US 11,857,635 B2
Linker compound, polyethylene glycol-linker conjugate and derivative thereof and polyethylene glycol-linker-drug conjugate
Zewang Feng, Tianjin (CN); Qingbin Wang, Tianjin (CN); Jinliang Wang, Tianjin (CN); Yanping Song, Tianjin (CN); Yanli Xiong, Tianjin (CN); Leimin Wang, Tianjin (CN); Jinghui Du, Tianjin (CN); and Xuan Zhao, Tianjin (CN)
Assigned to JenKem Technology Co., Ltd. (Tianjin), Tianjin (CN)
Filed by JENKEM TECHNOLOGY CO., LTD. (TIANJIN), Tianjin (CN)
Filed on Mar. 30, 2020, as Appl. No. 16/833,988.
Application 16/833,988 is a continuation of application No. PCT/CN2018/106972, filed on Sep. 21, 2018.
Claims priority of application No. 201710919466.5 (CN), filed on Sep. 30, 2017; application No. 201810186781.6 (CN), filed on Mar. 7, 2018; and application No. 201811043884.3 (CN), filed on Sep. 7, 2018.
Prior Publication US 2020/0289655 A1, Sep. 17, 2020
Int. Cl. A61K 47/60 (2017.01); A61K 31/704 (2006.01); A61P 35/00 (2006.01)
CPC A61K 47/60 (2017.08) [A61K 31/704 (2013.01); A61P 35/00 (2018.01)] 19 Claims
 
1. A polyethylene glycol-linker-drug conjugate, having a structure as follows:
(PEG-X-L-Y)n-D  (IX)
wherein, PEG is a polyethylene glycol residue,
X is a linking group of PEG and L, which is selected from one or a combination of several of —(CH2)a—, —(CH2)aCO—, —(CH2)aOCO—, —(CH2)aNHCO—, —NH(CH2)aCO—, —(CH2)aSO2—, —O(CH2)a—, —O(CH2)aCO—, —O(CH2)aOCO—, —O(CH2)aNHCO— and —O(CH2)aSO2—, and a is an integer of 0 to 10,
Y is a linking group of L and D, which is selected from one or a combination of several of —(CH2)r—,

OG Complex Work Unit Chemistry
—(CH2)rO—, —(CH2)rCO—, —(CH2)rNH—, —(CH2)rCONH—, —(CH2)rNHCO—, —(CH2)rSH—,

OG Complex Work Unit Chemistry
and r is an integer of 0 to 10,
R17 and R18 are independently selected from —H, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl and C4-10 alkylene cycloalkyl,
D is a bioactive agent containing m amido groups, and m is an integer of 1 to 500,
n is an integer, and 1≤n≤m,
L is a linker, having a structure as follows:

OG Complex Work Unit Chemistry
wherein, 1 is an integer of 1 to 5,
in the linker L-a, A is —COCH2NH—, —COCH(CH3)NH— or —COCH(CH(CH3)2)NH—;
in the linker L-b and L-c, A is one or a combination selected from amino acid residues, polypeptide residues,

OG Complex Work Unit Chemistry
—NHCO(CH2)i, —CONH(CH2)i—, —(CH2)iNH— and —CO(CR15R16)iNH—, and i is an integer of 0 to 6,
R1-7 and R9-11 are independently selected from —H, —F, —Cl, —Br, —I, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, C1-6 alkenyl, C6-12 aryl, C6-12 aralkyl, C3-12 aromatic or non-aromatic heterocyclyl, C3-12 heterocyclic alkyl and —(CH2)l—O—Z,
wherein Z is selected from —H, —CH3, —C(CH3)3, —CH2OCH3, —COCH3, —COC(CH3)3, —CH2CH═CH2, —Si(CH3)3,

OG Complex Work Unit Chemistry
R8 and R12 are independently selected from C1-6 alkyl,
R13-16 are independently selected from —H, and C1-6 alkyl, and
B is a linking group —B1—B2—,
wherein, B1 is selected from —(CH2)j—, —NHCO(CH2)j— and —CONH(CH2)j—, and j is an integer of 0 to 6, and
B2 is selected from —C═O, —C═S, —O—, —S—, —C(O)O—, —C(O)S—, —C(S)O— and —S—S—.