Conjugation of a cytotoxic drug with bis-linkage

Patent metadata

Field	Value
Publication number	US-2021369855-A1
Application number	US-202117387205-A
Country	US
Kind code	A1
Filing date	Jul 28, 2021
Priority date	Apr 6, 2017
Publication date	Dec 2, 2021
Grant date	—

Abstract

A conjugation of a cytotoxic drug to a cell-binding molecule with a bis-linker (dual-linker) as shown in Formula (I). Bis-linkage methods of making a conjugate of a cytotoxic drug/molecule to a cell-binding agent in a specific manner are also described, as well as application of the conjugates for the treatment of a cancer, or an autoimmune disease, or an infectious disease.wherein “” is an optional bond; X, Y, Z1, and Z2 are a functional group; m1 and n are a integer; L1 and L2 are a linker.

First claim

1 . A bis-linker compound containing a cytotoxic molecule of Formula (II):

wherein:
“—” represents a single bond; “ ” is a single bond, a double bond, a triple bond, or absent; provided that when represents a triple bond, both Lv 1 and Lv 2 are absent;
a cytotoxic molecule is a therapeutic drug/molecule/agent, or an immunotherapeutic protein/molecule, or a function molecule for enhancement of binding or stabilization of a cell-binding molecule, or a cell-surface receptor binding ligand, or for inhibition of cell proliferation, or for monitoring, detection or study of a cell-binding molecule action; or an analog, or prodrug, or a pharmaceutically acceptable salt, hydrate, or hydrated salt, or a crystalline structure, or an optical isomer, racemate, diastereomer or enantiomer, of an immunotherapeutic compound, a chemotherapeutic compound, an antibody (probody) or an antibody (probody) fragment; or siRNA or DNA molecule; or a cell surface binding ligand; or an analog or prodrug of a therapeutic drug selected from the group consisting of tubulysins, calicheamicins, auristatins, maytansinoids, CC-1065 analogs, morpholinos doxorubicins, taxanes, cryptophycins, amatoxins, epothilones, eribulin, geldanamycins, duocarmycins, daunomycins, methotrexates, vindesines, vincristines, and benzodiazepine dimers including dimers of pyrrolobenzodiazepine (PBD), tomaymycin, indolinobenzodiazepines, imidazobenzothiadiazepines, and oxazolidinobenzodiazepines;
m 1 is 1 to 20;
X and Y represent the same or different, and are independently, a functional group that links the cytotoxic molecule via a disulfide, thioether, thioester, peptide, hydrazone, ether, ester, carbamate, carbonate, amine (secondary, tertiary, or quaternary), imine, cycloheteroalkyl, heteroaromatic, alkoxime or amide bond; X and Y are independently selected from the group consisting of NH; NHNH; N(R 1 ); N(R 1 )N(R 2 ); O; S; S—S, O—NH, O—N(R 1 ), CH 2 —NH, CH 2 —N(R 1 ), CH═NH, CH═N(R 1 ), S(O), S(O 2 ), P(O)(OH), S(O)NH, S(O 2 )NH, P(O)(OH)NH, NHS(O)NH, NHS(O 2 )NH, NHP(O)(OH)NH, N(R 1 )S(O)N(R 2 ), N(R 1 )S(O 2 )N(R 2 ), N(R 1 )P(O)(OH)N(R 2 ), OS(O)NH, OS(O 2 )NH, OP(O)(OH)NH, C(O), C(NH), C(NR 1 ), C(O)NH, C(NH)NH, C(NR 1 )NH, OC(O)NH, OC(NH)NH; OC(NR 1 )NH, NHC(O)NH; NHC(NH)NH; NHC(NR 1 )NH, C(O)NH, C(NH)NH, C(NR 1 )NH, OC(O)N(R 1 ), OC(NH)N(R 1 ), OC(NR 1 )N(R 1 ), NHC(O)N(R 1 ), NHC(NH)N(R 1 ), NHC(NR 1 )N(R 1 ), N(R 1 )C(O)N(R 1 ), N(R 1 )C(NH)N(R 1 ), N(R 1 )C(NR 1 )N(R 1 ); C 1 -C 6 alkyl, C 2 -C 8 alkenyl, heteroalkyl, alkylcycloalkyl, or heterocycloalkyl; and C 3 -C 8 aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, and heteroaryl;
Z 1 and Z 2 are, the same or different, and are independently C(O)CH, C(O)C, C(O)CH 2 , ArCH 2 , C(O), NH; NHNH; N(R 1 ); N(R 1 )N(R 2 ); O; S; S—S, O—NH, O—N(R 1 ), CH 2 —NH, CH 2 —N(R 1 ), CH═NH, CH═N(R 1 ), S(O), S(O 2 ), P(O)(OH), S(O)NH, S(O 2 )NH, P(O)(OH)NH, NHS(O)NH, NHS(O 2 )NH, NHP(O)(OH)NH, N(R 1 )S(O)N(R 2 ), N(R 1 )S(O 2 )N(R 2 ), N(R 1 )P(O)(OH)N(R 2 ), OS(O)NH, OS(O 2 )NH, OP(O)(OH)NH, C(O), C(NH), C(NR 1 ), C(O)NH, C(NH)NH, C(NR 1 )NH, OC(O)NH, OC(NH)NH; OC(NR 1 )NH, NHC(O)NH; NHC(NH)NH; NHC(NR 1 )NH, C(O)NH, C(NH)NH, C(NR 1 )NH, OC(O)N(R 1 ), OC(NH)N(R 1 ), OC(NR 1 )N(R 1 ), NHC(O)N(R 1 ), NHC(NH)N(R 1 ), NHC(NR 1 )N(R 1 ), N(R 1 )C(O)N(R 1 ), N(R 1 )C(NH)N(R 1 ), N(R 1 )C(NR 1 )N(R 1 ); C 1 -C 8 alkyl, C 2 -C 8 heteroalkyl, alkylcycloalkyl, or heterocycloalkyl; or C 3 -C 8 aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, or heteroaryl;
L 1 and L 2 are, the same or different, and are independently selected from O; NH; S; NHNH; N(R 3 ); N(R 3 )N(R 3 ); C 1 -C 8 alkyl, amide, amines, imines, hydrazines, or hydrazones; C 2 -C 8 heteroalkyl, alkylcycloalkyl, ethers, esters, hydrazones, ureas, semicarbazides, carbazides, alkoxyamines, alkoxylamines, urethanes, amino acids, peptides, acyloxylamines, hydroxamic acids, or heterocycloalkyl; C 3 -C 8 aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, or heteroaryl; 1-8 amino acids; and polyethyleneoxy unit of formula (OCH 2 CH 2 ) p OR 3 , or (OCH 2 —CH(CH 3 )) p OR 3 , or NH(CH 2 CH 2 O) p R 3 , or NH(CH 2 CH(CH 3 )O) p R 3 , or N[(CH 2 CH 2 O) p R 3 ]—[(CH 2 CH 2 O) p′ R 3′ ], or (OCH 2 CH 2 ) p COOR 3 , or CH 2 CH 2 (OCH 2 CH 2 ) p COOR 3 , wherein p and p′ are independently an integer selected from 0 to about 5000, or a combination of two or more of above;
R 1 , R 2 , R 3 and R 3′ are independently H; C 1 -C 8 alkyl; C 2 -C 8 heteroalkyl, alkylcycloalkyl, or heterocycloalkyl; C 3 -C 8 aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, or heteroaryl; or C 2 -C 8 ester, ether, or amide; or 1-8 amino acids; or polyethyleneoxy having formula (OCH 2 CH 2 ) p or (OCH 2 CH(CH 3 )) p , wherein p is an integer from 0 to about 5000, or a combination of two or more of above;
or L 1 and L 2 independently have one or more linker components of 6-maleimidocaproyl (“MC”), maleimidopropanoyl (“MP”), valine-citrulline (“val-cit” or “vc”), alanine-phenylalanine (“ala-phe” or “af”), p-aminobenzyloxycarbonyl (“PAB”), 4-thiopentanoate (“SPP”), 4-(N-maleimidomethyl)cyclohexane-1 carboxylate (“MCC”), (4-acetyl)amino-benzoate (“SIAB”), 4-thio-butyrate (SPDB), 4-thio-2-hydroxysulfonyl-butyrate (2-Sulfo-SPDB), or a natural or unnatural peptide having 1-8 natural or unnatural amino acid units;
or L 1 and L 2 independently contain a self-immolative component, peptidic unit, a hydrazone bond, a disulfide, an ester, an oxime, an amide, or a thioether bond; the self-immolative unit being an aromatic compound that is electronically similar to para-aminobenzyl-carbamoyl (PAB) groups, 2-aminoimidazol-5-methanol derivatives, heterocyclic PAB analogs, beta-glucuronide, and ortho or para-aminobenzylacetals; or one of following structures:

wherein the (*) atom is a point of attachment of additional spacer or releasable linker units, or the cytotoxic molecule; X 1 , Y 1 , Z 2 and Z 3 are independently NH, O, or S; Z 1 is independently H, NHR 1 , OR 1 , SR 1 , or COX 1 R 1 , wherein X 1 and R 1 are defined above; v is 0 or 1; U 1 is independently H, OH, C 1 -C 6 alkyl, (OCH 2 CH 2 ) n , F, Cl, Br, I, OR 5 , SR 5 , NR 5 R 5 ′, N═NR 5 , N═R 5 , NR 5 R 5 ′,NO 2 , SOR 5 R 5 ′, SO 2 R 5 , SO 3 R 5 , OSO 3 R 5 , PR 5 R 5 ′, POR 5 R 5 ′, PO 2 R 5 R 5 ′, OPO(OR 5 )(OR 5 ′), or OCH 2 PO(OR 5 (OR 5 ′), wherein R 5 and R 5 ′ are independently selected from H, C 1 -C 8 alkyl; C 2 -C 8 alkenyl, alkynyl, heteroalkyl, or amino acid; C 3 -C 8 aryl, heterocyclic, carbocyclic, cycloalkyl, heterocycloalkyl, heteroaralkyl, alkylcarbonyl, or glycoside; or pharmaceutical cation salts;
or L 1 and L 2 independently have a non-self-immolative linker component containing one of following structures:

wherein the (*) atom is a point of attachment of additional spacer or releasable linker, or the cytotoxic molecule; X 1 , Y 1 , U 1 , R 5 , R 5 ′ are defined as above; r is 0-100; m and n are 0-6 independently;
or L 1 and L 2 independently are a releasable linker containing at least one bond that is capable of being broken under physiological conditions: a pH-labile, acid-labile, base-labile, oxidatively labile, metabolically labile, biochemically labil

Assignees

• Hangzhou Dac Biotech Co Ltd

Inventors

• Zhao Robert Yongxin
• Huang Yuanyuan
• Yang Qingliang
• Gai Shun
• Ye Hangbo
• Zhao Linyao
• Yang Chengyu
• Xu Yifang
• Guo Huihui
• Chao Minjun
• Tong Qianqian
• Li Wenjun
• Cai Xiang
• Zhou Xiaomai
• Xie Hongsheng
• Jia Junxiang
• Zhu Haifeng
• Guo Zhixiang
• Gao Shuihong
• Wang Chunyan
• Lin Chen
• Yang Yanlei
• Ye Zhicang
• Peng Jie
• Xu Jun
• Zuo Xiaotao
• Su Qingyu

Classifications

• A61K47/68035

  the drug being a pyrrolobenzodiazepine · CPC title

• A61K47/68031

  the drug being an auristatin · CPC title

• C07D513/22

  in which the condensed system contains four or more hetero rings · CPC title

• C07D498/04 Primary

  Ortho-condensed systems · CPC title

• C07D498/22

  in which the condensed system contains four or more hetero rings · CPC title