Pyrrolobenzodiazepine conjugates

Patent metadata

Field	Value
Publication number	US-11370801-B2
Application number	US-201816605962-A
Country	US
Kind code	B2
Filing date	Apr 18, 2018
Priority date	Apr 18, 2017
Publication date	Jun 28, 2022
Grant date	Jun 28, 2022

Abstract

A compound of formula I and salts and solvates thereof, wherein: R6 and R9 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR′, nitro, Me3Sn and halo; where R and R′ are independently selected from optionally substituted C1-12 alkyl, C3-20 heterocyclyl and C5-20 aryl groups; R7 is selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR′, nitro, Me3Sn and halo; R″ is a C3-12 alkylene group, which chain may be interrupted by one or more heteroatoms, e.g. O, S, NRN2 (where RN2 is H or C1-4 alkyl), and/or aromatic rings, e.g. benzene or pyridine; Y and Y′ are selected from O, S, or NH; R6, R7, R9 are selected from the same groups as R6, R7 and R9 respectively; R11b is selected from OH, ORA, where RA is C1-4 alkyl; and RL is a linker for connection to a cell binding agent.

First claim

The invention claimed is:

1. A compound of formula I:

R 6 and R 9 are independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, 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 7 is selected from 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 may be interrupted by one or more heteroatoms selected from O, S, NR N2 (where R N2 is H or C 1-4 alkyl), and/or aromatic rings selected from benzene or pyridine;
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;
R 11b is selected from OH, OR A , where R A is C 1-4 alkyl; and
R L is a linker for connection to a cell binding agent, which has the formula IIIa:

wherein
Q is:

where Q X is such that Q is an amino-acid residue, a dipeptide residue or a tripeptide residue;
X is:

where a=0 to 5, b=0 to 16, c=0 or 1, d=0 to 5;
G L is a linker for connecting to a Ligand Unit; and
either
(a) R 20 is H, and R 21 is OH or OR A , where R A is C 1-4 alkyl; or
(b) R 20 and R 21 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound; or
(c) R 20 is H and R 21 is SO z M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation; or
(d) R 20 is H and R 21 is H; or
(e) R 21 is OH or OR A , where R A is C 1-4 alkyl and R 20 is selected from:
(d-i)

(d-ii)

(d-iii)

 where R Z is selected from:
(z-i)

(z-ii) OC(═O)CH 3 ;
(z-iii) NO 2 ;
(z-iv) OMe; and
(z-v) —C(═)—X 1 —NHC(═O)X 2 —NH—R ZC , where —C(═O)—X 1 —NH— and —C(═O)—X 2 —NH— represent natural amino acid residues and R ZC is selected from Me, OMe, OCH 2 CH 2 OMe.

2. The compound according to claim 1 , wherein both and Y′ are O and R″ is:
(a) C 3-7 alkylene; or
(b) a group of formula:

where r is 1 or 2.

3. The compound according to claim 1 , wherein R 9 is H and R 6 is H.

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

5. The compound according to claim 1 , wherein RU is the same group as R 6 , R 7′ is the same group as R 7 , R 9′ is the same group as R 9 and Y′ is the same group as Y.

6. The compound according to claim 1 , wherein R 20 and R 21 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound.

7. The compound according to claim 1 , which is of formula Ia, Ib or Ic:

where R 1a is selected from methyl and benzyl;
R L and R 11b are as defined in claim 1 .

8. The compound according to claim 1 , wherein R 11b is OH.

9. The compound according to claim 1 , wherein Q is a dipeptide residue selected from:
CO -Phe-Lys- NH ,
CO -Val-Ala- NH ,
CO -Val-Lys- NH ,
CO -Ala-Lys- NH ,
CO -Val-Cit- NH ,
CO -Phe-Cit- NH ,
CO -Leu-Cit- NH ,
CO -Ile-Cit- NH ,
CO -Phe-Arg- NH , and
CO -Trp-Cit- NH .

10. The compound according to claim 1 , wherein a is 0.

11. The compound according to claim 1 , wherein b is 0 to 8.

12. The compound according to claim 1 , wherein d is 2.

13. The compound according to claim 1 , wherein G L is selected from:

where Ar represents a C 5-6 arylene group, and Hal represents I, Br or Cl.

14. The compound according to claim 13 , wherein G L is G L1-1 .

15. The compound according to claim 1 , wherein the compound is of formula Id:

where Q′ is selected from:
(a) —CH 2 —;
(b) —C 3 H 6 —; and
(c)

16. A conjugate of formula II:
L-(D L ) p   (II)

wherein L is a Ligand unit, D L is a Drug Linker unit of formula I′:

wherein R 6 , R 7 , R 9 , R 11b , Y, R″, Y′, R 6′ , R 7 , R 9′ , R 20 and R 21 , are as defined in claim 1 ;
R LL is a linker for connection to the ligand unit, which has the formula IIIa′:

where Q and X are as defined in claim 1 and G LL is a linker connected to a Ligand Unit;
and
wherein p is an integer of from 1 to 20.

17. The conjugate according to claim 16 , wherein is selected from:

where Ar represents a C 5-6 arylene group.

18. The conjugate according to claim 17 , wherein G LL is G LL1-1 .

19. The conjugate according to claim 16 , wherein D L is of formula (Id′):

where Q′ is selected from:
(a) —CH 2 —;
(b) —C 3 H 6 —; and
(c)

20. The conjugate according to claim 16 , wherein the Ligand Unit is an antibody or an active fragment thereof which binds to one or more tumor-associated antigens or cell-surface receptors selected from:
(1) BMPR1B;
(2) E16;
(3) STEAP1;
(4) 0772P;
(5) MPF;
(6) Napi3b;
(7) Sema 5b;
(8) PSCA hlg;
(9) ETBR;
(10) MSG783;
(11) STEAP2;
(12) TrpM4;
(13) CRIPTO;
(14) CD21;
(15) CD79b;
(16) FcRH2;
(17) H

Assignees

• Medimmune Ltd

Inventors

• Howard Philip Wilson
• Gregson Stephen John

Classifications

• A61K47/68035

  the drug being a pyrrolobenzodiazepine · CPC title

• A61K47/6855

  the tumour determinant being from breast cancer cell · CPC title

• A61K47/68

  the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment · CPC title

• C07D519/00 Primary

  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 · CPC title

• C07K5/06

  Dipeptides · CPC title