Heterocyclic compound and antitumor agent containing the same as active ingredient
The present invention relates to heterocyclic compounds represented by the formula I or pharmaceutically acceptable salts thereof and antitumor agents containing the heterocyclic compounds as effective components: wherein X represents nitrogen atom or CH; R 1 represents CH n F 3-n (wherein n is 1 or 2), hydroxy C 1 –C 6 alkyl, NHR 6 [wherein R 6 represents hydrogen atom or COR (wherein R represents hydrogen atom, C 1 –C 6 alkyl or C 1 –C 6 alkoxy)]; R 2 represents morpholino (which may be substituted with one to four C 1 –C 6 alkyl), thiomorpholino, piperidino, pyrrolidinyl (which may be substituted with hydroxy C 1 –C 6 alkyl), oxazolidinyl (which may be substituted with one or two C 1 –C 6 alkyl) or tetrahydro-1,4-thiazin-1-oxo-4-yl; R 3 and R 4 each represent hydrogen atom or C 1 –C 6 alkyl; and R 5 represents hydrogen atom, amino or hydroxyl.
1. A heterocyclic compound represented by the formula I or a pharmaceutically acceptable salt thereof:
wherein X represents nitrogen atom or CH;
R 1 represents CH n F 3-n (wherein n is 1 or 2), hydroxy C 1 –C 6 alkyl, NHR 6 (wherein R 6 represents a hydrogen atom or COR (wherein R represents a hydrogen atom, C 1 –C 6 alkyl or C 1 –C 6 alkoxy));
R 2 represents morpholino (which may be substituted with one to four C 1 –C 6 alkyl), thiomorpholino, piperidino, pyrrolidinyl (which may be substituted with hydroxy C 1 –C 6 alkyl), oxazolidinyl (which may be substituted with one or two C 1 –C 6 alkyl) or tetrahydro-1,4-thiazin-1-oxo-4-yl;
R 3 and R 4 each represent hydrogen atom or C 1 –C 6 alkyl; and
R 5 represents hydrogen atom, amino or hydroxyl.
2. The compound according to claim 1 , wherein R 1 is difluoromethyl.
3. The compound according to claim 1 , wherein R 1 is difluoromethyl, R 2 is morpholino which may be substituted with one to three methyl and R 3 and R 4 each are hydrogen atom or methyl.
4. The compound according to claim 1 wherein R 1 is difluoromethyl, R 2 is morpholino which may be substituted with one to three methyl, R 3 and R 4 each are hydrogen atom and R 5 is amino or hydroxyl.
5. The compound according to claim 1 , wherein R 1 is hydroxymethyl.
6. The compound according to claim 1 , wherein R 1 is hydroxymethyl, R 2 is morpholino which may be substituted with one or two methyl and R 3 and R 4 each are hydrogen atom or methyl.
7. The compound according to claim 1 , wherein R 1 is amino, formylamino or acetylamino.
8. The compound according to claim 1 , wherein R 1 is amino, formylamino or acetylamino, R 2 is morpholino which may be substituted with one or two methyl, and R 3 and R 4 each are hydrogen atom.
9. A pharmaceutical composition comprising at least one compound of claim 1 together with a pharmaceutically acceptable diluent or carrier.
10. The compound of claim 1 , wherein X is a nitrogen atom.
11. The compound of claim 1 , wherein X is CH.
12. The compound of claim 1 , wherein R 1 represents CH n F 3-n (wherein n is 1 or 2).
13. The compound of claim 1 , wherein R 1 represents hydroxy C 1 –C 6 alkyl.
14. The compound of claim 1 , wherein R 1 represents NHR 6 (wherein R 6 represents a hydrogen atom or COR (wherein R represents hydrogen atom, C 1 –C 6 alkyl or C 1 –C 6 alkoxy)).
15. The compound of claim 1 , wherein R 2 represents morpholino (which may be substituted with one to four C 1 –C 6 alkyl).
16. The compound of claim 1 , wherein R 2 represents thiomorpholino.
17. The compound of claim 1 , wherein R 2 represents piperidino.
18. The compound of claim 1 , wherein R 2 represents pyrrolidinyl (which may be substituted with hydroxy C 1 –C 6 alkyl).
19. The compound of claim 1 , wherein R 2 represents oxazolidinyl (which may be substituted with one or two C 1 –C 6 alkyl).
20. The compound of claim 1 , wherein R 2 represents tetrahydro-1,4-thiazin-1-oxo-4-yl.
21. The compound of claim 1 wherein R 3 and R 4 each represent a hydrogen atom.
22. The compound of claim 1 wherein R 3 and R 4 each represent C 1 –C 6 alkyl.
23. The compound of claim 1 wherein one of R 3 or R 4 is a hydrogen atom and the other is C 1 –C 6 alkyl.
24. The compound of claim 1 wherein R 5 represents a hydrogen atom.
25. The compound of claim 1 wherein R 5 represents amino.
26. The compound of claim 1 wherein R 5 represents hydroxyl.
27. A compound selected from the group consisting of:
2-(2-difluoromethylbenzimidazol-1-yl)-4-(cis-2,3-dimethylmorpholino)-6-morpholinopyrimidine,
2-(2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholinopyrimidine,
2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-thiomorpholinopyrimidine,
2-(2-difluoromethylbenzimidazol-1-yl)-4-(trans-2,3-dimethylmorpholino)-6-morpholinopyrimidine,
2-(2-difluoromethylbenzimidazol-1-yl)-4-(2,2-dimethylmorpholino)-6-morpholinopynmidine,
2-(2-difluoromethylbenzimidazol-1-yl)-4-(2-methylmorpholino)-6-morpholinopyrimidine,
2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-[2,2,5(R)-trimethylmorpholino]pyrimidine,
2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-[2,2,5(S)-trimethylmorpholino]pyrimidine,
4-(cis-2,3-dimethylmorpholino)-2-(2-fluoromethylbenzimidazol-1-yl)-6-morpholinopyrimidine,
2-(2-aminobenzimidazol-1-yl)-4-(cis-2,3-dimethylmorpholino)-6-morpholinopyrimidine,
2-(2-aminobenzimidazol-1-yl)-4-(trans-2,3-dimethylmorpholino)-6-morpholinopyrimidine,
4-(cis-2,3-dimethylmorpholino)-2-(2-hydroxymethylbenzimidazol-1-yl)-6-morpholinopyrimidine,
4-(cis-2,3-dimethylmorpholino)-2-(2-hydroxymethylbenzimidazol-1-yl)-6-piperidinopyrimidine,
4-(cis-2,3-dimethylmorpholino)-2-(2-hydroxymethylbenzimidazol-1-yl)-6-(2-hydroxymethylpyrrolidin-1-yl)pyrimidine,
2-(6-amino-2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholinopyrimidine,
2-(6-amino-2-difluoromethylbenzimidazol-1-yl)-4-(cis-2,3-dimethylmorpholino)-6-morpholinopyrimidine,
2-(2-difluoromethyl-5-hydroxybenzimidazol-1-yl)-4,6-dimorpholinopyrimidine,
2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-4-(2,2-dimethylmorpholino)-6-morpholinopyrimidine,
2-(2,4-diaminobenzimidazol-1-yl)-4-(2,2-dimethylmorpholino)-6-morpholinopyrimidine,
2-(2,4-diaminobenzimidazol-1-yl)-4,6-dimorpholinopyrimidine,
2-(2-amino-4-hydroxybenzimidazol-1-yl)-4-(2,2-dimethylmorpholino)-6-morpholinopyrimidine,
2-(2-difluoromethylbenzimidazol-1-yl)-4-(cis-2,3-dimethylmorpholino)-6-morpholino-1,3,5-triazine,
2-(2-difluoromethylbenzimidazol-1-yl)-4-(trans-2,3-dimethylmorpholino)-6-morpholino-1,3,5-triazine,
2-(2-difluoromethylbenzimidazol-1-yl)-4-(2,2-dimethylmorpholino)-6-morpholino-1,3,5-triazine,
2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-thiomorpholino-1,3,5-trazine,
2-(2-difluoromethylbenzimidazol-1-yl)-4-(2-methylmorpholino)-6-morpholino-1,3,5-trazine,
2-(2-difluoromethylbenzimidazol-1-yl)-4-(trans-2,5-dimethylmorpholino)-6-morpholino-1,3,5-triazine,
2-(2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine,
2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-[2,2,5(R)-trimethylmorpholino]-1,3,5-triazine,
2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-tetrahydro-1,4-thiazin-1-oxo-4-yl-1,3,5-triazine,
2-(2-acetylaminobenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine,
2-(2-acetylaminobenzimidazol-1-yl)-4-(trans-2,3-dimethylmorpholino)-6-morpholinopyrimidine,
2-(2-formylaminobenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine,
2-(2-propionylaminobenzimidazol-1-yl)-4-(trans-2,3-dimethylmorpholino)-6-morpholino-1,3,5-triazine,
2-(trans-2,3-dimethylmorpholino)-4-(2-formylaminobenzimidazol-1-yl)-6-morpholino-1,3,5-triazine,
4-(trans-2,3-dimethylmorpholino)-2-(2-formylaminobenzimidazol-1-yl)-6-morpholinopyrimidine,
2-(cis-2,6-dimethylmorpholino)-4-(2-formylaminobenzimidazol-1-yl)-6-morpholino-1,3,5-triazine,
2-(2-methoxycarbonylaminobenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine,
2-(2-aminobenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine,
2-(2-aminobenzimidazol-1-yl)-4-(trans-2,3-dimethylmorpholino)-6-morpholino-1,3,5-trazine,
2-(2-aminobenzimidazol-1-yl)-4-(cis-2,3-dimethylmorpholino)-6-piperidino-1,3,5-triazine,
2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-piperidino-1,3,5-triazine,
2-(2-difluoromethylbenzimidazol-1-yl)-4-(trans-2,3-dimethylmorpholino)-6-(2-hydroxymethylpyrrolidin-1-yl)-1,3,5-triazine,
2-(6-amino-2-difluoromethylbenzimidazol-1-yl)-4-(2,2-dimethylmorpholino)-6-morpholino-1,3,5-triazine,
2-(6-amino-2-difluoromethylbenzimidazol-1-yl)-4-(cis-2,3-dimethylmorpholino)-6-morpholino-1,3,5-triazine,
2-(4-amino-2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine,
2-(2-difluoromethyl-5-hydroxybenzimidazol-1-yl)-4-(cis-2,3-dimethylmorpholino)-6-morpholino-1,3,5-triazine,
2-(2-difluoromethyl-6-hydroxybenzimidazol-1-yl)-4-(2,2-dimethylmorpholino)-6-morpholino-1,3,5-triazine,
2-(2-difluoromethyl-5-hydroxybenzimidazol-1-yl)-4-(2,2-dimethyloxazolidin-3-yl)-6-morpholino-1,3,5-triazine,
2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine,
2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-4-(2,2-dimethylmorpholino)-6-morpholino-1,3,5-triazine,
2-(2,4-diaminobenzimidazol-1-yl)-4-(2,2-dimethylmorpholino)-6-morpholino-1,3,5-triazine,
2-(2,4-diaminobenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine, and
2-(2-amino-4-hydroxybenzimidazol-1-yl)-4-(2,2-dimethylmorpholino)-6-morpholino-1,3,5-triazine.
28. A compound which is 2-(2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine.
29. A method for treating cancer comprising:
administering to a subject in need thereof an amount of the compound of claim 1 sufficient to inhibit tumor growth,
wherein said cancer is solid human breast, lung or colon cancer.
30. The method of claim 29 , wherein said compound is administered orally.
31. The method of claim 29 , wherein said compound is administered parenterally.
32. The method of claim 29 , wherein a daily dosage ranging from 100 to 1,000 mg is administered to said subject.