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1. WO2018149382 - O-AMINOHETEROARYL ALKYNYL-CONTAINING COMPOUND, PREPARATION METHOD THEREFOR, AND USE THEREOF

Publication Number WO/2018/149382
Publication Date 23.08.2018
International Application No. PCT/CN2018/076423
International Filing Date 12.02.2018
IPC
C07D 213/73 2006.1
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
DHETEROCYCLIC COMPOUNDS
213Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
02having three double bonds between ring members or between ring members and non-ring members
04having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
60with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
72Nitrogen atoms
73Unsubstituted amino or imino radicals
C07D 213/75 2006.1
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
DHETEROCYCLIC COMPOUNDS
213Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
02having three double bonds between ring members or between ring members and non-ring members
04having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
60with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
72Nitrogen atoms
75Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
C07D 241/20 2006.1
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
DHETEROCYCLIC COMPOUNDS
241Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
02not condensed with other rings
10having three double bonds between ring members or between ring members and non-ring members
14with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
20Nitrogen atoms
A61K 31/4965 2006.1
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
33Heterocyclic compounds
395having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
495having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
4965Non-condensed pyrazines
A61K 31/44 2006.1
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
33Heterocyclic compounds
395having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
435having six-membered rings with one nitrogen as the only ring hetero atom
44Non-condensed pyridines; Hydrogenated derivatives thereof
A61P 35/00 2006.1
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
35Antineoplastic agents
CPC
A61K 31/44
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
33Heterocyclic compounds
395having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
435having six-membered rings with one nitrogen as the only ring hetero atom
44Non condensed pyridines; Hydrogenated derivatives thereof
A61K 31/496
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
33Heterocyclic compounds
395having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
495having six-membered rings with two ; or more; nitrogen atoms as the only ring heteroatoms, e.g. piperazine ; or tetrazines
496Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
A61K 31/4965
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
33Heterocyclic compounds
395having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
495having six-membered rings with two ; or more; nitrogen atoms as the only ring heteroatoms, e.g. piperazine ; or tetrazines
4965Non-condensed pyrazines
A61K 31/497
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
33Heterocyclic compounds
395having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
495having six-membered rings with two ; or more; nitrogen atoms as the only ring heteroatoms, e.g. piperazine ; or tetrazines
4965Non-condensed pyrazines
497containing further heterocyclic rings
A61P 35/00
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
35Antineoplastic agents
B01J 2231/44
BPERFORMING OPERATIONS; TRANSPORTING
01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
2231Catalytic reactions performed with catalysts classified in B01J31/00
40Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
44Allylic alkylation, amination, alkoxylation or analogues
Applicants
  • 中国科学院上海药物研究所 SHANGHAI INSTITUTE OF MATERIA MEDICA, CHINESE ACADEMY OF SCIENCES [CN]/[CN]
Inventors
  • 胡有洪 HU, Youhong
  • 耿美玉 GENG, Meiyu
  • 任文明 REN, Wenming
  • 丁健 DING, Jian
  • 官晓聪 GUAN, Xiaocong
  • 艾菁 AI, Jing
  • 王浪 WANG, Lang
  • 彭霞 PENG, Xia
  • 刘杨 LIU, Yang
  • 戴阳 DAI, Yang
  • 曾丽敏 ZENG, Limin
Agents
  • 北京坦路来专利代理有限公司 BEIJING TANLULAI PATENT AGENT LTD
Priority Data
201710090242.820.02.2017CN
Publication Language Chinese (zh)
Filing Language Chinese (ZH)
Designated States
Title
(EN) O-AMINOHETEROARYL ALKYNYL-CONTAINING COMPOUND, PREPARATION METHOD THEREFOR, AND USE THEREOF
(FR) COMPOSÉ CONTENANT UN ALCYNYLE O-AMINOHÉTÉROARYLE, SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION
(ZH) 含邻氨基杂芳环炔基的化合物及其制备方法和用途
Abstract
(EN) An o-aminoheteroaryl alkynyl-containing compound, a preparation method therefor, and a use thereof. The o-aminoheteroaryl alkynyl-containing compound has a structure represented by formula (I), and the compound of formula (I) has advantages of a high FGFR and RET double target inhibitory activity and a relatively low KDR activity, and the compound of formula (I) exhibits a strong inhibitory activity in a human lung cancer cell line NCI-H1581 and a gastric cancer cell line SNU16 as well as an RET-dependent sensitive cell line BaF3-CCDC6-Ret and a mutant thereof. Pharmacokinetic data showed that the o-aminoheteroaryl alkynyl-containing compound has druggability, and exhibits significant relevant inhibition of the growth of related tumors in a long-term animal model of drug efficacy and results in favorable animal condition at effective doses.
(FR) L'invention concerne un composé contenant un alcynyle o-aminohétéroaryle, son procédé de préparation et son utilisation. Le composé contenant un alcynyle o-aminohétéroaryle a une structure représentée par la formule (I), le composé de formule (I) présente les avantages d'une forte activité inhibitrice de double cible FGFR et RET et d'une activité KDR relativement faible, le composé de formule (I) présente une forte activité inhibitrice dans une lignée cellulaire NCI-H1581 du cancer du poumon humain et d'une lignée cellulaire SNU16 du cancer gastrique ainsi qu'une lignée cellulaire BaF3-CCDC6-ret sensible dépendante de RET et un mutant associé. Selon l'invention, des données pharmacocinétiques ont montré que le composé contenant un alcynyle o-aminohétéroaryle possède un potentiel médicamenteux, et présente une inhibition significative appropriée de la croissance des tumeurs associées dans un modèle animal à long terme d'efficacité médicamenteuse et conduit à un état de santé de l'animal favorable à des doses efficaces.
(ZH) 含邻氨基杂芳环炔基的化合物及其制备方法和用途,所述含邻氨基杂芳环炔基的化合物的结构如式(I)所示,所述式(I)化合物具有FGFR和RET双靶抑制活性高,并且KDR活性相对较低的优点,而且所述式(I)化合物在人肺癌NCI-H1581及胃癌细胞株SNU16及RET依赖性敏感细胞株BaF3-CCDC6-Ret及突变型均显示出了很强的抑制活性,通过药代数据表明所述含邻氨基杂芳炔基的化合物具有成药性,且在长期的动物药效模型上表现相关的明显抑制相关肿瘤的生长,在药效剂量下,动物状态好。
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