Conjugates of Pyrrolo[1,4]Benzodiazepine Dimers As Anticancer Agents

A process for the preparation of a conjugate, said process comprising:

• (i) bringing into contact and allowing to react an optionally buffered aqueous solution of a binding agent and a solution of a compound according to formula (I):
• wherein:
• represents a single bond or a double bond;
• R1 and R2, which are identical or different, represent, independently of one another:
• H, Hal or a (C1-C6)alkyl group optionally substituted by one or more substituent(s) chosen from:
• Hal, CN, NRR′, CF3, OR, an aryl or heteroaryl group, or S(O)qR with q=0, 1 or 2;
• or R1 and R2 together form a double bond ═CH2 or ═CH—CH3;
• R1′ and R2′, which are identical or different, represent, independently of one another:
• H, Hal or a (C1-C6)alkyl group optionally substituted by one or more substituent(s) chosen from:
• Hal, CN, NRR′, CF3, OR, an aryl or heteroaryl group, or S(O)qR with q=0, 1 or 2;
• or R1′ and R2′ together form a double bond ═CH2 or ═CH—CH3;
• Y and Y′, which are identical or different, represent, independently of one another, H or OR;
• M represents CH or N;
• ALK and ALK′, which are identical or different, represent, independently of one another, a (C1-C6)alkylene group;
• R and R′ represent, independently of one another, H or a (C1-C6)alkyl or aryl group optionally substituted by one or more substituent(s) chosen from:
• Hal, CN, NRR′, CF3, or an aryl or heteroaryl group;
• L represents an -L1-L2- group, wherein:
• L1 is attached to the aromatic ring comprising M via the ALK or OALK group and represents one of the following groups:
• -ALK-S—;
• —O-ALK-NR3-ALK-S—;
• and L2 represents the —CH2C(═O)—NR3—(CH2CH2O)i-ALK- group attached to L1 via —CH2C(═O)—;
• or L represents the —O-ALK-NR3-ALK-S—(CH2CH2O)i-ALK- group attached to the aromatic ring comprising M via the OALK group;
• R3 represents H or a (C1-C6)alkyl group;
• i represents an integer ranging from 1 to 40, rather from 1 to 20, preferably from 1 to 10;
• and
• Zb represents a single bond, —O— or —NH— and Rb represents H or a (C1-C6)alkyl, (C3-C7)cycloalkyl, aryl, heteroaryl or (C3-C7)heterocycloalkyl group;
• or Zb represents a single bond and Rb represents Hal;
• provided that when represents a single bond, then:
• represents a single bond;
• U and U′ each is H;
• and
• W and W′, which are identical or different, each represents, independently of one another, —OH, —OR, —OCOR, —COOR, —OCOOR, —OCONRR′, a cyclic carbamate such that N10 and C11 are included in a ring, —NRCONRR′, —OCSNHR, a cyclic thiocarbamate such that N10 and C11 are included in a ring, —SH, —SR, —SOR, —SOOR, —SO3−, —NRSOOR′, —NRR′, a cyclic amine such that N10 and C11 are included in a ring, —NROR′, —NRCOR′, —N3, —CN, Hal or a trialkylphosphonium or triarylphosphonium group;
• and
• (ii) optionally separating the conjugate formed in stage (i) from the compound of formula (I) and/or from the binding agent not having reacted and/or from the aggregates which might be formed.