Claims for Patent: 6,821,987

Summary for Patent: 6,821,987

Title:	Quinoline derivatives and quinazoline derivatives having azolyl group
Abstract:	An object of the present invention is to provide compounds having potent antitumor activity. The compounds according to the present invention are compounds represented by formula (I) or pharmaceutically acceptable salts or solvates thereof:wherein X and Z represent CH or N; Y represents O or S; R<1>, R<2>, and R<3 >represent H, alkoxy or the like; R<4 >represents H; R<5>, R<6>, R<7>, and R<8 >represent H, halogen, alkoxy or the like; R<9 >and R<10 >represent H, alkyl or the like; and R<11 >represents optionally substituted azolyl.
Inventor(s):	Kazuo Kubo, Teruyuki Sakai, Rika Nagao, Yasunari Fujiwara, Toshiyuki Isoe, Kazumasa Hasegawa
Assignee:	KH Neochem Co Ltd, Kyowa Kirin Co Ltd
Application Number:	US10/132,473
Patent Claims:	1. A compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof: wherein X and Z represent CH; Y represents O or S; R1, R2, and R3, which may be the same or different, represent a hydrogen atom, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, nitro, or amino and the C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl groups are optionally substituted by a halogen atom; hydroxyl; C1-4 alkyl; C1-4 alkoxycarbonyl; amino on which one or two hydrogen atoms are optionally substituted by C1-4 alkyl optionally substituted by hydroxyl or C1-4 alkoxy; group R12R13N—C(═O)—O— wherein R12 and R13, which may be the same or different, represent a hydrogen atom or C1-4 alkyl optionally substituted by hydroxyl or C1-4 alkoxy; or group R14—(S)m— wherein R14 represents a saturated or unsaturated three- to seven-membered carbocyclic or heterocyclic group optionally substituted by C1-4 alkyl and m is 0 or 1; R4 represents a hydrogen atom; R5, R6, R7, and R8, which may be the same or different, represent a hydrogen atom, a halogen atom, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, trifluoromethyl, nitro, or amino; R9 and R10, which may be the same or different, represent a hydrogen atom, C1-6 alkyl, or C1-4 alkylcarbonyl and the alkyl portion of the C1-6 alkyl or C1-4 alkylcarbonyl group is optionally substituted by a halogen atom; C1-4 alkoxy; amino optionally substituted by C1-4 alkyl optionally substituted by C1-4 alkoxy; or a saturated or unsaturated three- to seven-membered carbocyclic or heterocyclic group; and R11 represents azolyl on which one or more hydrogen atoms are optionally substituted by a halogen atom; C1-4 alkyl; C1-4 alkoxy; C1-4 alkylthio; trifluoromethyl; nitro; amino on which one or two hydrogen atoms are optionally substituted by C1-4 alkyl group(s) which may be the same or different; C1-4 alkoxycarbonyl C1-4 alkyl, C1-4 alkylcarbonyl, or C3-5 cyclic alkyl. 2. The compound according to claim 1, wherein R1, R9, and R10 represent a hydrogen atom. 3. The compound according to claim 1, which is represented by formula (Ia): wherein X represents CH, R15 and R16, which may be the same or different, represent C1-6 alkoxy, R17, R18, R19, and R20, which may be the same or different, represent a hydrogen atom, a halogen atom, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, trifluoromethyl, nitro, or amino, R21 represents azolyl on which one or more hydrogen atoms are optionally substituted by a halogen atom; C1-4 alkyl; C1-4 alkoxy; C1-4 alkylthio; trifluoromethyl; nitro; amino on which one or two hydrogen atoms are optionally substituted by C1-4 alkyl group(s) which may be the same or different; C1-4 alkoxycarbonyl C1-4 alkyl; C1-4 alkylcarbonyl; or C3-5 cyclic alkyl. 4. The compound according to claim 3, wherein R15 and R16 represent methoxy. 5. The compound according to claim 3, wherein at least one of R17, R18, R19, and R20 represents a halogen atom. 6. The compound according to claim 3, wherein at least one of R17, R18, R19, and R20 represents a chlorine or fluorine atom. 7. The compound according to claim 3, wherein at least one of R17, R18, R19, and R20 represents C1-4 alkyl. 8. The compound according to claim 3, wherein at least one of R17, R18, R19, and R20 represents C1-4 alkoxy. 9. The compound according to claim 3, wherein at least one of R17, R18, R19, and R20 represents C1-4 alkylthio, trifluoromethyl, nitro, or amino. 10. The compound according to claim 3, wherein R21 represents group (i): wherein Q represents O, S, or NH, and R22 and R23, which may be the same or different, represent a hydrogen atom; a halogen atom; C1-4 alkyl; C1-4 alkoxy; C1-4 alkylthio; trifluoromethyl; nitro; amino on which one or two hydrogen atoms are optionally substituted by C1-4 alkyl group(s) which may be the same or different; C1-4 alkoxycarbonyl C1-4 alkyl; C1-4 alkylcarbonyl; or C3-5 cyclic alkyl. 11. The compound according to claim 3, wherein R21 represent group (ii): wherein Q represents O, S, or NH, and R22 and R23, which may be the same or different, represent a hydrogen atom; a halogen atom; C1-4 alkyl; C1-4 alkoxy; C1-6 alkylthio; trifluoromethyl; nitro; amino on which one or two hydrogen atoms are optionally substituted by C1-4 alkyl group(s) which may be the same or different; C1-4 alkoxycarbonyl C1-4 alkyl; C1-4 alkylcarbonyl; or C3-5 cyclic alkyl. 12. The compound according to claim 3, wherein R21 represent group (iii): wherein Q represents O, S, or NH, and R22 and R23, which may be the same or different, represent a hydrogen atom; a halogen atom; C1-4 alkyl; C1-4 alkoxy; C1-4 alkylthio; trifluoromethyl; nitro; amino on which one or two hydrogen atoms are optionally substituted by C1-4 alkyl group(s) which may be the same or different; C1-4 alkoxycarbonyl C1-4 alkyl; C1-4 alkylcarbonyl; or C3-5 cyclic alkyl. 13. The compound according to claim 3, wherein R21 represents group (iv): wherein Q represents O, S, or NH, and R22 represents a hydrogen atom; a halogen atom; C1-4 alkyl; C1-4 alkoxy; C1-4 alkylthio; trifluoromethyl; nitro; amino on which one or two hydrogen atoms are optionally substituted by C1-4 alkyl group(s) which may be the same or different; C1-4 alkoxycarbonyl C1-4 alkyl; C1-4 alkylcarbonyl; or C3-5 cyclic alkyl. 14. The compound according to claim 3, wherein R21 represents optionally substituted thiazolyl. 15. The compound according to claim 3, wherein R21 represents optionally substituted oxazolyl. 16. The compound according to claim 3, wherein R21 represents optionally substituted isothiazolyl. 17. The compound according to claim 3, wherein R21 represents optionally substituted isoxazolyl. 18. The compound according to claim 3, wherein R21 represents optionally substituted pyrazolyl. 19. The compound according to claim 3, wherein R21 represents optionally substituted 1,2,4-thiadiazolyl. 20. The compound according to claim 3, wherein R21 represents optionally substituted 1,2,4-oxadiazolyl. 21. The compound according to claim 3, wherein R21 represents optionally substituted 1,3,4-thiadiazolyl. 22. The compound according to claim 3, wherein R21 represents optionally substituted 1,3,4-oxadiazolyl. 23. The compound according to claim 3, which is represented by formula (Ib): wherein MeO represents methoxy; X represents CH; R17, R18, R19, which may be the same or different, represent a hydrogen atom, a halogen atom, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, trifluoromethyl, nitro, or amino; and R21 represents group (i), (ii),(iii), or (iv): wherein Q represents O, S, or NH, and R22 and R23, which may be the same or different, represent a hydrogen atom; a halogen atom; C1-4 alkyl; C1-4 alkoxy; C1-4 alkylthio; trifluoromethyl; nitro; amino on which one or two hydrogen atoms are optionally substituted by C1-4 alkyl group(s) which may be the same or different; C1-4 alkoxycarbonyl C1-4 alkyl; C1-4 alkylcarbonyl; or C3-5 cyclic alkyl. 24. The compound according to claim 23, wherein R21 represents group (iii) wherein Q represents S. 25. The compound according to claim 24, wherein both R22 and R23 represent a hydrogen atom, or one of R22 and R23 represents a hydrogen atom and the other represents C1-4 alkyl. 26. The compound according to claim 1, which is N-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]-phenyl}-N′-(5-methyl-3-isoxazolyl)urea, or a pharmaceutically acceptable salt or solvate thereof. 27. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof as an active ingredient. 28. A method for treating a disease selected from the group consisting of diabetic retinopathy, chronic rheumatism, psoriasis, and atherosclerosis, comprising administering a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof to a mammal. 29. A method for inhibiting the angiogenesis of blood vessels, comprising bringing the compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof into contact with vascular endothelial cells. 30. A method for treating Kaposi's Sarcoma comprising administering a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof to a mammal. 31. A method for treating a malignant tumor comprising administering a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof to a mammal, wherein said malignant tumor is a lung tumor. 32. A method for treating a malignant tumor comprising administering a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof to a mammal, wherein said malignant tumor is a colon tumor. 33. The compound according to claim 1, wherein R11 represents wherein Q represents O, S, or NH, and R22 and R23, which may be the same or different, represent a hydrogen atom; a halogen atom; C1-4 alkyl; C1-4 alkoxy; C1-4 alkylthio; trifluoromethyl; nitro; amino on which one or two hydrogen atoms are optionally substituted by C1-4 alkyl group(s) which may be the same or different; C1-4 alkoxycarbonyl C1-4 alkyl; C1-4 alkylcarbonyl; or C3-5 cyclic alkyl. 34. The compound according to claim 33, wherein Q represents O, R22 represents C1-4 alkyl, and R23 represents hydrogen. 35. The compound according to claim 34, wherein R22 represents methyl. 36. The compound according to claim 1, wherein R11 represents optionally substituted isoxazolyl. 37. The compound according to claim 10, wherein Q represents O, R22 represents C1-4 alkyl, and R23 represents hydrogen. 38. The compound according to claim 37, wherein R22 represents methyl. 39. The compound according to claim 10, wherein R21 represents optionally substituted isoxazolyl. 40. The compound according to claim 23, wherein R18 represents halogen and R17 and R19 represent hydrogen. 41. The compound according to claim 23, wherein R18 represents chlorine and R17 and R19 represent hydrogen. 42. The compound according to claim 23, wherein R21 represents group (i). 43. The compound according to claim 42, wherein Q represents O. 44. The compound according to claim 43, wherein both R22 and R23 represent hydrogen, or one of R22 and R23 represents hydrogen and the other represents C1-4 alkyl. 45. The compound according to claim 44, wherein R22 represents C1-4 alkyl and R23 represents hydrogen. 46. The compound according to claim 45, wherein R22 represents methyl. 47. The compound according to claim 23, wherein R21 represents group (i), R18 represents halogen, R17 and R19 represent hydrogen, and Q represents O. 48. The compound according to claim 23, wherein R21 represents group (i), R18 represents chlorine, R17 and R19 represent hydrogen, and Q represents O. 49. The compound according to claim 23, wherein R21 represents group (i), R22 represents C1-4 alkyl, R23 represents hydrogen, and Q represents O. 50. The compound according to claim 23, wherein R21 represents group (i), R22 represents methyl, R23 represents hydrogen, and Q represents O. 51. The compound according to claim 23, wherein R21 represents group (i), R18 represents halogen, R17 and R19 represent hydrogen, Q represents O, R22 represents C1-4 alkyl, and R23 represents hydrogen. 52. The compound according to claim 23, wherein R21 represents group (i), R18 represents chlorine, R17 and R19 represent hydrogen, Q represents O, R22 represents C1-4 alkyl, and R23 represents hydrogen. 53. The compound according to claim 23, wherein R21 represents group (i), R18 represents halogen, R17 and R19 represent hydrogen, Q represents O, R22 represents methyl, and R23 represents hydrogen. 54. The compound according to claim 1, which is N-{3-chloro-4-[(6,7-dimethoxy-4-quinolyl)-oxy]phenyl}-N′-(3-isoxazolyl)urea or a pharmaceutically acceptable salt or solvate thereof. 55. The compound according to claim 1, which is N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-3-fluorophenyl}-N′-(3-isoxazolyl)urea or a pharmaceutically acceptable salt or solvate thereof. 56. The compound according to claim 1, which is N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-3-fluorophenyl}-N′-(5-methyl-3-isoxazolyl)urea or a pharmaceutically acceptable salt or solvate thereof. 57. The compound according to claim 1, which is N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-2-fluorophenyl}-N′-(5-methyl-3-isoxazolyl)urea or a pharmaceutically acceptable salt or solvate thereof.