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US 9,089,614 B2Granted
Hydrophilic self-immolative linkers and conjugates thereof
AssigneesBioAlliance C.V., AbGenomics International Inc.
InventorsRong-Hwa Lin, Shih-Yao Lin, Yu-Chi Hsieh, Chiu-Chen Huang
Life of this patent
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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.
Claims59
A compound of the formula (II):
- or a salt or solvate or stereoisomer thereof;
- wherein:
- D is a drug moiety;
- T is a targeting moiety;
- R1 is hydrogen, unsubstituted or substituted C1-3 alkyl, or unsubstituted or substituted heterocyclyl;
- L1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
- L2 is a bond or a second self-immolative linker;
- wherein if L1 is a second self-immolative linker or a cyclization self-elimination linker, then L2 is a bond;
- wherein if L2 is a second self-immolative linker, then L1 is a bond;
- L3 is a peptide linker;
- L4 is bond or a spacer;
- and
- A is an acyl unit.
10 more elements
A compound of Formula (XII)
- or a salt or solvate or stereoisomer thereof;
- wherein R is NO2 or NH2.
A method of preparing Compound X:
- or a salt or solvate or stereoisomer thereof;
- wherein:
- L2 is a bond or a second self-immolative linker;
- L3 is a peptide linker;
- L4 is bond or a spacer;
- and
- A is an acyl unit;
- and
- R1 is hydrogen, unsubstituted or substituted C1-3 alkyl, or unsubstituted or substituted heterocyclyl;
- comprising reacting Compound W:
- A-L4-L3-L2;
- and Compound I:
9 more elements
A method of preparing Compound Z:
- or a salt or solvate or stereoisomer thereof;
- wherein:
- D is a drug moiety;
- L1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
- L2 is a bond or a second self-immolative linker;
- wherein if L1 is a second self-immolative linker or a cyclization self-elimination linker, then L2 is a bond;
- wherein if L2 is a second self-immolative linker, then L1 is a bond;
- L3 is a peptide linker;
- L4 is bond or a spacer;
- and
- A is an acyl unit R1 is hydrogen, unsubstituted or substituted C1-3 alkyl, or unsubstituted or substituted heterocyclyl;
- comprising:
- reacting Compound X:
- and p-nitrophenyl chloroformate to form Compound Y:
- reacting Compound Y with a compound comprising L1-D.
12 more elements
A method of preparing Compound X1:
- or a salt or solvate or stereoisomer thereof;
- wherein:
- L2 is a bond or a second self-immolative linker;
- L3 is a peptide linker;
- and
- R1 is hydrogen, unsubstituted or substituted C1-3 alkyl, or unsubstituted or substituted heterocyclyl;
- comprising:
- reacting Compound W1:
- L3-L2;
- and Compound I:
7 more elements
A method of preparing Compound Y1:
- or a salt or solvate or stereoisomer thereof;
- wherein:
- D is a drug moiety;
- L1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
- L2 is a bond or a second self-immolative linker;
- wherein if L1 is a second self-immolative linker or a cyclization self-elimination linker, then L2 is a bond;
- wherein if L2 is a second self-immolative linker, then L1 is a bond;
- L3 is a peptide linker;
- and
- R1 is hydrogen, unsubstituted or substituted C1-3 alkyl, or unsubstituted or substituted heterocyclyl;
- comprising:
- reacting Compound X1:
- and a compound comprising L1-D.
10 more elements
A method of preparing Compound Z:
- or a salt or solvate or stereoisomer thereof;
- wherein:
- D is a drug moiety;
- L1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
- L2 is a bond or a second self-immolative linker;
- wherein if L1 is a second self-immolative linker or a cyclization self-elimination linker, then L2 is a bond;
- wherein if L2 is a second self-immolative linker, then L1 is a bond;
- L3 is a peptide linker;
- L4 is bond or a spacer;
- A is an acyl unit;
- and
- R1 is hydrogen, unsubstituted or substituted C1-3 alkyl, or unsubstituted or substituted heterocyclyl;
- comprising:
- reacting Compound Y1:
- and a compound comprising A-L4.
12 more elements
A compound of formula:
- or a salt or solvate or stereoisomer thereof;
- wherein:
- L2 is a bond or a second self-immolative linker;
- L3 is a peptide linker;
- L4 is bond or a spacer;
- and
- A is an acyl unit;
- and
- R1 is hydrogen, unsubstituted or substituted C1-3 alkyl, or unsubstituted or substituted heterocyclyl.
6 more elements
A compound of formula:
- or a salt or solvate or stereoisomer thereof;
- wherein:
- D is a drug moiety;
- L1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
- L2 is a bond or a second self-immolative linker;
- wherein if L1 is a second self-immolative linker or a cyclization self-elimination linker, then L2 is a bond;
- wherein if L2 is a second self-immolative linker, then L1 is a bond;
- L3 is a peptide linker;
- L4 is bond or a spacer;
- and
- A is an acyl unit;
- and
- R1 is hydrogen, unsubstituted or substituted C1-3 alkyl, or unsubstituted or substituted heterocyclyl.
10 more elements
A compound of formula:
- or a salt or solvate or stereoisomer thereof;
- wherein:
- L2 is a bond or a second self-immolative linker;
- L3 is a peptide linker;
- and
- R1 is hydrogen, unsubstituted or substituted C1-3 alkyl, or unsubstituted or substituted heterocyclyl.
3 more elements
A compound of formula:
- or a salt or solvate or stereoisomer thereof;
- wherein:
- D is a drug moiety;
- L1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
- L2 is a bond or a second self-immolative linker;
- wherein if L1 is a second self-immolative linker or a cyclization self-elimination linker, then L2 is a bond;
- wherein if L2 is a second self-immolative linker, then L1 is a bond;
- L3 is a peptide linker;
- and
- R1 is hydrogen, unsubstituted or substituted C1-3 alkyl, or unsubstituted or substituted heterocyclyl.
7 more elements
Dependencies are inferred from the claim text.