Linker containing arylnitro, antibody-drug conjugate containing linker and use of linker
AssigneeAcademy of Military Medical Sciences
InventorsXinbo Zhou, Yanming Wang, Song Li, Wu Zhong, Shiyong Fan, Dian Xiao, Junhai Xiao, Zhibing Zheng, Xingzhou Li, Yunde Xie, Ruiyuan Cao, Xiaokui Wang
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Abstract
The present application relates to a linker containing arylnitro, an antibody-drug conjugate the linker and use of the linker, as well as a pharmaceutical composition comprising the antibody-drug conjugate and use of the antibody-drug conjugate for treatment and/or prevention of a disease
Claims18
A compound represented by Formula I or a salt thereof,
- wherein:
- R1 is hydrogen, methyl, ethyl, n-propyl or isopropyl;
- R2 is hydrogen, methyl, ethyl, n-propyl or isopropyl;
- R3 is
- R4 is
- and in
- the two carbonyl groups are located on the same side of the C═C double bond, which is a cis structure, R11 is a C1-6 linear or branched alkyl, and R11 is optionally mono- or multi-substituted by one or more substituents selected from the group consisting of:
- halogen and C1-4 alkoxy;
- X is oxygen atom (O), nitrogen atom (N) or sulfur atom (S);
- Ar is aryl, heteroaryl, aryl-fused-heterocyclyl or heteroaryl-fused-heterocyclyl;
- R5 is hydrogen, methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine, bromine, iodine, hydroxyl or cyano;
- R6 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, fluorine, chlorine, bromine, iodine, hydroxyl, nitro or cyano;
- R7 is hydrogen, methyl, ethyl, n-propyl or isopropyl;
- R8 is hydrogen, methyl, ethyl, n-propyl or isopropyl;
- R9 is hydrogen, methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine, bromine, iodine, hydroxyl or cyano;
- q is 0, 1, 2 or 3;
- p is 0, 1, 2 or 3;
- a is 0, 1, 2, 3 or 4;
- L is —(CH2)iO(CH2)j—, —(CH2)iO(CH2)j—C(O)—, —(CH2)i—C(O)NH—(CH2)j—, —(CH2CH2O)i—(CH2)j—C(O)—, —(CH2)i—(CH2CH2O)j—C(O)—, —(OCH2CH2)i—, —(CH2)m—, —(CH2)k—C(O)NH—(CH2CH2O)g—(CH2)h—C(O)—, —(CH2)r—C(O)—, —(CH2)b—C(O)NH—CH[(CH2)d—NHC(O)—(CH2CH2O)e—(CH2)f—CH3]—,
- W represents a linking group, and is —NH—CH2—C(O)—NH—, —NH—CH2—CH2—C(O)—NH—, —C(O)—NH—, —NH—C(O)—, —O—, —S—, —NH—, —N(CH3)—, —C(O)— or —NH—CH(R10)—C(O)—NH—;
- R10 is —H, —CH3, —C3H6, —CH—(CH3)2, —CH2—CH(CH3)2, —CH(CH3)—CH2—CH3, —CH2—C6H5, —C8NH6, —CH2—C6H4—OH, —CH2—COOH, —CH2—CONH2, —(CH2)2—COOH, —(CH2)4—NH2, —(CH2)2—CONH2, —(CH2)—S—CH3, —CH2—OH, —CH(CH3)—OH or —CH2—SH;
- m is 1, 2, 3, 4, 5, 6, 7, 8 or 9;
- each i is independently 1, 2, 3, 4, 5, 6, 7, 8 or 9;
- each j is independently 1, 2, 3, 4, 5, 6, 7, 8 or 9;
- r is 1, 2, 3, 4, 5, 6, 7, 8 or 9;
- k is 1, 2, 3, 4, 5 or 6;
- g is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
- h is 1, 2, 3, 4, 5 or 6;
- b is 1, 2, 3, 4, 5 or 6;
- d is 1, 2, 3, 4, 5 or 6;
- e is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
- f is 1, 2, 3, 4, 5 or 6.
A compound represented by Formula II or a salt thereof,
- wherein:
- R1 is hydrogen, methyl, ethyl, n-propyl or isopropyl;
- R2 is hydrogen, methyl, ethyl, n-propyl or isopropyl;
- R4 is
- and in
- the two carbonyl groups are located on the same side of the C═C double bond, which is a cis structure, R11 is a C1-6 linear or branched alkyl, and R11 is optionally mono- or multi-substituted by one or more substituents selected from the group consisting of:
- halogen and C1-4 alkoxy;
- X is oxygen atom (O), nitrogen atom (N) or sulfur atom (S);
- Ar is aryl, heteroaryl, aryl-fused-heterocyclyl or heteroaryl-fused-heterocyclyl;
- R5 is hydrogen, methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine, bromine, iodine, hydroxyl or cyano;
- R6 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, fluorine, chlorine, bromine, iodine, hydroxyl, nitro or cyano;
- R7 is hydrogen, methyl, ethyl, n-propyl or isopropyl;
- R8 is hydrogen, methyl, ethyl, n-propyl or isopropyl;
- q is 0, 1, 2 or 3;
- p is 0, 1, 2 or 3;
- L is —(CH2)iO(CH2)j—, —(CH2)i—(CH2)j—C(O)—, —(CH2)i—C(O)NH—(CH2)j—, —(CH2CH2O)i—(CH2)j—C(O)—, —(CH2)i—(CH2CH2O)j—C(O)—, —(OCH2CH2)i—, —(CH2)m—, —(CH2)r—C(O)—, —(CH2)k—C(O)NH—(CH2CH2O)g—(CH2)h—C(O)—, —(CH2)b—C(O)NH—CH[(CH2)d—NHC(O)—(CH2CH2O)e—(CH2)f—CH3]—,
- W represents a linking group, and is —NH—CH2—C(O)—NH—, —NH—CH2—CH2—C(O)—NH—, —C(O)—NH—, —NH—C(O)—, —O—, —S—, —NH—, —N(CH3)—, —C(O)— or —NH—CH(R10)—C(O)—NH—, further preferably —NH—CH2—C(O)—NH—, —C(O)—NH—, —NH—C(O)— or —O—;
- R10 is —H, —CH3, —C3H6, —CH—(CH3)2, —CH2—CH(CH3)2, —CH(CH3)—CH2—CH3, —CH2—C6H5, —C8NH6, —CH2—C6H4—OH, —CH2—COOH, —CH2—CONH2, —(CH2)2—COOH, —(CH2)4—NH2, —(CH2)2—CONH2, —(CH2)—S—CH3, —CH2—OH, —CH(CH3)—OH or —CH2—SH;
- m is 1, 2, 3, 4, 5, 6, 7, 8 or 9;
- each i is independently 1, 2, 3, 4, 5, 6, 7, 8 or 9;
- each j is independently 1, 2, 3, 4, 5, 6, 7, 8 or 9;
- r is 1, 2, 3, 4, 5, 6, 7, 8 or 9;
- k is 1, 2, 3, 4, 5 or 6;
- g is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
- h is 1, 2, 3, 4, 5 or 6;
- b is 1, 2, 3, 4, 5 or 6;
- d is 1, 2, 3, 4, 5 or 6;
- e is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
- f is 1, 2, 3, 4, 5 or 6;
- B is an active compound, selected from the group consisting of drug, cytotoxin, detection reagent, diagnostic reagent and targeting carrier;
- B is coupled to the site* or site** through a N atom or O atom in the active compound molecule;
- t is 0 or 1.
A compound represented by Formula III or Formula III′ or a salt thereof,
- wherein:
- R1 is hydrogen, methyl, ethyl, n-propyl or isopropyl;
- R2 is hydrogen, methyl, ethyl, n-propyl or isopropyl;
- X is oxygen atom (O), nitrogen atom (N) or sulfur atom (S);
- Ar is aryl, heteroaryl, aryl-fused-heterocyclyl or heteroaryl-fused-heterocyclyl;
- R6 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, fluorine, chlorine, bromine, iodine, hydroxyl, nitro or cyano;
- R7 is hydrogen, methyl, ethyl, n-propyl or isopropyl;
- R8 is hydrogen, methyl, ethyl, n-propyl or isopropyl;
- q is 0, 1, 2 or 3;
- p is 0, 1, 2 or 3;
- L is —(CH2)iO(CH2)j—, —(CH2)iO(CH2)j—C(O)—, —(CH2)i—C(O)NH—(CH2)j—, —(CH2CH2O)i—(CH2)j—C(O)—, —(CH2)i—(CH2CH2O)j—C(O)—, —(OCH2CH2)i—, —(CH2)m—, —(CH2)r—C(O)—, —(CH2)k—C(O)NH—(CH2CH2O)g—(CH2)h—C(O)—, —(CH2)b—C(O)NH—CH[(CH2)d—NHC(O)—(CH2CH2O)e—(CH2)f—CH3]—,
- W represents a linking group, and is —NH—CH2—C(O)—NH—, —NH—CH2—CH2—C(O)—NH—, —C(O)—NH—, —NH—C(O)—, —O—, —S—, —NH—, —N(CH3)—, —C(O)— or —NH—CH(R10)—C(O)—NH—, further preferably —NH—CH2—C(O)—NH—, —C(O)—NH—, —NH—C(O)— or —O—;
- R10 is —H, —CH3, —C3H6, —CH—(CH3)2, —CH2—CH(CH3)2, —CH(CH3)—CH2—CH3, —CH2—C6H5, —C8NH6, —CH2—C6H4—OH, —CH2—COOH, —CH2—CONH2, —(CH2)2—COOH, —(CH2)4—NH2, —(CH2)2—CONH2, —(CH2)—S—CH3, —CH2—OH, —CH(CH3)—OH or —CH2—SH, preferably;
- m is 1, 2, 3, 4, 5, 6, 7, 8 or 9;
- each i is independently 1, 2, 3, 4, 5, 6, 7, 8 or 9;
- each j is independently 1, 2, 3, 4, 5, 6, 7, 8 or 9;
- r is 1, 2, 3, 4, 5, 6, 7, 8 or 9;
- k is 1, 2, 3, 4, 5 or 6;
- g is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
- h is 1, 2, 3, 4, 5 or 6;
- b is 1, 2, 3, 4, 5 or 6;
- d is 1, 2, 3, 4, 5 or 6;
- e is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
- f is 1, 2, 3, 4, 5 or 6;
- B is an active compound, selected from the group consisting of drug, cytotoxin, detection reagent, diagnostic reagent and targeting carrier;
- B is coupled to the site* or site** through a N atom or O atom in the active compound molecule;
- t is 0 or 1;
- A is a targeting compound, selected from the group consisting of:
- protein, antibody, polypeptide, enzyme and small molecule;
- n is a number between 0.5 and 8.5.
Dependencies are inferred from the claim text.