Camptothecin derivatives and polymeric conjugates thereof

A method of preparing a camptothecin analog, comprising:

• a) reacting a camptothecin derivative of the formula:
• wherein:
• R1 is selected from the group consisting of amino acid residues, peptide residues containing form about 2 to about 10 amino acids, Y3—(L2)p—A2 and R2;
• Y3 is O, S or NR3;
• p is zero or one;
• L2 is a bifunctional linker;
• A2 is selected from the group consisting of hydrogen, amino protecting groups, NR8R9, amino acid residues, peptide residues containing from about 2 to about 10 amino acids, polymeric residues, R10, SR11, NC(O)R12;
• D3-D7 are independently selected from the group consisting of H, C1-8 straight or branched alkyls, substituted C1-8 straight or branched alkyls, aryls, substituted aryls, arylalkyls, substituted aryalkyls, C1-8 alkylaryls, C1-8 alkoxys, C1-8 hydroxy-alkyls, C1-8 aminoalkoxy, aryloxys, gycals, CO2R13, R14, nitro, cyano, halo, hydroxyl, amino, SR15, NR16R17 or OR18, where D4 and D5 optionally, when taken together, form a saturated 3-7 membered heterocyclic ring which may contain O, S or NR19 groups, where R19 is hydrogen or a C1-6 alkyl;
• D8-D9 are independently selected from the group consisting of H, C1-8 straight or branched alkyls, substituted C1-8 straight or branched alkyls, aryls, substituted aryls, arylalkyls, substituted aryalkyls, C1-8 alkylaryls and C1-8 hydroxyalkyls;
• D10 is H, and
• R2-18 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-19 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cyloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, substituted C1-6 heteroalkyls, C1-6 alkoxy, phenoxy and C1-6 heteroalkoxy;
• with a blocked bifunctional spacer to form a protected intermediate, and
• b) deprotecting said protected intermediate and reacting the resultant deprotected intermediate with an activated polymer under conditions sufficient to cause a polymeric conjugate to be formed.

A method of preparing a polymer conjugate, comprising

• a) reacting a compound of the formula
• wherein:
• D3-D7 are independently selected from the group consisting of H, C1-8 straight or branched alkyls, substituted C1-8 straight or branched alkyls, aryls, substituted aryls, arylalkyls, substituted aryalkyls, C1-8 alkylaryls, C1-8 alkoxys, C1-8 hydroxy-alkyls, C1-8 aminoalkoxy, aryloxys, gycals, CO2R13, R14, nitro, cyano, halo, hydroxyl amino, SR15, NR16R17 or OR18, where D4 and D5 optionally, when taken together, form a saturated 3-7 membered heterocyclic ring which may contain O, S or NR19 groups, where R19 is hydrogen or a C1-6 alkyl;
• D8-D9 are independently selected from the group consisting of H, C1-8 straight or branched alkyls, substituted C1-8 straight or branched alkyls, aryls, substituted aryls, arylalkyls, substituted aryalkyls, C1-8 alkylaryls and C1-8 hydroxyalkyls;
• D10 is H, and
• R8-18 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-19 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C1-6 substituted cyloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, substituted C1-6 heteroalkyls, C1-6 alkoxy, phenoxy and C1-6 heteroalkoxy;
• with a blocked bifunctional spacer in an inert solvent under conditions sufficient to open the E lactone and form a protected intermediate of formula (VI)
• wherein R35 is a residue of a blocked bifunctional spacer;
• b) acylating the C17 OH of said blocked intermediate;
• and
• c) deblocking said blocked intermediate and reacting at least about 2 equivalents of the resultant deblocked intermediate with an activated polymer under conditions sufficient to cause a polymeric conjugate to be formed.