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US 8,299,067 B2Granted
5-demethoxyfumagillol and derivatives thereof
AssigneesVersitech Limited, Morningside Ventures Limited
InventorsDan Yang, Chengyong Li, Shiwu Chen
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Abstract
Provided herein are 5-demethoxyfumagillol and its derivatives. Also provided herein are methods of making the 5-demethoxyfumagillol and derivatives. Also provided herein are biological activities of the 5-demethoxyfumagillol and derivatives and methods of using same for treating diseases.
Claims12
A 5-demethoxyfumagillol derivative of Formula (XI) :
- or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R13 is hydrogen, or unsubstituted or substituted aryl, alkyl, cycloalkyl, alkenyl, alkynyl, arylalkyl, alkylaryl, heterocycloalkyl, heteroaryl, or —(CH2)k—N3;
- Z is a bond, methylene, O, or NR13;
- Y is —CH2—R4, —CH2—OR5, —C(═O)—R6 or —C(═O)—OR7;
- where each of R4, R5, R6 and R7 is independently H, alkyl, aryl, arylalkyl, alkylaryl, trialkylsilyl, methoxymethyl, dialkylamino, diarylamino or alkylarylamino;
- each of n and m is independently an integer from 0 to 5, wherein when Z is a bond, the sum of n and m is 5, when Z is methylene, O, or NR13, the sum of n and m is 4;
- and k is an integer from 1 to 10.
3 more elements
A process of making a 5-demethoxyfumagillol derivative having formula (XI) :
- or a stereoisomer thereof, wherein the process comprises the steps of:
- (a) reacting a keto epoxide comprising Formula (VIII):
- or a stereoisomer thereof,
- with a first base that is a tri-sec-butylborohydride salt to form 5-demethoxyfumagillol of Formula (XII):
- or a stereoisomer thereof;
- (b) contacting the 5-demethoxyfumagillol of Formula (XII) or a stereoisomer thereof with a phenylchloroformate in the presence of a second base to form an active intermediate of Formula (XIII),
- or a stereoisomer thereof, and
- (c) reacting the active intermediate of Formula (XIII) with an amine of Formula (XV) :
- or stereoisomer thereof in the presence of a third base, wherein R1 is tosyl, mesyl, triflyl or nonflyl;
- R2 is hydrogen or OR3 where R3 is H, alkyl, acyl, aryl, arylalkyl or alkylaryl;
- X is NO2 or hydrogen;
- R13 is hydrogen, or unsubstituted or substituted aryl, alkyl, cycloalkyl, alkenyl, alkynyl, arylalkyl, alkylaryl, heterocycloalkyl, heteroaryl, or —(CH2)k—N3;
- Z is a bond, methylene, O, or NR13;
- Y is —CH2—R4, —CH2—OR5, —C(═O)—R6 or —C(═O)—OR7 where each of R4, R5, R6 and R7 is independently H, alkyl, aryl, arylalkyl, alkylaryl, trialkylsilyl, methoxymethyl, dialkylamino, diarylamino or alkylarylamino;
- and each of n and m is independently an integer from 0 to 5 and wherein when Z is a bond, the sum of n and m is 5, when Z is methylene, O, or NR13, the sum of n and m is 4;
- k is an integer from 1 to 10;
- and each of the second base and the third base is independently pyridine or triethylamine.
14 more elements
Dependencies are inferred from the claim text.