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EP-4737459-A1 - TETRODOTOXIN DERIVATIVE COMPOUND AND USE THEREOF AS SODIUM CHANNEL BLOCKER

EP4737459A1EP 4737459 A1EP4737459 A1EP 4737459A1EP-4737459-A1

Abstract

The present invention relates to a compound having an inhibitory effect on a plurality of sodium ion channels or a pharmaceutically acceptable derivative thereof, a pharmaceutical composition thereof and use thereof as a pan sodium ion channel blocker.

Inventors

  • LEI, Lijun
  • YAN, Xuhui
  • WANG, Chengxi
  • GUO, Zhaoxiang
  • HUANG, Chengyang
  • LIU, Pi
  • ZHONG, Yun
  • JIANG, BIAO
  • ZHU, Wenfeng

Assignees

  • Vastpro (Shanghai) Pharmaceutical Technology Development Co., Ltd.

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. A compound having a structure of formula (I) or a pharmaceutically acceptable derivative thereof: wherein, X is absent or selected from the group consisting of -(CH 2 ) m - and wherein - CH 2 - is optionally replaced by -O- or carbonyl or optionally substituted with at least one R X ; Y 1 and Y 2 are each independently selected from the group consisting of methylene, O, S and NH, wherein methylene and NH are optionally substituted with at least one R X ; R 1 and R 3 are each independently selected from the group consisting of hydrogen, hydroxyl, amino, cyano, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkyl-C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 1-8 alkyl-C 3-8 heterocyclyl, C 6-10 aryl, C 1-8 alkyl-C 6-10 aryl, C 5-10 heteroaryl and C 1-8 alkyl-C 5-10 heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with at least one R X ; R 2 is selected from the group consisting of hydrogen, hydroxyl, amino, formyl, acetyl, C 1- 8 alkyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, -(C=O)OR 10 and -O(C=O)R 11 , wherein the formyl, acetyl, alkyl, cycloalkyl and heterocyclyl are optionally substituted with at least one R X ; each R 4 is independently selected from the group consisting of hydrogen, deuterium, hydroxyl, halogen, -OR 12 and C 1-8 alkyl; or R 3 and R 4 together with the atom(s) to which they are attached form a 5-12 membered heterocycle, wherein the heterocycle is optionally substituted with at least one R X ; R 5 is selected from the group consisting of hydrogen, deuterium, tritium, hydroxyl, halogen, C 1-8 alkyl, C 3-8 cycloalkyl and -OR 13 ; R 6 is selected from the group consisting of hydroxyl, mercapto, amino, azido, halogen, cyano, C 1-12 alkyl, C 2-8 alkenyl, -O-C 1-12 alkyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 6-10 aryl, C 5- 10 heteroaryl, -(C=O)-R 14 , guanidino, ureido, -(OCH 2 CH 2 ) n -OH, wherein the alkyl, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, guanidino and ureido are optionally substituted with at least one R X ; or R 5 and R 6 together with the atom(s) to which they are attached form a 3-12 membered heterocycle, wherein the heterocycle is optionally substituted with at least one R X ; R 7 is selected from the group consisting of hydrogen, deuterium, tritium, hydroxyl, halogen, C 1-4 alkyl, -O-C 1-4 alkyl, C 3-8 cycloalkyl and C 3-8 heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl are optionally substituted with at least one R X ; R 8 is selected from the group consisting of hydrogen, deuterium, tritium, hydroxyl, halogen, C 1-8 alkyl, C 3-8 cycloalkyl and -OR 15 ; or R 4 and R 8 together with the atom(s) to which they are attached form a 5-12 membered heterocycle, wherein the heterocycle is optionally substituted with at least one R X ; R 9 is selected from the group consisting of hydrogen, deuterium, tritium, hydroxyl, C 1-8 alkyl, C 3-8 cycloalkyl and -OR 16 ; R 10 and R 11 are each independently selected from the group consisting of C 1-8 alkyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 6-20 aryl, C 1-8 alkyl-C 6-20 aryl, C 5-20 heteroaryl and C 1-8 alkyl-C 5- 20 heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with at least one R X ; each of R 12 , R 13 , R 14 , R 15 and R 16 is independently selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, C 3-8 cycloalkyl, C 1-8 alkyl-C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 1-8 alkyl-C 3-8 heterocyclyl, C 6-10 aryl, C 1-8 alkyl-C 6-10 aryl, C 5-10 heteroaryl, and C 1-8 alkyl-C 5-10 heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with at least one R X ; R 6' is selected from the group consisting of hydrogen, hydroxyl, amino, cyano, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkyl-C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 1-8 alkyl-C 3-8 heterocyclyl, C 6-10 aryl, C 1-8 alkyl-C 6-10 aryl, C 5-10 heteroaryl and C 1-8 alkyl-C 5-10 heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with at least one R X ; R 6" is selected from the group consisting of hydroxyl, mercapto, amino, halogen, C 1-12 alkyl, C 2-8 alkenyl, -O-C 1-12 alkyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 6-10 aryl and C 5-10 heteroaryl, wherein the alkyl, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with at least one R X ; each R X is independently selected from the group consisting of hydrogen, halogen, hydroxyl, carboxyl, amino, cyano, formyl, C 1-8 alkyl, -O-C 1-8 alkyl, C 2-8 alkenyl, C 3-20 cycloalkyl, C 1-8 alkyl-C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 1-8 alkyl-C 3-8 heterocyclyl, C 6-10 aryl, C 1-8 alkyl-C 6-10 aryl, C 5-10 heteroaryl, C 1-8 alkyl-C 5-10 heteroaryl, wherein the amino, formyl, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with at least one R Y ; each R Y is independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, carboxyl, formyl, acetyl, C 1-8 alkyl, -O-C 1-8 alkyl, C 3-8 cycloalkyl, -O-C 3-8 cycloalkyl, C 3-8 heterocyclyl, -O-C 3-8 heterocyclyl, C 1-8 alkyl-C 3-8 heterocyclyl, C 6-10 aryl, -O-C 6-10 aryl, C 1-8 alkyl-C 6-10 aryl, C 5-10 heteroaryl, -O-C 5-10 heteroaryl and C 1-8 alkyl-C 5-10 heteroaryl, wherein the formyl, acetyl, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with at least one halogen, hydroxyl, or R Y1 ; each R Y1 is independently selected from the group consisting of amino, C 1-8 alkyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 6-1O aryl, and C 5-10 heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with at least one R Y2 ; each R Y2 is independently selected from the group consisting of amino, C 1-8 alkyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 6-10 aryl, and C 5-10 heteroaryl; when X is methylene and R 1 , R 2 and R 3 are hydrogen at the same time, R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are not hydroxyl at the same time; m is an integer selected from 0-6; n is an integer selected from 1-12; t is an integer selected from 0-4.
  2. The compound according to claim 1 or a pharmaceutically acceptable derivative thereof, wherein X is selected from the group consisting of methylene, carbonyl and
  3. The compound according to claim 1 or 2 or a pharmaceutically acceptable derivative thereof, wherein R 1 is hydrogen.
  4. The compound according to any one of claims 1-3 or a pharmaceutically acceptable derivative thereof, wherein R 2 is selected from the group consisting of hydrogen, acetyl and - (C=O)OR 10 .
  5. The compound according to claim 4 or a pharmaceutically acceptable derivative thereof, wherein R 10 is selected from the group consisting of benzyl and cyclopentyl.
  6. The compound according to any one of claims 1-5 or a pharmaceutically acceptable derivative thereof, wherein R 3 is selected from the group consisting of hydrogen, C 1-8 alkyl, C 3- 8 cycloalkyl, C 1-8 alkyl-C 3-8 cycloalkyl and C 1-8 alkyl-C 6-10 aryl, wherein the alkyl, cycloalkyl and aryl are optionally substituted with at least one R X .
  7. The compound according to claim 6 or a pharmaceutically acceptable derivative thereof, wherein R X is selected from the group consisting of hydroxyl and carboxyl.
  8. The compound according to claim 6 or a pharmaceutically acceptable derivative thereof, wherein R 3 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, preferably hydrogen and
  9. The compound according to any one of claims 1-8 or a pharmaceutically acceptable derivative thereof, wherein R 4 is selected from the group consisting of hydrogen, deuterium and hydroxyl.
  10. The compound according to any one of claims 1-9 or a pharmaceutically acceptable derivative thereof, wherein R 3 and R 4 together with the atom(s) to which they are attached form a 6-membered heterocycle.
  11. The compound according to claim 10 or a pharmaceutically acceptable derivative thereof, wherein R 3 and R 4 together with the atom(s) to which they are attached form a heterocycle selected from the group consisting of
  12. The compound according to any one of claims 1-11 or a pharmaceutically acceptable derivative thereof, wherein R 5 is hydroxyl.
  13. The compound according to any one of claims 1-12 or a pharmaceutically acceptable derivative thereof, wherein R 6 is selected from the group consisting of hydroxyl, amino, cyano, -O-C 1-12 alkyl, guanidino, ureido, C 3-8 heterocyclyl and wherein the amino, alkyl, guanidino and heterocyclyl are optionally substituted with at least one R X .
  14. The compound according to claim 13 or a pharmaceutically acceptable derivative thereof, wherein R X is selected from the group consisting of halogen, hydroxyl, amino, formyl, C 1-8 alkyl, C 3-20 cycloalkyl, C 1-8 alkyl-C 6-10 aryl, C 3-8 heterocyclyl and wherein the amino, formyl, alkyl, cycloalkyl and heterocyclyl are optionally substituted with at least one R Y .
  15. The compound according to claim 14 or a pharmaceutically acceptable derivative thereof, wherein R Y is selected from the group consisting of halogen, hydroxyl, carboxyl, formyl, acetyl and C 1-8 alkyl, wherein the formyl is optionally substituted with hydroxyl or R Y1 ; R Y1 is selected from the group consisting of amino, the amino is optionally substituted with R Y2 ; R Y2 is selected from the group consisting of C 1-8 alkyl.
  16. The compound according to claim 13 or a pharmaceutically acceptable derivative thereof, wherein R 6' is selected from the group consisting of hydrogen and methyl.
  17. The compound according to claim 13 or pharmaceutically acceptable derivative thereof, wherein R 6" is selected from the group consisting of C 1-12 alkyl, C 3-8 cycloalkyl, C 6-10 aryl and C 5-10 heteroaryl, wherein the alkyl, cycloalkyl, aryl and heteroaryl are optionally substituted with at least one R X .
  18. The compound according to claim 17 or a pharmaceutically acceptable derivative thereof, wherein R X is selected from the group consisting of halogen, C 1-8 alkyl, -O-C 1-8 alkyl, C 3-20 cycloalkyl and C 6-10 aryl, wherein the alkyl, cycloalkyl and aryl are optionally substituted with at least one R Y .
  19. The compound according to claim 18 or a pharmaceutically acceptable derivative thereof, wherein R Y is halogen, the halogen is fluorine.
  20. The compound according to claim 17 or a pharmaceutically acceptable derivative thereof, wherein R 6" is selected from the group consisting of methyl, trifluoromethyl, propyl, isopropyl,

Description

Technical Field Provided is a compound having an inhibitory effect on a plurality of sodium ion channels or a pharmaceutically acceptable derivative thereof, a pharmaceutical composition thereof and use thereof as a pan sodium ion channel blocker. Background Tetrodotoxin (TTX) is an amino perhydroquinazolin type compound having the following structure: Tetrodotoxin has a local stimulation effect on the intestinal tract and rapidly acts on nerve terminals and nerve centers after absorption, which can block sodium ion channels on nerve excitation membranes with high selectivity and high affinity, and hinder nerve conduction, thereby causing nerve paralysis and death. Clinically, tetrodotoxin is mainly used for analgesia, local anesthesia, sedation, antispasmodic, hypotension, anti-arrhythmia, etc., but is greatly limited in application due to its strong toxicity. Voltage-gated sodium channels (VGSC) are microporous transmembrane glycoproteins widely distributed on excitable cell membranes such as neurons, are mainly responsible for transmembrane transport of Na+, and are the most important ion channels required for neurons to produce excitability and exert normal electrophysiological functions. The voltage-gated sodium channel consists of an α subunit and multiple β subunits. α subunit is the main functional unit, and 9 subtypes (Nav1.1 to Nav1.9) have been found at present, which are surrounded by 4 highly similar homologous domains to form a central pore of an ion channel, and each domain has 6 α helical transmembrane fragments (S1-S6), wherein the amino acid sequence of S4 is highly conserved and is considered as a voltage receptor of a voltage-gated sodium channel. There are four subtypes of β subunits (β1-β4), which play an auxiliary role in localization and stability of α subunit on the membrane, and participate in regulating the voltage sensitivity and inactivation process of α subunit. Voltage-gated sodium channels of different animals have wide homology, but they also have great differences. The sodium ion channels are divided into TTX sensitive (TTX-S) and TTX insensitive (TTX-R) according to the sensitivity blocked by tetrodotoxin (TTX). TTX-R-type sodium ion channels include Nav1.5, Nav1.8, and Nav1.9, and the rest are TTX-S-type sodium ion channels. Nav1.7 is a transmembrane protein encoded by SCN9A, specifically expressed on peripheral sensory nerve terminals and sympathetic ganglion neurons, and mainly expressed on large-diameter dorsal root ganglion (DRG) neurons and unmyelinated small-diameter DRG, that is, expressed on 85% of nociceptors, indicating that Nav1.7 has a very critical effect on pain conduction. Nav1.7 plays a central role in pain signaling and maintenance and has become a very important target for the development of an analgesic drug. The compound according to the present disclosure is structurally modified and optimized over tetrodotoxin, and the obtained tetrodotoxin derivative innovative molecules have significant inhibitory activity against TTX-S type sodium ion channels (including Nav1.1, Nav1.2, Nav1.3, Nav1.4, Nav1.6 and Nav1.7) and is a pan sodium ion channel blocker. In the prior art, derivatives based on tetrodotoxin are mainly derived from separation and extraction from nature. For example, 4,9-anhydro TTX (Nakamura M, Yasumoto T. Tetrodotoxin years in puffer fish [J]. Toxicon, 1985, 232): 271-276.), 6-epi TTX, 11-deoxy TTX (Yasumoto T, Yotsu M, Murata M, et al. New tetradotoxin analogs from the nenops ensauda [J] .j.am.chem.soc, 1988, 110(7): 2344-2345.) and the like. Laboratory synthesis of some derivatives of tetrodotoxin are also reported. For example, 11-Deoxytetrodotoxin (J. AM. CHEM. SOC. 2002, 124, 7847-7852), 8,11-Dioxytetrodotoxin (Chem. Eur. J. 2004, 10, 452-462), and the like. Summary In the first aspect, provided is a compound having a structure of formula (I) or a pharmaceutically acceptable derivative thereof: wherein, X is absent or selected from the group consisting of -(CH2)m- and wherein - CH2- is optionally replaced by -O- or carbonyl or optionally substituted with at least one RX;Y1 and Y2 are each independently selected from the group consisting of methylene, O, S and NH, wherein methylene and NH are optionally substituted with at least one RX;R1 and R3 are each independently selected from the group consisting of hydrogen, hydroxyl, amino, cyano, C1-8 alkyl, C3-8 cycloalkyl, C1-8 alkyl-C3-8 cycloalkyl, C3-8 heterocyclyl, C1-8 alkyl-C3-8 heterocyclyl, C6-10 aryl, C1-8 alkyl-C6-10 aryl, C5-10 heteroaryl and C1-8 alkyl-C5-10 heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with at least one RX;R2 is selected from the group consisting of hydrogen, hydroxyl, amino, formyl, acetyl, C1-8 alkyl, C3-8 cycloalkyl, C3-8 heterocyclyl, -(C=O)OR10 and -O(C=O)R11, wherein the formyl, acetyl, alkyl, cycloalkyl and heterocyclyl are optionally substituted with at least one RX;each R4 is independently selecte