Patent ID: 6620843
Filing Date: 2003-09-16
Classification: A61K,A61P,Y10S

Abstract:
A method for inhibiting the growth of a solid tumor, comprising administering to a subject in need of such treatment, in a pharmaceutically acceptable vehicle, an effective amount of a triptolide prodrug, or a pharmaceutically acceptable salt thereof, having a structure selected from: whereX1 is OH or OR1, and X2 and X3 are independently OH, OR1 or H, with the proviso that at least one of X1, X2 and X3 is OR1, and at least one of X2 and X3 is H; and R1 is â€”C(O)â€”Yâ€”Z, wherein Y is a branched or unbranched C1-C6 alkyl or alkenyl chain; and Z is COOR2, NR3R3â€², or +NR4R4â€²R4â€³, where R2 is H or a cation; R3 and R3â€² are independently H or branched or unbranched C1-C6 alkyl, hydroxyalkyl, or alkoxyalkyl, or R3 and R3â€² taken together form a 5- to 7-member heterocyclic ring whose ring atoms are selected from the group consisting of carbon, nitrogen, oxygen and sulfur, wherein said ring atoms include 2 to 6 carbon atoms, one or more nitrogen atoms, and optionally one or more oxygen or sulfur atoms, and said ring is unsubstituted or is substituted with one or more groups selected from R5, OR5, NR5R6, SR5, NO2, CN, C(O)R5, C(O)NR5R6, OC(O)R5, OC(O)NR5R6, and halogen, where R5 and R6 are independently hydrogen, lower alkyl or lower alkenyl; and R4, R4â€², and R4â€³ are independently branched or unbranched C1-C6 alkyl, hydroxyalkyl, or alkoxyalkyl; â€ƒwhere OR7 is selected from (i) a carboxylic ester, carbonate, or inorganic ester, having a central atom selected from carbon, sulfur, phosphorus, nitrogen, and boron, and having linked to said central atom at least one group of the form â€”Yâ€”Zâ€² or â€”Oâ€”Yâ€”Zâ€², where Y is a branched or unbranched C1-C6 alkyl or alkenyl chain, and Zâ€² is hydrogen or a polar group selected from keto, aldehyde, carboxylate, carboxylic ester, hydroxy, alkoxy, polyether, thiol, alkylthio, amino, cyano, nitro, sulfate, nitrate, phosphate, or a 5- to 7-membered heterocycle having ring atoms selected from carbon, nitrogen, oxygen, and sulfur, and three to six carbon ring atoms, and (ii) a mono-, di- or trisaccharide linked to C14 at an anomeric center; and OR9 is OH or Oâ€”(C&boxH;O)R, where R is lower alkyl; â€ƒwhere OR11 is selected from (i) â€”Oâ€”Yâ€”Z or â€”Oâ€”(C&boxH;O)â€”Yâ€”Z, where Y is a branched or unbranched C1-C6 alkyl or alkenyl chain, and Z is hydrogen or a polar group selected from keto, aldehyde, carboxylate, carboxylic ester, amino, alkylamino, hydroxy, alkoxy, polyether, thiol, alkylthio, cyano, nitro, inorganic ester, or a 5- to 7-member heterocyclic ring whose ring atoms are selected from the group consisting of carbon, nitrogen, oxygen and sulfur, where the ring atoms include 3 to 6 carbon atoms, and (ii) a mono-, di- or trisaccharide linked to C14 at an anomeric center; and OR9 is â€”Oâ€”(C&boxH;O)R, where R is lower alkyl; and whereR12 is a leaving group selected from the group consisting of alkyl sulfonate, fluoroalkyl sulfonate, aryl sulfonate, fluorosulfonate, nitrate, alkyl phosphate, alkyl borate, trialkylammonium, and dialkylsulfonium; and OR9 is OH or Oâ€”(C&boxH;O)â€”R, where R is lower alkyl.