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US 11,629,122 B2Granted
Linkers for antibody drug conjugates
AssigneeBoard of Regents, The University of Texas System
InventorsKyoji Tsuchikama, Yasuaki Anami, Chisato Tsuchikama, Ningyang Zhang, Zhiqiang An
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Abstract
In one aspect, the present disclosure provides compounds of the formula (I): wherein the variables are as defined herein. In another aspect, the present disclosure provides compounds of the formula (V): wherein the variables are as defined herein. In another aspect, the present disclosure also provides methods of preparing the compounds disclosed herein. In another aspect, the present disclosure provides antibody drug conjugates comprising compounds of the present disclosure. In another aspect, the present disclosure also provides pharmaceutical compositions and methods of use of the compounds and anti-body drug conjugates disclosed herein.
Claims18
A compound of the formula:
- wherein:
- A1, A2, and A3 are each independently alkanediylC1-12, arenediylC1-12, heteroarenediylC1-12, cycloalkanediylC1-12, heterocycloalkanediylC1-12, or a substituted version thereof, or a canonical amino acid residue;
- X, Y, and Z are each independently —[O(CH2)q]—, —[O(CHW′)q]—, or —[O(CW′W″)q]—;
- wherein:
- W′ and W″ are each independently amino, hydroxy, halo, mercapto, alkylC1-12, cycloalkylC1-12, alkenylC1-12, alkynylC1-12, arylC1-12, aralkylC1-12, heteroarylC1-12, heteroaralkylC1-12, heterocycloalkylC1-12, acylC1-12, acyloxyC1-12, alkylaminoC1-12, or a substituted version of thereof;
- q is 1-3;
- m, n, o, and p are each independently 0-12;
- r is 1, 2, or 3;
- R1, R2, and R3 are each independently —NH2, —NHR4, —NR4R5, —N3, or a conjugating group;
- wherein:
- R4 and R5 are each independently alkylC1-12, cycloalkylC1-12, alkenylC1-12, alkynylC1-12, arylC1-12, aralkylC1-12, heteroarylC1-12, heteroaralkylC1-12, heterocycloalkylC1-12, acylC1-12, acyloxyC1-12, alkylaminoC1-12, or a substituted version thereof, or a monovalent amino protecting group;
- or
- R4 and R5 are taken together and is a divalent amino protecting group;
- provided that at least one of R1, R2, and R3 is —NH2 and at least one of R1, R2, and R3 is —N3;
- or a compound of the formula:
- or a pharmaceutically acceptable salt thereof.
13 more elements
A compound of the formula:
- wherein:
- X1 is a covalent bond, alkanediyl(C≤12), or substituted alkanediyl(C≤12);
- R1 is hydrogen, —(OCH2CH2)n1ZR6, or substituted —(OCH2CH2)n1ZR6, wherein:
- n1 is 0-50;
- and
- R6 is hydrogen, hydroxy, amine, mercapto, hydroxylamine, hydrazine, or azide;
- or
- alkyl(C≤12), alkenyl(C≤12), alkynyl(C≤12), alkylhydrazine(C≤12), or a substituted version of any of these groups;
- a polyglycine comprising from 1 to 6 glycine units;
- or
- a substructure of the formula:
- wherein:
- A1 and A2 are each independently absent or arenediyl(C≤12), substituted arenediyl(C≤12), heteroarenediyl(C≤12), or substituted heteroarenediyl(C≤12), and form a fused arene(C≤12), substituted arene(C≤12), heteroarene(C≤12), or substituted heteroarene(C≤12);
- A4 or A5 are each independently selected from a covalent bond, alkanediyl(C≤8), or substituted alkanediyl(C≤8);
- Rd, Re, Re′, and Rh are each independently selected from hydrogen, halo, sulfate, tosylate, mesylate, aryl(C≤8), or substituted aryl(C≤8);
- Rf is halo;
- Rg is amine, hydrazine, alkylamino(C≤8), substituted alkylamino(C≤8), dialkylamino(C≤8), substituted dialkylamino(C≤8), alkylhydrazine(C≤8), or substituted alkylhydrazine(C≤8);
- X4 is O, N, CH2, or X4 is alkanediyl(C≤8) or substituted alkanediyl(C≤8) that forms a fused cycloalkane group consisting of 3 to 8 ring atoms;
- R16 is hydroxy, amino, or oxo;
- R17 is carboxy;
- or
- alkyl(C≤12), amido(C≤12), aryl(C≤12), heteroaryl(C≤12), —C(O)NR20R20′, or a substituted version of any of these groups wherein:
- R20 and R20′ are each independently hydrogen;
- or
- alkyl(C≤12), aryl(C≤12), or a substituted version of either of these groups;
- R18 and R19 are each independently hydroxy, amino, halo;
- or
- alkyl(C≤12), aryl(C≤12), or a substituted version of either of these groups;
- Z is a covalent bond, alkanediyl(C≤12), —C(O)-alkanediyl(C≤12), —C(O)-alkanediyl(C≤12)—C(O)NH—, or a substituted version of any of these groups;
- R2 is hydrogen, alkyl(C≤12), substituted alkyl(C≤12), acyl(C≤12), substituted acyl(C≤12), or a monovalent amino protecting group;
- W is a covalent bond or a polyvalent polymer having 21 connection points;
- n3 is 1 to 20 provided that when W is a covalent bond then n3 is 1 and when W is a polyvalent polymer then n3 is less than or equal to one less than the number of connection points;
- Each X is independently a covalent bond, alkanediyl(C≤12), or substituted alkanediyl(C≤12);
- Each X2 is independently alkanediyl(C≤12) or substituted alkanediyl(C≤12);
- Each R3 is independently hydroxy, or amino;
- or
- alkoxy(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), heteroaryl(C≤12), or a substituted version of any of these groups;
- or
- —X9—C(O)R7, wherein:
- X9 is O, —NRb—, or a covalent bond;
- Rb is hydrogen, alkyl(C≤6), substituted alkyl(C≤6), or a monovalent amino protecting group;
- R7 is hydroxy or amino;
- or
- alkoxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), or a substituted version of any of these groups;
- or
- -A3SO2NR21R21′, -A3P(O)(OH)OR22, or -A3SO2OR22′, wherein:
- A3 is O, —NRc—, or a covalent bond;
- Rc is hydrogen, alkyl(C≤6), substituted alkyl(C≤6), or a monovalent amino protecting group;
- R21, R21′, R22, and R22′ are each independently hydrogen, alkyl(C≤12), cycloalkyl(C≤12), aryl(C≤12), heteroaryl(C≤12), aralkyl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups;
- Each R23 is independently the side chain moiety of alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, a hydroxyl-protected version of tyrosine, or an amino-protected version of tryptophan;
- and
- Each R24 is independently the side chain moiety of alanine, ornithine, lysine, arginine, citrulline, or an amino-protected version thereof;
- Each Q is independently a group of the formula:
- wherein:
- Each R5 is independently hydrogen or —C(O)—R8, wherein:
- R8 is a chemotherapeutic agent;
- Each X5 is independently a covalent bond, O, S, —NH—, alkanediyl(C≤12), substituted alkanediyl(C≤12), —(OCH2CH2)n2—, or substituted —(OCH2CH2)n2—, wherein:
- n2 is 0-50;
- or
- a group of the formula:
- wherein:
- Ra and Ra′ are each independently hydrogen, alkyl(C≤12), or substituted alkyl(C≤12);
- X6 is O or —NR26R26′—, wherein:
- R26 and R26′ are each independently alkyl(C≤12) or substituted alkyl(C≤12);
- X7 is a covalent bond, O, S, —NH—, —(OCH2CH2)n3—, or substituted —(OCH2CH2)n3—, wherein:
- n3 is 0-50;
- or
- a group of the formula:
- wherein:
- Y1 is O or S;
- Y2 is O, S, —NH—, or —NR27—, wherein:
- R27 is alkyl(C≤12) or substituted alkyl(C≤12);
- and
- X8 is a covalent bond, O, S, —NH—, —(OCH2CH2)n3—, or substituted —(OCH2CH2)n3—;
- or a pharmaceutically acceptable salt thereof.
72 more elements
A compound of the formula:
- wherein:
- X1 is alkyl(C≤12) or substituted alkyl(C≤12);
- R2 is hydrogen, alkyl(C≤12), substituted alkyl(C≤12), acyl(C≤12), substituted acyl(C≤12), or a monovalent amino protecting group;
- W is a covalent bond or a polyvalent polymer having 21 connection points;
- n3 is 1 to 20 provided that when W is a covalent bond n3 is 1 and when W is a polyvalent polymer n3 is less than or equal to one less than the number of connection points;
- Each X is independently a covalent bond, alkanediyl(C≤12), or substituted alkanediyl(C≤12);
- Each X2 is independently alkanediyl(C≤12) or substituted alkanediyl(C≤12);
- Each R3 is independently hydroxy, or amino;
- or
- alkoxy(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), heteroaryl(C≤12), or a substituted version of any of these groups;
- or
- —X9—C(O)R7, wherein:
- X9 is O, —NRb—, or a covalent bond;
- Rb is hydrogen, alkyl(C≤6), substituted alkyl(C≤6), or a monovalent amino protecting group;
- R7 is hydroxy or amino;
- or
- alkoxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), or a substituted version of any of these groups;
- or
- -A3SO2NR21R21′, -A3P(O)(OH)OR22, or -A3SO2OR22′, wherein:
- A3 is O, —NRc—, or a covalent bond;
- Rc is hydrogen, alkyl(C≤6), substituted alkyl(C≤6), or a monovalent amino protecting group;
- R21, R21′, R22, and R22′ are each independently hydrogen, alkyl(C≤12), cycloalkyl(C≤12), aryl(C≤12), heteroaryl(C≤12), aralkyl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups;
- Each R23 is independently the side chain moiety of alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, a hydroxyl-protected version of tyrosine, or an amino-protected version of tryptophan;
- and
- Each R24 is independently the side chain moiety of alanine, ornithine, lysine, arginine, citrulline, or an amino-protected version thereof;
- Each Q is independently a group of the formula:
- wherein:
- Each R5 is independently hydrogen or —C(O)—R8, wherein:
- R8 is a chemotherapeutic agent;
- Each X5 is independently a covalent bond, O, S, —NH—, alkanediyl(C≤12), substituted alkanediyl(C≤12), —(OCH2CH2)n2—, or substituted —(OCH2CH2)n2—, wherein:
- n2 is 0-50;
- or
- a group of the formula:
- wherein:
- Ra and Ra′ are each independently hydrogen, alkyl(C≤12), or substituted alkyl(C≤12);
- X6 is O or —NR26R26′—, wherein:
- R26 and R26′ are each independently alkyl(C≤12) or substituted alkyl(C≤12);
- X7 is a covalent bond, O, S, —NH—, —(OCH2CH2)n3—, or substituted —(OCH2CH2)n3—, wherein:
- n3 is 0-50;
- or
- a group of the formula:
- wherein:
- Y1 is O or S;
- Y2 is O, S, —NH—, or —NR27—, wherein:
- R27 is alkyl(C≤12) or substituted alkyl(C≤12);
- and
- X8 is a covalent bond, O, S, —NH—, —(OCH2CH2)n3—, or substituted —(OCH2CH2)n3—;
- or a pharmaceutically acceptable salt thereof.
45 more elements
Dependencies are inferred from the claim text.