CA2485424A1 - Cytotoxic agents comprising polyethylene glycol-containing taxanes and their therapeutic use - Google Patents

Cytotoxic agents comprising polyethylene glycol-containing taxanes and their therapeutic use Download PDF

Info

Publication number
CA2485424A1
CA2485424A1 CA002485424A CA2485424A CA2485424A1 CA 2485424 A1 CA2485424 A1 CA 2485424A1 CA 002485424 A CA002485424 A CA 002485424A CA 2485424 A CA2485424 A CA 2485424A CA 2485424 A1 CA2485424 A1 CA 2485424A1
Authority
CA
Canada
Prior art keywords
cr13r14
och2ch2
carbon atoms
alkyl
conr12
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CA002485424A
Other languages
French (fr)
Other versions
CA2485424C (en
Inventor
Ravi V. J. Chari
Michael Louis Miller
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Immunogen Inc
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of CA2485424A1 publication Critical patent/CA2485424A1/en
Application granted granted Critical
Publication of CA2485424C publication Critical patent/CA2485424C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • A61K47/56—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • 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
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
    • 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

Abstract

A cytotoxic agent comprising one or more polyethylene glycol-containing taxanes linked to a cell binding agent. A therapeutic composition for killin g selected cell populations comprising: (A) a cytotoxic amount of one or more polyethylene glycol-containing 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 polyethylene glycol-containing taxanes linked to a cell binding agent.

Claims (50)

1. A taxane comprising a polyethylene glycol-containing linking group at C-7 or C-10.
2. The taxane of claim 1, wherein the polyethylene glycol-containing linking group comprises a thiol or disulfide as a linking moiety.
3. The taxane of claim 2, wherein the polyethylene glycol-containing linking group is carried on a side chain that is a linear or branched, aromatic or heterocyclic group.
4. The taxane of claim 1, wherein the polyethylene glycol-containing linking group is cleavable.
5. The taxane of claim 1, wherein the polyethylene glycol-containing linking group is acid labile, photolabile, peptidase labile, or esterase labile.
6. The taxane of claim 1, wherein the polyethylene glycol-containing linking group is not cleavable.
7. The taxane of claim 1, wherein the substituent comprising the polyethylene glycol-containing linking group is selected from the group consisting of:
-(CR13R14)l(CH2)m(C R13R14)l(OCH2CH2)nO(C R13R14)l(CH2)m(C R13R14)lSZ, -CO(C R13R14)l(CH2)m(C R13R14)l (OCH2CH2)nO(C R13R14)l(CH2)m(C R13R14)l SZ, -CONR12(C R13R14)l(CH2)m(C R13R14)l(OCH2CH2)nO(C R13R14)l(CH2)m(CR13R14)l SZ, -(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCO(CR13R14)l(CH2)m(CR13R14)lSZ, -(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n NR12CO(CR13R14)l(CH2)m(CR13R14)lSZ, -(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCONR12(CR13R14)l(CH2)m(CR13R14)lSZ, -CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nOCO(CR13R14)l(CH2)m(CR13R14)l SZ, -CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nNR12CO(CR13R14)l(CH2)m(CR13R14)l SZ, -CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nOCONR12(CR13R14)l(CH2)m(CR13R14)l SZ, -CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nOCO(CR13R14)l(CH2)m(CR13R14)l SZ, -CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nNR12CO(CR13R14)l(CH2)m(CR13R14)l SZ, -CONR12(CR13R14)l(CH2)m(CR13R14)t(OCH2CH2)n OCONR12(CR13R14)l(CH2)m(CR13R14)l SZ, -CO-morpholino-X(OCH2CH2)n SZ, -CO-piperazino-X(OCH2CH2)n SZ, -CO-piperidino-X(OCH2CH2)n SZ, and -CO-N-methylpiperazino-X(OCH2CH2)n SZ, wherein Z is H or SR, X is a linear alkyl or branched alkyl having 1-10 carbon atoms, R and R12 are the same or different and represent linear alkyl, branched alkyl or cyclic alkyl having 1 to 10 carbon atoms, or simple or substituted aryl having 1 to 10 carbon atoms or heterocyclic, and R12 can in addition be H, R13 and R14 are same or different and represent H or linear alkyl, branched alkyl or cyclic alkyl having 1 to 10 carbon atoms, or aryl, l is 0 or an integer from 1 to 10, m is an integer of 1 to 10, and n is 2 to 1000.
8. A compound of formula (I):
wherein:
R1 is H, an electron withdrawing group, or an electron donating group;
42~

R1' and R1" are the same or different and are H, an electron withdrawing group, or an electron donating group;
R2 is -(CR13R14)l(CH2)m(C R13R14)l(OCH2CH2)n O(C R13R14)l(CH2)m(C R13R14)l SZ, -CO(C R13R14)l(CH2)m(C R13R14)l(OCH2CH2)n O(C R13R14)l(CH2)m(C R13R14)l SZ, -CONR12(C R13R14)l(CH2)m(C R13R14)l(OCH2CH2)n O(C R13R14)(CH2)m(CR13R14)l SZ, -(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCO(CR13R14)l(CH2)m(CR13R14)l SZ, -(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n NR12CO(CR13R14)l(CH2)m(CR13R14)l SZ, -(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCONR12(CR13R14)l(CH2)m(CR13R14)l SZ, -CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCO(CR13R14)l(CH2)m(CR13R14)l SZ, -CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n NR12CO(CR13R14)l(CH2)m(CR13R14)l SZ, -CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCONR12(CR13R14)l(CH2)m(CR13R14)l SZ, -CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCO(CR13R14)l(CH2)m(CR13R14)l SZ, -CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n NR12CO(CR13R14)l(CH2)m(CR13R14)l SZ, -CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCONR12(CR13R14)l(CH2)m(CR13R14)l SZ, -CO-morpholino-X(OCH2CH2)n SZ, -CO-piperazino-X(OCH2CH2)n SZ, -CO-piperidino-X(OCH2CH2)n SZ, and -CO-N-methylpiperazino-X(OCH2CH2)n SZ, wherein Z is H or SR, X is a linear alkyl or branched alkyl having 1-10 carbon atoms, R and R12 are the same or different and represent linear alkyl, branched alkyl or cyclic alkyl having 1 to 10 carbon atoms, or simple or substituted aryl having 1 to 10 carbon atoms or heterocyclic, and R12 can in addition be H, R13 and R14 are same or different and represent H or linear alkyl, branched alkyl or cyclic alkyl having 1 to 10 carbon atoms, or aryl, 1 is 0 or an integer from 1 to 10, m is an integer of 1 to 10, and n is 2 to 1000;
R3 is aryl, or is linear, branched or cyclic alkyl having 1 to 10 carbon atoms;
R4 is -OC(CH3)3 or -C6H5; and R5 is H, a heterocyclic, a linear, branched, or cyclic ester or ether having from 1 to 10 carbon atoms or a carbamate of formula -CNR10R11, wherein R10 and R11 are the same or different and are H, linear, branched, or cyclic alkyl having 1 to 10 atoms or simple or substituted aryl having 1 to 10 carbon atoms.
9. A compound of formula (I):
wherein:
R1 is H, an electron withdrawing group, or an electron donating group;
R1' and R1" are the same or different and are H, an electron withdrawing group, or an electron donating group;
R2 is H, a heterocyclic, 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 atoms or simple or substituted aryl having 1 to 10 carbon atoms;
R3 is aryl, or is linear, branched or cyclic alkyl having 1 to 10 carbon atoms;
R4 is -OC(CH3)3 or -C6H5; and R5 is -(CR13R14)l(CH2)m(C R13R14)l(OCH2CH2)n O(C R13R14)l(CH2)m(C R13R14)l SZ, -CO(C R13R14)OCH2)m(C R13R14)l(OCH2CH2)n O(C R13R14)l(CH2)m(C R13R14)l SZ, -CONR12(C R13R14)l(CH2)m(C R13R14)l(OCH2CH2)n O(C R13R14)l(CH2)m(CR13R14)l SZ, -(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCO(CR13R14)l(CH2)m(CR13R14)l SZ, -(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n NR12CO(CR13R14)l(CH2)m(CR13R14)l SZ, -(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCONR12(CR13R14)l(CH2)m(CR13R14)l SZ, -CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCO(CR13R14)l(CH2)m(CR13R14)l SZ, -CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n NR12CO(CR13R14)l(CH2)m(CR13R14)l SZ, -CO(CR13R14)t(CH2)m(CR13R14)l(OCH2CH2)n OCONR12(CR13R14)l(CH2)m(CR13R14)l SZ, -CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCO(CR13R14)l(CH2)m(CR13R14)l SZ, -CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n NR12CO(CR13R14)l(CH2)m(CR13R14)l SZ, -CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCONR12(CR13R14)l(CH2)m(CR13R14)l SZ, -CO-morpholino-X(OCH2CH2)n SZ, -CO-piperazino-X(OCH2CH2)n SZ, -CO-piperidino-X(OCH2CH2)n SZ, and -CO-N-methylpiperazino-X(OCH2CH2)n SZ, wherein Z is H or SR, X is a linear alkyl or branched alkyl having 1-10 carbon atoms, R and R12 are the same or different and represent linear alkyl, branched alkyl or cyclic alkyl having 1 to 10 carbon atoms, or simple or substituted aryl having 1 to
10 carbon atoms or heterocyclic, and R12 can in addition be H, R13 and R14 are same or different and represent H or linear alkyl, branched alkyl or cyclic alkyl having 1 to 10 carbon atoms, or aryl, 1 is 0 or an integer from 1 to 10, m is an integer of 1 to 10, and n is 2 to 1000.
10. The compound of claim 8 or 9, wherein R1 is H, F, NO2, CN, Cl, CHF2, CF3, -OCH3, -OCH2CH3, -NR6R7, or -OR8.
11. The compound of claim 8 or 9, wherein R1 is OMe, OEt, Cl, F, NO2, or CF3.
12. The compound of claim 8 or 9, wherein R1 is in the meta position, R1' is OMe, and R1" is H.
13. The compound of claim 8 or 9, wherein R1' and R1" are the same or different and are H, F, NO2, CN, Cl, CHF2, CF3, -OCH3, OCH2CH3, -NR6R7, or -OR8, wherein:
R6 and R7 are the same or different and are each H, linear, branched, or cyclic alkyl groups having 1 to 10 carbon atoms, or simple or substituted aryl having 1 to 10 carbon atoms, and R8 is linear, branched or cyclic alkyl having 1 to 10 carbon atoms.
14. The compound of claim 13, wherein R6 and R7 are same or different and are each H, or are alkyl or aryl having 1 to 4 carbon atoms.
15. The compound of claim 13, wherein -NR6R7 is dimethyl amino, diethyl amino, dipropyl amino, or dibutyl amino, where the butyl moiety is any of primary, secondary, tertiary or isobutyl..
16. The compound of claim 8 or 9, wherein R3 is -CH2CH(CH3)2 or -CH=C(CH3)2.
17. The compound of claim 8 or 9, wherein R4 is -OC(CH3)3 or -C6H5.
18. The compound of claim 8, wherein R5 is H, -COCH3, -COCH2CH3 and -COCH2CH2CH3.
19. The compound of claim 9, wherein R2 is H, -COCH3, -COCH2CH3 and -COCH2CH2CH3.
20. The compound of claim 8, wherein R5 is H, or -CONHCH2CH3, -CONHCH2CH2CH3, -CO-morpholino, -CO-piperazino, -CO-piperidino, or -CO-N-methylpiperazino.
21. The compound of claim 9, wherein R2 is H, or -CONHCH2CH3, -CONHCH2CH2CH3, -CO-morpholino, -CO-piperazino, -CO-piperidino, or -CO-N-methylpiperazino.
22. A cytotoxic agent comprising one or more taxanes linked to a cell binding agent through a polyethylene glycol-containing linking group at C-7 or C-10 of at least one of the taxanes.
23. The cytotoxic agent of claim 22, wherein the polyethylene glycol-containing linking group comprises a thiol or disulfide as the linking moiety.
24. The cytotoxic agent of claim 22, wherein the polyethylene glycol-containing linking group is carried on a side chain that is a linear or branched, aromatic or heterocyclic group.
25. The cytotoxic agent of claim 22, wherein at least one of the taxanes is linked to the cell binding agent through a cleavable linking group.
26. The cytotoxic agent of claim 25, wherein the cleavable linking group is acid labile, photolabile, peptidase labile or esterase labile.
27. The cytotoxic agent of claim 22, wherein at least one of the taxanes is linked to the cell binding agent through a non-cleavable linking group.
28. The cytotoxic agent of claim 22, wherein the substituent comprising the polyethylene glycol-containing linking group is selected from the group consisting of:

-(CR13R14)l(CH2)m(C R13R14)l(OCH2CH2)n O(C R13R14)l(CH2)m(C R13R14)l SZ, -CO(C R13R14)l(CH2)m(C R13R14)l(OCH2CH2)n O(C R13R14)l(CH2)m(C R13R14)l SZ, -CONR12(C R13R14)l(CH1)m(C R13R14)l(OCH2CH2)n O(C R13R14)l(CH2)m(CR13R14)l SZ, -(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCO(CR13R14)l(CH2)m(CR13R14)l SZ, -(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n NR12CO(CR13R14)l(CH2)m(CR13R14)l SZ, -(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCONR12(CR13R14)l(CH2)m(CR13R14)l SZ, -CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCO(CR13R14)l(CH2)m(CR13R14)l SZ, -CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n NR12CO(CR13R14)l(CH2)m(CR13R14)l SZ, -CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCONR12(CR13R14)l(CH2)m(CR13R14)l SZ, -CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCO(CR13R14)l(CH2)m(CR13R14)l SZ, -CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n NR12CO(CR13R14)l(CH2)m(CR13R14)l SZ, -CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCONR12(CR13R14)l(CH2)m(CR13R14)l SZ, -CO-morpholino-X(OCH2CH2)n SZ, -CO-piperazino-X(OCH2CH2)n SZ, -CO-piperidino-X(OCH2CH2)n SZ, and -CO-N-methylpiperazino-X(OCH2CH2)n SZ, wherein Z is H or SR, X is a linear alkyl or branched alkyl having 1-10 carbon atoms, R and R12 are the same or different and represent linear alkyl, branched alkyl or cyclic alkyl having 1 to 10 carbon atoms, or simple or substituted aryl having 1 to 10 carbon atoms or heterocyclic, and R12 can in addition be H, R13 and R14 are same or different and represent H or linear alkyl, branched alkyl or cyclic alkyl having 1 to 10 carbon atoms, or aryl, l is 0 or an integer from 1 to 10, m is an integer of 1 to 10, and n is 2 to 1000.
29. The cytotoxic agent of claim 22, wherein the cell binding agent is an antibody or an antibody fragment.
30. The cytotoxic agent of claim 22, wherein the cell binding agent is an antibody, a single chain antibody or a binding fragment of an antibody or single chain antibody.
31. The cytotoxic agent of claim 22, wherein the cell binding agent is a monoclonal antibody, a single chain monoclonal antibody or a binding fragment of a single chain monoclonal antibody a monoclonal antibody which is or is not humanized or resurfaced or chimeric.
32. The cytotoxic agent of claim 31, wherein the cell binding agent binds specifically to the CD33 antigen.
33. The cytotoxic agent of claim 31, wherein the cell binding agent binds specially to the CD56 antigen.
34. The cytotoxic agent of claim 22, wherein the cell binding agent is an interferon, a lymphokine, a hormone, a vitamin, a growth factor, a colony-stimulating factor, or transferrin.
35. The cytotoxic agent of claim 22, wherein the cell binding agent is epidermal growth factor, transforming growth factor, vascular endothelial growth factor, fibroblast growth factor, insulin like growth factor 1 and 2, platelet derived growth factor, melanocyte stimulating hormone, thyroid stimulating hormone, somatostatin, estrogen, estrogen analogue, androgen, androgen analogue, or folate.
36. A therapeutic composition comprising:
(A) An effective amount of a cytotoxic agent comprising one or more taxanes linked to a cell binding agent through a polyethylene glycol-containing linking group at C-7 or C-10 of at least one of the taxanes; and (B) A pharmaceutically acceptable carrier, diluent, or excipient.
37. The therapeutic composition of claim 36, wherein the polyethylene glycol-containing linking group comprises a thiol or disulfide as the linking moiety.
38. The therapeutic composition of claim 36, wherein the polyethylene glycol-containing linking group is carried on a side chain that is a linear or branched, aromatic or heterocyclic group.
39. The therapeutic composition of claim 36, wherein at least one of the taxanes is linked to the cell binding agent through a cleavable linking group.
40. The therapeutic composition of claim 39, wherein the cleavable linking group is acid labile, photolabile, peptidase labile or esterase labile.
41. The therapeutic composition of claim 36, wherein at least one of the taxanes is linked to the cell binding agent through a non-cleavable linking group.
42. The therapeutic composition of claim 36, wherein the substituent comprising the polyethylene glycol-containing linking group is selected from the group consisting of:
-(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n O(CR13R14)l(CH2)m(CR13R14)l SZ, -CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n O(CR13R14)l(CH2)m(CR13R14)l SZ, -CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n O(CR13R14)l(CH2)m(CR13R14)l SZ, -(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCO(CR13R14)l(CH2)m(CR13R14)l SZ, -(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n NR12CO(CR13R14)l(CH2)m(CR13R14)l SZ, -(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCONR12(CR13R14)l(CH2)m(CR13R14)l SZ, -CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCO(CR13R14)l(CH2)m(CR13R14)l SZ, -CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n NR12CO(CR13R14)l(CH2)m(CR13R14)l SZ, -CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCONR12(CR13R14)l(CH2)m(CR13R14)l SZ, -CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCO(CR13R14)l(CH2)m(CR13R14)l SZ
-CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n NR12CO(CR13R14)l(CH2)m(CR13R14)l SZ, -CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCONR12(CR13R14)l(CH2)m(CR13R14)l SZ, -CO-morpholino-X(OCH2CH2)n SZ, -CO-piperazino-X(OCH2CH2)n SZ, -CO-piperidino-X(OCH2CH2)n SZ, and -CO-N-methylpiperazino-X(OCH2CH2)n SZ, wherein Z is H or SR, X is a linear alkyl or branched alkyl having 1-10 carbon atoms, R and R12 are the same or different and represent linear alkyl, branched alkyl or cyclic alkyl having 1 to 10 carbon atoms, or simple or substituted aryl having 1 to 10 carbon atoms or heterocyclic, and R12 can in addition be H, R13 and R14 are same or different and represent H or linear alkyl, branched alkyl or cyclic alkyl having 1 to 10 carbon atoms, or aryl, l is 0 or an integer from 1 to 10, m is an integer of 1 to 10, and n is 2 to 1000.
43. The therapeutic composition of claim 36 or 37, wherein the cell binding agent is an antibody or an antibody fragment.
44. The therapeutic composition of any one of claims 36, 37, 38 or 42, wherein the cell binding agent is an antibody, a single chain antibody or a binding fragment of an antibody or single chain antibody.
45. The therapeutic composition of any one of claims 36, 37, 38 or 42, wherein the cell binding agent is a monoclonal antibody, a single chain monoclonal antibody or a binding fragment of a single chain monoclonal antibody a monoclonal antibody which is or is not humanized or resurfaced or chimeric?.
46. The therapeutic composition of claim 45, wherein the cell binding agent binds specifically to the CD33 antigen.
47. The therapeutic composition of claim 45, wherein the cell binding agent binds specifically to the CD 19 antigen.
48. The therapeutic composition of any one of claims 36, 37, 38 or 42, wherein the cell binding agent is an interferon, a lymphokine, a hormone, a vitamin, a growth factor, a colony-stimulating factor, or transferrin.
49. The therapeutic composition of any one of claims 36, 37, 38 or 42, wherein the cell binding agent is epidermal growth factor, , transforming growth factor, vascular endothelial growth factor, fibroblast growth factor, insulin like growth factor 1 and 2, platelet derived growth factor, somatostatin, melanocyte stimulating hormone, thyroid stimulating hormone, estrogen, estrogen analogue, androgen, androgen analogue, or folate.
50. A method of killing selected cell populations comprising contacting target cells or tissue containing target cells with a cytotoxic amount of the cytotoxic agent of any one of claims 22 to 35.
CA2485424A 2002-05-14 2003-02-11 Cytotoxic agents comprising polyethylene glycol-containing taxanes and their therapeutic use Expired - Fee Related CA2485424C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US10/144,042 US6596757B1 (en) 2002-05-14 2002-05-14 Cytotoxic agents comprising polyethylene glycol-containing taxanes and their therapeutic use
US10/144,042 2002-05-14
PCT/US2003/002675 WO2003097625A1 (en) 2002-05-14 2003-02-11 Cytotoxic agents comprising polyethylene glycol-containing taxanes and their therapeutic use

Publications (2)

Publication Number Publication Date
CA2485424A1 true CA2485424A1 (en) 2003-11-27
CA2485424C CA2485424C (en) 2010-12-14

Family

ID=22506806

Family Applications (1)

Application Number Title Priority Date Filing Date
CA2485424A Expired - Fee Related CA2485424C (en) 2002-05-14 2003-02-11 Cytotoxic agents comprising polyethylene glycol-containing taxanes and their therapeutic use

Country Status (6)

Country Link
US (1) US6596757B1 (en)
EP (1) EP1506181A4 (en)
JP (2) JP2005533026A (en)
AU (1) AU2003210731C1 (en)
CA (1) CA2485424C (en)
WO (1) WO2003097625A1 (en)

Families Citing this family (90)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU768027B2 (en) * 1999-02-24 2003-11-27 Uab Research Foundation, The Taxane derivatives for targeted therapy of cancer
US7875612B2 (en) 2001-04-24 2011-01-25 Purdue Research Foundation Folate mimetics and folate-receptor binding conjugates thereof
US20100056762A1 (en) 2001-05-11 2010-03-04 Old Lloyd J Specific binding proteins and uses thereof
ES2552281T3 (en) 2001-05-11 2015-11-26 Ludwig Institute For Cancer Research Ltd. Specific binding proteins and uses thereof
ATE426414T1 (en) * 2002-05-15 2009-04-15 Endocyte Inc VITAMIN-MITOMYCIN CONJUGATES
BR0313197A (en) * 2002-08-02 2005-08-09 Immunogen Inc Cytotoxic agents containing potent taxanes and their therapeutic use
US7390898B2 (en) * 2002-08-02 2008-06-24 Immunogen Inc. Cytotoxic agents containing novel potent taxanes and their therapeutic use
TWI367096B (en) 2003-01-27 2012-07-01 Endocyte Inc Vitamin-receptor binding drug delivery conjugates and pharmaceutical compositions
KR101424624B1 (en) 2003-05-14 2014-07-31 이뮤노젠 아이엔씨 Drug Conjugate Composition
US7834155B2 (en) 2003-07-21 2010-11-16 Immunogen Inc. CA6 antigen-specific cytotoxic conjugate and methods of using the same
WO2005079861A2 (en) * 2004-02-13 2005-09-01 Safeway Investments Ltd. Polymeric water soluble prodrugs
WO2006012527A1 (en) * 2004-07-23 2006-02-02 Endocyte, Inc. Bivalent linkers and conjugates thereof
CA2486285C (en) * 2004-08-30 2017-03-07 Viktor S. Goldmakher Immunoconjugates targeting syndecan-1 expressing cells and use thereof
CN101023119B (en) 2004-09-22 2010-05-05 日本化药株式会社 Novel block copolymer, micelle preparation, and anticancer agent containing the same as active ingredient
EP1688415A1 (en) * 2004-12-07 2006-08-09 Aventis Pharma S.A. Cytotoxic agents comprising new C-2 modified taxanes
EP1669358A1 (en) 2004-12-07 2006-06-14 Aventis Pharma S.A. Cytotoxic agents comprising new taxanes
US20110166319A1 (en) * 2005-02-11 2011-07-07 Immunogen, Inc. Process for preparing purified drug conjugates
AU2006213662B2 (en) 2005-02-11 2010-08-05 Immunogen, Inc. Process for preparing stable drug conjugates
CN101175757B (en) * 2005-03-16 2012-11-14 恩多塞特公司 Synthesis and purification of pteroic acid and conjugates thereof
NZ623901A (en) 2005-08-03 2015-10-30 Immunogen Inc Immunoconjugate formulations
KR20130113543A (en) 2005-08-19 2013-10-15 엔도사이트, 인코포레이티드 Multi-drug ligand conjugates
US20080280937A1 (en) * 2005-08-19 2008-11-13 Christopher Paul Leamon Ligand Conjugates of Vinca Alkaloids, Analogs, and Derivatives
AU2006283726C1 (en) 2005-08-24 2015-05-07 Immunogen, Inc. Process for preparing maytansinoid antibody conjugates
EP1806365A1 (en) 2006-01-05 2007-07-11 Boehringer Ingelheim International GmbH Antibody molecules specific for fibroblast activation protein and immunoconjugates containing them
JP5249016B2 (en) * 2006-03-28 2013-07-31 日本化薬株式会社 Taxane polymer conjugates
KR20090009241A (en) 2006-05-18 2009-01-22 니폰 가야꾸 가부시끼가이샤 Polymer conjugate of podophyllotoxin
CN101622276B (en) * 2006-07-18 2015-04-22 赛诺菲-安万特 Antagonist antibody against EphA2 for the treatment of cancer
US20090239782A1 (en) * 2006-10-03 2009-09-24 Masaharu Nakamura High-molecular weight conjugate of resorcinol derivatives
EP1914242A1 (en) * 2006-10-19 2008-04-23 Sanofi-Aventis Novel anti-CD38 antibodies for the treatment of cancer
EP2080779B1 (en) 2006-11-06 2016-05-18 Nippon Kayaku Kabushiki Kaisha Polymeric derivative of nucleic acid metabolic antagonist
EP2090607B1 (en) 2006-11-08 2015-05-20 Nippon Kayaku Kabushiki Kaisha Polymeric derivative of nucleic acid metabolic antagonist
US9090693B2 (en) 2007-01-25 2015-07-28 Dana-Farber Cancer Institute Use of anti-EGFR antibodies in treatment of EGFR mutant mediated disease
WO2008101231A2 (en) * 2007-02-16 2008-08-21 Endocyte, Inc. Methods and compositions for treating and diagnosing kidney disease
EP2481427A1 (en) * 2007-03-14 2012-08-01 Endocyte, Inc. Folate-Tubulysin conjugates
MX2009009782A (en) 2007-03-15 2010-09-10 Ludwig Inst Cancer Res Treatment method using egfr antibodies and src inhibitors and related formulations.
RU2523909C2 (en) * 2007-06-25 2014-07-27 Эндосайт, Инк. Conjugates, containing hydrophilic spacers of linkers
US9877965B2 (en) 2007-06-25 2018-01-30 Endocyte, Inc. Vitamin receptor drug delivery conjugates for treating inflammation
PE20120259A1 (en) 2007-08-09 2012-04-04 Boehringer Ingelheim Int ANTI-CD37 ANTIBODIES
WO2009023265A1 (en) 2007-08-14 2009-02-19 Ludwig Institute For Cancer Research Monoclonal antibody 175 targeting the egf receptor and derivatives and uses thereof
JP5349318B2 (en) * 2007-09-28 2013-11-20 日本化薬株式会社 Steroids polymer conjugates
US9187521B2 (en) 2007-10-25 2015-11-17 Endocyte, Inc. Tubulysins and processes for preparing
PT2242772E (en) * 2007-12-26 2015-02-09 Biotest Ag Immunoconjugates targeting cd138 and uses thereof
JP2011508738A (en) * 2007-12-26 2011-03-17 バイオテスト・アクチエンゲゼルシヤフト Method and agent for improving targeting of CD138 expressing tumor cells
EP2801584B1 (en) 2007-12-26 2019-07-10 Biotest AG Agents targeting CD138 and uses thereof
US9011864B2 (en) * 2007-12-26 2015-04-21 Biotest Ag Method of decreasing cytotoxic side-effects and improving efficacy of immunoconjugates
EP2258397B1 (en) * 2008-03-18 2017-10-11 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of physiologically active substance
US8236319B2 (en) 2008-04-30 2012-08-07 Immunogen, Inc. Cross-linkers and their uses
SG189817A1 (en) * 2008-04-30 2013-05-31 Immunogen Inc Potent conjugates and hydrophilic linkers
WO2009136572A1 (en) 2008-05-08 2009-11-12 日本化薬株式会社 Polymer conjugate of folic acid or folic acid derivative
EP2431403B1 (en) 2009-05-15 2016-09-28 Nipponkayaku Kabushikikaisha Polymer conjugate of bioactive substance having hydroxy group
ES2726945T3 (en) 2009-06-03 2019-10-10 Immunogen Inc Conjugation Methods
JP2013504585A (en) 2009-09-09 2013-02-07 セントローズ， エルエルシー Extracellular targeted drug complex
EP2486023A4 (en) 2009-10-06 2014-05-07 Immunogen Inc Potent conjugates and hydrophilic linkers
CN102933231B (en) 2010-02-10 2015-07-29 伊缪诺金公司 CD20 antibody and uses thereof
ME03447B (en) 2010-03-04 2020-01-20 Macrogenics Inc Antibodies reactive with b7-h3, immunologically active fragments thereof and uses thereof
JP5856069B2 (en) 2010-11-17 2016-02-09 日本化薬株式会社 Polymer derivatives of novel cytidine antimetabolites
US20130295052A1 (en) * 2010-11-19 2013-11-07 Manu Chaudhary Novel conjugates for targeted drug delivery
ME03353B (en) 2011-03-29 2019-10-20 Immunogen Inc Preparation of maytansinoid antibody conjugates by a one-step process
WO2012135517A2 (en) 2011-03-29 2012-10-04 Immunogen, Inc. Preparation of maytansinoid antibody conjugates by a one-step process
SG195072A1 (en) 2011-05-21 2013-12-30 Macrogenics Inc Cd3-binding molecules capable of binding to human and non-human cd3
ES2622578T3 (en) 2011-06-10 2017-07-06 Mersana Therapeutics, Inc. Protein-polymer-drug conjugates
RU2623426C2 (en) 2011-09-11 2017-06-26 Ниппон Каяку Кабусики Кайся Method of obtaining a block copolymer
BR112014013694A2 (en) 2011-12-08 2017-06-13 Biotest Ag method to treat a disease and kit
US10080805B2 (en) 2012-02-24 2018-09-25 Purdue Research Foundation Cholecystokinin B receptor targeting for imaging and therapy
US20140080175A1 (en) 2012-03-29 2014-03-20 Endocyte, Inc. Processes for preparing tubulysin derivatives and conjugates thereof
EP2841099A1 (en) 2012-04-26 2015-03-04 Boehringer Ingelheim International GmbH Combination of cd37 antibodies with bendamustine
EP2849783A1 (en) 2012-05-16 2015-03-25 Boehringer Ingelheim International GmbH Combination of cd37 antibodies with further agents
EP2849784A1 (en) 2012-05-16 2015-03-25 Boehringer Ingelheim International GmbH Combination of cd37 antibodies with ice (ifosfamide, carboplatin, etoposide)
NZ707091A (en) 2012-10-04 2018-12-21 Immunogen Inc Use of a pvdf membrane to purify cell-binding agent cytotoxic agent conjugates
EA201590622A1 (en) 2012-10-16 2015-10-30 Эндосайт, Инк. CONJUGATES FOR DELIVERY OF MEDICINES CONTAINING NOT MEETING IN THE NATURE OF AMINO ACID AND METHODS OF APPLICATION
US10131682B2 (en) 2012-11-24 2018-11-20 Hangzhou Dac Biotech Co., Ltd. Hydrophilic linkers and their uses for conjugation of drugs to a cell binding molecules
JP6334553B2 (en) 2012-12-10 2018-05-30 メルサナ セラピューティクス，インコーポレイティド Protein-polymer-drug conjugate
US10226535B2 (en) 2012-12-10 2019-03-12 Mersana Therapeutics, Inc. Auristatin compounds and conjugates thereof
US9872918B2 (en) 2012-12-12 2018-01-23 Mersana Therapeutics, Inc. Hydroxyl-polymer-drug-protein conjugates
CN105813655B (en) 2013-10-11 2022-03-15 阿萨纳生物科技有限责任公司 Protein-polymer-drug conjugates
AU2014331714B2 (en) 2013-10-11 2019-05-02 Mersana Therapeutics, Inc. Protein-polymer-drug conjugates
EP3104880B1 (en) 2014-02-14 2020-03-25 MacroGenics, Inc. Improved methods for the treatment of vascularizing cancers
US10464955B2 (en) 2014-02-28 2019-11-05 Hangzhou Dac Biotech Co., Ltd. Charged linkers and their uses for conjugation
CN113350518A (en) 2015-07-12 2021-09-07 杭州多禧生物科技有限公司 Conjugated bridge linkers to cell binding molecules
US9839687B2 (en) 2015-07-15 2017-12-12 Suzhou M-Conj Biotech Co., Ltd. Acetylenedicarboxyl linkers and their uses in specific conjugation of a cell-binding molecule
EP3331569A1 (en) 2015-08-07 2018-06-13 Gamamabs Pharma Antibodies, antibody drug conjugates and methods of use
WO2017194568A1 (en) 2016-05-11 2017-11-16 Sanofi Treatment regimen using anti-muc1 maytansinoid immunoconjugate antibody for the treatment of tumors
NZ752394A (en) 2016-11-14 2021-07-30 Hangzhou Dac Biotech Co Ltd Conjugation linkers, cell binding molecule-drug conjugates containing the likers, methods of making and uses such conjugates with the linkers
US11135307B2 (en) 2016-11-23 2021-10-05 Mersana Therapeutics, Inc. Peptide-containing linkers for antibody-drug conjugates
CA3066754A1 (en) 2017-06-22 2018-12-27 Mersana Therapeutics, Inc. Methods of producing drug-carrying polymer scaffolds and protein-polymer-drug conjugates
US11401336B2 (en) 2018-02-21 2022-08-02 Celgene Corporation BCMA-binding antibodies and uses thereof
CN113365664A (en) 2018-10-29 2021-09-07 梅尔莎纳医疗公司 Cysteine engineered antibody-drug conjugates with peptide-containing linkers
IL294321A (en) 2020-01-09 2022-08-01 Mersana Therapeutics Inc Site specific antibody-drug conjugates with peptide-containing linkers
WO2022010797A2 (en) 2020-07-07 2022-01-13 Bionecure Therapeutics, Inc. Novel maytansinoids as adc payloads and their use for the treatment of cancer
EP3970752A1 (en) 2020-09-17 2022-03-23 Merck Patent GmbH Molecules with solubility tag and related methods

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993024476A1 (en) 1992-06-04 1993-12-09 Clover Consolidated, Limited Water-soluble polymeric carriers for drug delivery
US5547981A (en) * 1993-03-09 1996-08-20 Enzon, Inc. Taxol-7-carbazates
US5824701A (en) * 1993-10-20 1998-10-20 Enzon, Inc. Taxane-based prodrugs
AU768027B2 (en) * 1999-02-24 2003-11-27 Uab Research Foundation, The Taxane derivatives for targeted therapy of cancer
AU765588C (en) * 1999-11-24 2004-12-16 Immunogen, Inc. Cytotoxic agents comprising taxanes and their therapeutic use
WO2001074399A1 (en) * 2000-03-30 2001-10-11 Ajinomoto Co., Inc. Drugs retained in target tissue over long time

Also Published As

Publication number Publication date
AU2003210731C1 (en) 2009-11-05
JP2005533026A (en) 2005-11-04
JP2011042679A (en) 2011-03-03
AU2003210731B8 (en) 2009-06-25
EP1506181A1 (en) 2005-02-16
CA2485424C (en) 2010-12-14
US6596757B1 (en) 2003-07-22
WO2003097625A1 (en) 2003-11-27
AU2003210731A1 (en) 2003-12-02
EP1506181A4 (en) 2006-11-08
AU2003210731B2 (en) 2009-06-11

Similar Documents

Publication Publication Date Title
CA2485424A1 (en) Cytotoxic agents comprising polyethylene glycol-containing taxanes and their therapeutic use
CA2388063A1 (en) Cytotoxic agents comprising taxanes and their therapeutic use
JP2005533026A5 (en)
JP2003514903A5 (en)
CA2494049A1 (en) Dehydrophenylahistins and analogs thereof and the synthesis of dehydrophenylahistins and analogs thereof
KR960701045A (en) ANTI-TUMOR COMPOUNDS, PHARMACEUTICAL COMPOSITIONS, METHODS FOR PREPARATION THEREOF AND FOR TREATMENT
RU2011136686A (en) NEW DERIVATIVES OF BENZODIAZEPINE
HUP0202572A2 (en) Organic silicon compounds
ATE294592T1 (en) CONJUGATES CONTAINING THIOETHER
RU2009102243A (en) CAMPTOTECINE DERIVATIVES WITH ANTITUMOR ACTIVITY
RU2000128058A (en) ECTEINASCIDINES, PHARMACEUTICAL COMPOSITION CONTAINING THEM AND METHOD FOR TREATING TUMORS
EP1484058A3 (en) Pharmaceutical composition for inhibiting altering gene expression and for inducing differentiation in non-malignant cells
CA2441398A1 (en) Lipid lowering biphenylcarboxamides
WO2001026629A3 (en) Neutral-cationic lipid for nucleic acid and drug delivery
AU581324B2 (en) Substituted 6-phenyl-4,5-dihydro pyradazin-3-ones
RU2008111492A (en) COMBINATIONS (COMPOSITIONS) INCLUDING DMXAA FOR TREATMENT OF CANCER
JP2019507126A5 (en)
CA2395980A1 (en) 10, 11-difluoromethylenedioxycamptothecin compounds with topoisomerase i inhibition
YU46699A (en) Improved method for producing thiazolidinediones, and new thiazolidinediones
WO2005007079A3 (en) Inactivators and bivalent inhibitors of glyoxalase i and methods of inhibiting tumor growth
DE60201903D1 (en) IRON POWDER COMPOSITION WITH AN AMID LUBRICANT AND METHOD FOR THE PRODUCTION THEREOF
KR960703623A (en) Improvements to Pro Drugs (lmprovements relating to prodrugs)
DE69824855D1 (en) MACROCYCLIC LACTONS, COMPOSITIONS AND METHODS OF USE
CA2432027A1 (en) Novel bifunctional chelating compounds containing hydroxamic acid residues
AR002249A1 (en) A COMPOUND OF OXAZOLE, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN IT, A PROCESS FOR THE PREPARATION OF THE SAME AND AN INTERMEDIATE COMPOUND FOR SUCH A PROCESS.

Legal Events

Date Code Title Description
EEER Examination request
MKLA Lapsed

Effective date: 20130211