Targeted pyrrolobenzodiazapine conjugates

Patent metadata

Field	Value
Publication number	US-10561739-B2
Application number	US-201916381448-A
Country	US
Kind code	B2
Filing date	Apr 11, 2019
Priority date	Apr 15, 2010
Publication date	Feb 18, 2020
Grant date	Feb 18, 2020

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 method for preparing a Drug linker compound, or a salt thereof, the method comprising the steps of:
a) contacting a PBD compound having the formula of:

wherein —R 2 has the formula of:

wherein A is a C 5-7 aryl group and X is

wherein R N is selected from the group consisting of H and C 1-4 alkyl;
the asterisk indicates the point of attachment to Q 2 , and either:
(i) Q 1 is a single bond and Q 2 is a single bond or —Z—(CH 2 ) n —, wherein Z is selected from the group consisting of a single bond, O, S and NH; and subscript n is from 1 to 3, or
(ii) Q 1 is —CH═CH— and Q 2 is a single bond;
and
R 12 is a C 5-10 aryl group, substituted by a group selected from the group consisting of —OH, —CO 2 H, and —C 2 R O , where R O is 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, 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, wherein C 3-20 heterocyclyl is a monovalent moiety derived from 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;
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,
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 , wherein R N2 is H or C 1-4 alkyl, and/or by an aromatic ring;
Y and Y′ are independently 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, with a peptide coupling agent and a compound of formula G 1 -L 1 , wherein
L 1 is a dipeptide of formula —NH—X 1 —X 2 —CO 2 H, wherein —NH— is the amino group of X 1 , and CO 2 H is the carboxylic acid functional group of X 2 for peptide coupling by the peptide coupling agent to the nitrogen atom of X of the PBD compound and wherein the peptide is cleavable by the action of an enzyme for release of the PBD compound; and
G 1 is a Stretcher Unit for connection to an antibody or antigen-binding fragment thereof, wherein G 1 is comprised of a maleimide group for reaction with a reactive thiol functional group provided by the antibody or antigen-binding fragment for said connection, and wherein G 1 further comprises the functionality —CO— connected directly to the amino terminus of X 1 , thereby forming an amide link with —X 1 —,
wherein said contacting provides the Drug Linker compound having the formula of G 1 -L 1 -D, wherein G 1 is the Stretcher Unit and L 1 and D correspond in structure to the dipeptide and PBD compound, respectively.

2. The method of claim 1 , wherein G 1 is selected from the group consisting of:

wherein the asterisk indicates the point of attachment to the amino group of X 1 and subscript n is an integer ranging from 0 to 6,

wherein the asterisk indicates the point of attachment to the amino group of X 1 , subscript n is 0 or 1, and subscript m is an integer ranging from 0 to 30,

wherein the asterisk indicates the point of attachment to the amino group of X 1 and subscript n is an integer ranging from 0 to 6, and

wherein the asterisk indicates the point of attachment to the amino group of X 1 , subscript n is 0 or 1, and subscript m is an integer ranging from 0 to 30.

3. The method of claim 1 , wherein R 7 is selected from the group consisting of H, OH and OR.

4. The method of claim 2 , wherein R 7 is a C 1-4 alkyloxy group.

5. The method of claim 2 , wherein Y and Y′ are O.

6. The method of claim 5 , wherein R″ is C 3-7 alkylene.

7. The method of claim 6 , wherein R 9 is H.

8. The conjugate according to claim 7 , wherein R 6 is selected from the group consisting of H and halo.

9. The conjugate according to claim 1 , wherein A is phenyl, X is —NH 2 , and Q 1 is a single bond.

10. The conjugate according to claim 9 , wherein Q 1 is a single bond and Q 2 is a single bond.

11. The method of claim 1 , wherein R 12 is a C 5-7 aryl group optionally substituted by one or more substituents selected from the group consisting of halo, nitro, cyano, C 1-7 alkoxy, C 5-20 aryloxy, C 3-20 heterocyclyoxy, C 1-7 alkyl, C 3-7 heterocyclyl and bis-oxy-C 1-3 alkylene, wherein the C 1-7 alkoxy group is optionally substituted by an amino group, and if the C 3-7 heterocyclyl group is a C 6 nitrogen containing heterocyclyl group, it is optionally substituted by a C 1-4 alkyl group.

12. The method of claim 11 , wherein the C 5-7 aryl group is an optionally substituted phenyl group.

13. The method of claim 12 , wherein R 12 bears one to three substituent groups.

14. The method of claim 1 , wherein R 6′ , R 7′ , R 9′ , and Y′ are the same as R 6 , R 7 , R 9 , and Y, respectively.

15. The method of claim 1 , wherein G is:

wherein the asterisk indicates the point of attachment to L 1 ; and subscript n is an integer ranging from 0 to 6.

16. The method of claim 15 , wherein subscript n is 5.

17. The method of claim 16 , wherein the dipeptide is selected from the group consisting of valine-alanine, valine-citrulline and phenylalanine-lysine.

18. The conjugate of claim 1 , wherein the PBD compound has the formula:

19. The method of claim 1 , wherein G 1 -L 1 -D has the formula:

wherein subscript n is an integer ranging from 1 to 11; R′ is —CH 3 and R″ is CH(CH 3 ) 2 .

20. The method of claim 1 , wherein G 1 -L 1 -D has the formula:

21. The method of claim 1 , wherein the peptide coupling agent is N-ethoxylcarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ).

22. The method of claim 21 , wherein G 1 -L 1 -D has the formula of:

Assignees

• Seattle Genetics Inc
• Medimmune Ltd

Inventors

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

Classifications

• A61P43/00

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

• A61P37/06

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

• A61P37/02

  Immunomodulators · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title