US2021113710A1PendingUtilityA1
Hydrophilic self-immolative linkers and conjugates thereof
Est. expiryDec 21, 2032(~6.4 yrs left)· nominal 20-yr term from priority
A61K 47/6803A61K 47/6851A61K 47/68031A61K 31/404C07K 17/06C07D 241/36A61K 47/6889A61K 47/6863A61K 47/60A61K 31/496C07D 295/192A61K 47/6817A61P 35/00A61K 47/65A61K 38/06C07D 417/14A61K 31/407A61P 15/00A61P 11/00C07D 295/182A61P 1/18C07K 7/02A61P 1/04
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Claims
Abstract
The present disclosure provides compounds with a hydrophilic self-immolative linker, which is cleavable under appropriate conditions and incorporates a hydrophilic group to provide better solubility of the compound. The compounds of the present disclosure comprise a drug moiety, a targeting moiety capable of targeting a selected cell population, and a linker which contains an acyl unit, an optional spacer unit for providing distance between the drug moiety and the targeting moiety, a peptide linker which can be cleavable under appropriate conditions, a hydrophilic self-immolative linker, and an optional second self-immolative spacer or cyclization self-elimination linker.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of the formula (I):
or a salt or solvate or stereoisomer thereof;
wherein:
D is drug moiety;
T is a targeting moiety;
X is a hydrophilic self-immolative linker;
L 1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
L 2 is a bond or a second self-immolative linker;
wherein if L 1 is a second self-immolative linker or a cyclization self-elimination linker, then L 2 is a bond;
wherein if L 2 is a second self-immolative linker, then L l is a bond;
L 3 is a peptide linker;
L 4 is bond or a spacer; and
A is an acyl unit.
2 . A compound of the formula (II):
or a salt or solvate or stereoisomer thereof;
wherein:
D is drug moiety;
T is a targeting moiety;
R 1 is hydrogen, unsubstituted or substituted C 1-3 alkyl, or unsubstituted or substituted heterocyclyl;
L 1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
L 2 is a bond or a second self-immolative linker;
wherein if L 1 is a second self-immolative linker or a cyclization self-elimination linker, then L 2 is a bond;
wherein if L 2 is a second self-immolative linker, then L 1 is a bond;
L 3 is a peptide linker;
L 4 is bond or a spacer; and
A is an acyl unit.
3 . A compound of the formula (Ia):
or a salt or solvate or stereoisomer thereof;
wherein:
p is 1 to 20;
D is drug moiety;
T is a targeting moiety;
X is a hydrophilic self-immolative linker;
L 1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
L 2 is a bond or a second self-immolative linker;
wherein if L 1 is a second self-immolative linker or a cyclization self-elimination linker, then L 2 is a bond;
wherein if L 2 is a second self-immolative linker, then L 1 is a bond;
L 3 is a peptide linker;
L 4 is bond or a spacer; and
A is an acyl unit.
4 . A compound of the formula (II):
or a salt or solvate or stereoisomer thereof;
wherein:
p is 1 to 20;
D is drug moiety;
T is a targeting moiety;
R 1 is hydrogen, unsubstituted or substituted C 1-3 alkyl, or unsubstituted or substituted heterocyclyl;
L 1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
L 2 is a bond or a second self-immolative linker;
wherein if L 1 is a second self-immolative linker or a cyclization self-elimination linker, then L 2 is a bond;
wherein if L 2 is a second self-immolative linker, then L 1 is a bond;
L 3 is a peptide linker;
L 4 is bond or a spacer; and
A is an acyl unit.
5 . The compound of claim 3 or 4 , wherein p is 1 to 4.
6 . The compound of any one of claims 1 to 5 , wherein L 1 is a bond.
7 . The compound of any one of claims 1 to 5 , wherein L 1 is a second self-immolative linker or a cyclization self-elimination linker.
8 . The compound of claim 7 , wherein L 1 is an aminobenzyloxycarbonyl linker.
9 . The compound of claim 7 , wherein L 1 is selected from the group consisting of
wherein n is 1 or 2.
10 . The compound of claim 7 , wherein L 1 is selected from the group consisting of
11 . The compound of any one of claims 1 to 10 , wherein L 2 is a bond.
12 . The compound of claim 6 , wherein L 2 is a second self-immolative linker.
13 . The compound of claim 12 , wherein L 2 is an aminobenzyloxycarbonyl linker.
14 . The compound of claim 12 , wherein L 2 is selected from
wherein n is 1 or 2.
15 . The compound of any one of claims 1 to 14 , wherein L 3 is a peptide linker of 1 to 10 amino acid residues.
16 . The compound of claim 15 , wherein L 3 is a peptide linker of 2 to 4 amino acid residues.
17 . The compound of any one of claims 1 to 5 , wherein L 3 is a peptide linker comprising at least one lysine or arginine residue.
18 . The compound of any one of claims 1 to 16 , wherein L 3 is a peptide linker comprising an amino acid residue selected from lysine, D-lysine, citrulline, arginine, proline, histidine, ornithine and glutamine
19 . The compound of any of claims 1 to 16 , wherein L 3 is a peptide linker comprising an amino acid residue selected from valine, isoleucine, phenylalanine, methionine, asparagine, proline, alanine, leucine, tryptophan, and tyrosine.
20 . The compound of claim 15 , wherein L 3 is a dipeptide unit selected from valine-citrulline, proline-lysine, methionine-D-lysine, asparagine-D-lysine, isoleucine-proline, phenylalanine- lysine, and valine-lysine.
21 . The compound of claim 20 , wherein L 3 is valine-citrulline.
22 . The compound of any one of claims 1 to 21 , wherein L 4 is a bond.
23 . The compound of any one of claims 1 to 21 , wherein L 4 is a spacer.
24 . The compound of claim 23 , wherein the spacer is polyalkylene glycol, alkylene, alkenylene, alkynylene, or polyamine.
25 . The compound of claim 23 , wherein L 4 is L 4a -C(O), L 4a -C(O)—NH, L 4a -S(O) 2 , or L 4a -S(O) 2 —NH, wherein each L 4 a is independently polyalkylene glycol, alkylene, alkenylene, alkynylene, or polyamine
26 . The compound of claim 23 , wherein L 4 is L 4a -C(O), wherein L 4a is polyalkylene glycol, alkylene, alkenylene, alkynylene, or polyamine
27 . The compound of claim 23 , wherein L 4 is L 4a -C(O), wherein L 1 is a polyalkylene glycol.
28 . The compound of claim 23 , wherein L 4 is L 4a -C(O), wherein L 1 is a polyethylene glycol.
29 . The compound of claim 23 , wherein the spacer is of the formula —CH 2 —(CH 2 —O—CH 2 )m-CH 2 —C(O)—, wherein m is an integer from 0 to 30.
30 . The compound of claim 23 , wherein L 4 is L 4a -C(O), wherein L 1 is alkylene.
31 . The compound of any of claims 1 to 30 , wherein A is selected from the group consisting of
wherein each Q 2 is NH or O, and each q is independently an integer from 1 to 10.
32 . The compound of claim 31 , wherein A is selected from the group consisting of
wherein each Q 2 is independently NH or O and each q is independently an integer from 1 to 10.
33 . The compound of claim 32 , wherein q is 2, 3, 4, or 5.
34 . The compound of any of claims 1 to 30 , wherein A is selected from the group consisting of
wherein each Q 2 is independently NH or O.
35 . The compound of any one of claims 1 to 34 , wherein T is an antibody targeting molecule.
36 . The compound of claim 35 , wherein T is h5F1Ca.1 or c5D7.
37 . The compound of claim 35 or 36 , wherein one or more amino acid residues of the heavy chain and/or the light chain is replaced with a cysteine residue.
38 . The compound of any one of claims 35 - 37 , wherein one or more amino acid residues of the heavy chain is replaced with a cysteine residue.
39 . The compound of any one of claims 35 - 37 , wherein one or more amino acid residues of the Fc region of the antibody is replaced with a cysteine residue.
40 . The compound of claim 39 , wherein the one or more amino acid residues of the Fc region of the antibody is at position 157, 169 and/or 442 using EU numbering.
41 . The compound of any one of claims 35 - 40 , wherein D is linked to T by way of the added cysteine residue.
42 . The compound of any one of claims 1 to 41 , wherein D is an amino-containing drug moiety, wherein the drug is connected to L 1 or X through the amino group.
43 . The compound of claim 42 , wherein D is duocarmycin, dolastatin, tubulysin, doxorubicin (DOX), paclitaxel, or mitomycin C (MMC), or an amino derivative thereof.
44 . The compound of claim 42 , wherein D is an amino derivative of duocarmycin selected from the group consisting of
45 . The compound of claim 42 , wherein D is dolastatin:
46 . The compound of any one of claims 1 to 5 , wherein -A-L 4 -L 3 -L 2 - is
47 . The compound of any one of claims 1 to 5 , wherein -A-L 4 -L 3 -L 2 -X-L 1 -D is:
48 . The compound of any one of claims 1 to 5 , wherein -A-L 4 -L 3 -L 2 -X-L 1 -D is:
49 . The compound of any one of claims 1 to 5 , wherein -A-L 4 -L 3 -L 2 -X-L 1 -D is:
50 . A pharmaceutical composition comprising a compound of any one of claims 1 to 49 , or a salt or solvate or stereoisomer thereof; and a pharmaceutically acceptable carrier.
51 . A method of killing a cell, comprising administering to the cell an amount of the compound of any one of claims 1 to 49 , or a salt or solvate or stereoisomer thereof, sufficient to kill the cell.
52 . The method of claim 51 , wherein the cell is a cancer cell.
53 . The method of claim 52 , wherein the cancer cell is a gastric cancer cell, pancreatic cancer cell, colorectal cancer cell, lung cancer cell or ovarian cancer cell.
54 . A method of treating cancer in an individual in need thereof comprising administering to the individual an effective amount of a compound of any one of claims 1 to 49 , or a salt or solvate or stereoisomer thereof.
55 . The method of claim 54 , wherein the cancer is gastric cancer, pancreatic cancer, colorectal cancer, lung cancer or ovarian cancer.
56 . A kit comprising a compound of any one of claims 1 to 49 , or a salt or solvate or stereoisomer thereof.
57 . The kit of claim 56 , further comprising instructions for use in the treatment of cancer.
58 . A process for making a compound of formula (II):
or a salt or solvate or stereoisomer thereof;
wherein:
D is drug moiety;
T is an antibody;
R 1 is hydrogen, unsubstituted or substituted C 1-3 alkyl, or unsubstituted or substituted heterocyclyl;
L 1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
L 2 is a bond or a second self-immolative linker;
wherein if L 1 is a second self-immolative linker or a cyclization self-elimination linker, then L 2 is a bond;
wherein if L 2 is a second self-immolative linker, then L 1 is a bond;
L 3 is a peptide linker;
L 4 is bond or a spacer; and
A is an acyl unit;
comprising reacting an antibody with Compound Z:
or a salt or solvate or stereoisomer thereof.
59 . A process for making a compound of formula (IIa):
or a salt or solvate or stereoisomer thereof;
wherein:
p is 1 to 20;
D is drug moiety;
T is an antibody;
R 1 is hydrogen, unsubstituted or substituted C 1-3 alkyl, or unsubstituted or substituted heterocyclyl;
L 1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
L 2 is a bond or a second self-immolative linker;
wherein if L 1 is a second self-immolative linker or a cyclization self-elimination linker, then L 2 is a bond;
wherein if L 2 is a second self-immolative linker, then L 1 is a bond;
L 3 is a peptide linker;
L 4 is bond or a spacer; and
A is an acyl unit;
comprising reacting an antibody with Compound Z:
or a salt or solvate or stereoisomer thereof.
60 . The process of claim 59 , wherein the antibody comprises one or more sulfhydryl groups.
61 . A compound, or a salt or solvate or stereoisomer thereof, wherein the compound is prepared by a process according to any one of claims 58 to 60 , wherein the antibody comprises one or more sulfhydryl groups.
62 . A pharmaceutical composition comprising the compound of claim 61 , or a salt or solvate or stereoisomer thereof, and a pharmaceutically acceptable carrier.
63 . A compound of Formula (XII)
or a salt or solvate or stereoisomer thereof; wherein R is NO 2 or NH 2 .
64 . A method of preparing Compound X:
or a salt or solvate or stereoisomer thereof;
wherein:
L 2 is a bond or a second self-immolative linker;
wherein if L 1 is a second self-immolative linker or a cyclization self-elimination linker, then L 2 is a bond;
wherein if L 2 is a second self-immolative linker, then L 1 is a bond;
L 3 is a peptide linker;
L 4 is bond or a spacer; and
A is an acyl unit; and
R 1 is NO 2 or NH 2 ;
comprising reacting Compound W: A-L 4 -L 3 -L 2 ; and Compound I:
65 . A method of preparing Compound Z:
or a salt or solvate or stereoisomer thereof;
wherein:
D is drug moiety;
L 1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
L 2 is a bond or a second self-immolative linker;
wherein if L 1 is a second self-immolative linker or a cyclization self-elimination linker, then L 2 is a bond;
wherein if L 2 is a second self-immolative linker, then L 1 is a bond;
L 3 is a peptide linker;
L 4 is bond or a spacer; and
A is an acyl unit
R 1 is NO 2 or NH 2 ;
comprising: reacting Compound X:
and p-nitrophenylchloroformate to form Compound Y:
reacting Compound Y with a compound comprising L 1 -D.
66 . A method of preparing Compound X 1 :
or a salt or solvate or stereoisomer thereof;
wherein:
L 2 is a bond or a second self-immolative linker;
wherein if L 1 is a second self-immolative linker or a cyclization self-elimination linker, then L 2 is a bond;
wherein if L 2 is a second self-immolative linker, then L 1 is a bond;
L 3 is a peptide linker; and
R 1 is NO 2 or NH 2 ;
comprising: reacting Compound W 1 : L 3 -L 2 ; and Compound I:
67 . A method of preparing Compound Y 1 :
or a salt or solvate or stereoisomer thereof;
wherein:
D is drug moiety;
L 1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
L 2 is a bond or a second self-immolative linker;
wherein if L 1 is a second self-immolative linker or a cyclization self-elimination linker, then L 2 is a bond;
wherein if L 2 is a second self-immolative linker, then L 1 is a bond;
L 3 is a peptide linker; and
R 1 is NO 2 or NH 2 ;
comprising: reacting Compound X 1 :
and a compound comprising L 1 -D.
68 . A method of preparing Compound Z:
or a salt or solvate or stereoisomer thereof;
wherein:
D is drug moiety;
L 1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
L 2 is a bond or a second self-immolative linker;
wherein if L 1 is a second self-immolative linker or a cyclization self-elimination linker, then L 2 is a bond;
wherein if L 2 is a second self-immolative linker, then L 1 is a bond;
L 3 is a peptide linker;
L 4 is bond or a spacer;
A is an acyl unit; and
R 1 is NO 2 or NH 2 ;
comprising: reacting Compound Y 1 :
and a compound comprising A-L 4 .
69 . A compound of formula:
or a salt or solvate or stereoisomer thereof;
wherein:
L 2 is a bond or a second self-immolative linker;
wherein if L 1 is a second self-immolative linker or a cyclization self-elimination linker, then L 2 is a bond;
wherein if L 2 is a second self-immolative linker, then L 1 is a bond;
L 3 is a peptide linker;
L 4 is bond or a spacer; and
A is an acyl unit; and
R 1 is NO 2 or NH 2 .
70 . A compound of formula:
or a salt or solvate or stereoisomer thereof;
wherein:
D is drug moiety;
L 1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
L 2 is a bond or a second self-immolative linker;
wherein if L 1 is a second self-immolative linker or a cyclization self-elimination linker, then L 2 is a bond;
wherein if L 2 is a second self-immolative linker, then L 1 is a bond;
L 3 is a peptide linker;
L 4 is bond or a spacer; and
A is an acyl unit; and
R 1 is NO 2 or NH 2 .
71 . A compound of formula:
or a salt or solvate or stereoisomer thereof;
wherein:
L 2 is a bond or a second self-immolative linker;
wherein if L 1 is a second self-immolative linker or a cyclization self-elimination linker, then L 2 is a bond;
wherein if L 2 is a second self-immolative linker, then L 1 is a bond;
L 3 is a peptide linker; and
R 1 is NO 2 or NH 2 .
72 . A compound of formula:
or a salt or solvate or stereoisomer thereof;
wherein:
D is drug moiety;
L 1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
L 2 is a bond or a second self-immolative linker;
wherein if L 1 is a second self-immolative linker or a cyclization self-elimination linker, then L 2 is a bond;
wherein if L 2 is a second self-immolative linker, then L 1 is a bond;
L 3 is a peptide linker; and
R 1 is NO 2 or NH 2 .Cited by (0)
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