Cytotoxic agents containing novel potent taxanes and their therapeutic use
Included within the scope of the present invention are potent taxanes and taxanes containing a linking group. Also included is a cytotoxic agent comprising one or more taxanes linked to a cell binding agent. A therapeutic composition for inducing cell death in selected cell populations comprising: (A) a cytotoxic amount of one or more taxanes covalently bonded to a cell binding agent through a linking group, and (B) a pharmaceutically acceptable carrier, diluent or excipient is also included. A method for inducing cell death in selected cell populations comprising contacting target cells or tissue containing target cells with an effective amount of a cytotoxic agent comprising one or more taxanes linked to a cell binding agent is included as well.
1. A compound represented by the following formula:
wherein:
R 2 and R 5 are the same or different and are H; or together with the oxygen atoms at the C-10 and C-7 positions, respectively, a heterocyclic or aryl ether, a heterocyclic or aryl ester, a heterocyclic or aryl carbamate, a linear, branched or cyclic alkyl ester having from 1 to 10 carbon atoms in the alkyl, a linear, branched or cyclic alkenyl ester having from 2 to 10 carbon atoms in the alkenyl, a linear, branched or cyclic alkyl ether having from 1 to 10 carbon atoms, a linear, branched or cyclic alkenyl ether having from 1 to 10 carbon atoms, a carbamate of the formula —OCOX, wherein X is a nitrogen-containing heterocyclic, or a carbamate of the formula —OCONR 10 R 11 , wherein R 10 and R 11 are the same or different and are H, linear, branched or cyclic alkyl having 1 to 10 carbon atoms, or simple or substituted aryl;
R 3 and R 4 are the same or different and are alkyl or alkenyl having from 1 to 10 carbon atoms, cycloalkyl or cycloalkenyl having from 3 to 10 carbon atoms, heterocyclic, or substituted heterocyclic; R 4 together with the —CONH— group at the C-3′ position can also be a carbamate formed from any of alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heterocyclic, substituted aryl or substituted heterocyclic and an oxygen atom; and
R 19 is —COR 20 wherein R 20 is selected from the group consisting of disubstituted aryls and trisubstituted aryls, wherein the substituent is an electron withdrawing group or an electron donating group.
2. The compound of claim 1 , wherein the electron withdrawing group is —F, —NO 2 , —CN, —Cl, —CHF 2 or —CF 3 .
3. The compound of claim 1 , wherein the electron donating group is —OCH 3 , —OCH 2 CH 3 , —NR 7 R 8 or —OR 9 , wherein R 7 and R 8 are the same or different and are linear, branched or cyclic alkyl groups having from 1 to 10 carbon atoms, or simple or substituted aryl, and R 9 is linear, branched or cyclic alkyl having from 1 to 10 carbon atoms.
4. A compound represented by the following formula:
wherein:
R 2 is together with the oxygen atom at the C-10 position, a heterocyclic or aryl ether, a heterocyclic or aryl ester, a heterocyclic or aryl carbamate, a linear, branched or cyclic alkyl ester having from 1 to 10 carbon atoms in the alkyl, a linear, branched or cyclic alkenyl ester having from 2 to 10 carbon atoms in the alkenyl, a linear, branched or cyclic alkyl ether having from 1 to 10 carbon atoms, a linear, branched or cyclic alkenyl ether having from 1 to 10 carbon atoms, a carbamate of the formula —OCOX, wherein X is a nitrogen-containing heterocyclic, or a carbamate of the formula —OCONR 10 R 11 , wherein R 10 and R 11 are the same or different and are H, linear, branched or cyclic alkyl having 1 to 10 carbon atoms, or simple or substituted aryl;
R 3 and R 4 are the same or different and are alkyl or alkenyl having from 1 to 10 carbon atoms, cycloalkyl or cycloalkenyl having from 3 to 10 carbon atoms, heterocyclic, or substituted heterocyclic; R 4 together with the —CONH— group at the C-3′ position can also be a carbamate formed from any of alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heterocyclic, substituted aryl or substituted heterocyclic and an oxygen atom;
R 5 is H; and
R 19 is —COR 20 wherein R 20 is selected from the group consisting of disubstituted aryls and trisubstituted aryls, wherein the substituent is an electron withdrawing group or an electron donating group.
5. The compound of claim 4 , wherein the electron withdrawing group is —F, —NO 2 , —CN, —Cl, —CHF 2 or —CF 3 .
6. The compound of claim 4 , wherein the electron donating group is —OCH 3 , —OCH 2 CH 3 , —NR 7 R 8 or —OR 9 , wherein R 7 and R 8 are the same or different and are linear, branched or cyclic alkyl groups having from 1 to 10 carbon atoms, or simple or substituted aryl, and R 9 is linear, branched or cyclic alkyl having from 1 to 10 carbon atoms.
7. A compound represented by the following formula:
wherein:
R 2 is H;
R 3 and R 4 are the same or different and are alkyl or alkenyl having from 1 to 10 carbon atoms, cycloalkyl or cycloalkenyl having from 3 to 10 carbon atoms, heterocyclic, or substituted heterocyclic; R 4 together with the —CONH— group at the C-3′ position can also be a carbamate formed from any of alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heterocyclic, substituted aryl or substituted heterocyclic and an oxygen atom;
R 5 is together with the oxygen atom at the C-7 position, a heterocyclic or aryl ether, a heterocyclic or aryl ester, a heterocyclic or aryl carbamate, a linear, branched or cyclic alkyl ester having from 1 to 10 carbon atoms in the alkyl, a linear, branched or cyclic alkenyl ester having from 2 to 10 carbon atoms in the alkenyl, a linear, branched or cyclic alkyl ether having from 1 to 10 carbon atoms, a linear, branched or cyclic alkenyl ether having from 1 to 10 carbon atoms, a carbamate of the formula —OCOX, wherein X is a nitrogen-containing heterocyclic, or a carbamate of the formula —OCONR 10 R 11 , wherein R 10 and R 11 are the same or different and are H, linear, branched or cyclic alkyl having 1 to 10 carbon atoms, or simple or substituted aryl; and
R 19 is —COR 20 wherein R 20 is selected from the group consisting of disubstituted aryls and trisubstituted aryls, wherein the substituent is an electron withdrawing group or an electron donating group.
8. The compound of claim 7 , wherein the electron withdrawing group is —F, —NO 2 , —CN, —Cl, —CHF 2 or —CF 3 .
9. The compound of claim 7 , wherein the electron donating group is —OCH 3 , —OCH 2 CH 3 , —NR 7 R 8 or —OR 9 , wherein R 7 and R 8 are the same or different and are linear, branched or cyclic alkyl groups having from 1 to 10 carbon atoms, or simple or substituted aryl, and R 9 is linear, branched or cyclic alkyl having from 1 to 10 carbon atoms.
10. A compound represented by the following formula:
wherein:
R 2 and R 5 are the same or different and are H; or together with the oxygen atoms at the C-10 and C-7 positions, respectively, a heterocyclic or aryl ether, a heterocyclic or aryl ester, a heterocyclic or aryl carbamate, a linear, branched or cyclic alkyl ester having from 1 to 10 carbon atoms in the alkyl, a linear, branched or cyclic alkenyl ester having from 2 to 10 carbon atoms in the alkenyl, a linear, branched or cyclic alkyl ether having from 1 to 10 carbon atoms, a linear, branched or cyclic alkenyl ether having from 1 to 10 carbon atoms, a carbamate of the formula —OCOX, wherein X is a nitrogen-containing heterocyclic, or a carbamate of the formula —OCONR 10 R 11 , wherein R 10 and R 11 are the same or different and are H, linear, branched or cyclic alkyl having 1 to 10 carbon atoms, or simple or substituted aryl;
R 3 and R 4 are the same or different and are alkyl or alkenyl having from 1 to 10 carbon atoms, cycloalkyl or cycloalkenyl having from 3 to 10 carbon atoms, heterocyclic, or substituted heterocyclic; R 4 together with the —CONH— group at the C-3′ position can also be a carbamate formed from any of said alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heterocyclic, substituted aryl or substituted heterocyclic and an oxygen atom; and
R 19 is —COR 20 wherein R 20 is selected from the group consisting of 2,5-disubstituted aryls and trisubstituted aryls, wherein the substituent is an electron withdrawing group or an electron donating group.
11. The compound of claim 10 , wherein the electron withdrawing group is —F, —NO 2 , —CN, —Cl, —CHF 2 or —CF 3 .
12. The compound of claim 10 , wherein the electron donating group is —OCH 3 , —OCH 2 CH 3 , —NR 7 R 8 or —OR 9 , wherein R 7 and R 8 are the same or different and are linear, branched or cyclic alkyl groups having from 1 to 10 carbon atoms, or simple or substituted aryl, and R 9 is linear, branched or cyclic alkyl having from 1 to 10 carbon atoms.
13. The compound of claim 10 , wherein the 2,5-disubstituted aryl is 2,5-dimethoxy phenyl.
14. The compound of claim 1 , wherein R 3 is substituted or unsubstituted heterocyclic, and R 19 is —COR 20 wherein R 20 is dimethoxy phenyl.
15. The compound of claim 1 , wherein R 4 is substituted or unsubstituted heterocyclic, and R 19 is —COR 20 wherein R 20 is dimethoxy phenyl.
16. The compound of claim 1 , wherein R 4 together with the —CONH— group at the C-3′ position is a carbamate formed from substituted or unsubstituted heterocyclic and an oxygen atom, and R 19 is —COR 20 wherein R 20 is dimethoxy phenyl.
17. The compound of claim 4 , wherein R 3 is substituted or unsubstituted heterocyclic, and R 19 is —COR 20 wherein R 20 is dimethoxy phenyl.
18. The compound of claim 4 , wherein R 4 is substituted or unsubstituted heterocyclic, and R 19 is —COR 20 wherein R 20 is dimethoxy phenyl.
19. The compound of claim 4 , wherein R 4 together with the —CONH— group at the C-3′ position is a carbamate formed from substituted or unsubstituted heterocyclic and an oxygen atom, and R 19 is —COR 20 wherein R 20 is dimethoxy phenyl.
20. The compound of claim 7 , wherein R 3 is substituted or unsubstituted heterocyclic, and R 19 is —COR 20 wherein R 20 is dimethoxy phenyl.
21. The compound of claim 7 , wherein R 4 is substituted or unsubstituted heterocyclic, and R 19 is —COR 20 wherein R 20 is dimethoxy phenyl.
22. The compound of claim 7 , wherein R 4 together with the —CONH— group at the C-3′ position is a carbamate formed from substituted or unsubstituted heterocyclic and an oxygen atom, and R 19 is —COR 20 wherein R 20 is dimethoxy phenyl.
23. The compound of claim 10 , wherein R 3 is substituted or unsubstituted heterocyclic.
24. The compound of claim 10 , wherein R 4 is substituted or unsubstituted heterocyclic.
25. The compound of claim 10 , wherein R 4 together with the —CONH— group at the C-3′ position is a carbamate formed from substituted or unsubstituted heterocyclic and an oxygen atom.
26. The compound of claim 1 , wherein R 20 is disubstituted phenyl.
27. The compound of claim 4 , wherein R 20 is disubstituted phenyl.
28. The compound of claim 7 , wherein R 20 is disubstituted phenyl.
29. The compound of claim 27 , wherein R 20 is dimethoxy phenyl.
30. The compound of claim 28 , wherein R 20 is dimethoxy phenyl.
31. The compound of claim 29 , wherein R 20 is dimethoxy phenyl.
32. The compound of claim 30 , wherein R 20 is dimethoxy phenyl having at least one meta-methoxy.
33. The compound of claim 31 , wherein R 20 is dimethoxy phenyl having at least one meta-methoxy.
34. The compound of claim 32 , wherein R 20 is dimethoxy phenyl having at least one meta-methoxy.
35. The compound of claim 1 , wherein R 3 and R 4 may be the same or different, and each represents furyl, thiopheneyl, n-butenyl, iso-butenyl or tert-butyl.
36. The compound of claim 4 , wherein R 3 and R 4 may be the same or different, and each represents furyl, thiopheneyl, n-butenyl, iso-butenyl or tert-butyl.
37. The compound of claim 7 , wherein R 3 and R 4 may be the same or different, and each represents furyl, thiopheneyl, n-butenyl, iso-butenyl or tert-butyl.
38. The compound of claim 10 , wherein R 3 and R 4 may be the same or different, and each represents furyl, thiopheneyl, n-butenyl, iso-butenyl or tert-butyl.