Targeted pyrrolobenzodiazapine conjugates

Patent metadata

Field	Value
Publication number	US-9592240-B2
Application number	US-201614995944-A
Country	US
Kind code	B2
Filing date	Jan 14, 2016
Priority date	Apr 15, 2010
Publication date	Mar 14, 2017
Grant date	Mar 14, 2017

Abstract

Provided are Conjugate comprising PBDs conjugated to a targeting agent and methods of using such PBDs.

First claim

The invention claimed is:

1. A Conjugate having formula I:
L-(LU-D)p  (I)

or a pharmaceutically acceptable salt thereof;
wherein L is a Ligand Unit selected from the group consisting of a full length antibody and an antigen binding fragment of a full length antibody;
LU is a Linker unit of formula X:

wherein E is of formula:

 the asterisk indicates the point of attachment to a Drug Unit and the wavy line indicates the point of attachment to the Ligand Unit, and
wherein:
-A 1 - is selected from the group consisting of:

wherein n is 0 to 6;

wherein n is 0 to 6;

wherein n is 0 or 1, and m is 0 to 30; and

wherein n is 0 or 1, and m is 0 to 30;
wherein the asterisk indicates the point of attachment to the nitrogen atom of Formula X, and the wavy line indicates the point of attachment to the Ligand unit;
p is 1 to 20; and
D is a Drug unit, wherein the Drug Unit is a PBD dimer of formula I:

wherein:
R 2 is of formula II:

wherein A is a C 5-7 aryl group, X is attached to the carbonyl carbon of Formula X and is selected from the group consisting of: —O—, —S—, —NH(C═O)—, and —N(R N )—, wherein R N is selected from the group consisting of H, C 1-4 alkyl and (C 2 H 4 O) m CH 3 , wherein m is 1 to 3; and either:
(i) Q 1 is a single bond and Q 2 is selected from the group consisting of a single bond and —Z—(CH 2 ) n —, wherein Z is selected from the group consisting of a single bond, O, S and NH and n is from 1 to 3, or
(ii) Q 1 is —CH═CH— and Q 2 is a single bond;
R 12 is a C 5-10 aryl group, optionally substituted by one or more substituents selected from the group consisting of halo, nitro, cyano, C 1-7 alkoxy, C 1-7 alkyl, C 3-7 heterocyclyl, dimethyl-aminopropyloxy, piperazinyl and bis-oxy-C 1-3 alkylene;
R 6 and R 9 are independently selected from the group consisting of H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo;
R 7 is selected from the group consisting of H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo, wherein R and R′ are independently selected from the group consisting of optionally substituted C 1-12 alkyl, C 3-20 heterocyclyl and C 5-20 aryl groups; and either:
(a) R 10 is H, and R 11 is OH or OR A , wherein R A is C 1-4 alkyl,
(b) R 10 and R 11 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound, or
(c) R 10 is H and R 11 is SO z M, wherein z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;
R″ is a C 3-12 alkylene group, which chain is optionally interrupted by one or more heteroatoms that are selected from the group consisting of O, S, and NH, or by an aromatic ring;
Y and Y′ are selected from the group consisting of O, S, and NH;
R 6′ , R 7′ , R 9′ are selected from the same groups as R 6 , R 7 and R 9 , respectively, and R 10′ and R 11′ are the same as R 10 and R 11 , respectively, wherein if R 11 and R 11′ are SO z M, then each M is a monovalent pharmaceutically acceptable cation or together is a divalent pharmaceutically acceptable cation;

wherein C 3-20 heterocyclyl is a monovalent moiety obtained by removing a hydrogen atom of a heterocyclic compound which has 3 to 20 ring atoms, of which 1 to 10 are heteroatoms selected from the group consisting of N, O and S; and
wherein C 3-7 heterocyclyl is a monovalent moiety obtained by removing a hydrogen atom of a heterocyclic compound which has 3 to 7 ring atoms, of which 1 to 4 are heteroatoms selected from the group consisting of N, O and S.

2. The Conjugate according to claim 1 wherein -LU-D is

wherein the wavy line indicates covalent attachment to the Ligand unit.

3. The Conjugate according to claim 2 wherein the Ligand unit is an antibody or an antigen-binding fragment thereof.

4. The Conjugate according to claim 3 wherein the monoclonal antibody is a humanized 1F6 antibody.

5. A compound having formula:
G 1 -L 1 -L 2 -D,
or a pharmaceutically acceptable salt thereof,
wherein -L 1 -L 2 - has the structure of formula X′:

wherein E is of formula:

 the asterisk indicates the point of attachment to a Drug Unit, and the way line indicates the point of attachment to G 1 , wherein:
G 1 - is selected from the group consisting of:

wherein n is 0 to 6;

wherein n is 0 to 6;

wherein n is 0 or 1, and m is 0 to 30;

wherein n is 0 or 1, and m is 0 to 30; and

wherein the asterisk indicates the point of attachment to the nitrogen atom of Formula X′, and D is a Drug unit, wherein the Drug Unit is a PBD dimer having formula I:

wherein:
R 2 is of formula II:

wherein A is a C 5-7 aryl group, X is attached to the carbonyl carbon of Formula X and is selected from the group consisting of: —O—, —S—, —NH(C═O)—, and —N(R N )—, wherein R N is selected from the group consisting of H, C 1-4 alkyl and (C 2 H 4 O) m CH 3 , wherein m is 1 to 3; and either:
(i) Q 1 is a single bond and Q 2 is selected from the group consisting of a single bond and —Z—(CH 2 ) n —, wherein Z is selected from the group consisting of a single bond, O, S and NH; and n is from 1 to 3, or
(ii) Q 1 is —CH═CH— and Q 2 is a single bond;
R 12 is a C 5-10 aryl group, optionally substituted by one or more substituents selected from the group consisting of halo, nitro, cyano, ether, C 1-7 alkoxy, C 3-7 heterocyclyl, dimethyl-aminopropyloxy, piperazinyl and bis-oxy-C 1-3 alkylene;
R 6 and R 9 are independently selected from the group consisting of H, R, OH, OR, SH, SR, NH 2 , NHR, NRR', nitro, Me 3 Sn and halo;
R 7 is selected from the group consisting of H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo, wherein R and R′ are

Assignees

• Seattle Genetics Inc
• Medimmune Ltd

Inventors

• Howard Philip Wilson
• Jeffrey Scott
• Burke Patrick
• Senter Peter

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title