Compounds and conjugates thereof

Patent metadata

Field	Value
Publication number	US-11446292-B2
Application number	US-202117348236-A
Country	US
Kind code	B2
Filing date	Jun 15, 2021
Priority date	Mar 29, 2019
Publication date	Sep 20, 2022
Grant date	Sep 20, 2022

Abstract

A conjugate comprising the following topoisomerase inhibitor derivative (A*):

with a linker for connecting to a Ligand Unit, wherein the linker is attached in a cleavable manner to the amino residue. The Ligand Unit is preferably an antibody. Also provided is A* with the linking unit attached, and intermediates for their synthesis, as well as the released warhead.

First claim

The invention claimed is:

1. A compound with the formula I:

and salts and solvates thereof, wherein R L is (Ia):

wherein
Q is:

(a) a dipeptide residue selected from:
NH -Phe-Lys- C═O ,
NH -Val-Ala- C═O ,
NH -Val-Lys- C═O ,
NH Ala-Lys- C═O ,
NH -Val-Cit- C═O ,
NH -Phe-Cit- C═O ,
NH -Leu-Cit- C═O ,
NH -Ile-Cit- C═O ,
NH -Phe-Arg- C═O ,
NH -Trp-Cit- C═O , and
NH -Gly-Val- C═O ; or

(b) a tripeptide residue selected from:
NH -Glu-Val-Ala- C═O ,
NH -Glu-Val-Cit- C═O ,
NH -αGlu-Val-Ala- C═O , and
NH -αGlu-Val-Cit- C═O ; or

(c) a tetrapeptide residue selected from:
NH -Gly-Gly-Phe-Gly C═O ; and
NH -Gly-Phe-Gly-Gly C═O ;
X is:

where a=0 to 5, b1=0 to 16, b2=0 to 16, c1=0 or 1, c2=0 or 1, d=0 to 5,

wherein at least b1 or b2=0 and at least c1 or c2=0; and
G L , is selected from:

2. The compound according to claim 1 , wherein a is:
(a) 0 to 3; or
(b) 0 or 1; or
(c) 0.

3. The compound according to claim 1 , wherein b1 is:
(a) 0 to 8; or
(b) 0; or
(c) 2; or
(d) 3; or
(e) 4; or
(f) 5; or
(g) 8.

4. The compound according to claim 1 , wherein b2 is:
(a) 0 to 8; or
(b) 0; or
(c) 2; or
(d) 3; or
(e) 4; or
(f) 5; or
(g) 8.

5. The compound according any to claim 1 , wherein
(i) c1 is:
(a) 0; or
(b) 1; and
(ii) c2 is:
(a) 0; or
(b) 1;
wherein at least one of c1 and c2 is 0.

6. The compound according to claim 1 , wherein d is:
(a) 0 to 3; or
(b) 1 or 2; or
(c) 2; or
(d) 5.

7. The compound according to claim 1 , wherein:
(a) a is 0, b1 is 0, c1 is 1, c2 is 0 and d is 2, and b2 is 0, 2, 3, 4, 5 or 8; or
(b) a is 1, b2 is 0, c1 is 0, c2 is 0 and d is 0, and b1 is 0, 2, 3, 4, 5 or 8; or
(c) a is 0, b1 is 0, c1 is 0, c2 is 0 and d is 1, and b2 is 0, 2, 3, 4, 5 or 8; or
(d) b1 is 0, b2 is 0, c1 is 0, c2 is 0, one of a and d is 0, and the other of a and d is 1 or 5; or
(e) a is 1, b2 is 0, c1 is 0, c2 is 1, d is 2, and b1 is 0, 2, 3, 4, 5 or 8.

8. A compound according to claim 1 , wherein G L is selected from G L1-1 G L1-2 .

9. A conjugate of formula IV:
L-(D L ) p   (IV)

or a pharmaceutically acceptable salt or solvate thereof, wherein L is a Ligand unit, D L is a Drug Linker unit that is of formula III:

R LL is a linker connected to the Ligand unit that is (Ia):

where Q and X are as defined in claim 1 and G LL is a linker connected to a Ligand Unit, wherein G LL is selected from

p is an integer of from 1 to 20,
and wherein the Ligand Unit is an antibody or an active fragment thereof.

10. The conjugate according to claim 9 , wherein G LL is selected from G LL1-1 and G LL1-2 .

11. A mixture of conjugates according to claim 9 , wherein the average drug loading per antibody in the mixture of antibody-drug conjugates is 1 to 10.

12. A pharmaceutical composition comprising the conjugate of claim 9 and a pharmaceutically acceptable diluent, carrier or excipient.

13. A compound according to claim 1 that is 1-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)-N—((S)-1-(((S)-1-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-4-yl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-amide.

14. A compound according to claim 1 that is (S)-2-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)acetamido)-N—((S)-1-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-4-yl)amino)-1-oxopropan-2-yl)-3-methylbutanamide.

15. A compound according to claim 1 that is N—((S)-1-(((S)-1-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-4-yl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)-4,7,10,13,16-pentaoxanonadec-18-ynamide.

Assignees

• Medimmune Ltd

Inventors

• Howard Philip Wilson
• Dickinson Niall
• Cailleau Thais
• Masterson Luke
• Goundry William

Classifications

• A61K31/4745 Primary

  condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48) · CPC title

• A61K47/6889

  Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment · CPC title

• A61K47/545

  Heterocyclic compounds (A61K47/558 takes precedence) · CPC title

• C07D491/22 Primary

  in which the condensed system contains four or more hetero rings · CPC title

• A61K47/6855

  the tumour determinant being from breast cancer cell · CPC title