Water-soluble drugs and methods for their production

A method of rendering soluble in water a water-insoluble drug, which method comprises:

• (i) providing a water-insoluble drug comprising a side-chain that can react with a bifunctional linking molecule;
• (ii) contacting said water-insoluble drug with said bifunctional linking molecule to obtain a first derivative comprising a maleimide side-chain;
• and
• (iii) contacting said first derivative with a thio containing polar moiety (X—SH) to obtain a water-soluble compound of the formula
• wherein:
• A is a water-insoluble drug selected from the group consisting of geldanamycin or a derivative thereof;
• B1 and B2 together are a spacer moiety,
• wherein B1 is selected from the group consisting of methylenyl, an amido, —N═, an amino, and a thiol maleimido, and
• B2 is selected from the group consisting of a C1-C19 alkylamido, a C1-C19 alkyl, a C2-C19 alkenyl, a C2-C19 alkynyl, a C1-C19 hydroxyalkyl, a C1-C19 alkyl carbamoyl, a C1-C19 alkylcarbonyl, and an aralkyl, any of which can be further substituted with one or more residues, which can be the same or different, selected from the group consisting of a nitro, a halo, an azido, a hydroxy, an amido and an amino group;
• and
• X is a polar moiety selected from the group consisting of an amino acid residue, a peptide residue, a polypeptide residue, and a protein residue;
• wherein the geldanamycin derivative is a compound of the formula
• wherein R2 is a halo or —OR8 when there is a single bond between R2 and the carbon at position 11, wherein R8 is selected from the group consisting of hydrogen, a C1-C8 alkylamido, a C1-C8 alkyl, a C2-C8 alkenyl, a C2-C8 alkynyl, a C1-C8 hydroxyalkyl, a C1-C8 alkyl carbamoyl, a C1-C8 alkylcarbonyl, and an aralkyl, any of the R8 groups can be substituted with one or more substituents, which can be the same or different, selected from the group, consisting of nitro, a halo, azido, hydroxy, an amido, and an amino group, or
• R2 is oxo (═O) or oximino (═NOH) when there is a double bond between R2 and the carbon at position 11,
• R3 is selected from the group consisting of hydrogen and a group of the formula
• wherein R5, R6, and R7 are each independently selected from the group consisting of hydrogen, a halo, an azido, a nitro, a C1-C8 alkyl, a C1-C8 alkoxy, an aryl, a cyano, and an NR10R11R12, wherein R10, R11, and R12 are each independently selected from the group consisting of hydrogen and a C1-C3 alkyl,
• R4 is selected from the group consisting of hydrogen, a halo, a C1-C8 alkylamino, and a C1-C8 dialkylamino, and
• the bond between the carbons at positions 4 and 5 can be a single bond or a double bond,
• or a pharmaceutically acceptable salt of said compound.