Cytotoxic benzodiazepine derivatives
AssigneeImmunoGen, Inc.
InventorsRavi V.J. Chari, Michael Louis Miller, Manami Shizuka
Life of this patent
Estimating the term…
Abstract
The invention relates to novel benzodiazepine derivatives with antiproliferative activity and more specifically to novel benzodiazepine compounds of formula (I)-(VII). The invention also provides conjugates of the benzodiazepine compounds linked to a cell-binding agent. The invention further provides compositions and methods useful for inhibiting abnormal cell growth or treating a proliferative disorder in a mammal using the compounds or conjugates of the invention.
Claims32
A compound represented by any one of the following formulas:
- or a pharmaceutically acceptable salt thereof, wherein:
- the double line between N and C represents a single bond or a double bond, provided that when it is a double bond, X is absent and Y is —H, and when it is a single bond, X is selected from —H, or an amine protecting group;
- Y is selected from —H, —OR, —OCOR′, —SR, —NR′R″, —SO3M, —SO2M or —OSO3M, wherein M is —H or a cation;
- R is —H, an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms or a PEG group —(CH2CH2O)n—Rc, wherein n is an integer from 1 to 24, and Rc is a linear or branched alkyl having 1 to 4 carbon atoms;
- R′ and R″ are the same or different, and are selected from —H, —OR, —NRRg′, —COR, an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, an optionally substituted aryl having from 6 to 18 carbon atoms, an optionally substituted 3- to 18-membered heterocyclic ring having 1 to 6 heteroatoms selected from O, S, N and P, a PEG group —(CH2CH2O)n—Rc, wherein n is an integer from 1 to 24, preferably n is 2, 4 or 8;
- and Rg′ is —H, an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms or a PEG group —(CH2CH2O)n—Rc;
- X′ is selected from the group consisting of —H, —OH, an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, phenyl, and an amine-protecting group;
- Y′ is selected from the group consisting of —H, an oxo group, an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms;
- Rx is a linear or branched alkylene having 1 to 6 carbon atoms, optionally substituted with a charged substituent or an ionizable group Q;
- Re is —H or a linear or branched alkyl having 1 to 6 carbon atoms;
- G is selected from —CH— or —N—;
- Zs is —H, —SRd, or is selected from any one of the following formulas:
- wherein:
- q is an integer from 1 to 5;
- Rd is a linear or branched alkyl having 1 to 6 carbon atoms or is selected from phenyl, nitrophenyl, dinitrophenyl, carboxynitrophenyl, pyridyl and nitropyridyl;
- n′ is an integer from 2 to 6;
- U is —H or —SO3M;
- and
- M is —H or a cation.
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A conjugate comprising a cytotoxic compound and a cell-binding agent (CBA), wherein the cytotoxic compound is covalently linked to the CBA, and wherein said cytotoxic compound is represented by any one of the following formulas:
- or a pharmaceutically acceptable salt thereof, wherein:
- the double line between N and C represents a single bond or a double bond, provided that when it is a double bond, X is absent and Y is —H, and when it is a single bond, X is selected from —H, or an amine protecting group;
- Y is selected from —H, —OR, —OCOR′, —SR, —NR′R″, —SO3M, —SO2M or —OSO3M, wherein M is —H or a cation;
- R is —H, an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms or a PEG group —(CH2CH2O)n—Rc, wherein n is an integer from 1 to 24, and Rc is a linear or branched alkyl having 1 to 4 carbon atoms;
- R′ and R″ are the same or different, and are selected from —H, —OR, —NRRg′, —COR, an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, an optionally substituted aryl having from 6 to 18 carbon atoms, an optionally substituted 3- to 18-membered heterocyclic ring having 1 to 6 heteroatoms selected from O, S, N and P, a PEG group —(CH2CH2O)n—Rc, wherein n is an integer from 1 to 24, preferably n is 2, 4 or 8;
- and Rg′ is —H, an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms or a PEG group —(CH2CH2O)n—Rc;
- X′ is selected from the group consisting of —H, —OH, an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, phenyl, and an amine-protecting group;
- Y′ is selected from the group consisting of —H, an oxo group, an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms;
- Rx is a linear or branched alkylene having 1 to 6 carbon atoms, optionally substituted with a charged substituent or an ionizable group Q;
- Re is —H or a linear or branched alkyl having 1 to 6 carbon atoms;
- G is selected from —CH— or —N—;
- Zs1 is selected from any one of the following formulas:
- wherein:
- q is an integer from 1 to 5;
- Rd is a linear or branched alkyl having 1 to 6 carbon atoms or is selected from phenyl, nitrophenyl, dinitrophenyl, carboxynitrophenyl, pyridyl and nitropyridyl;
- n is an integer from 2 to 6;
- U is —H or —SO3M;
- and
- M is —H+ or a cation.
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The conjugate of claim 26, wherein Re is —H or —Me.
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Dependencies are inferred from the claim text.