Claims
- 1. A compound of Formula I:
- 2. A compound of Formula II:
- 3. A compound of Formula III:
- 4. A compound of Formula IV:
- 5. A compound of claim 1, wherein
- 6. A compound of claim 1, which is one of
4-(Benzothiazol-6-ylamino)-6-(ethyl-benzylamino)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-(methyl-benzylamino)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-(benzylamino)-[1,3,5]triazin-2-ol; (R)-4-(Benzothiazol-6-ylamino)-6-(1-phenylethylamino)-[1,3,5]triazin-2-ol; (S)-4-(Benzothiazol-6-ylamino)-6-(1-phenylethylamino)-[1,3,5]triazin-2-ol; (R)-4-(Benzothiazol-6-ylamino)-6-(methyl-1-phenylethylamino)-[1,3,5]triazin-2-ol; (S)-4-(Benzothiazol-6-ylamino)-6-(methyl-1-phenylethylamino)-[1,3,5]triazin-2-ol; (R)-4-(Benzothiazol-6-ylamino)-6-(ethyl-1-phenylethylamino)-[1,3,5]triazin-2-ol; (S)-4-(Benzothiazol-6-ylamino)-6-(ethyl-1-phenylethylamino)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-(1-methyl-1-phenylethylamino)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-(2-phenylethylamino)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-(methyl-2-phenylethylamino)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-(ethyl-2-phenylethylamino)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-(2-chloro-benzylamino)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-(2-fluoro-benzylamino)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-[(pyridin-3-ylmethyl)-amino]-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-(2,6-difluoro-benzylamino)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-[methyl-(2-pyridin-2-yl-ethyl)amino]-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-[pyridin-2-ylmethyl)-amino]-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-[benzyl-(1-benzyl-pyrrolidin-3-yl)-amino]-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-(3-fluoro-benzylamino)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-(2-chloro-6-methyl-benzylamino)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-(N′-methyl-N′-phenyl-hydrazino)-[1,3,5]triazin-2-ol; 4-(benzothiazol-6-ylamino)-6-[(pyridin-4-ylmethyl)-amino]-[1,3,5]triazin-2-ol; 4-Benzothiazol-6-ylamino)-6-(2-pyridin-3-yl-ethylamino)-[1,3,5]triazin-2-ol; 4-Benzothiazol-6-ylamino)-6-(1-phenyl-propylamino)-[1,3,5]triazin-2-ol; 4-Benzothiazol-6-ylamino)-6-(2-pyridin-2-yl-ethylamino)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-(1-naphthalen-1-yl-ethylamino)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-(3-hydroxymethyl-phenylamino)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-(quinolin-5-ylamino)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-(4-hydroxy-naphthalen-1-ylamino)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-(1H-indazol-6-ylamino)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-[(1H-indazol-6-yl)-methylamino]-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-(1-methyl-1H-indazol-6-ylamino)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-(6-hydroxy-naphthalen-1-ylamino)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-(3-hydroxy-phenylamino)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-[2-(2-hydroxyethyl)-phenylamino]-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-(5-thiophen-2-yl-2H-pyrazol-3-ylamino)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-(2-phenyl-2H-pyrazol-3-ylamino)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-(2,4-difluoro-benzylamino)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-phenylamino-[1,3,5]triazin-2-ol; 4-(1H-Indazol-6-ylamino)-6-(1-methyl-1-phenylethylamino)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-(2-hydroxy-1-phenylethylamino)-[1,3,5]triazin-2-ol; 4-(1H-Indazol-5-ylamino)-6-(1-methyl-1-phenylethylamino)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-7-ylamino)-6-(1-methyl-1-phenylethylamino)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-[(furan-2-yl-methyl)amino]-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-[(thiophen-2-yl-methyl)amino]-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-[(furan-3-ylmethyl)-amino-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-[(thiophen-3-yl-methyl)amino]-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-(benzyl-pyrrolidin-3-ylamino)-[1,3,5]triazin-2-ol; 3-{[4-(Benzothiazol-6-ylamino)-6-hydroxy-[1,3,5]triazin-2-yl]-benzylamino}-propane-1,2-diol; 4-(Benzothiazol-6-ylamino)-6-[benzyl-(3-morpholin-4-ylpropyl)-amino]-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-{benzyl-[3-(4-methyl-piperazin-1-yl)-propyl]-amino}-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-[benzyl-(3-dimethylamino-propyl)-amino]-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-[benzyl-(2-piperazin-1-ylethyl)-amino]-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-[benzyl-(2-morpholin-4-ylethyl)-amino]-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-[benzyl-(2-dimethylamino-ethyl)-amino]-[1,3,5]triazin-2-ol; 4-(2-Amino-benzothiazol-6-ylamino)-6-(1-methyl-1-phenylethylamino)-[1,3,5]triazin-2-ol; 4-(1-Methyl-1-phenylethylamino)-6-(quinolin-6-ylamino)-[1,3,5]triazin-2-ol; 4-(Quinolin-6-ylamino)-6-(N-ethylbenzylamino)-[1,3,5]triazin-2-ol; 4-(Quinolin-6-ylamino)-6-(N-methylbenzylamino)-[1,3,5]triazin-2-ol; 4-(Quinolin-6-ylamino)-6-(1-methyl-1-phenylethylamino)-[1,3,5]triazin-2-ol; N-[4-(Benzothiazol-6-ylamino)-6-(1-methyl-1-phenylethylamino)-[1,3,5]triazin-2-yl]-hydroxylamine; 4-(Benzothiazol-6-ylamino)-6-[(4-fluoro-3-trifluoromethylbenzyl)amino]-[1,3,5]triazin-2-ol; 4-(Quinolin-6-ylamino)-6-[(4-fluoro-3-trifluoromethylbenzyl)amino]-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-(ethyl-(pyridin-2-ylmethyl)amino)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-(N-benzylisopropylamino)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-(ethyl-(2-fluorobenzyl)amino]-[1,3,5]trizin-2-ol; 4-(Benzothiazol-6-ylamino)-6-[benzyl-(2,2,2-trifluoroethyl)amino]-[1,3,5]triazin-2-ol; 3-[[4-(Benzothiazol-6-ylamino)-6-hydroxy-[1,3,5]triazin-2-yl]-(1-phenylethyl)amino]propane-1,2-diol; 4-(Benzothiazol-6-ylamino)-6-(ethyl-(pyridin-2-ylmethyl)amino)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-(N-(2-fluorobenzyl)isopropylamino)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-[ethyl-(1H-indazol-6-yl)amino]-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-{benzyl-[2-(3H-imidazol-4-yl)ethyl]amino}-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-{2-fluorobenzyl-[2-(3H-imidazol-4-yl)ethyl]amino}-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-[benzyl-(3-imidazol-1-yl-propyl)amino]-[1,3,5]triazin-2-ol; 4-{[4-(Benzothiazol-6-ylamino)-6-hydroxy-[1,3,5]triazin-2-yl]-benzylamino}butyric acid; 4-(Benzothiazol-6-ylamino)-6-{(2-piperazin-1-ylethyl)-quinolin-5-ylamino}-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-{benzyl-[2-(3H-imidazol-4-yl)ethyl]amino}-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-ylamino)-6-(N-benzylpropylamino)-[1,3,5]triazin-2-ol; and pharmaceutically acceptable salts thereof.
- 7. A compound of claim 3, which is one of
4-(Benzothiazol-6-yl-amino)-6-(2-methyl-pyrrolidin-1-yl)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-yl-amino)-6-(2-benzyl-pyrrolidin-1-yl)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-yl-amino)-6-(2,6-dimethyl-piperidin-1-yl)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-yl-amino)-6-(2,5-dimethyl-pyrrolidin-1-yl)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-yl-amino)-6-(2-phenyl-pyrrolidin-1-yl)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-yl-amino)-6-(3-phenyl-thiomorpholin-4-yl)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-yl-amino)-6-(2-phenyl-thiomorpholin-4-yl)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-yl-amino)-6-(thiomorpholin-4-yl)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-yl-amino)-6-(3-methyl-piperidin-1-yl)-[1,3,5]triazin-2-ol; 4-(Benzothiazol-6-yl-amino)-6-(morpholin-4-yl)-[1,3,5]triazin-2-ol; and pharmaceutically acceptable salts thereof.
- 8. A pharmaceutical composition, comprising a compound of any one of claims 1 to 4 and a pharmaceutically acceptable carrier.
- 9. A pharmaceutical composition, comprising a compound of claim 5 and a pharmaceutically acceptable carrier.
- 10. A pharmaceutical composition, comprising a compound of claim 6 or 7 and a pharmaceutically acceptable carrier.
- 11. A method of preparing the compounds of Formulae I and III where R is —OH, comprising the steps of:
a) displacing one of three displaceable groups at the 2-, 4- and 6-positions, respectively, of a 1,3,5-triazine ring with 4-methoxybenzyl alcohol to give a 2-(4-methoxybenzyloxy)-[1,3,5]triazine; b) displacing the second displaceable group with a primary or secondary alkyl or aromatic amine (i) to give a 4-amino-2-(4-methoxybenzyloxy)-[1,3,5]triazine; and c) displacing the third displaceable group with a primary or secondary alkyl or aromatic amine (ii) under microwave conditions with concomitant loss of the p-methoxybenzyl group to give a 4,6-diamino-(2-hydroxy)-[1,3,5]triazine.
- 12. A method of preparing the compounds of Formulae II and IV, comprising the steps of:
a) displacing one of three displaceable groups at the 2-, 4- and 6-positions, respectively, of a 1,3,5-triazine ring with 4-methoxybenzyl alcohol to give a 2-(4-methoxybenzyloxy)-[1,3,5]triazine; b) displacing the second displaceable group with a primary or secondary alkyl or aromatic amine (i) to give a 4-amino-2-(4-methoxybenzyloxy)-[1,3,5]triazine; c) displacing the third displaceable group with a primary or secondary alkyl or aromatic amine (ii) under microwave conditions with concomitant loss of the p-methoxybenzyl group to give a 4,6-diamino-(2-hydroxy)-[1,3,5]triazine; and d) adding an acylating, sulfonylating or phosphorylating agent to the 4,6-diamino-(2-hydroxy)-[1,3,5]triazine to give a 4,6-diamino-(2-O-acyl)-[1,3,5]triazine, a 4,6-diamino-(2-O-sulfonyl)-[1,3,5]triazine or a 4,6-diamino-(2-O-phosphoryl)-[1,3,5]triazine, respectively.
- 13. A method of claim 11 or 12, wherein the displaceable groups are chlorines.
- 14. A method of preparing the compounds of Formulae I and III where R is —OH, comprising the steps of:
aa) displacing one of three displaceable groups at the 2-, 4- and 6-positions, respectively, of a 1,3,5-triazine ring with a primary or secondary alkyl or aromatic amine (i) to give a 2-amino-[1,3,5]triazine; bb) displacing the second displaceable group with a primary or secondary alkyl or aromatic amine (ii) to give a 2,4-diamino-[1,3,5]triazine; and cc) displacing the third displaceable group with water under acidic conditions to give a 4,6-diamino-(2-hydroxy)-[1,3,5]triazine.
- 15. A method of preparing the compounds of Formulae I and III where R is —NHOH, comprising the steps of:
aa) displacing one of three displaceable groups at the 2-, 4- and 6-positions, respectively, of a 1,3,5-triazine ring with a primary or secondary alkyl or aromatic amine (i) to give a 2-amino-[1,3,5]triazine; bb) displacing the second displaceable group with a primary or secondary alkyl or aromatic amine (ii) to give a 2,4-diamino-[1,3,5]triazine; and cc) displacing the third displaceable group with hydroxylamine under acidic conditions to give a 4,6-diamino-([1,3,5]triazin-2-yl)-hydroxylamine.
- 16. A method of preparing the compounds of Formulae II and IV, comprising the steps of:
aa) displacing one of three displaceable groups at the 2-, 4- and 6-positions, respectively, of a 1,3,5-triazine ring with a primary or secondary alkyl or aromatic amine (i) to give a 2-amino-[1,3,5]triazine; bb) displacing the second displaceable group with a primary or secondary alkyl or aromatic amine (ii) to give a 2,4-diamino-[1,3,5]triazine; cc) displacing the third displaceable group with water under acidic conditions to give a 4,6-diamino-(2-hydroxy)-[1,3,5]triazine; and dd) adding an acylating, sulfonylating or phosphorylating agent to the 4,6-diamino-(2-hydroxy)-[1,3,5]triazine to give a 4,6-diamino-(2-O-acyl)-[1,3,5]triazine, a 4,6-diamino-(2-O-sulfonyl)-[1,3,5]triazine or a 4,6-diamino-(2-O-phosphoryl)-[1,3,5]triazine, respectively.
- 17. A method for inhibiting protein tyrosine kinase activity, comprising contacting the kinase with an effective inhibitory amount of at least one compound of any one of claims 1 to 4.
- 18. A method for inhibiting protein tyrosine kinase activity, comprising contacting the kinase with an effective inhibitory amount of at least one compound of claim 5.
- 19. A method for inhibiting protein tyrosine kinase activity, comprising contacting the kinase with an effective inhibitory amount of at least one compound of claim 6 or 7.
- 20. A method for inhibiting protein tyrosine kinase activity in vitro, comprising contacting the kinase with at least one compound of any one of claims 1 to 4.
- 21. A method for inhibiting protein tyrosine kinase activity in vitro, comprising contacting the kinase with at least one compound of claim 5.
- 22. A method for inhibiting protein tyrosine kinase activity in vitro, comprising contacting the kinase with at least one compound of claim 6 or 7.
- 23. A method for inhibiting protein tyrosine kinase activity in cells, comprising contacting the kinase with at least one compound of any one of claims 1 to 4.
- 24. A method for inhibiting protein tyrosine kinase activity in cells, comprising contacting the kinase with at least one compound of claim 5.
- 25. A method for inhibiting protein tyrosine kinase activity in cells, comprising contacting the kinase with at least one compound of claim 6 or 7.
- 26. A method for inhibiting protein tyrosine kinase activity in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound of any one of claims 1 to 4.
- 27. A method for inhibiting protein tyrosine kinase activity in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound of claim 5.
- 28. A method for inhibiting protein tyrosine kinase activity in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound of claim 6 or 7.
- 29. A method according to claim 17, wherein the protein tyrosine kinase is VEGFR-2 (KDR), c-fins, c-met or tie-2.
- 30. A method according to claim 26, wherein the protein tyrosine kinase is VEGFR-2 (KDR), c-fms, c-met or tie-2.
- 31. A method of treating cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound of any one of claims 1 to 4.
- 32. A method of treating cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound of claim 5.
- 33. A method of treating cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound of claim 6 or 7.
- 34. A method of treating vascular diseases in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound of any one of claims 1 to 4.
- 35. A method of treating vascular diseases in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound of claim 5.
- 36. A method of treating vascular diseases in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound of claim 6 or 7.
- 37. A method of treating ocular diseases in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound of any one of claims 1 to 4.
- 38. A method of treating ocular diseases in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound of claim 5.
- 39. A method of treating ocular diseases in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound of claim 6 or 7.
- 40. A method of treating restenosis in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound of any one of claims 1 to 4.
- 41. A method of treating restenosis in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound of claim 5.
- 42. A method of treating restenosis in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound of claim 6 or 7.
- 43. A pharmaceutical dosage form comprising a pharmaceutically acceptable carrier and from about 0.5 mg to about 10 g of at least one compound of any one of claims 1 to 7.
- 44. A dosage form according to claim 43 adapted for parenteral or oral administration.
PRIORITY CLAIM
[0001] This application claims benefit under 35 U.S.C. § 119(e) to Provisional Application No. 60/414,636, filed Oct. 1, 2002.
Provisional Applications (1)
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Number |
Date |
Country |
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60414636 |
Oct 2002 |
US |