Cytotoxic benzodiazepine derivatives

A method of treating a cancer in a mammal comprising administering to said mammal a therapeutically effective amount of a conjugate comprising a cytotoxic compound and a cell binding agent (CBA), wherein the cytotoxic compound comprises a linking group which covalently links the cytotoxic compound to the CBA, and wherein said cytotoxic compound represented by the following structural formula:

• 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, or a linear or branched alkyl having 1 to 4 carbon atoms, and when it is a single bond, X is —H, the linking group, or an amine protecting moiety;
• Y is a leaving group selected from —OR, —OCOR′, —OCOOR′, —OCONR′R″, —NR′R″, —NR′COR″, —NR′NR′R″, an optionally substituted 5- or 6-membered nitrogen-containing heterocycle, a guanidinum represented by —NR′(C═NH)NR′R″, an amino acid, or a peptide represented by —NRCOP′, wherein P′ is an amino acid or a polypeptide containing between 2 to 20 amino acid units, —SR, —SOR′, —SO2M, —SO3M, —OSO3M, halogen, cyano and an azido;
• M is —H or a cation;
• R, for each occurrence, is independently selected from the group consisting of —H, an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, a polyethylene glycol unit —(CH2CH2O)n—Rc, an optionally substituted aryl having 6 to 18 carbon atoms, an optionally substituted 5- to 18-membered heteroaryl ring containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 3- to 18-membered heterocyclic ring containing 1 to 6 heteroatoms independently selected from O, S, N and P;
• R′ and R″ are each independently selected from —H, —OH, —OR, —NHR, —NR2, —COR, an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, a polyethylene glycol unit —(CH2CH2O)n—Rc, and an optionally substituted 3-18-membered heterocyclic ring having 1 to 6 heteroatoms independently selected from O, S, N and P;
• Rc is —H or an optionally substituted linear or branched alkyl having 1 to 4 carbon atoms, or the linking group;
• n is an integer from 1 to 24;
• X′ is selected from —H, an amine-protecting group, the linking group, an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, a polyethylene glycol unit —(CH2CH2O)n—Rc, an optionally substituted aryl having 6 to 18 carbon atoms, an optionally substituted 5- to 18-membered heteroaryl ring containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an optionally substituted 3- to 18-membered heterocyclic ring containing 1 to 6 heteroatoms independently selected from O, S, N and P;
• Y′ is selected from —H, an oxo group, the linking group, an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, an optionally substituted 6- to 18-membered aryl, an optionally substituted 5- to 18-membered heteroaryl ring containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 3 to 18-membered heterocyclic ring having 1 to 6 heteroatoms;
• R6 is —H, —R, —OR, —SR, —NR′R″, —NO2, halogen or the linking group;
• A and A′ are the same or different, and are independently selected from —O—, oxo (—C(═O)—), —CRR′O—, —CRR′—, —S—, —CRR′S—, —N(R5)— and —CRR′N(R5)—,
• R5 for each occurrence is independently —H or an optionally substituted linear or branched alkyl having 1 to 10 carbon atoms;
• L′, L″, and L′″ are the same or different, and are independently selected from —H, an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, a polyethylene glycol unit —(OCH2CH2)n—Rc, halogen, guanidinium [—NH(C═NH)NH2], —OR, —NR′R″, —NO2, —NR′COR″, —SR, a sulfoxide represented by —SOR′, a sulfone represented by —SO2R′, a sulfonate —SO3M, a sulfate —OSO3M, a sulfonamide represented by —SO2NR′R″, cyano, an azido, —COR′, —OCOR′, —OCONR′R″ and the linking group, provided only one of L′, L″, and L′″ is the linking group;
• and
• G is selected from —CH— or —N—,
• provided that the compound is not any one of the following compounds:
• wherein the cancer is selected from the group consisting of leukemia, lymphoma, multiple myeloma, cervical cancer, non-small cell lung cancer, small-cell lung cancer, head and neck cancer and colon cancer;
• and
• the optional substituent described above is a linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, aryl, heteroaryl, heterocycyclyl, halogen, —NH(C═NH)NH2, —OR100, NR101R102, —NO2, —NR101COR102, —SR100, —SOR101, —SO2R101, —SO3M, —OSO3M, —SO2NR101R102, cyano, an azido, —COR101, —OCOR101, —OCONR101R102 and a polyethylene glycol unit (—OCH2CH2)nR101 wherein M is H or a cation;
• R100, R101, R102 and R103 are each independently selected from the group consisting of H, linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, a polyethylene glycol unit (—OCH2CH2)n—R104, an aryl having from 6 to 10 carbon atoms, a heterocyclic ring having from 3 to 10 carbon atoms and a heteroaryl having 5 to 10 carbon atoms;
• n is an integer from 1 to 24, and R104 is H or a linear or branched alkyl having 1 to 4 carbon atoms, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclcyl in the groups represented by R100, R101, R102, R103 and R104 are optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —CN, —NO2 and unsubstituted linear or branched alkyl having 1 to 4 carbon atoms.