Cytotoxic benzodiazepine derivatives

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:
• CBA is an antibody;
• one of L′, L″, and L′″ is represented by the following formula:
• —Z1—P—Z2—Rx-J′ (A′)
• and the other two 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, —(CH2CH2O)n—Rc, halogen, —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′, and —OCONR′R″;
• one of the Z1 and Z2 is —C(═O)—, and the other is —NR5—;
• P is an amino acid residue or a peptide containing between 2 to 20 amino acid residues;
• Rx is an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms;
• J′ is a moiety comprising —C(═O)—;
• 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 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 monocyclic heterocycle, —NR′(C═NH)NR′R″, an amino acid residue, or a peptide represented by —NRCOP′, —SR, —SOR′, halogen, cyano, azido, —OSO3H, —SO3H, H2S2O5, PO3SH3, PO2S2H2, POS3H2, PS4H2, (RiO)2PS(ORi), RiS—, RiSO, RiSO2, RiSO3, HS2O3, HS2O4, P(═S)(ORk′)(S)(OH), Rk′C(═O)NOH and HOCH2SO2−, or a mixture thereof, wherein Ri is a linear or branched alkyl having 1 to 10 carbon atoms and is substituted with at least one substituent selected from —N(Rj)2, —CO2H, —SO3H, and —PO3H;
• Ri can be further optionally substituted with a substituent for an alkyl described herein;
• Rj is a linear or branched alkyl having 1 to 6 carbon atoms;
• Rk′ is a linear, branched or cyclic alkyl, alkenyl or alkynyl having 1 to 10 carbon atoms, aryl, heterocyclyl or heteroaryl;
• P′ is an amino acid residue or a polypeptide containing 2 to 20 amino acid residues;
• 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, —(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, —(CH2CH2O)n—Rc, and an optionally substituted 3- to 18-membered heterocyclic ring having 1 to 6 heteroatoms independently selected from O, S, N and P;
• Rc is —H or a substituted or unsubstituted linear or branched alkyl having 1 to 4 carbon atoms;
• n is an integer from 1 to 24;
• R1, R2, R3, R4, R1′, R2′, R3′ and R4′ are each 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, —(CH2CH2O)n—Rc, halogen, NH(C═NH)NH2, —OR, —NR′R″, —NO2, —NCO, —NR′COR″, —SR, —SOR′, —SO2R′, —SO3H, —OSO3H, —SO2NR′R″, cyano, an azido, —COR′, —OCOR′, and —OCONR′R″;
• R6 is —H, —R, —OR, —SR, —NR′R″, —NO2, or halogen;
• G is —CH— or —N—;
• A and A′ are the same or different, and are independently selected from —O—, —C(═O)—, —CRR′O—, —CRR′—, —S—, —CRR′S—, —NR5 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;
• wherein the optional substituent described above is a linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, aryl, heteroaryl, heterocyclyl, halogen, —NH(C═NH)NH2, —OR100, NR101R102, —NO2, —NR101COR102, —SR100, —SOR101, —SO2R101, —SO3M, —OSO3M, —SO2NR101R102, cyano, an azido, —COR101, —OCOR101, —OCONR101R102 or a polyethylene glycol unit (—CH2CH2O)R101, wherein M is H or a cation;
• R100, R101, and R102 are each independently selected from H, linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, a polyethylene glycol unit (—CH2CH2O)n—R104, wherein n is an integer from 1 to 24, 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;
• and R104 is H or a linear or branched alkyl having 1 to 4 carbon atoms, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl in the groups represented by R100, R101, R102 and R104 are optionally substituted with one or more substituents independently selected from halogen, —OH, —CN, —NO2 and unsubstituted linear or branched alkyl having 1 to 4 carbon atoms.