Method for preparing crambescidin core acid intermediates and their use for preparing crambescidin alkaloid analogs as therapeutic agents 机翻标题: 暂无翻译,请尝试点击翻译按钮。

公开号/公开日
WO2004028452 A2 2004-04-08 [WO200428452]WO2004028452 A3 2004-05-21 [WO200428452] / 2004-04-082004-05-21
申请号/申请日
2003WO-US29888 / 2003-09-23
发明人
OVERMAN LARRY E;STAPPENBECK FRANK;MCDONALD ANDREW I;ARON ZACHARY D;
申请人
UNIVERSITY OF CALIFORNIA;
主分类号
IPC分类号
A01N-043/54A61KC07D-239/00C07D-491/22
摘要
(WO200428452) The invention provides methods to synthesize zwitterionic pentacyclic crambescidin core intermediates having the carboxylate side chain in the natural axial orientation, and a range of crambescidin alkaloid analogs.
机翻摘要
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地址
代理人
代理机构
;
优先权号
2002US-10255994 2002-09-24
主权利要求
(WO200428452) What is claimed is: 1. A pentacyclic compound of formula I : Wherein RI is a hydrocarbyl group with from 1 to 20 atoms or is absent; wherein R2 is absent or is selected from the group consisting of H, alkyl, aryl, heteroaryl, carboxy, carboxylate anion, phosphonate, phosphate, sulphonate, sulphate, borate, boronate and amine. 2. The pentacyclic compound of claim 1, wherein the hydrocarbyl group of RI is selected from the group consisting of saturated, unsaturated, cyclic, acyclic, straight, branched chiral and achiral hydrocarbyl groups. 3. The pentacyclic compound of claim 1, wherein one or more carbon in RI is replaced with one or more elements selected from O, S, or NR3, wherein R3 is alkyl, cycloalkyl or acyl. 4. The pentacyclic compound of claim 1, wherein one or more carbons in RI is substituted with alkyl, aryl, aralkyl, heteroalkyl or a heteroaralkyl group. 5. The pentacyclic compound of claim 4, which further comprises one or more groups selected from the group consisting of halo, nitro, cyano, trifluoromethyl, hydroxy, thio, methylthio, amino, substituted amino, acylamino, aminoalkylamino, guanidino, carboxyl and carboalkoxy. 6. The pentacyclic compound of claim 1, wherein any one carbon in RI is substituted with an aryl or heteroaryl group having from 6 to 14 carbon atoms. 7. The pentacyclic compound of claim 6, wherein the aryl or heteroaryl group is selected from the group consisting of phenyl, naphthyl, biphenylyl, furyl, thienyl, pyrrolyl, imidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, thianaphthyl and indolyl. 8. The pentacyclic compound of claim 1, wherein the alkyl, aryl, heteroaryl group is substituted with one or more groups selected from the group consisting of halo, nitro, cyano, trifluoromethyl, hydroxy, thio, methylthio, amino, substituted amino, acylamino and guanidino. 9. The pentacyclic compound of claim 1, wherein R2 is an amine or amide. 10. The pentacyclic compound of claim 9, wherein the amine is NR4R5or "■caroxamide-C0-NR4R5)where R4and R5are selected from the group consisting of H, alkyl, aralkyl, carboxyalkyl, amino-iminomethyl, hydroxyalkyl, acyl, aminoalkyl. 11. The pentacyclic compound of claim 10, wherein the amino-iminomethyl group is -C=N-R6(-NR7). 12. The pentacyclic compound of claim 11 , wherein R6 and R7 is H or alkyl. 13. The pentacyclic compound of claim 12, wherein R6 and R7 form a cyclic structure. 14. The pentacyclic compound of claim 10, wherein the carboxyalkyl is substituted at the alkyl carbon by hydroxyalkyl, alkyl, thioalkyl, aminoalkyl, carboxyalkyl, amidoalkyl, guanidinoalkyl, aminoalkylaminoalkyl, hydroxyalkylaminoalkyl and acyl derivatives thereof. 15. The pentacyclic compound of claim 14, wherein the aminoalkyl is substituted with one or more hydroxy groups. 16. The pentacyclic compound of claim 10, wherein j and R5combine to form a cyclic ring. 17. The pentacyclic compound of claim 16, wherein the cyclic ring is substituted with a heteroatom. 18. The pentacyclic compound of claim 16, wherein the heteroatom is O(morpholino). 19. The pentacyclic compound of claim 17, wherein the heteroatom is NR8where R8is selected from the group consisting of H(piperazino), alklyl (alkyl piperazino), carboxyalkyl, hydroxyalkyl and aminoalkyl. 20. The pentacyclic compound of claim 10, wherein the amino-iminomethyl has the formula -C=N-R6(-NR7), and Re and R7are selected from H and alkyl, or are bridged with 2 to 4 carbons to form a cyclic structure, provided that when R2is carboxylate anion or carboxamine, where -NR^s is hydroxyspermidine, then Ri is not a saturated carbon chain with 16 carbons. 21. The compound of claim 1 , wherein Ri is -CH2-CH=CH-, R2is phenyl. 22. The compound of claim 1, wherein RI is H and R2 is absent. 23. The compound of claim 1, wherein RI is alkyl, R2 is absent. 24. The compound of claim 23, wherein the alkyl group is decyl. 25. The compound of claim 1 , wherein RI is -(CH2-CH2-O-)n, R2 is alkyl. 26. The compound of claim 25, wherein n is 1 -6, and R2 is ethyl. 27. The compound of claim 25, wherein RI is -(CH2-CH2-O-)n, and R2 further comprises NR4R5. 28. The compound of claim 27, wherein n is 1-6 and R4 and R5 are H. 29. The compound of claim 27, wherein n is 1-6, and R4 and R5 are amino- iminomethyl of formula -C=N-R6(-NR7). 30. The compound of claim 29, wherein R6 and R7 are H or alkyl. 31. The compound of claim 30, wherein R6 and R7 form a cyclic structure. 32. The compound of claim 1, wherein RI is a carboxyalkyl [CH2-(CH2)n] group, n = 1-20; and R2 is an alkyl group. 33. The compound of claim 1, wherein where RI is a carboxyalkyl [CH2-(CH2)n] group, n = 1-20; and R2 is an allyl group. 34. A pentacyclic zwitterionic compound having the carboxylate side chain at C 14 in natural axial orientation of the formula:  35. A pentacyclic compound of the formula:  wherein, n = 1-20 36. A pentacyclic compound of the formula:  wherein, n = 1-20, and X = any pharmaceutically acceptable counterion. 37. A pentacyclic compound of the formula: wherein, n = 1-20 38. A pentacyclic compound of the formula: wherein, X = any pharmaceutically acceptable counterion. 39. A method for synthesizing the pentacyclic compound of claim 1 which comprises reacting a compound of formula:  wherein, TBDMS is an alcohol protecting group with a c : wherein TIPS is an alcohol protecting group to produce a compound of the formula: OTIPS wherein TBPS and TIPS are alcohol protecting groups which is converted by deprotection, incorporation of ammonia, and cyclization to pentacyclic compound having the ester side chain in natural axial orientation of the formula: wherein X = any pharmaceutically acceptable counterion. 40. A method for synthesizing the pentacyclic compound of claim 21, wherein RI is propenyl and R2 is phenyl which comprises reacting a compound of formula: O O OTBDMS wherein, TBDMS is an alcohol protecting group with a : wherein TIPS is an alcohol protecting group to produce a compound of the formula:  15 wherein TBPS and TIPS are alcohol protecting groups which is converted by deprotection, incorporation of ammonia, and cyclization to pentacyclic compound of claim 18 having the ester side chain in natural axial orientation of the formula:  wherein, X = any pharmaceutically acceptable counterion. 41. A method of synthesizing a pentacyclic zwitterionic compound of the formula:  which comprises Palladium mediated deprotection of ester side chain of compound of claim 39 or 40. 42. A method of synthesizing crambescidin 431 of the formula: Wherein X = any pharmaceutically acceptable carrier, and which comprises esterification of pentacyclic zwitterionic compound of claim 34 with ethanol. 43. A method for synthesizing an allyl ester side chain analog of the formula: Wherein, n = 1-20, and X = any pharmaceutically acceptable counterion. which comprises reacting the pentacyclic zwitterionic compound of claim 34 with an ω-iodoester of formula: o i — tf^cT^ wherein n = 1-20 44. A method ofsynthesizing a pentacyclic compound of the formula:  wherein n = 1-20 which comprises palladium mediated deprotection of ester side chain of compound prepared by the method of claim 43. 45. A method of synthesizing a pentacyclic compound of the formula: wherein, n = 1-20, and X = any pharmaceutically acceptable counterion. which comprises reacting the reacting the pentacyclic compound of claim 34 with the compound of formula: NHBOC NHBOC wherein BOC = an amine protecting group to produce a compound of the formula:  which is subsequently deprotected to produce a crambescidin 800 analog. 46. A method to synthesize the pentacyclic compound of claim 12 or 13, wherein the R1-R2 comprises a guanidino alkyloxy group of structure -(CH^n-lSffl C-NH , comprising: (a) treating the pentacyclic zwitterionic core acid of claim 34 with an amino alcohol of structure HO(CH2)n-NH2 to provide an amino alkyl ester; which is (b) treated with alkyl-S-C-NH2(=NH) to produce the pentacyclic compound of claim 12 or 13, wherein R1-R2 comprises a guanidino alkyloxy group of structure -(CH2)n-NH=C-NH2. 47. An antitumor composition comprising a compound of any one of claim 1 or 34-38 in admixture with a pharmaceutically acceptable carrier. 48. An antiviral composition comprising a compound of any one of claim 1 or 34-38 in admixture with a pharmaceutically acceptable carrier. 49. An antifungal composition comprising a compound of any one of claim 1 or 34- 38 in admixture with a pharmaceutically acceptable carrier. 50. A Ca2+ channel blocker composition comprising a compound of any one of claim 1 or 34-38 in admixture with a pharmaceutically acceptable carrier. 51. A method for treating tumors comprising administering to a subject in need of said treatment, an amount of compound of any one of claim 1 or 34-38 effective to reduce the tumor load in the subject. 52. A method for treating viral infections comprising administering to a subject in need of said treatment, an amount of compound of any one of claim 1 or 34-38 effective to reduce the viral load in the subject. 53. A method for treating fungal infections comprising administering to a subject in need of said treatment, an amount of compound of any one of claim 1 or 34-38 effective to reduce the fungus load in the subject.
法律状态
(WO200428452) LEGAL DETAILS FOR WO2004028452  Actual or expected expiration date=2006-03-24    Legal state=DEAD    Status=LAPSED     Event publication date=2003-09-23  Event code=WO/APP  Event indicator=Pos  Event type=Examination events  Application details  Application country=WO WOUS0329888  Application date=2003-09-23  Standardized application number=2003WO-US29888     Event publication date=2004-04-08  Event code=WO/A2  Event type=Examination events  International application published without international search report  Publication country=WO  Publication number=WO2004028452  Publication stage Code=A2  Publication date=2004-04-08  Standardized publication number=WO200428452     Event publication date=2004-04-08  Event code=WO/AK  Event indicator=Pos  Event type=Designated states  Designated states AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW    Event publication date=2004-04-08  Event code=WO/AL  Event indicator=Pos  Event type=Designated states  Designated countries for regional patents GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG    Event publication date=2004-05-21  Event code=WO/A3  Event indicator=Pos  Event type=Examination events  Later publication of ISR with revised front page  Publication country=WO  Publication number=WO2004028452  Publication stage Code=A3  Publication date=2004-05-21  Standardized publication number=WO200428452     Event publication date=2004-06-24  Event code=WO/DFPE  Event type=Examination events  Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)    Event publication date=2006-03-24  Event code=WO/EETL  Event type=Event indicating Not In Force  PCT Application validity period expired. LEGAL DETAILS FOR DESIGNATED STATE AU2003282807  Actual or expected expiration date=2005-07-21    Legal state=DEAD    Status=LAPSED   Corresponding cc:  Designated or member state=AU Corresponding appl: AU2003282807  Application date in the designated or member state=2003-09-23   Application number in the designated or member state=2003AU-0282807 Corresponding cc:  Designated or member state=AU Corresponding pat: AU2003282807  Publication stage code in the designated or member state=A1  Publication date in the designated or member state=2004-04-19   Publication number in the designated or member state=AU2003282807    Event publication date=2005-07-21  Event code=AU/STCHG  Patent Status changed by the national office Corresponding cc:  Designated or member state=AU  LEGAL DETAILS FOR DESIGNATED STATE JP  Actual or expected expiration date=2006-08-21    Legal state=DEAD    Status=LAPSED   Corresponding cc:  Designated or member state=JP     Event publication date=2006-08-21  Event code=WO/WWW  Event indicator=Neg  Event type=Event indicating Not In Force  Wipo information: withdrawn in national office Corresponding cc:  Designated or member state=JP     Event publication date=2006-08-21  Event code=WO/NENP  Event type=Event indicating Not In Force  Non-entry into the national phase in: Corresponding cc:  Designated or member state=JP
专利类型码
A2A3
国别省市代码
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