US2022211863A1PendingUtilityA1
Compounds and conjugates thereof
Est. expiryMar 29, 2039(~12.7 yrs left)· nominal 20-yr term from priority
Inventors:Philip Wilson HowardNiall DickinsonThais CailleauLuke MastersonWilliam Robert Fraser Goundry
Y02P20/55A61K 47/65A61K 47/6803C07K 5/06052A61K 47/545A61K 47/68037A61K 31/4745C07D 491/22A61K 47/6855A61P 35/00A61K 47/6889
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Claims
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.
Claims
exact text as granted — not AI-modified1 . A compound with the formula I:
and salts and solvates thereof, wherein R L is a linker for connection to a Ligand Unit, which is selected from:
(ia):
wherein
Q is:
where Q X is such that Q is an amino-acid residue, a dipeptide residue, a tripeptide residue or a tetrapeptide residue;
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;
G L is a linker for connecting to a Ligand Unit;
(ib):
where R L1 and R L2 are independently selected from H and methyl, or together with the carbon atom to which they are bound form a cyclopropylene or cyclobutylene group; and
e is 0 or 1.
2 . The compound according to claim 1 , wherein R L is of formula Ia.
3 . The compound according to claim 2 , wherein Q is:
(a) an amino acid residue selected from: Phe, Lys, Val, Ala, Cit, Leu, Ile, Arg, and Trp; or (b) 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
(c) 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
(d) a tetrapeptide residue selected from:
NH -Gly-Gly-Phe-Gly C═O ; and
NH -Gly-Phe-Gly-Gly C═O .
4 . The compound according to either claim 2 or claim 3 , wherein a is:
(a) 0 to 3; or
(b) 0 or 1; or
(c) 0.
5 . The compound according to any one of claims 2 to 4 , 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.
6 . The compound according to any one of claims 2 to 4 , 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.
7 . The compound according any to one of claims 2 to 6 , 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.
8 . The compound according to any one of claims 2 to 7 , wherein d is:
(a) 0 to 3; or
(b) 1 or 2; or
(c) 2; or
(d) 5.
9 . The compound according to any one of claims 2 to 8 , 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.
10 . The compound according to any one of claims 2 to 9 , wherein G L is selected from
where Ar represents a C 5-6 arylene group, and X represents C 1-4 alkyl.
11 . A compound according to claim 10 , wherein G L is selected from G L1-1 and G L1-2 .
12 . The compound according to claim 1 , wherein R L is of formula Ib, and:
(a) both R L1 and R L2 are H; or (b) R L1 is H and R L2 is methyl; or (c) both R L1 and R L2 are methyl; or (d) wherein R L1 and R L2 together with the carbon atom to which they are bound form a cyclopropylene group; or (e) wherein R L1 and R L2 together with the carbon atom to which they are bound form a cyclobutylene group.
13 . 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 selected from
(ia′):
where Q and X are as defined in any one of claims 1 to 9 and G LL is a linker connected to a Ligand Unit; and
(ib′):
where R L1 and R L2 are as defined in either claim 1 or claim 12 ; and
p is an integer of from 1 to 20.
14 . The conjugate according to claim 13 , wherein G LL is selected from:
where Ar represents a C 5-6 arylene group and X represents C 1-4 alkyl.
15 . The conjugate according to claim 14 , wherein G LL is selected from G LL1-1 and G LL1-2 .
16 . The conjugate according to any one of claims 13 to 15 , wherein the Ligand Unit is an antibody or an active fragment thereof.
17 . The conjugate according to claim 16 , wherein the drug loading (p) of drugs (D) to antibody (Ab) is an integer from 1 to about 10.
18 . A mixture of conjugates according to either claim 16 or claim 17 , wherein the average drug loading per antibody in the mixture of antibody-drug conjugates is about 1 to about 10.
19 . A pharmaceutical composition comprising the conjugate or mixture of any one of claims 13 to 18 and a pharmaceutically acceptable diluent, carrier or excipient.
20 . The conjugate or mixture according to any one of claims 13 to 18 , or the pharmaceutical composition according to claim 19 , for use in the treatment of a proliferative disease in a subject.
21 . The conjugate, mixture or pharmaceutical composition according to claim 20 , wherein the disease is cancer.
22 . Use of a conjugate or mixture according to any one of claims 13 to 18 , or the pharmaceutical composition according to claim 19 in a method of medical treatment.
23 . A method of medical treatment comprising administering to a patient the pharmaceutical composition of claim 19 .
24 . The method of claim 23 wherein the method of medical treatment is for treating cancer.
25 . The compound A:
as a single enantiomer or in an enantiomerically enriched form.
26 . A compound with the formula VI:
where Q is as in either claim 1 or 3 .Join the waitlist — get patent alerts
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