Triptolide prodrugs having high aqueous solubility

A compound having the structure Ic:

• where
• OR3 is OH or O—(C═O)R, where R is lower alkyl;
• and
• R2 is —(C═O)—Y—Z, where Y represents a branched or unbranched C1-C6 alkyl or alkenyl chain, and Z represents hydrogen, or, preferably, a polar group selected from keto, aldehyde, carboxylate, carboxylic ester, hydroxy, alkoxy, polyether, thiol, alkylthio, amino, ammonium, alkylamino, alkylammonium, cyano, nitro, sulfate, nitrate, phosphate, or a 5- to 7-membered 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.

A compound having the structure Id:

• where
• OR3 is OH or O—(C═O)R, where R is lower alkyl, and
• each group R4 is independently lower alkyl or together said groups form a 5- to 7-membered heterocycle having ring atoms selected from carbon, nitrogen, oxygen, and sulfur, and three to six carbon ring atoms;
• or a pharmaceutically acceptable salt thereof.

A compound having the stricture II:

• where R5 is selected from (a)-(d) below:
• where
• each R′ is independently lower alkyl, n=1-4, and X=CH2, O, or NR″, where R″ is H or lower alkyl;
• and
• and OR3 is —O—(C═O)R, where R is lower alkyl.

A compound having the structure Ia:

• where
• R1 is selected from (a)-(d) below:
• where
• each R′ is independently lower alkyl, n=1-4, and X=CH2, O, or NR″, where R″ is H or lower alkyl;
• and
• OR3 is OH or O—(C═O)R, where R is lower alkyl.

A method of effecting immunosuppression, comprising administering to a subject in need of such treatment, in a pharmaceutically acceptable vehicle, an effective amount of a compound having the structure selected from the group consisting of Ia, Ib, Ic, Id, II, and III:

• where
• each of OR1 and OR5 is independently 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 oxygen atom and at least one group —Y—Z or —O—Y—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, hydroxy, alkoxy, polyether, thiol, alkylthio, amino, ammonium, alkylamino, alkylammonium, 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;
• R2 is —(C═O)—Y—Z, where Y represents a branched or unbranched C1-C6 alkyl or alkenyl chain, and Z represents hydrogen, or, preferably, a polar group selected from keto, aldehyde, carboxylate, carboxylic ester, hydroxy, alkoxy, polyether, thiol, alkylthio, amino, ammonium, alkylamino, alkylammonium, cyano, nitro, sulfate, nitrate, phosphate, or a 5- to 7-membered 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;
• R3 is H or —(C═O)R, where R is lower alkyl;
• each group R4 is independently lower alkyl or together said groups form a 5- to 7-membered heterocycle having ring atoms selected from carbon, nitrogen, oxygen, and sulfur, and three to six carbon ring atoms;
• and
• R6 is a leaving group selected from the group consisting of alkyl sulfonate, fluoroalkyl sulfonate, aryl sulfonate, fluorosulfonate, trifluoroacetate, trichloroacetate, trichloroacetimidoyloxy, nitrate, alkyl phosphate, alkyl borate, trialkylammonium, and dialkylsulfonium.