Conjugates of CC-1065 analogs and bifunctional linkers
This invention relates to novel analogs of the DNA-alkylating agent CC-1065 and to their conjugates. Furthermore this invention concerns intermediates for the preparation of said agents and conjugates. The conjugates are designed to release their (multiple) payload after one or more activation steps and/or at a rate and time span controlled by the conjugate in order to selectively deliver and/or controllably release one or more of said DNA alkylating agents. The agents, conjugates, and intermediates can be used to treat an illness that is characterized by undesired (cell) proliferation. As an example, the agents and the conjugates of this invention may be used to treat a tumor.
1. A compound having the formula
wherein R is (CH 2 CH 2 O) 2 H, (CH 2 ) 3 C(O)NH 2 , (CH 2 ) 4 C(NH 2 )COOH, (CH 2 ) 3 COOH, (CH 2 ) 3 NHC(O)NH 2 , or (CH 2 CH 2 O) 3 H; q ranges from 1 to 4; and Ab is selected from trastuzumab or an epitope-binding functional fragment of trastuzumab.
2. The compound according to claim 1 , wherein R is (CH 2 CH 2 O) 2 H.
3. The compound according to claim 2 , wherein Ab is trastuzumab.
4. The compound according to claim 1 , wherein q is approximately 2.
5. A composition comprising a mixture of at least two compounds according to claim 1 , wherein said at least two compounds have the same R substituents but different values for q.
6. The composition according to claim 5 , wherein Ab in said at least two compounds is trastuzumab.
7. The composition according to claim 6 , wherein the mixture of compounds has an average q value of approximately 2.
8. The composition according to claim 7 , wherein R is (CH 2 CH 2 O) 2 H.
9. A pharmaceutical composition, comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
10. A pharmaceutical composition, comprising a compound according to claim 3 and a pharmaceutically acceptable carrier.
11. The compound according to claim 1 , wherein R is (CH 2 ) 4 C(NH 2 )COOH.