Cytotoxic agents comprising new maytansinoids

A compound represented by formula 4:

• wherein:
• Y represents (CR7R8)l(CR5R6)m(CR3R4)nCR1R2SZ, wherein:
• R1 and R2 are each independently linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, phenyl substituted with at least one alkyl containing from 1-4 carbon atoms, or an alkoxy, halogen or nitro, or heterocyclic aromatic or heterocyclic radical, and in addition R2 can be H;
• R3, R4, R5, R6, R7 and R8 are each independently H, linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, phenyl substituted with at least one alkyl containing from 1-4 carbon atoms, or an alkoxy, halogen or nitro, or heterocyclic aromatic or heterocyclic radical;
• l, m and n are each independently an integer of from 1 to 5, and in addition n can be 0;
• and
• Z is H, SR or —COR, wherein R is linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, or simple aryl or aryl substituted with at least one alkyl containing from 1-4 carbon atoms, or an alkoxy, halogen or nitro, or heterocyclic aromatic or heterocyclic radical,
• wherein said heterocyclic aromatic radical or said heterocyclic radical is a 3-10 membered ring containing one or two heteroatoms selected from N, O or S.

A method of esterification of maytansinol to give a maytansinoid of the formula 42′:

• wherein:
• Y2′ represents (CR7R8)l(CR9═CR10)p(C≡C)qAo(CR5R6)mDu(CR11═CR12)r(C≡C)sBt(CR3R4)nCR1R2SZ2, wherein:
• R1 and R2 are each independently linear alkyl or alkenyl having carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, phenyl substituted with at least one alkyl containing from 1-4 carbon atoms, or an alkoxy, halogen or nitro, or heterocyclic aromatic or heterocyclic radical, and in addition R2 can be H;
• A, B, and D each independently is cycloalkyl or cycloalkenyl having 3 to 10 carbon atoms, simple aryl or aryl substituted with at least one alkyl containing from 1-4 carbon atoms, or an alkoxy, halogen or nitro, or heterocyclic aromatic or heterocyclic radical;
• R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 are each independently H, linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, phenyl substituted with at least one alkyl containing from 1-4 carbon atoms, or an alkoxy, halogen or nitro, or heterocyclic aromatic or heterocyclic radical;
• l, m, n, o, p, q, r, s, t and u are each independently 0 or an integer of from 1 to 5, provided that at least two of l, m, n, o, p, q, r, s, t and u are not zero at any one time;
• and
• Z2 is SR or —COR, wherein R is linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3-10 carbon atoms, or simple aryl or aryl substituted with at least one alkyl containing from 1-4 carbon atoms, or an alkoxy, halogen or nitro, or heterocyclic aromatic or heterocyclic radical, said method comprising reacting maytansinol of the structure 11 at the C-3:
• with a compound of formula (III′-L), (III′-D), or (III′-D, L):
• wherein:
• Y2′ represents (CR7R8)l(CR9═CR10)p(C≡C)qAo(CR5R6)mDu(CR11═CR12)r(C≡C)sBt(CR3R4)nCR1R2S2, wherein:
• R1 and R2 are each independently linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, phenyl substituted with at least one alkyl containing from 1-4 carbon atoms, or an alkoxy, halogen or nitro, or heterocyclic aromatic or heterocyclic radical, and in addition R2 can be H;
• A, B, and D each, independently is cycloalkyl or cycloalkenyl having 3-10 carbon atoms, simple aryl or aryl substituted with at least one alkyl containing from 1-4 carbon atoms, or an alkoxy, halogen or nitro, or heterocyclic aromatic or heterocyclic radical;
• R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 are each independently H, linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, phenyl substituted with at least one alkyl containing from 1-4 carbon atoms, or an alkoxy, halogen or nitro, or heterocyclic aromatic or heterocyclic radical;
• l, m, n, o, p, q, r, s, t and u are each independently 0 or an integer of from 1 to 5, provided that at least two of l, m, n, o, p, q, r, s t and u are not zero at any one time;
• and
• Z2 is SR or —COR, wherein R is linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, or simple aryl or aryl substituted with at least one alkyl containing from 1-4 carbon atoms, or an alkoxy, halogen or nitro, or heterocyclic aromatic or heterocyclic radical,
• wherein said heterocyclic aromatic radical or said heterocyclic radical is a 3-10 membered ring containing one or two heteroatoms selected from N, O or S.

A method of esterification of maytansinol to give a maytansinoid of the formula 42:

• wherein:
• Y2 represents (CR7R8)l(CR5R6)m(CR3R4)nCR1R2SZ2, wherein:
• R1 and R2 are each independently linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, phenyl substituted with at least one alkyl containing from 1-4 carbon atoms, or an alkoxy, halogen or nitro, or heterocyclic aromatic or heterocyclic radical, and in addition R2 can be H;
• R3, R4, R5, R6, R7 and R8 are each independently H, linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, phenyl substituted with at least one alkyl containing from 1-4 carbon atoms, or an alkoxy, halogen or nitro, or heterocyclic aromatic or heterocyclic radical;
• l, m and n are each independently an integer of from 1 to 5, and in addition n can be 0;
• Z2 is SR or —COR, wherein R is linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, or simple aryl or aryl substituted with at least one alkyl containing from 1-4 carbon atoms, or an alkoxy, halogen or nitro, or heterocyclic aromatic or heterocyclic radical;, said method comprising reacting maytansinol of the structure 11 at the C-3:
• with a compound of formula (III-L), (III-D), or (III-D, L):
• wherein:
• Y2 represents (CR7R8)l(CR5R6)m(CR3R4)nCR1R2SZ2, wherein:
• R1 and R2 are each independently linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, phenyl substituted with at least one alkyl containing from 1-4 carbon atoms, or an alkoxy, halogen or nitro, or heterocyclic aromatic or heterocyclic radical, and in addition R2 can be H;
• R3, R4, R5, R6, R7 and R8 are each independently H, linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, phenyl substituted with at least one alkyl containing from 1-4 carbon atoms, or an alkoxy, halogen or nitro, or heterocyclic aromatic or heterocyclic radical;
• l, m and n are each independently an integer of from 1 to 5, and in addition n can be 0;
• Z2 is SR or —COR, wherein R is linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3-10 carbon atoms, or simple aryl or aryl substituted with at least one alkyl containing from 1-4 carbon atoms, or an alkoxy, halogen or nitro, or heterocyclic aromatic or heterocyclic radical,
• wherein said heterocyclic aromatic radical or said heterocyclic radical is a 3-10 membered ring containing one or two heteroatoms selected from N, O or S.