbonylamino, C2-6 alkoxycarbonylamino, [(C2-6)alkoxycarbonyl][(C1-6)alkyl]amino, bis[(C2-6)alkoxycarbonyl(C1-6)alkyl]amino, C2-6 alkoxycarbonylamino(C1-6)alkyl or aminocarbonyl; X is a covalent bond, C(O), S(O)2, C(O)O or C(O)N(R7); R6 is hydrogen, trifluoromethyl, optionally substituted C1-6 alkyl, optionally substituted C3-7 cycloalkyl, optionally substituted C3-7 cycloalkyl(C1-6)alkyl, optionally substituted aryl, optionally substituted aryl(C1-6)alkyl, optionally substituted C3-7 heterocycloalkyl, optionally substituted C3-7 heterocycloalkyl-(C1-6)alkyl, optionally substituted heteroaryl or optionally substituted heteroaryl(C1-6)alkyl; and R7 is hydrogen or C1-6 alkyl. |
| Claim: |
2. A compound according to claim 1 wherein R3 is: [chemical expression included] |
| Claim: |
3. A compound according to claim 1 wherein R4 and R5 are each independently hydrogen, C1-6 alkyl, hydroxy, hydroxy(C1-6)alkyl, carboxy, C2-6 alkoxycarbonyl, azido or amino. |
| Claim: |
4. A compound according to claim 2 wherein R4 and R5 are each independently hydrogen, C1-6 alkyl, hydroxy, hydroxy(C1-6)alkyl, carboxy, C2-6 alkoxycarbonyl, azido or amino. |
| Claim: |
5. A compound or pharmaceutically acceptable salt, solvate or N-oxide thereof according to claim 1, having the following formula (IIA): [chemical expression included] wherein R11 is halogen; and R12 is halogen, nitro, cyano, C2-6 alkynyl, hydroxy(C1-6)alkyl or formyl. |
| Claim: |
6. A compound according to claim 5, wherein R11 is fluoro or chloro. |
| Claim: |
7. A compound according to claim 5 wherein R12 is iodo. |
| Claim: |
8. A compound or pharmaceutically acceptable salt, solvate or N-oxide thereof according to claim 5, having the following formula (IIB): [chemical expression included] |
| Claim: |
9. A compound according to claim 8, wherein R11 is fluoro or chloro. |
| Claim: |
10. A compound according to claim 8 wherein R12 is iodo. |
| Claim: |
11. A compound or pharmaceutically acceptable salt, solvate or N-oxide thereof according to claim 5, having the following formula (IIC): [chemical expression included] |
| Claim: |
12. A compound according to claim 11, wherein R11 is fluoro or chloro. |
| Claim: |
13. A compound according to claim 11 wherein R12 is iodo. |
| Claim: |
14. A compound or pharmaceutically acceptable salt, solvate or N-oxide thereof according to claim 5, having the following formula (IID): [chemical expression included] |
| Claim: |
15. A compound according to claim 14, wherein R11 is fluoro or chloro. |
| Claim: |
16. A compound according to claim 14 wherein R12 is iodo. |
| Claim: |
17. A compound or pharmaceutically acceptable salt, solvate or N-oxide thereof according to claim 1, which is selected from the group consisting of: 2-({2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl}carbonyl)-isoxazolidin-4-ol; (4R)-2-({2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl}carbonyl)-isoxazolidin-4-ol; (4S)-2-({2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl}carbonyl)-isoxazolidin-4-ol; 2-({2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl}sulfonyl)-isoxazolidin-4-ol; [(S)-4-Aminoisoxazolidin-2-yl][2-(2-fluoro-4-iodophenylamino)thieno[2,3-b]pyridin-3-yl]methanone; (4-Azidoisoxazolidin-2-yl)[2-(2-fluoro-4-iodophenylamino)thieno[2,3-b]pyridin-3-yl]-methanone; (4-Aminoisoxazolidin-2-yl)[2-(2-fluoro-4-iodophenylamino)thieno[2,3-b]pyridin-3-yl]-methanone; 2-[2-(2-Fluoro-4-iodophenylamino)thieno[2,3-b]pyridine-3-carbonyl]-5-methyl-isoxazolidine-5-carboxylic acid methyl ester; [2-(2-Fluoro-4-iodophenylamino)thieno[2,3-b]pyridin-3-yl][5-(hydroxymethyl)-5-methyl-isoxazolidin-2-yl)methanone; 2-[2-(2-Fluoro-4-iodophenylamino)thieno[2,3-b]pyridine-3-carbonyl]-5-methyl-isoxazolidine-5-carboxylic acid; Benzyl 1-({2-[(2-fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl}carbonyl)-tetrahydro-1H-pyrrolo[3,4-c]isoxazole-5(3H)-carboxylate; and {2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl}(hexahydro-1H-pyrrolo[3,4-c]isoxazol-1-yl)methanone. |
| Claim: |
18. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt, solvate, or N-oxide thereof according to claim 1, and a pharmaceutically acceptable carrier. |
| Claim: |
19. A method for the treatment or prevention of a disorder for which the administration of a selective MEK inhibitor is indicated which comprises administering to a patient in need of such treatment an effective amount of a compound or pharmaceutically acceptable salt, solvate, or N-oxide thereof according to claim 1. |
| Claim: |
20. A method according to claim 19, wherein the disorder is selected from the group consisting of an autoimmune or inflammatory disorder, a cardiovascular disorder, a proliferative disorder, an oncological condition, and pain or a nociceptive disorder. |
| Claim: |
21. A method according to claim 20, wherein the disorder is an autoimmune or inflammatory disorder. |
| Claim: |
22. A method according to claim 21, wherein the autoimmune or inflammatory disorder is selected from the group consisting of rheumatoid arthritis, osteoarthritis, multiple sclerosis, asthma, inflammatory bowel disease, psoriasis and transplant rejection. |
| Claim: |
23. A method according to claim 20, wherein the disorder is a cardiovascular disorder. |
| Claim: |
24. A method according to claim 23, wherein the cardiovascular disorder is selected from the group consisting of thrombosis, cardiac hypertrophy, hypertension and irregular contractility of the heart. |
| Claim: |
25. A method according to claim 20, wherein the disorder is a proliferative disorder. |
| Claim: |
26. A method according to claim 25, wherein the proliferative disorder is restenosis. |
| Claim: |
27. A method according to claim 20, wherein the disorder is an oncological condition. |
| Claim: |
28. A method according to claim 27, wherein the oncological condition is selected from the group consisting of leukemia, glioblastoma, lymphoma, melanoma, and human cancers of the liver, bone, skin, brain, pancreas, lung, breast, stomach, colon, rectum, prostate, ovary and cervix. |
| Claim: |
29. A method according to claim 20, wherein the disorder is pain or a nociceptive disorder. |
| Claim: |
30. A method according to claim 29, wherein the pain or nociceptive disorder is selected from the group consisting of chronic pain and neuropathic pain. |
| Current U.S. Class: |
514/301 |
| Current International Class: |
61; 07; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61 |
| رقم الانضمام: |
edspap.20110021558 |
| قاعدة البيانات: |
USPTO Patent Applications |