# US 2014/0155590 A1 · Conjugates of Pyrrolo[1,4]Benzodiazepine Dimers As Anticancer Agents

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- Number: US 2014/0155590 A1
- Document ID: US20140155590A1
- Status: Published application
- Kind: A1
- Application number: 13/923,544
- Filed: 2013-06-21
- Published: 2014-06-05
- Earliest claimed: 2009-08-25
- Assignees: Sanofi
- Applicants: Sanofi
- Inventors: Alain Commercon; Laurence Gauzy-Lazo
- Web page: https://patentgrep.com/patent/US20140155590A1

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 35/00: Antineoplastic agents
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to pyrrolo[1,4]benzodiazepine (PBD) dimer conjugates, to the compositions comprising them and to their therapeutic application, in particular as anticancer agents. The invention also relates to the process for the preparation of the conjugates, to their application as anticancer agents and to the dimers themselves.

## Claims

### Claim at position 1

-9. (canceled)

### Claim 10

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.

### Claim 11 (depends on 10)

The process according to claim 10, in which the —C(═O)ZbRb group of said compound of formula (I) is reactive with regard to the chemical groups present on the binding agent, in particular with regard to the amino groups present on an antibody, so as to ensure the attachment of the compound of formula (I) to the binding agent by formation of a covalent bond.

### Claim 12 (depends on 10)

The process according to claim 10, in which step (ii) comprises:
separating the conjugate which has formed in stage (i) from the unreacted binding agent and from the aggregates possibly present in the solution;
or
separating the conjugate of stage (i) only from the unreacted compound of formula (I) and from the aggregates which might be formed and leaving in the solution the binding agent which might not have reacted.

### Claim 13 (depends on 10)

The process according to claim 10, in which the binding agent is a ligand, a protein, an antibody, a protein or antibody fragment, a peptide, an oligonucleotide or an oligosaccharide.

### Claim 14 (depends on 10)

The process according to claim 10, in which the reaction takes place at a temperature of between 20 and 40° C. and/or the duration of the reaction varies between 1 and 24 h.

### Claim 15 (depends on 10)

The process according to claim 10, in which, after stage (i) or (ii), the solution of the conjugate is subjected to a stage (iii) of ultrafiltration and/or of diafiltration.

### Claim at position 8

-38. (canceled)

### Claim 39 (depends on 10)

The process according to claim 10, wherein the compound of formula (I) is according to formula:

### Claim 40 (depends on 10)

The process according to claim 10, wherein the compound of formula (I) is according to formula (IA) or (IB):

### Claim 41 (depends on 10)

The process according to claim 10, wherein each of Y and Y′ represent, independently, a (C1-C4)alkoxy group.

### Claim 42 (depends on 41)

The process according to claim 41, wherein each of Y and Y′ represent a methoxy group.

### Claim 43 (depends on 10)

The process according to claim 10, wherein L is:
-ALK-S—CH2C(═O)—NH—(CH2CH2O)i—CH2CH2—;
—O-ALK-NR3-ALK-S—CH2C(═O)—NH—(CH2CH2O)i—CH2CH2;
or
—O-ALK-NR3-ALK-S—(CH2CH2O)i—CH2CH2.

### Claim 44 (depends on 10)

The process according to claim 10, wherein L is:

### Claim 45 (depends on 10)

The process according to claim 10, wherein L is:

### Claim 46 (depends on 10)

The process according to claim 10, wherein —COZbRb represents:
—COOH;
—COO(C1-C6)alkyl, —COOCH3, —COOCH2CH═CH2;
in which IG represents one or more inductive group,

### Claim 47 (depends on 46)

The process according to claim 46, in which IG represents:

### Claim 48 (depends on 10)

The process according to claim 10, wherein the compound of formula (I)
is