Tocopherols, tocotrienols, other chroman and side chain derivatives and uses thereof
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-031/47
A61K-031/355
A61K-031/352
C07D-311/66
C07D-311/00
C07D-311/70
C07D-311/72
출원번호
US-0644418
(2003-08-20)
등록번호
US-7312232
(2007-12-25)
발명자
/ 주소
Sanders,Bob G.
Kline,Kimberly
Hurley,Laurence
Gardner,Robb
Menchaca,Marla
Yu,Weiping
Ramanan,Puthucode N.
Liu,Shenquan
Israel,Karen
출원인 / 주소
Research Development Foundation
대리인 / 주소
Fulbright & Jaworski L.L.P.
인용정보
피인용 횟수 :
5인용 특허 :
31
초록▼
The present invention provides an antiproliferative compound having the structural formula wherein X is oxygen, nitrogen or sulfur; Y is selected from the group consisting of oxygen, nitrogen and sulfur wherein when Y is oxygen or nitrogen, n is 1 and when Y is sulfur, n is 0. Also provided is a
The present invention provides an antiproliferative compound having the structural formula wherein X is oxygen, nitrogen or sulfur; Y is selected from the group consisting of oxygen, nitrogen and sulfur wherein when Y is oxygen or nitrogen, n is 1 and when Y is sulfur, n is 0. Also provided is a method for inducing apoptosis in a cell comprising administering a composition comprising a compound having said structural formula.
대표청구항▼
What is claimed is: 1. A method for the treatment of a cell proliferative disease comprising administering to an animal a pharmacologically effective dose of a compound having a structural formula: wherein X is oxygen, nitrogen or sulfur; Y is oxygen, NH or NCH3; R1 is--(CH2)1-5CO2H,--(CH2)7CO2H,
What is claimed is: 1. A method for the treatment of a cell proliferative disease comprising administering to an animal a pharmacologically effective dose of a compound having a structural formula: wherein X is oxygen, nitrogen or sulfur; Y is oxygen, NH or NCH3; R1 is--(CH2)1-5CO2H,--(CH2)7CO2H,--CH2CONH2,--CH2CO2CH3,--CH2CON(CH2CO2H)2,--(CH2)2OH,--(CH2)3NH3Cl, or--(CH2)2OSO3NHEt3; R2 and R3 are independently--H or--CH3; R4 methyl; R5 is--C17H35 (unbranched),--C13H27 (unbranched),--C7H15 (unbranched),--CH3,--CO2H, with the proviso that R1 can not be--(CH2)3CO2H nor--(CH2)2OH when R2, R3, R4 are each--CH3, X and Y are each oxygen and R5 is a pharmaceutical composition thereof. 2. The method of claim 1, wherein said compound is selected from the group consisting of 2,5,7,8-tetramethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy)acetic acid, 2,5,7,8-tetramethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy) propionic acid, 2,5,7,8-tetramethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy) valeric acid, 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy) hexanoic acid, 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy) octanoic acid, 2,5,8-trimethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy)acetic acid, 2,7,8-trimethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy)acetic acid, 2,8-dimethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy)acetic acid, 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy) acetamide, methyl 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy) acetate, 2-(N,N-(carboxymethyl)-2(2,5,7,8-tetramethyl-(2R-(4R,8R, 12-trimethyltridecyl)chroman-6-yloxy)acetic acid, 2,5,7,8-tetramethyl-(2RS-(4RS,8RS,12-trimethyltridecyl)chroman-6-yloxy) acetic acid, 2,5,7,8-tetramethyl-(2R-(carboxy)chroman-6-yloxy))acetic acid, 2,5,7,8-tetramethyl-2R-(2RS,6RS,10-trimethylundecyl)chroman-6-yloxy)acetic acid, 2,5,7,8,-tetramethyl-2R-(2,6,10-trimethyl-1,3,5,9 E:Z decatetraen)chroman-6-yloxy)acetic acid, 3-(2,5,7,8-tetramethyl-(2R-(4R,8,12-trimethyltridecyl)chroman-6-yloxy) propyl-1-ammonium chloride, 2-(2,5,7,8-tetramethyl-(2R-(4R,8,12-trimethyltridecyl)chroman-6-yloxy) triethylammonium sulfate, 2,5,7,8-tetramethyl-(2R-(heptyl)chroman-6-yloxy)acetic acid, 2,5,7,8,-tetramethyl-(2R-(tridecyl)chroman-6-yloxy)acetic acid, 2,5,7,8,-tetramethyl-(2R-(heptadecyl)chroman-6-yloxy)acetic acid, 2,5,7,8,-tetramethyl-2R-(4,8,-dimethyl-1,3,7 E:Z nonotrien)chroman-6-yloxy)acetic acid, (R)-2[(2,5,7,8-tetramethyl-2-(3 propene methyl ester)chroman-6-yloxy]acetic acid, 2,5,7,8-tetramethyl-(2R-(methylpropionate)chroman-6-yloxy)acetic acid, 1-aza-αtocopherol-6-yloxyl-acetic acid, 1-aza-α-tocopherol-6-yloxyl-methyl acetate, 1-aza-N-methyl-α-tocopherol-6-yloxyl-methyl acetate, and 1-aza-N-methyl-α-tocopherol-6-yloxyl-acetic acid. 3. The method of claim 1, wherein said compound exhibits an anti-proliferative effect comprising apoptosis, DNA synthesis arrest, cell cycle arrest, or cellular differentiation. 4. The method of claim 1, wherein said animal is a human. 5. The method of claim 1, wherein said composition is administered in a dose of from about 1 mg/kg to about 60 mg/kg. 6. The method of claim 1, wherein administration of said composition is selected from the group consisting of oral, topical, intraocular, intranasal, parenteral, intravenous, intramuscular, or subcutaneous. 7. The method of claim 1, wherein said cell proliferative disease is a neoplastic disease, a non-neoplastic disease or a non-neoplastic disorder. 8. The method of claim 7, wherein said neoplastic disease is selected from the group consisting of ovarian cancer, cervical cancer, endometrial cancer, bladder cancer, lung cancer, breast cancer, testicular cancer, prostate cancer, gliomas, fibrosarcomas, retinoblastomas, melanomas, soft tissue sarcomas, osteosarcomas, leukemias, colon cancer, carcinoma of the kidney, pancreatic cancer, basal cell carcinoma, and squamous cell carcinoma. 9. A method for the treatment of a cell proliferative disease comprising administering to an animal a pharmacologically effective dose of 6-(2,4-dinitrophenylazo)-2,5,7,8-tetramethyltridecyl))-1,2,3, 4-tetrahydroquinoline, 2,5,7,8-tetramethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-3-ene-6-yloxy) acetic acid or 6-(2,5,7,8-tetramethyl-(2R-(4R,8,12-trimethyltridecyl)chroman)acetic acid. 10. The method of claim 9, wherein said compound exhibits an anti-proliferative effect comprising apoptosis, DNA synthesis arrest, cell cycle arrest, or cellular differentiation. 11. The method of claim 9, wherein said animal is a human. 12. The method of claim 9, wherein said composition is administered in a dose of from about 1 mg/kg to about 60 mg/kg. 13. The method of claim 9, wherein administration of said composition is selected from the group consisting of oral, topical, intraocular, intranasal, parenteral, intravenous, intramuscular, or subcutaneous. 14. The method of claim 9, wherein said cell proliferative disease is a neoplastic disease, a non-neoplastic disease or a non-neoplastic disorder. 15. The method of claim 14, wherein said neoplastic disease is selected from the group consisting of ovarian cancer, cervical cancer, endometrial cancer, bladder cancer, lung cancer, breast cancer, testicular cancer, prostate cancer, gliomas, fibrosarcomas, retinoblastomas, melanomas, soft tissue sarcomas, osteosarcomas, leukemias, colon cancer, carcinoma of the kidney, pancreatic cancer, basal cell carcinoma, and squamous cell carcinoma. 16. A method of inducing apoptosis of a cell, comprising the step of contacting said cell with a pharmacologically effective dose of a compound having a structural formula wherein X is oxygen, nitrogen or sulfur; Y is oxygen, NH or NCH3; R1 is--(CH2)1-5CO2H,--(CH2)7CO2H,--CH2CONH2,--CH2CO2CH3,--CH2CON(CH2CO2H)2,--(CH2)2OH,--(CH2)3NH3Cl, or--(CH2)2OSO3NHEt3; R2 and R3 are independently--H or--CH3; R4 methyl; R5 is--C17H35 (unbranched),--C13H27 (unbranched),--C7H15 (unbranched),--CH3,--CO2H, with the proviso that R1 can not be--(CH2)3CO2H nor--(CH2)2OH when R2, R3, R4 are each--CH3, X and Y are each oxygen and R5 is a pharmaceutical composition thereof. 17. The method of claim 16, wherein said compound is selected from the group consisting of 2,5,7, 8-tetramethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy)acetic acid, 2,5,7,8-tetramethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy) propionic acid, 2,5,7,8-tetramethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy) valeric acid, 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy) hexanoic acid, 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy) octanoic acid, 2,5,8-trimethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy)acetic acid, 2,7,8-trimethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy)acetic acid, 2,8-dimethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy)acetic acid, 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy) acetamide, methyl 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy) acetate, 2-(N,N-(carboxymethyl)-2(2,5,7,8-tetramethyl-(2-(R4R,8R, 12-trimethyltridecyl)chroman-6-yloxy)acetic acid, 2,5,7,8-tetramethyl-(2RS-(4RS,8RS,12-trimethyltridecyl)chroman-6-yloxy) acetic acid, 2,5,7,8-tetramethyl-(2R-(carboxy)chroman-6-yloxy))acetic acid, 2,5,7,8-tetramethyl-2R-(2RS,6RS,10-trimethylundecyl)chroman-6-yloxy)acetic acid, 2,5,7,8,-tetramethyl-2R-(2,6,10-trimethyl-1,3,5,9 E:Z decatetraen)chroman-6-yloxy)acetic acid, 3-(2,5,7,8-tetramethyl-(2R-(4R,8,12-trimethyltridecyl)chroman-6-yloxy) propyl-1-ammonium chloride, 2-(2,5,7,8-tetramethyl-(2R-(4R,8,12-trimethyltridecyl)chroman-6-yloxy) triethylammonium sulfate, 2,5,7,8-tetramethyl-(2R-(heptyl)chroman-6-yloxy)acetic acid, 2,5,7,8,-tetramethyl-(2R-(tridecyl)chroman-6-yloxy)acetic acid, 2,5,7,8,-tetramethyl-(2R-(heptadecyl)chroman-6-yloxy)acetic acid, 2,5,7,8,-tetramethyl-2R-(4,8,-dimethyl-1,3,7 E:Z nonotrien)chroman-6-yloxy)acetic acid, (R)-2[(2,5,7,8-tetramethyl-2-(3 propene methyl ester)chroman-6-yloxy]acetic acid, 2,5,7,8-tetramethyl-(2R-(methyl propionate)chroman-6-yloxy)acetic acid, 1-aza-α-tocopherol-6-yloxyl-acetic acid, 1-aza-α-tocopherol-6-yloxyl-methyl acetate, 1-aza-N-methyl-α-tocopherol-6-yloxyl-methyl acetate, and 1-aza-N-methyl-α-tocopherol-6-yloxyl-acetic acid. 18. The method of claim 16, wherein said method is useful in the treatment of a cell proliferative disease. 19. A method of inducing apoptosis of a cell, comprising the step of contacting said cell with a pharmacologically effective dose of 6-(2,4-dinitrophenylazo)-2,5,7,8-tetramethyltridecyl))-1,2,3, 4-tetrahydroquinoline, 2,5,7,8-tetramethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-3-ene-6-yloxy) acetic acid or 6-(2,5,7,8-tetramethyl-(2R-(4R,8,12-trimethyltridecyl)chroman)acetic acid. 20. The method of claim 19, wherein said method is useful in the treatment of a cell proliferative disease. 21. The method of claim 1, wherein the compound has a structural formula wherein X is oxygen; Y is oxygen, NH or NCH3; R1 is--(CH2)1-3CO2H,--CH2CON(CH2CO2H)2,--(CH2)3NH3Cl, or--(CH2)2OSO3NHEt3; R2 and R3 are independently--H or--CH3; R4 methyl; R5 is C17H35 (unbranched), with the proviso that R1 can not be--(CH2)3CO2H when R2, R3, R4 are each--CH3, Y is oxygen and R5 is a pharmaceutical composition thereof. 22. The method of claim 21, wherein Y is oxygen in the structural formula for the compound. 23. The method of claim 21, wherein Y is NH in the structural formula for the compound. 24. The method of claim 23, wherein the compound is 1-aza-α-tocopherol-6-yloxyl-acetic acid. 25. The method of claim 21, wherein Y is NCH3 in the structural formula for the compound. 26. The method of claim 25, wherein the compound is 1-aza-N-methyl-α-tocopherol-6-yloxyl-acetic acid. 27. The method of claim 21, wherein R5 in the structural formula for the compound is: 28. The method of claim 27, wherein the compound is 2,5,7,8,-tetramethyl-2R-(4,8,-dimethyl-1,3,7 E:Z nonotrien)chroman-6-yloxy)acetic acid. 29. The method of claim 21, wherein R5 in the structural formula for the compound is--C17H35 (unbranched). 30. The method of claim 29, wherein the compound is 2,5,7,8,-tetramethyl-(2R-(heptadecyl)chroman-6-yloxy)acetic acid. 31. The method of claim 21, wherein R5 in the structural formula for the compound is: 32. The method of claim 31, wherein the compound is 2,5,7,8-tetramethyl-2R-(2RS,6RS,10-trimethylundecyl)chroman-6-yloxy)acetic acid. 33. The method of claim 21, wherein R4 is--CH3 in the structural formula for the compound. 34. The method of claim 21, wherein R3 is--H in the structural formula for the compound. 35. The method of claim 34, wherein the compound is 2,5,8-trimethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy)acetic acid. 36. The method of claim 34, wherein the compound is 2,8-dimethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy)acetic acid. 37. The method of claim 21, wherein R2 is--H in the structural formula for the compound. 38. The method of claim 37, wherein the compound is 2,7,8-trimethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy)acetic acid. 39. The method of claim 21, wherein, R1 is--CH2CO2H in the structural formula for the compound. 40. The method of claim 39, wherein the compound is 2,5,7,8-tetramethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy)acetic acid. 41. The method of claim 39, wherein the compound is 2,5,7,8-tetramethyl-(2RS-(4RS,8RS,12-trimethyltridecyl)chroman-6-yloxy) acetic acid. 42. The method of claim 21, wherein, R1 is--CH2CON(CH2CO2H)2 in the structural formula for the compound. 43. The method of claim 42, wherein the compound is 2-(N,N-(carboxymethyl)-2(2,5,7,8-tetramethyl-(2R-(4R,8R, 12-trimethyltridecyl)chroman-6-yloxy)acetic acid. 44. The method of claim 21, wherein, R1 is--(CH2)3NH3Cl in the structural formula for the compound. 45. The method of claim 44, wherein the compound is 3-(2,5,7,8-tetramethyl-(2R-(4R,8,12-trimethyltridecyl)chroman-6-yloxy) propyl-1-ammonium chloride. 46. The method of claim 21, wherein R1 is--(CH2)2OSO3NHEt3 in the structural formula for the compound. 47. The method of claim 46, wherein the compound is 2-(2,5,7,8-tetramethyl-(2R-(4R,8,12-trimethyltridecyl)chroman-6-yloxy) triethylammonium sulfate. 48. The method of claim 16, wherein the compound has a structural formula wherein X is oxygen; Y is oxygen, NH or NCH3; R1 is--(CH2)1-3CO2H,--CH2CON(CH2CO2H)2,--(CH2)3NH3Cl, or--(CH2)2OSO3NHEt3; R2 and R3 are independently--H or--CH3; R4 methyl; R5 is--C17H35 (unbranched), with the proviso that R1 can not be--(CH2)3CO2H when R2, R3, R4 are each--CH3, Y is oxygen and R5 is a pharmaceutical composition thereof. 49. The method of claim 48, wherein Y is oxygen in the structural formula for the compound. 50. The method of claim 48, wherein Y is NH in the structural formula for the compound. 51. The method of claim 50, wherein the compound is 1-aza-α-tocopherol-6-yloxyl-acetic acid. 52. The method of claim 48, wherein Y is NCH3 in the structural formula for the compound. 53. The method of claim 52, wherein the compound is 1-aza-N-methyl-α-tocopherol-6-yloxyl-acetic acid. 54. The method of claim 48, wherein R5 in the structural formula for the compound is: 55. The method of claim 54, wherein the compound is 2,5,7,8,-tetramethyl-2R-(4,8,-dimethyl-1,3,7 E:Z nonotrien)chroman-6-yloxy)acetic acid. 56. The method of claim 48, wherein R5 in the structural formula for the compound is--C17H35 (unbranched). 57. The method of claim 56, wherein the compound is 2,5,7,8,-tetramethyl-(2R-(heptadecyl)chroman-6-yloxy)acetic acid. 58. The method of claim 48, wherein R5 in the structural formula for the compound is: 59. The method of claim 58, wherein the compound is 2,5,7,8-tetramethyl-2R-(2RS,6RS,10-trimethylundecyl)chroman-6-yloxy)acetic acid. 60. The method of claim 48, wherein R4 is--CH3 in the structural formula for the compound. 61. The method of claim 48, wherein R3 is--H in the structural formula for the compound. 62. The method of claim 61, wherein the compound is 2,5,8-trimethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy)acetic acid. 63. The method of claim 61, wherein the compound is 2,8-dimethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy)acetic acid. 64. The method of claim 48, wherein R2 is--H in the structural formula for the compound. 65. The method of claim 64, wherein the compound is 2,7,8-trimethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy)acetic acid. 66. The method of claim 48, wherein, R1 is--CH2CO2H in the structural formula for the compound. 67. The method of claim 66, wherein the compound is 2,5,7,8-tetramethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy)acetic acid. 68. The method of claim 66, wherein the compound is 2,5,7,8-tetramethyl-(2RS-(4RS,8RS,12-trimethyltridecyl)chroman-6-yloxy) acetic acid. 69. The method of claim 48, wherein, R1 is--CH2CON(CH2CO2H)2 in the structural formula for the compound. 70. The method of claim 69, wherein the compound is 2-(N,N-(carboxymethyl)-2(2,5,7,8-tetramethyl-(2R-(4R,8R, 12-trimethyltridecyl)chroman-6-yloxy)acetic acid. 71. The method of claim 48, wherein, R1 is--(CH2)3NH3Cl in the structural formula for the compound. 72. The method of claim 71, wherein the compound is 3-(2,5,7,8-tetramethyl-(2R-(4R,8,12-trimethyltridecyl)chroman-6-yloxy) propyl-1-ammonium chloride. 73. The method of claim 48, wherein R1 is--(CH2)2OSO3NHEt3 in the structural formula for the compound. 74. The method of claim 73, wherein the compound is 2-(2,5,7,8-tetramethyl-(2R-(4R,8,12-trimethyltridecyl)chroman-6-yloxy) triethylammonium sulfate.
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