Antitumor compounds have the five membered fused ring ecteinascidin structure of the formula (XIV). The present compounds lack a 1,4-bridging group as found in the ecteinascidins. They have at the C-1 position a substituent selected from an optionally protected or derivatised aminomethylene group or
Antitumor compounds have the five membered fused ring ecteinascidin structure of the formula (XIV). The present compounds lack a 1,4-bridging group as found in the ecteinascidins. They have at the C-1 position a substituent selected from an optionally protected or derivatised aminomethylene group or an optionally protected or derivatised hydroxymethylene group
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The invention claimed is: 1. A compound of the formula: wherein: R1 is selected from the group consisting of--CH2--NHRa and--CH2--ORa, where Ra is selected from the group consisting of alkyl-CO--; haloalkyl-CO--; haloalkyl-O--CO--; arylalkenyl-CO--; heteroaryl-CO--; alkenyl-CO--; and amino acid
The invention claimed is: 1. A compound of the formula: wherein: R1 is selected from the group consisting of--CH2--NHRa and--CH2--ORa, where Ra is selected from the group consisting of alkyl-CO--; haloalkyl-CO--; haloalkyl-O--CO--; arylalkenyl-CO--; heteroaryl-CO--; alkenyl-CO--; and amino acid acyl; R5 is--OR", where R" is selected from the group consisting of H and C1-C4 alkyl-CO--; R18 is--OH; and R21is--CN; or a pharmaceutically acceptable salt thereof. 2. A compound as claimed in claim 1, which is of the formula: wherein R1, R5, R18, and R21 are as defined in claim 1. 3. A compound as claimed in claim 1 or 2, wherein R1 is--CH2--NHRa. 4. A compound as claimed in claim 1 or 2, wherein Ra is-aa-Rb where aa is amino acid acyl and Rb is selected from the group consisting of H; alkyl-CO--; haloalkyl-CO--; haloalkyl-O--CO--; arylalkyl-CO--; arylalkenyl-CO--; heteroaryl-CO--; alkenyl-CO--; and amino acid acyl. 5. A compound as claimed in claim 4, wherein said amino acid acyl is further substituted with at least one Ra group. 6. A compound as claimed in claim 4, wherein R1 is--CH2--NH-aa-Rb where aa is an amino acid acyl and Rb is selected from the group consisting of hydrogen; arylalkenyl-CO--; haloalkyl-CO--; alkyl-CO--; arylalkyl-CO--; and amino acid acyl. 7. A compound as claimed in claim 6, wherein R1 is--CH2--NH-aa-Rb where aa is alanine and Rb is selected from the group consisting of hydrogen, CF3CO--, trans(trifluoromethyl)cinnamoyl, cinnamoyl, C3F7CO--, butyryl, 3-chioroproprionoyl, hydrocinnamoyl, phenylacetyl, and acetyl. 8. A compound as claimed in claim 3, wherein R1 is--CH2--NHRa where Ra is selected from the group consisting of alkyl-CO--; alkenyl-CO--; arylalkenyl-CO--; and heteroaryl-CO. 9. A compound as claimed in claim 8, wherein R1 is--CH2--NHRa where Ra is selected from the group consisting of acetyl, isovaleryl, decanoyl, and cinnamoyl. 10. A compound as claimed in claim 1 or 2, wherein R1 is--CH2--ORa where Ra is selected from the group consisting of a protected cysteine; alkyl-CO--; and arylalkenyl-CO. 11. A compound as claimed in claim 10, wherein R1 is--CH2--ORa where Ra is selected from the group consisting of butyryl; trans(trifluoromethyl)cinnamoyl; and cinnamoyl. 12. A compound as claimed in claim 1 or 2 wherein R5 is--OCOCH3. 13. A compound as claimed in claim 12, wherein R1 is--CH2--NHRa where Ra is selected from the group consisting of acetyl, isovaleryl, decanoyl, cinnamoyl, propionyl, myristoyl, stearoyl, hexanoyl, crotonyl, and chloronicotinoyl. 14. A compound as claimed in claim 12, wherein R1 is--CH2--ORa where Ra is selected from the group consisting of butyryl; trans(trifluoromethyl)cinnamoyl; and cinnamoyl. 15. A compound as claimed in claim 8, wherein R1 is--CH2--NHRa where Ra is selected from the group consisting of propionyl, myristoyl, stearoyl, hexanoyl, crotonyl, and chloronicotinoyl. 16. A compound of general structure: wherein R21 is--CN, and Ra, R5, R18, and R1, and are each independently selected from the groups defined below: Ra X5 R18 R1 OH OH CH2NHRa OAc CH2ORa COCH2CH2CH3 COCH═CHPh COCH═CHArCF3 COCH(CH3)NHCOCH2CH2Ph CO-(S)-CH(CH3)NHCOCF3 CO-(R)-CH(CH3)NHCOCF3 CO-(S)-CH(NHCbz)CH(CH3)2 CSNHPh or a pharmaceutically acceptable salt thereof. 17. A compound of general structure I: wherein Rb, R5, R1, R18, and R21 are each independently selected from the groups defined below: R1 is--CH2--NH--CO--CHCH3--NHRb Rb R5 R18 R21 H OH OH CN OAc COCH2CH2CH3 COCH2Ph COCH2CH2Ph COCH═CHPh Boc CSNHPh; or a pharmaceutically acceptable salt thereof. 18. A compound selected from the following formulae: or a pharmaceutically acceptable salt thereof. 19. The compound of claim 2, wherein the compound is of the formula: or a pharmaceutically acceptable salt thereof. 20. The compound of claim 2, wherein the compound is of the formula: or a pharmaceutically acceptable salt thereof. 21. A pharmaceutical composition comprising a compound of the formula: wherein: R1 is selected from the group consisting of--CH2--NHRa and--CH2--ORa, where Ra is selected from the group consisting of alkyl-CO--; haloalkyl-CO--; haloalkyl-O--CO--; arylalkenyl-CO--; heteroaryl-CO--; alkenyl-CO--; and amino acid acyl; R5 is--OR", where R" is selected from the group consisting of H and C1-C4 alkyl-CO--; R18 is--OH; and R21 is--CN; or a pharmaceutically acceptable salt thereof; together with a pharmaceutical acceptable carrier. 22. A composition as claimed in claim 21, wherein said compound is of the formula: wherein R1, R5, R18, and R21 are as defined in claim 21. 23. A method of treating a mammal affected by lung cancer, colon cancer, kidney cancer, prostate cancer, melanoma or leukemia which comprises administering to the affected mammal a therapeutically effective amount of a compound of the formula: wherein: R1 is selected from the group consisting of--CH2--NHRa and--CH2--ORa, where Ra is selected from the group consisting of alkyl-CO--; haloalkyl-CO--; haloalkyl-O--CO--; arylalkenyl-CO--; heteroaryl-CO--; alkenyl-CO--; and amino acid acyl; R5 is--OR", where R" is selected from the group consisting of H and C1-C4 alkyl-CO--; R18 --OH; and R21 is--CN; or a pharmaceutically acceptable salt thereof. 24. The method of claim 23, wherein said mammal is a human. 25. The method of claim 24, wherein said compound is administered by intravenous infusion. 26. The method as claimed in claim 23, wherein said compound is of the formula: wherein R1, R5, R18, and R21 are as defined in claim 23. 27. A compound having the formula or a pharmaceutically acceptable salt thereof. 28. A compound as defined in claim 1, which is of the formula: wherein R1, R5, and R21 are as defined in claim 1. 29. A compound as claimed in claim 28, wherein R1 is--CH2--NHRa. 30. A compound as claimed in claim 28, wherein Ra is-aa-Rb where aa is amino acid acyl and Rb is selected from the group consisting of H; alkyl-CO--; haloalkyl-CO--; haloalkyl-O--CO--; arylalkyl-CO--; arylalkenyl-CO--; heteroaryl-CO--; alkenyl-CO--; amino acid acyl. 31. A compound as claimed in claim 30, wherein said amino acid acyl is further substituted with at least one Ra group. 32. A compound as claimed in claim 30, wherein R1 is--CH2--NH-aa-Rb where aa is an amino acid acyl and Rb is selected from the group consisting of hydrogen; arylalkenyl-CO--; haloalkyl-CO--; alkyl-CO--; arylalkyl-CO--; and amino acid acyl. 33. A compound as claimed in claim 32, wherein R1 is--CH2--NH-aa-Rb where aa is alanine and Rb is selected from the group consisting of hydrogen, CF3CO--, trans(trifluoromethyl)cinnamoyl, cinnamoyl, C3F7CO--, butyryl, 3-chloropropionoyl, hydrocinnamoyl, phenylacetyl, and acetyl. 34. A compound as claimed in claim 29, wherein R1 is--CH2--NHRa where Ra is selected from the group consisting of alkyl-CO--; alkenyl-CO--; arylalkenyl-CO--; and heteroaryl-CO--. 35. A compound as claimed in claim 34, wherein R1 is--CH2--NHRa where Ra is selected from the group consisting of acetyl, isovaleryl, decanoyl, and cinnamoyl. 36. A compound as claimed in claim 28, wherein R1 is--CH2--ORa where Ra is selected from the group consisting of a protected cysteine; alkyl-CO--and arylalkenyl-CO--. 37. A compound as claimed in claim 36, wherein R1 is--CH2--ORa where Ra is selected from the group consisting of butyryl; trans(trifluoromethyl)cinnamoyl and cinnamoyl. 38. A compound as claimed in claim 28, wherein R5 is--OCOCH3. 39. A compound as claimed in claim 38, wherein R1 is--CH2--NHRa where Ra is selected from the group consisting of acetyl, isovaleryl, decanoyl, cinnamoyl, propionyl, myristoyl, stearoyl, hexanoyl, crotonyl, and chloronicotinoyl. 40. A compound as claimed in claim 38, wherein R1 is--CH2--ORa where Ra is selected from the group consisting of butyryl; trans(trifluoromethyl)cinnamoyl; and cinnamoyl. 41. A compound as claimed in claim 34, wherein R1 is--CH2--NHRa where Ra is selected from the group consisting of propionyl, myristoyl, stearoyl, hexanoyl, crotonyl, and chloronicotinoyl. 42. A compound of general structure (II): wherein Ra, R5, R18, R1, and R21 are each independently selected from the groups defined below: Ra R5 R18 R1 R21 COCH2CH2CH3 OH OH CH2NHRa CN OAc CH2ORa COCH═CHPh COCH(CH3)NHCOCH2CH2Ph CO--(S)--CH(CH3)NHCOCF3 CO--(R)--CH(CH3)NHCOCF3 CO--(S)--CH(NHCbz)CH(CH3)2 CSNHPh or a pharmaceutically acceptable salt thereof. 43. A compound of general structure II: wherein Rb, R5, R1, R18 and R21 are each independently selected from the groups defined below: R1 is--CH2--NH--CO--CHCH3--NHRb Rb R5 R18 R21 H OH OH CN COCH2CH2CH3 OAc COCH2Ph COCH2CH2Ph COCH═CHPh Boc CSNHPh; or a pharmaceutically acceptable salt thereof. 44. A compound of a formula selected from the following general structures (III) and (IV): wherein R', X2, R1, and R6 are each independently selected from the groups defined below: R' X2 R1 R6 CH2CH═CH2 OH OH CN COCH2CH3 OAc OAc CO(CH2)4CH3 OCOOCH2CH═CH2 OCOCH2C6H11 CO(CH2)12CH3 OCOCF3 OCOCH2CH2C6H11 CO(CH2)16CH3 OCOCH2Cl OCOCH2CH2CH3 COCH2C6H11 OCOCH2CH2Cl OCO(CH2)4CH3 COCH2CH2C6H11 OCOCF2CF2CF3 OCO(CH2)8CH3 COCH═CHCH3 OCO(CH2)16CH3 COCH(CH3)NHCOCH2CH2Ph CO--(S)--CH(NHCbz)CH(CH3)2 or a pharmaceutically acceptable salt thereof. 45. A compound of general structure V: wherein X2, R1, R6, and R are each independently selected from the groups defined below: R' X2 R1 R6 OH OH CN CH2CH═CH2 OAc OAc COCH2CH3 OCOOCH2CH═CH2 OCOCH2C6H11 CO(CH2)4CH3 OCOCF3 OCOCH2CH2C6H11 CO(CH2)12CH3 OCOCH2Cl OCOCH2CH2CH3 CO(CH2)16CH3 OCOCH2CH2Cl OCO(CH2)4CH3 COCH2CH2C6H11 OCOCF2CF2CF3 OCO(CH2)8CH3 COCH2CH2C6H11 OCO(CH2)16CH3 COCH2Ph COCH2CH2Ph COCH═CHCH3 COCH(CH3)NHCOCH2CH2Ph CO-(S)-CH(CH3)NHCOCF3 CO-(R)-CH(CH3)NHCOCF3 CO-(S)-CH(NHCbz)CH(CH3)2 Boc or a pharmaceutically acceptable salt thereof. 46. A compound selected from the following formulae: or a pharmaceutically acceptable salt thereof. 47. The compound of claim 46 which is of the formula: or a pharmaceutically acceptable salt thereof. 48. The compound of claim 46, which is of the formula: or a pharmaceutically acceptable salt thereof. 49. The compound of claim 46, which is of the formula: or a pharmaceutically acceptable salt thereof. 50. The compound of claim 46, which is of the formula: or a pharmaceutically acceptable salt thereof. 51. The compound of claim 46, which is of the formula: or a pharmaceutically acceptable salt thereof. 52. A compound of the formula: wherein: R1 is--CH2--ORa, where Ra is selected from the group consisting of alkyl-CO--; haloalkyl-CO--; cycloalkylalkyl-CO--; haloalkyl-O--CO--; arylalkenyl-CO--; heteroaryl-CO--; alkenyl-CO--; alkenyl; and amino acid acyl; R5 is--OR", where R" is selected from the group consisting of H; alkyl-CO--; cycloalkyl-CO--; and haloalkyl-CO--; R18 is--OR, where R is selected from the group consisting of H, alkyl-CO--; cycloalkylalkyl-CO--; and R21 is--CN; or a pharmaceutically acceptable salt thereof. 53. A compound according to claim 52, which is of the formula: wherein R1, R5, R18, and R21 are as defined in claim 52. 54. A compound according to claim 52, which is of the formula: wherein R1, R5, R18, and R21 are as defined in claim 52. 55. A compound according to claim 53 or 54, wherein R1 is--CH2--ORa where Ra is selected from the group consisting of a protected cysteine; alkyl-CO--; arylalkenyl-CO--; a cysteine derivative of the formula ProtSH-S--CH2--C(═NOProtOH)-CO--where ProtSH is a protecting group for thiol and ProtOH is a protecting group hydroxy; and a cysteine derivative of formula ProtSH-S--CH═C(--OProtOH)-CO--, where ProtSH is a protecting group for thiol and ProtOH is a protecting group for hydroxy. 56. A compound according to claim 55, wherein R1 is--CH2--ORa where Ra is selected from the group consisting of S--Fm--O-TBDMS-cysteine; butyryl; (trifluoromethyl)cinnamoyl; cinnamoyl; a cysteine derivative of the formula ProtSH-S--CH2--C(═NOProtOH)-CO--, where ProtSH is Fm and ProtOH is methoxy; and a cysteine derivative of formula ProtSH-S--CH2═C(--OProtOH)-CO--, where ProtSH is Fm and ProtOH is MOM. 57. A composition as claimed in claim 21, wherein said compound is of the formula: wherein R1, R5, and R21 are as defined in claim 21. 58. A pharmaceutical composition comprising a compound of the formula: wherein: R1 is--CH2--ORa, where Ra is selected from the group consisting of alkyl-CO--; haloalkyl-CO--; cycloalkylalkyl-CO--; haloalkyl-O--CO--; arylalkenyl-CO--; heteroaryl-CO--; alkenyl-CO--; alkenyl; and amino acid acyl; R5 is--OR", where R" is selected from the group consisting of H; alkyl-CO--; cycloalkyl-CO--; and haloalkyl-CO--; R18 is--OR, where R is selected from the group consisting of H, alkyl-CO--; cycloalkylalkyl-CO--; and R21 R is--CN; or a pharmaceutically acceptable salt thereof; together with a pharmaceutically acceptable carrier. 59. A composition as claimed in claim 58, wherein said compound is of the formula: wherein R1, R5, R18, and R21 are as defined in claim 58. 60. A composition as claimed in claim 58 wherein said compound is of the formula: wherein R1, R5, R18, and R21 are as defined in claim 58. 61. The method as claimed in claim 23, wherein said compound is of the formula: wherein R1, R5, and R21 are as defined in claim 23. 62. The method of claim 61, wherein said mammal is a human. 63. The method of claim 62, wherein said compound is administered by intravenous infusion. 64. A method of treating a mammal affected by lung cancer, colon cancer, kidney cancer, prostate cancer, melanoma or leukemia which comprises administering to the affected mammal a therapeutically effective amount of a compound of the formula: wherein: R1 is--CH2--ORa, where Ra is selected from the group consisting of alkyl-CO--; haloalkyl-CO--; cycloalkylalkyl-CO--; haloalkyl-O--CO--; arylalkenyl-CO--; heteroaryl-CO--; alkenyl-CO--; alkenyl; and amino acid acyl; R5 is--OR", where R" is selected from the group consisting of H; alkyl-CO--; cycloalkyl-CO--; and haloalkyl-CO--; R18 is--OR, where R is selected from the group consisting of H, alkyl-CO--; cycloalkylalkyl-CO--; and R21 is--CN; or a pharmaceutically acceptable salt thereof. 65. The method as claimed in claim 64, wherein said compound is of the formula: wherein R1, R5, R18, and R21 are as defined in claim 64. 66. The method as claimed in claim 64, wherein said compound is of the formula: wherein R1, R5, R18, and R21 are as defined in claim 64.
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이 특허에 인용된 특허 (13)
Rinehart Kenneth (Urbana IL) Ryuichi Sakai (Urbana IL) Holt Tom G. (Westfield NJ), Compositions comprising ecteinascidins and a method of treating herpes simplex virus infections therewith.
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