CA2388063A1 - Cytotoxic agents comprising taxanes and their therapeutic use - Google Patents

Cytotoxic agents comprising taxanes and their therapeutic use Download PDF

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CA2388063A1
CA2388063A1 CA002388063A CA2388063A CA2388063A1 CA 2388063 A1 CA2388063 A1 CA 2388063A1 CA 002388063 A CA002388063 A CA 002388063A CA 2388063 A CA2388063 A CA 2388063A CA 2388063 A1 CA2388063 A1 CA 2388063A1
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carbon atoms
branched
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CA2388063C (en
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Ravi V. J. Chari
Walter A. Blattler
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Immunogen Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6881—Cluster-antibody conjugates, i.e. the modifying agent consists of a plurality of antibodies covalently linked to each other or of different antigen-binding fragments covalently linked to each other
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

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.</SD OAB>

Claims (44)

1. A compound represented by formula (I):
wherein:
R1 is H, an electron withdrawing group, or an electron donating group, and R1' and R1" are the same or different, and are H, an electron withdrawing group, or an electron donating group;
R2 is heterocyclic, a linear, branched, or cyclic ester or ether having from 1 to carbon atoms or a carbamate of the formula -CNR10R11, wherein R10 and R11 are the same or different and are H, linear, branched or cyclic alkyl having 1 to 10 carbon atoms or aryl;

R3 is aryl, or a linear, branched, or cyclic alkyl having from 1 to 10 carbon atoms;
R4 is -OC(CH3)3 or phenyl;
R5 is a linking group; and R6 is heterocyclic, H, a linear, branched, or cyclic ester or ether having from 1 to 10 carbon atoms or a carbamate of the formula CNR10R11, wherein R10 and R11 are the same or different and are H, linear, branched or cyclic alkyl having 1 to 10 carbon atoms or aryl.
2. The compound of claim 1, wherein R1 is F, NO2, CN, Cl, CHF2, CF3, -OCH3, -OCH2CH3, or -NR7R8, wherein:
R7 and R8 are the same or different and are linear, branched, or cyclic alkyl having 1 to 10 carbon atoms or simple or substituted aryl having 1 to 10 carbon atoms.
3. The compound of claim 2, wherein R7 and R8 each has 1 to 4 carbon atoms.
4. The compound of claim 2 or 3, wherein R7 and R8 are the same.
5. The compound of claim 1, wherein R2 is -COC2H5, -CH2CH3, -CONHCH2CH3, -CO-morpholino, -CO-piperidino, -CO-piperazino, or -CO-N-methylpiperazino.
6. The compound of claim 1, wherein R5 is a thiol- or disulfide-containing linking group.
7. The compound of claim 6, wherein R5 is -(CH2)n SZ, -CO(CH2)n SZ, -(CH2)n CH(CH3)SZ, -CO(CH2)n CH(CH3)SZ, -(CH2)n C(CH3)2SZ, -CO(CH2)n C(CH3)2SZ, -CONR12(CH2)n SZ, -CONR12(CH2)n CH(CH3)SZ, -CONR12(CH2)n C(CH3)2SZ, -CO-morpholino-XSZ, -CO-piperidino-XSZ, -CO-piperazino-XSZ, or -CO-N-methylpiperazino-XSZ, wherein Z is H or SR, wherein R and R12 are the same or different and are linear alkyl, branched alkyl or cyclic alkyl having from 1 to 10 carbon atoms, or simple or substituted aryl having from 1 to 10 carbon atoms or heterocyclic, and R12 in addition can be H, X is a linear alkyl or branched alkyl having 1-10 carbon atoms, and n is an integer of 1 to 10.
8. The compound of claim 1, wherein R1 is in the meta position and R1' and R1"
are H.
9. A compound represented by formula (I):
wherein:

R1 is H, an electron withdrawing group, or an electron donating group, and R1' and R1" are the same or different, and are H, an electron withdrawing group, or an electron donating group;

R2 is heterocyclic, linear, branched, or cyclic ester or ether having from 1 to carbon atoms or a carbamate of the formula CNR10R11, wherein R10 and R11 are the same or different and are H, linear, branched or cyclic alkyl having 1 to 10 carbon atoms or aryl;
R3 is -CH=C(CH3)2;
R4 is -OC(CH3)3 or phenyl;
R5 is a linking group; and R6 is heterocyclic, H, a linear, branched, or cyclic ester or ether having from 1 to 10 carbon atoms or a carbamate of the formula CNR10R11, wherein R10 and R11 are the same or different and are H, linear, branched or cyclic alkyl having 1 to
10 carbon atoms or aryl.

10. The compound of claim 9, wherein R1 is F, NO2, CN, Cl, CHF2, CF3, -OCH3, -OCH2CH3, or -NR7R8, wherein:
R7 and R8 are the same or different and are linear, branched, or cyclic alkyl having 1 to 10 carbon atoms or simple or substituted aryl having 1 to 10 carbon atoms.
11. The compound of claim 10, wherein R7 and R8 each has 1 to 4 carbon atoms.
12. The compound of claim 10 or 11, wherein R7 and R8 are the same.
13. The compound of claim 9, wherein R2 is -COC2H5, -CH2CH3, -CONHCH2CH3, -CO-morpholino, -CO piperidino, -CO-piperazino, or -CO-N-methylpiperazino.
14. The compound of claim 9, wherein R5 is a thiol- or disulfide-containing linking group.
15. The compound of claim 14, wherein R5 is -(CH2)n SZ, -CO(CH2)n SZ, -(CH2)n CH(CH3)SZ, -CO(CH2)n CH(CH3)SZ, -(CH2)n C(CH3)2SZ, -CO(CH2)n C(CH3)2SZ, -CONR12(CH2)n SZ, -CONR12(CH2)n CH(CH3)SZ, -CONR12(CH2)n C(CH3)2SZ, -CO-morpholino-XSZ, -CO-piperidino-XSZ, -CO-piperazino-XSZ, or -CO-N-methylpiperazino-XSZ wherein Z is H or SR, wherein R and R12 are the same or different and are linear alkyl, branched alkyl or cyclic alkyl having from 1 to 10 carbon atoms, or simple or substituted aryl having from 1 to 10 carbon atoms or heterocyclic, and R12 in addition can be H, X is a linear alkyl or branched alkyl having 1-10 carbon atoms, and n is an integer of 1 to 10.
16. The compound of claim 9, wherein R1 is in the meta position and R1' and R1" are H.
17. A compound represented by formula (I):
wherein:

R1 is H, an electron withdrawing group, or an electron donating group, and R1' and R1" are the same or different, and are H, an electron withdrawing group, or an electron donating group;
R2 is a linking group;
R3 is aryl, or is a linear, branched, or cyclic alkyl having from 1 to 10 carbon atoms;
R4 is -OC(CH3)3 or phenyl;
R5 is heterocyclic, H, a linear, branched, or cyclic ester or ether having from 1 to 10 carbon atoms or a carbamate of the formula CNR10R11, wherein R10 and R11 are the same or different and are H, linear, branched or cyclic alkyl having 1 to 10 carbon atoms or aryl; and R6 is heterocyclic, H, a linear, branched, or cyclic ester or ether having from 1 to 10 carbon atoms or a carbamate of the formula CNR10R11, wherein R10 and R11 are the same or different and are H, linear, branched or cyclic alkyl having 1 to 10 carbon atoms or aryl.
18. The compound of claim 17, wherein at least one of R1 is F, NO2, CN, Cl, CHF2, CF3, -OCH3, -OCH2CH3, or -NR7R8 wherein:
R7 and R8 are the same or different and are linear, branched, or cyclic alkyl having 1 to 10 carbon atoms or simple or substituted aryl having 1 to 10 carbon atoms.
19. The compound of claim 18, wherein R7 and R8 each has 1 to 4 carbon atoms.
20. The compound of claim 18 and 19, wherein R7 and R8 are the same.
21. The compound of claim 17, wherein R2 is a thiol- or disulfide-containing linking group.
22. The compound of claim 21 wherein R2 is -(CH2)n SZ, -CO(CH2)n SZ, -(CH2)n CH(CH3)SZ, -CO(CH2)n CH(CH3)SZ, -(CH2)n C(CH3)2SZ, -CO(CH2)n C(CH3)2SZ, -CONR12(CH2)n SZ, -CONR12(CH2)n CH(CH3)SZ, -CONR12(CH2)n C(CH3)2SZ, -CO-morpholino-XSZ, -CO-piperidino-XSZ, -CO-piperazino-XSZ, or -CO-N-methylpiperazino-XSZ wherein Z is H or SR, wherein R and R12 are the same or different and are linear alkyl, branched alkyl or cyclic alkyl having from 1 to 10 carbon atoms, or simple or substituted aryl having from 1 to 10 carbon atoms or heterocyclic, and R12 in addition can be H, X is a linear alkyl or branched alkyl having 1-10 carbon atoms, and n is an integer of 1 to 10.
23. The compound of claim 17, wherein R5 is -COC2H5, -CH2CH3, -CONHCH2CH3, -CO-morpholino, -CO-piperidino, -CO-piperazino, or CO-N-methylpiperazino.
24. The compound of claim 17, wherein R1 is in the meta position and R1' and R1"
are H.
25. A compound represented by formula (I):
wherein:
R1 is H, an electron withdrawing group, or an electron donating group, and R1' and R1" are the same or different and are H, an electron withdrawing group, or an electron donating group;
R2 is heterocyclic, H a linear, branched, or cyclic ester or ether having from to 10 carbon atoms or a carbamate of the formula CNR10R11, wherein R10 and R11 are the same or different and are H, linear, branched or cyclic alkyl having 1 to 10 carbon atoms or aryl;
R3 is aryl, or is a linear, branched or cyclic alkyl having from 1 to 10 carbon atoms;
R4 is -OC(CH3)3 or phenyl;

R5 is heterocyclic, H, a linear, branched, or cyclic ester or ether having from 1 to 10 carbon atoms or a carbamate of the formula CNR10R11, wherein R10 and R11 are the same or different and are H, linear, branched or cyclic alkyl having 1 to 10 carbon atoms or aryl;
R6 is a linking group.
26. The compound of claim 25, wherein R1 is F, NO2, CN, Cl, CHF2, CF3, -OCH3, -OCH2CH3, or -NR7R8 wherein:
R7 and R8 are the same or different and are linear, branched, or cyclic alkyl having 1 to 10 carbon atoms or simple or substituted aryl having 1 to 10 carbon atoms.
27. The compound of claim 26, wherein R7 and R8 each has 1 to 4 carbon atoms.
28. The compound of claim 26 or 27, wherein R7 and R8 are the same.
29. The compound of claim 25, wherein R2 is -COC2H5, -CH2CH3, -CONHCH2CH3, -CO-morpholino, -CO-piperidino, -CO-piperazino, or -CO-N-methylpiperazino.
30. The compound of claim 25, wherein R6 is a thiol- or disulfide-containing linking group.
31. The compound of claim 30, wherein R6 is -(CH2)n SZ, -CO(CH2)n SZ, -(CH2)n CH(CH3)SZ, -CO(CH2)n CH(CH3)SZ, -(CH2)n C(CH3)2SZ, -CO(CH2)n C(CH3)2SZ, -CONR12(CH2)n SZ, -CONR12(CH2)n CH(CH3)SZ, -CONR12(CH2)n C(CH3)2SZ, -CO-morpholino-XSZ, -CO-piperidino-XSZ, -CO-piperazino-XSZ, or -CO-N-methylpiperazino-XSZ wherein:
Z is H or SR, wherein R and R12 are the same or different and are linear alkyl, branched alkyl or cyclic alkyl having from 1 to 10 carbon atoms, or simple or substituted aryl having from 1 to 10 carbon atoms or heterocyclic, and R12 in addition can be H, X is a linear alkyl or branched alkyl having 1-10 carbon atoms, and n is an integer of 1 to 10.
32. The compound of claim 25, wherein R1 is in the meta position and R1' and R1"
are H.
33. 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:

R1 is H, an electron withdrawing group, or an electron donating group, and R1' and R1" are the same or different and are H, an electron withdrawing group, or an electron donating group;
R2 is a heterocyclic, linear, branched, or cyclic ester or ether having from 1 to carbon atoms or a carbamate of the formula CNR10R11; wherein R10 and R11 are the same or different and are H, linear, branched or cyclic alkyl having 1 to 10 carbon atoms or aryl;
R3 is aryl, or is a linear, branched, or cyclic alkyl having from 1 to 10 carbon atoms;
R4 is -OC(CH3)3 or phenyl;
R5 is a linking group; and R6 is a heterocyclic, H, linear, branched, or cyclic ester or ether having from 1 to 10 carbon atoms or a carbamate of the formula CNR10R11, wherein R10 and R11 are the same or different and are H, linear, branched or cyclic alkyl having 1 to 10 carbon atoms or aryl.
34. 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:
R1 is H, an electron withdrawing group, or an electron donating group, and R1' and R1" are the same or different and are H, an electron withdrawing group, or an electron donating group;
R2 is a heterocyclic, linear, branched, or cyclic ester or ether having from 1 to carbon atoms or a carbamate of the formula CNR10R11, wherein R10 and R11 are the same or different and are H, linear, branched or cyclic alkyl having 1 to 10 carbon atoms or aryl;
R3 is -CH=C(CH3)2;

R4 is -OC(CH3)3 or phenyl;
R5 is a linking group; and R6 is heterocyclic, H, a linear, branched, or cyclic ester or ether having from 1 to 10 carbon atoms or a carbamate of the formula CNR10R11, wherein R10 and R11 are the same or different and are H, linear, branched or cyclic alkyl having 1 to 10 carbon atoms or aryl.
35. 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:

R1 is H, an electron withdrawing group, or an electron donating group, and R1' and R1" are the same or different and are H, an electron withdrawing group, or an electron donating group;
R2 is a linking group;
R3 is aryl, or is a linear, branched, or cyclic alkyl having from 1 to 10 carbon atoms;
R4 is -OC(CH3)3 or phenyl;
R5 is a heterocyclic, H, linear, branched, or cyclic ester or ether having from 1 to 10 carbon atoms or a carbamate of the formula CNR10R11, wherein R10 and R11 are the same or different and are H, linear, branched or cyclic alkyl having 1 to 10 carbon atoms or aryl; and R6 is heterocyclic, H, a linear, branched, or cyclic ester or ether having from 1 to 10 carbon atoms or a carbamate of the formula CNR10R11, wherein R10 and R11 are the same or different and are H, linear, branched or cyclic alkyl having 1 to 10 carbon atoms or aryl.
36. 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:
R1 is H, an electron withdrawing group, or an electron donating group, and R1' and R1" are the same or different and are H, an electron withdrawing group, or an electron donating group;
R2 is heterocyclic, H, a linear, branched, or cyclic ester or ether having from 1 to 10 carbon atoms or a carbamate of the formula CNR10R11, wherein R10 and R11 are the same or different and are H, linear, branched or cyclic alkyl having 1 to 10 carbon atoms or aryl;
R3 is aryl, or is a linear, branched or cyclic alkyl having from 1 to 10 carbon atoms;

R4 is -OC(CH3)3 or phenyl;
R5 is heterocyclic, H, a linear, branched, or cyclic ester or ether having from 1 to 10 carbon atoms or a carbamate of the formula CNR10R11, wherein R10 and R11, are the same or different and are H, linear, branched or cyclic alkyl having 1 to 10 carbon atoms or aryl;
R6 is a linking group.
37. A therapeutic composition comprising:
(A) a therapeutically effective amount of the cytotoxic agent of any one of claims 33, 34, 35 or 36; and (B) a pharmaceutically acceptable carrier.
38. The cytotoxic agent of any one of claims 33, 34, 35, or 36 wherein the cell binding agent is selected from the group consisting of antibodies, an antibody fragment, interferons, lymphokines, hormones, vitamins, growth factors, colony stimulating factors, and transferrin.
39. The cytotoxic agent of any one of claims 33, 34, 35, or 36 wherein the cell binding agent is an antibody.
40. The cytotoxic agent of any one of claims 33, 34, 35, or 36 wherein the cell binding agent is a monoclonal antibody.
41. The cytotoxic agent of any one of claims 33, 34, 35, or 36 wherein the cell binding agent is an antigen specific antibody fragment.
42. The cytotoxic agent of any one of claims 33, 34, 35, or 36 wherein the antibody fragment is sFV, Fab, Fab', or F(ab')2.
43. The cytotoxic agent of any one of claims 33, 34, 35, or 36 wherein the cell binding agent is a growth factor or colony stimulating factor.
44. A method of killing selected cell populations comprising contacting target cells or tissue containing target cells with an effective amount of the cytotoxic agent of any one of claims 33, 34, 35 or 36.
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HK1049997B (en) 2007-02-23
EP1242401B1 (en) 2006-12-27
WO2001038318A1 (en) 2001-05-31
ATE349438T1 (en) 2007-01-15
US7550609B2 (en) 2009-06-23
PT1242401E (en) 2007-03-30
US20070196332A1 (en) 2007-08-23
JP2003514903A (en) 2003-04-22
US20070197775A1 (en) 2007-08-23
ES2276708T3 (en) 2007-07-01
DE60032633D1 (en) 2007-02-08
NZ517772A (en) 2004-03-26
US20040087649A1 (en) 2004-05-06
US7585857B2 (en) 2009-09-08
US6436931B1 (en) 2002-08-20
US20020013485A1 (en) 2002-01-31
US20060106090A1 (en) 2006-05-18
US7528130B2 (en) 2009-05-05
US6340701B1 (en) 2002-01-22
US7476669B2 (en) 2009-01-13
CA2388063C (en) 2010-06-08
US7217819B2 (en) 2007-05-15
US7276499B2 (en) 2007-10-02
DE60032633T2 (en) 2007-10-04
US6706708B2 (en) 2004-03-16
US20020086897A1 (en) 2002-07-04
US20080027130A1 (en) 2008-01-31
US20050272729A1 (en) 2005-12-08
US20060122259A1 (en) 2006-06-08
US6372738B2 (en) 2002-04-16
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