IPC분류정보
국가/구분 |
United States(US) Patent
등록
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국제특허분류(IPC7판) |
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출원번호 |
US-0765515
(2001-01-19)
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발명자
/ 주소 |
- Danishefsky, Samuel J.
- Zhou, Bishan
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출원인 / 주소 |
- The Trustees of Columbia University in the City of New York
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대리인 / 주소 |
White, John P.Cooper & Dunham LLP
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인용정보 |
피인용 횟수 :
16 인용 특허 :
3 |
초록
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Compounds of the saframycin-ecteinascidin series with cytotoxic properties having the following general formula, their uses and synthesis, are disclosed: wherein R1and R4is H, a C1to C4alkyl group, or an acyl group; wherein R2is an ether, ester, amide, or a phthalimide group; wherein R3is =O, O
Compounds of the saframycin-ecteinascidin series with cytotoxic properties having the following general formula, their uses and synthesis, are disclosed: wherein R1and R4is H, a C1to C4alkyl group, or an acyl group; wherein R2is an ether, ester, amide, or a phthalimide group; wherein R3is =O, OH, an ether group, an acyl group such as OC(O)Me, OC(O)Bn and OC(O)Et, or a sulfide group; wherein R5is H, halogen, OH, an ether group, an acyl group, or an amide group; wherein R6is =O, OH, OCH3,CN, or an acyloxy group; wherein R7,is =O, OH, halogen, an ether group, or an acyl group; wherein R8and R9are independently H, CH3,OCH3,OC2H5,CF3,halogen such as Br and F, or R8and R9are joined together as a methylenedioxy group, or other five or six membered ring; wherein R10and R11are independently CH3,OCH3,OC2H5,SCH3,or SC2H5; wherein R12is H, a C1to C4alkyl group, or an acyl group; and wherein the chiral center marked * has the R or the S configuration.
대표청구항
▼
Compounds of the saframycin-ecteinascidin series with cytotoxic properties having the following general formula, their uses and synthesis, are disclosed: wherein R1and R4is H, a C1to C4alkyl group, or an acyl group; wherein R2is an ether, ester, amide, or a phthalimide group; wherein R3is =O, O
Compounds of the saframycin-ecteinascidin series with cytotoxic properties having the following general formula, their uses and synthesis, are disclosed: wherein R1and R4is H, a C1to C4alkyl group, or an acyl group; wherein R2is an ether, ester, amide, or a phthalimide group; wherein R3is =O, OH, an ether group, an acyl group such as OC(O)Me, OC(O)Bn and OC(O)Et, or a sulfide group; wherein R5is H, halogen, OH, an ether group, an acyl group, or an amide group; wherein R6is =O, OH, OCH3,CN, or an acyloxy group; wherein R7,is =O, OH, halogen, an ether group, or an acyl group; wherein R8and R9are independently H, CH3,OCH3,OC2H5,CF3,halogen such as Br and F, or R8and R9are joined together as a methylenedioxy group, or other five or six membered ring; wherein R10and R11are independently CH3,OCH3,OC2H5,SCH3,or SC2H5; wherein R12is H, a C1to C4alkyl group, or an acyl group; and wherein the chiral center marked * has the R or the S configuration. d a compound of Formula III; wherein R1and R2are as defined in Formula I and each R4is independently alkyl, aryl or isoalkyl; b) alkylating the product of step (a) to yield a compound of Formula IV; wherein R1,R2and R3are as defined in Formula I and R4is as defined in Formula III; and c) deprotecting the product of step (b) to yield a compound of Formula I. 2. A method for synthesizing a compound having Formula V: wherein R1and R2are independently hydrogen, NR10R11,(NR10R11)alkyl, alkyl, fluoro or chloro, wherein R10and R11are independently hydrogen, alkyl, alkanoyl, acyl, alkoxy, or arylalkyl optionally substituted with up to three groups that are independently halogen, alkoxy, nitro, or alkyl; R3is independently alkyl, alkoxyalkyl, alkyl-thio-alkyl, cyanoalkyl, or arylalkyl optionally substituted with up to three groups that are independently halogen, alkoxy, nitro, or alkyl; R5is an acid labile protecting moiety; and R6is a phosphorous containing moiety; comprising: a) introducing a 5',3'-bridging silyl protecting group to a compound of Formula II to yield a compound of Formula III; b) alkylating the product of step (a) to yield a compound of Formula IV; c) introducing at least one exocyclic amine protecting moiety to the product of step (b) provided that at least one of R1or R2in step (b) is amino; d) deprotecting the product of step (c) to yield a compound of Formula I; and e) introducing an acid labile protecting moiety followed by a phosphorous containing moiety to the product of step (d) to yield a compound of Formula V. 3. The method of claim 1 or 2, wherein R4is tert-butyl. 4. The method of claim 1 or 2, wherein R1is amino and R2is H. 5. The method of claim 1 or 2, wherein R1and R2are amino. 6. The method of claim 1 or 2, wherein R1is chloro and R2is H. 7. The method of claim 1, wherein the compound of Formula I is 2'-O-methyl adenosine. 8. The method of claim 2, wherein the compound of Formula V is 5'-O-dimethoxytrityl-2'-O-methyl-N2-benzoyl adenosine 3'-O-(2-cyanoethyl-N,N-diisopropylphosphoramidite). 9. The method of claim 1 or 2, wherein said alkylation in step (b) is conducted in the presence of an alkyl halide and a base. 10. A method for synthesizing a compound having Formula VI: wherein R3is independently alkyl, alkoxyalkyl, alkyl-thio-alkyl, cyanoalkyl, or arylalkyl optionally substituted with up to three groups that are independently halogen, alkoxy, nitro, or alkyl; and R7is H, acyl, or arylalkanoyl, comprising: a) introducing a 5',3'-bridging silyl protecting group to inosine to yield a compound of Formula VII; wherein each R4is independently alkyl, aryl or isoalkyl; b) introducing an imidazole moiety to the product of step (a) to yield a compound of Formula VIII; wherein each R4is independently alkyl, aryl or isoalkyl; c) alkylating the product of step (b) to yield a compound of Formula IX; wherein each R4is independently alkyl, aryl or isoalkyl and R3is as defined in Formula VI; d) aminating the product of step (c) to yield a compound of Formula X; wherein R3and R7are as defined in Formula VI; and e) desilylating the product of step (d) to yield a compound of Formula VI. 11. A method for synthesizing a compound having Formula VI, comprising: a) introducing a 5',3'-bridging silyl protecting group to inosine to yield a compound of Formula XI; wherein each R4is independently alkyl aryl or isoalkyl; b) introducing an imidazole moiety to the product of step (a) to yield a compound of Formula XII; wherein each R4is independently alkyl, aryl or isoalky l; c) alkylating the product of step (b) to yield a compound of Formula XIII; wherein R3is as defined in Formula VI and each R4is independently alkyl, aryl or isoalkyl; d) aminating the product of step (c) to yield a compound of Formula XIV; wherein R3and R7are as defined in Formula VI; and e) desilylating the product of step (d) to yield a compound of Formula VI. 12. The method of any of claim 10 or 11, further comprising the step of: a) introducing an acid labile protecting moiety followed by a phosphorous containing moiety to the product of step (e) to yield a compound of Formula XV; wherein R7and R3are as defined in Formula VI, R5is an acid labile protecting moiety and R6is a phosphorous containing moiety. 13. The method of claim 10, wherein R4is isopropyl. 14. The method of claim 11, wherein R4is tert-butyl. 15. The method of any of claim 10 or 11, wherein R3is methyl. 16. The method of claim 12, wherein R3is methyl. 17. The method of claim 10 or 11, wherein the compound of Formula VI is 2'-O-methyl adenosine. 18. The method of claim 10 or 11, wherein the alkylation in step (c) is in the presence of methyl iodide and sodium hydride. 19. The method of claim 12, wherein the acyl moiety is a benzoyl moiety. 20. The method of claim 12, wherein the compound of Formula XV is 5'-O-dimethoxytrityl-2'-O-methyl-N2-benzoyl adenosine 3'-O-(2-cyanoethyl-N,N-diisopropylphosphoramidite). 21. A method for synthesizing a compound having Formula XVI: wherein R8is a succinate moiety, aklylsilyl moiety, or H; and R9is an acid labile protecting moiety or H, comprising: a) depyrimidination of a compound of formula XVII; wherein R8is an silylalkyl moiety to yield a compound of Formula XVI, wherein R8is an silylalkyl moiety; and R9is H; b) introducing an acid labile protecting moiety to the product of step (a) to yield a compound of Formula XVI, wherein R8is an silylalkyl moiety and R9is an acid labile protecting moiety; c) deprotecting the product of step (b) to yield a compound for Formula XVI, wherein R8is H and R9is an acid labile protecting moiety; and d) introducing a succinate moiety to the product of step (c) to yield a compound of Formula XVI, wherein R8is a succinate moiety and R9is an acid labile protecting moiety. 22. A method for synthesizing a compound having Formula XVI: wherein R8is a phosphorous containing moiety, aklylsilyl moiety, or H; and R9is an acid labile protecting moiety or H, comprising: a) depyrimidination of a compound of formula XVII; wherein R8is an aklylsilyl moiety to yield a compound of Formula XVI, wherein R8is an silylalkyl moiety and R9is H; b) introducing an acid labile protecting moiety to the product of step (a) to yield a compound of Formula XVI, wherein R8is an silylalkyl moiety and R9is an acid labile protecting moiety; c) deprotecting the product of step (b) to yield a compound for Formula XVI, wherein R8is H and R9is an acid labile protecting moiety; and d) introducing a phosphorous containing moiety to the product of step (c) under conditions suitable to yield a compound of Formula XVI, wherein R8is a phosphorous containing moiety and R9is an acid labile protecting moiety. 23. The method of claim 21 or 22, wherein the silylalkyl moiety of Formula XVII is tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or triisopropylsilyl. 24. The method of claim 21 or 22, wherein step (b) comprises treatment of the product of step (a) with a silylating reagent and a catalyst followed by hydrogenation and selective desilylation to yield said compound of Formula XVI, wherein R8is an silyl
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