Pyrrolobenzodiazepines and targeted conjugates

Patent metadata

Field	Value
Publication number	US-9387259-B2
Application number	US-201214351172-A
Country	US
Kind code	B2
Filing date	Oct 12, 2012
Priority date	Oct 14, 2011
Publication date	Jul 12, 2016
Grant date	Jul 12, 2016

Abstract

This invention relates to pyrrolobenzodiazepines (PBDs), in particular pyrrolobenzodiazepine dimers having a C2-C3 double bond and an aryl group at the C2 position in each monomer unit, and their inclusion in targeted conjugates. The differing substituent groups may offer advantages in the preparation and use of the compounds, particularly in their biological properties and the synthesis of conjugates, and the biological properties of these conjugates.

First claim

The invention claimed is:

1. A compound with the formula I:

or a pharmaceutically acceptable salt thereof,
wherein:
R 2 is of formula III:

where A is a C 5-7 aryl group, X is selected from the group consisting of:

and NHR N , wherein R N is selected from the group consisting of H and C 1-4 alkyl and either
(i) Q 1 is a single bond, and Q 2 is selected from a single bond and —Z—(CH 2 ) n —, where 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, substituted by a group selected from the group consisting of OH, CO 2 H, and CO 2 R O , where R O is selected from C 1-4 alkyl;
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, NHRR′, nitro, Me 3 Sn and halo;
where R and R′ are independently selected from optionally substituted C 1-12 alkyl, C 3-20 heterocyclyl and C 5-20 aryl groups;
either:
(a) R 10 is H, and R 11 is OH, OR A , where 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, where 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 selected from the group consisting of O, S, and NR N2 where R N2 is H or C 1-4 alkyl, and/or 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 , wherein if R 11 and R 11′ are SO z M, M may represent a divalent pharmaceutically acceptable cation.

2. A compound according to claim 1 , wherein R 7 is a C 1-4 alkyloxy group.

3. A compound according to claim 1 , wherein Y is O and R″ is C 3-7 alkylene.

4. A compound according to claim 1 , wherein R 9 is H and R 6 is selected from H and halo.

5. A compound according to claim 1 , wherein A is phenyl and X is NH 2 .

6. A compound according to claim 1 , wherein Q 1 is a single bond.

7. A compound according to claim 6 , wherein Q 2 is a single bond.

8. A compound according to claim 6 , wherein Q 2 is —Z—(CH 2 ) n —, Z is O or S and n is 1 or 2.

9. A compound according to claim 1 , wherein R 12 is phenyl.

10. A compound according to claim 1 , wherein R 12 is selected from the group consisting of: 4-hydroxy-phenyl, 3-hydroxyphenyl, 4-carboxy-phenyl, 3-carboxy-phenyl, 4-methyloxycarbonyl-phenyl, 3-methyloxycarbonyl-phenyl, 4-ethyloxycarbonyl-phenyl and 4-ethyloxycarbonyl-phenyl.

11. A compound according to claim 1 , wherein R 10 and R 11 form a nitrogen-carbon double bond.

12. A compound according to claim 1 , wherein R 6′ , R 7′ , R 9′ , R 10′ , R 11′ and Y′ are the same as R 6 , R 7 , R 9 , R 10 , R 11 and Y respectively.

13. A compound according to claim 1 , selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

14. A compound of formula II:

wherein:
R 2 is of formula III:

wherein A is a C 5-7 aryl group, X is selected from the group consisting of:

and NHR N , wherein R N is selected from the group consisting of H and C 1-4 alkyl and either
(i) Q 1 is a single bond, and Q 2 is selected from a single bond and —Z—(CH 2 ) n —, where 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, substituted by a group selected from the group consisting of OH, CO 2 H, and CO 2 R O , where R O is selected from C 1-4 alkyl;
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, NHRR′, nitro, Me 3 Sn and halo;
where R and R′ are independently selected from optionally substituted C 1-12 alkyl, C 3-20 heterocyclyl and C 5-20 aryl groups;
R″ is a C 3-12 alkylene group, which chain is optionally interrupted by one or more heteroatoms selected from the group consisting of O, S, and NR N2 , where R N2 is H or C 1-4 alkyl, and/or an aromatic ring;
Y and Y′ are selected from O, S, or NH;
R 6′ , R 7′ , R 9′ are selected from the same groups as R 6 , R 7 and R 9 respectively;
and either:
(a) R 10 is carbamate nitrogen protecting group, and R 11 is O-Prot O , wherein Prot O is an oxygen protecting group; or
(b) R 10 is a hemi-aminal nitrogen protecting group and R 11 is an oxo group;

and R 10′ and R 11′ are the same as R 10 and R 11 .

15. A compound according to claim 14 , wherein R 10 is Troc and R 11 is OTBS.

16. A compound according to claim 14 , wherein R 11 is oxo and R 10 is SEM.

17. A Conjugate having formula IV:
L-(LU-D) p   (IV)

or a pharmaceutically acceptable salt thereof;
wherein L is a Ligand unit selected from an antibody and an antigen-binding fragment of an antibody,
LU is a Linker unit is -A 1 -L 1 -, wherein A 1 is selected from the group consisting of:

where the asterisk indicates the point of attachment to L 1 , the wavy line indicates the point of attachment to the Ligand unit, and n is 0 to 6;

where the asterisk indicates the point of attachment to L 1 , the wavy line indicates the point of attachment to the Ligand unit, and n is 0 to 6;

where the asterisk indicates the point of attachment to L 1 , the wavy line indicates the point of attachment to the Ligand unit, n is 0 or 1, and m is 0 to 30; and

where the asterisk indicates the point of attachment to L 1 , the wavy line indicates the point of attachment to the Ligand unit, n is 0 or 1, and m is 0 to 30; and
L 1 comprises an amino acid sequence which is cleavable by the action of an enzyme,
p is 1 to 20; and
D is a Drug unit which is a PBD dimer with the formula

Assignees

• Seattle Genetics Inc
• Medimmune Ltd

Inventors

• Jeffrey Scott
• Burke Patrick
• Howard Philip Wilson

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P37/06

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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title