Cytotoxic agents comprising taxanes and their therapeutic use
A cytotoxic agent comprising one or more taxanes linked to a cell binding agent. A therapeutic composition for killing 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. A method for killing 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. Novel sulfur-containing taxanes.
1. A compound represented by formula (I):
wherein:
R 1 and R 1 ′ are the same or different and are —F, —NO 2 , —CN, Cl —CHF 2 , —CF 3 , —NR 7 R 8 , or —OR 9 , wherein R 7 and R 8 are the same or different and are linear alkyl having 1 to 10 carbon atoms, branched or cyclic alkyl having 3 to 10 carbon atoms, or simple or substituted phenyl or naphthyl, and R 9 is linear alkyl having 1 to 10 carbon atoms, or branched or cyclic alkyl having 3 to 10 carbon atoms;
R 1 ″ is H;
R 2 is —(CH 2 ) n SZ, —CO(CH 2 ) n SZ, —(CH 2 ) n CH(CH 3 )SZ, —CO(CH 2 ) n CH(CH 3 )SZ, —(CH 2 ) n C(CH 3 ) 2 SZ, —CO(CH 2 ) n C(CH 3 ) 2 SZ, —CONR 12 (CH 2 ) n CH(CH 3 )SZ, —CONR 12 (CH 2 ) n C(CH 3 ) 2 SZ, —CO-morpholino-XSZ, —CO-piperazino-XSZ, —CO-piperidino-XSZ, or —CO-N-methylpiperazino-XSZ,
wherein Z is H or SR, wherein R and R 12 are the same or different and are linear alkyl having 1 to 10 carbon atoms, branched or cyclic alkyl having 3 to 10 carbon atoms, or simple or substituted phenyl, naphthyl or heterocyclic, and R 12 in addition can be H, X is linear alkyl having 1-10 carbon atoms or branched alkyl having 3-10 carbon atoms, and n is an integer of 1 to 10;
R 3 is —CH═C(CH 3 ) 2 ;
R 4 is —OC(CH 3 ) 3 or phenyl;
R 5 together with the oxygen atom at the C-7 position forms a linear ether having from 1 to 10 carbon atoms, or a branched or cyclic ether having from 3 to 10 carbon atoms; and
R 6 is H.
2. The compound of claim 1 , wherein R 7 and R 8 each has 1 to 4 carbon atoms.
3. The compound of claim 1 , wherein R 7 and R 8 are the same.
4. The compound of claim 1 , wherein R 1 is in the meta position.
5. The compound of claim 1 , wherein R 1 and R 1 ′ are —OCH 3 .
6. A cytotoxic agent comprising one or more taxanes covalently bonded to a cell binding agent through a linking group, wherein at least one of said taxanes is a compound represented by formula (I):
wherein:
R 1 and R 1 ′ are the same or different and are —F, —NO 2 , —CN, Cl —CHF 2 , —CF 3 , —NR 7 R 8 , or —OR 9 , wherein R 7 and R 8 are the same or different and are linear alkyl having 1 to 10 carbon atoms, branched or cyclic alkyl having 3 to 10 carbon atoms, or simple or substituted phenyl or naphthyl, and R 9 is linear alkyl having 1 to 10 carbon atoms, or branched or cyclic alkyl having 3 to 10 carbon atoms;
R 1 ″ is H;
R 2 is —(CH 2 ) n SZ, —CO(CH 2 ) n SZ, —(CH 2 ) n CH(CH 3 )SZ, —CO(CH 2 ) n CH(CH 3 )SZ, —(CH 2 ) n C(CH 3 ) 2 SZ, —CO(CH 2 ) n C(CH 3 ) 2 SZ, —CONR 12 (CH 2 ) n CH(CH 3 )SZ, —CONR 12 (CH 2 ) n C(CH 3 ) 2 SZ, —CO-morpholino-XSZ, —CO-piperazino-XSZ, —CO-piperidino-XSZ, or —CO-N-methylpiperazino-XSZ,
wherein Z is H or SR, wherein R and R 12 are the same or different and are linear alkyl having 1 to 10 carbon atoms, branched or cyclic alkyl having 3 to 10 carbon atoms, or simple or substituted phenyl, naphthyl or heterocyclic, and R 12 in addition can be H, X is linear alkyl having 1-10 carbon atoms or branched alkyl having 3-10 carbon atoms, and n is an integer of 1 to 10;
R 3 is —CH═C(CH 3 ) 2 ;
R 4 is —OC(CH 3 ) 3 or phenyl;
R 5 together with the oxygen atom at the C-7position forms a linear ether having from 1 to 10 carbon atoms, or a branched or cyclic ether having from 3 to 10 carbon atoms; and
R 6 is H.
7. The cytotoxic agent of claim 6 , wherein R 7 and R 8 each has 1 to 4 carbon atoms.
8. The cytotoxic agent of claim 6 , wherein R 7 and R 8 are the same.
9. The cytotoxic agent of claim 6 , wherein R 1 is in the meta position.
10. The cytotoxic agent of claim 6 , wherein R 1 and R 1 ′ are —OCH 3 .
11. The cytotoxic agent of claim 6 , wherein the cell binding agent is selected from the group consisting of antibodies, an antigen specific antibody fragment, interferons, lymphokines, hormones, vitamins, growth factors, colony stimulating factors, and nutrient-transport molecules.
12. The cytotoxic agent of claim 11 , wherein the cell binding agent is an antibody or an antigen specific antibody fragment thereof.
13. The cytotoxic agent of claim 11 , wherein the cell binding agent is a monoclonal antibody or an antigen specific antibody fragment thereof.
14. The cytotoxic agent of claim 13 , wherein the antigen specific antibody fragment is selected from the group consisting of sFV, Fab, Fab′, and F(ab′) 2 .
15. The cytotoxic agent of claim 11 , wherein the cell binding agent is a hormone.
16. The cytotoxic agent of claim 15 , wherein the hormone is insulin, thyrotropin releasing hormones (TRH), thyroid stimulating hormone (TSH), melanocyte-stimulating hormone (MSH), or a steroid hormone.
17. The cytotoxic agent of claim 11 , wherein the cell binding agent is a vitamin.
18. The cytotoxic agent of claim 17 , wherein the vitamin is folic acid.
19. The cytotoxic agent of claim 11 , wherein the cell binding agent is a growth factor.
20. The cytotoxic agent of claim 19 , wherein the growth factor is epidermal growth factor (EGF) or transforming growth factor α (TGF-α).
21. A therapeutic composition comprising a therapeutically effective amount of the cytotoxic agent of claim 6 , and a pharmaceutically acceptable carrier.