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HETEROCYCLIC DERIVATIVES AS Nav1.7 and Nav1.8 BLOCKERS

A compound and cycloalkyl technology, applied in anti-inflammatory agents, drug combinations, non-central analgesics, etc., can solve problems such as incomplete curative effect, low efficiency, and limitations, and achieve good selectivity, high selectivity, and improved Effect of side effect properties

Pending Publication Date: 2021-07-23
RAQUALIA PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In the clinic, voltage-gated sodium channel blockers (e.g., lidocaine, halexin) have been used in pain management, however the potency of these blockers is incomplete due to low potency and especially targeting Nav1. 5 (e.g., arrhythmias) are limited by undesired side effects due to non-subtype selectivity,

Method used

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  • HETEROCYCLIC DERIVATIVES AS Nav1.7 and Nav1.8 BLOCKERS
  • HETEROCYCLIC DERIVATIVES AS Nav1.7 and Nav1.8 BLOCKERS
  • HETEROCYCLIC DERIVATIVES AS Nav1.7 and Nav1.8 BLOCKERS

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0920] Example 1: (S)-2-acetamido-N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)isonicotinamide

[0921] Add (S)-1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-amine dihydrochloride (20 mg, 0.059 mmol, amine-1 ), 2-acetamidoisonicotinic acid (11 mg, 0.059 mmol, carboxylic acid-1) and triethylamine (0.041 mL, 0.30 mmol) were mixed in DMF (0.5 mL) and HBTU (27 mg, 0.071 mmol). The mixture was diluted with water (3 mL) and extracted with EtOAc (3 mLx2). The combined organic fractions were dried over sodium sulfate. The organic layer was purified by NH-silica gel column chromatography, eluting with EtOAc, and then by preparative LC-MS to obtain the title compound 6.0 mg (24% yield).

[0922] Regarding the other examples, they were prepared following a method similar to that described in Example 1, using the appropriate amine and carboxylic acid (refer to Table 1). Unless otherwise specified in the synthesis section, the reaction materials are commerc...

Embodiment 2、5、6、7、8、9、10、11、16、20、21、22、23、24、25、26、27、28、37、38、39、41、42、46、47、48、49

[0980] Embodiment 2, 5, 6, 7, 8, 9, 10, 11, 16, 20, 21, 22, 23, 24, 25, 26, 27, 28, 37, 38, 39, 41, 42, 46, 47, 48, 49, 50, 51, 52, 53, 55, 56, 57, 58, 59, 60, 73, 77, 78, 79, 80, 81, 82, 83, 84, 88, 92, 93, 95, 96, 99, 103, 104, 107, 109, 114, 116, 117, 118, 119, 120, 121, 123, 125, 126, 127, 128, 129 and 132.

[0981] FRET analysis

[0982] This screen was used to determine the effect of compounds on human Nav1.8 channel and human Nav1.5 channel using cell imaging technology based on Hamamatsu Photonics' Functional Drug Screening System (FDSS). Changes in membrane potential were monitored by FRET technology using a pair of fluorescent membrane potential dyes, DiSBAC2(3) and CC2-DMPE.

[0983] Cell maintenance:

[0984] HEK293 cells expressing human Nav1.8 channels or human Nav1.5 channels were cultured in T225 flasks under 5% CO 2 Bring to approximately 80% confluence in a humidified incubator. The medium composition of HEK293 cells expressing the channel of human Nav1....

Embodiment 7

[1007] The compound of embodiment 7 is to the IC of Nav1.8 50 The value is 2 μM.

[1008] For all compounds tested, the ratio of activity on Nav1.5 to Nav1.7 or Nav1.8 was more than three-fold. For example, in Example 7, the activity on Nav1.5 and the activity on Nav1.8 were greater than 30 μM and 2 μM, respectively.

[1009] Electrophysiological Analysis

[1010] Whole cell patch clamp recording is used to assess the potency or selectivity of Na (sodium) channel blockers on voltage-gated sodium channels in humans. Use 0.05% Trypsin (Trypsin)-EDTA or Accutase to dissociate Na channel expressing cells, and then inoculate on coverslips for 2-24 hours.

[1011] Manual patch-clamp recordings were performed at room temperature using a voltage-clamp amplifier (Axon Instruments or HEKA electronik). Electrodes were drawn using a P-97 electrode puller (Sutter Instrument). The electrode resistance is 1-3 MΩ when the intracellular solution is full. The current is low-pass filtered ...

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Abstract

The present invention relates to heterocyclic derivatives which have blocking activities of voltage gated sodium channels as the Nav1.7 and Nav1.8 channels, and which are useful in the treatment or prevention of disorders and diseases in which voltage gated sodium channels are involved. The invention also relates to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which voltage gated sodium channels are involved.

Description

technical field [0001] The present invention relates to a heterocyclic derivative which is a sodium channel blocker and can be used in various therapeutic applications, especially in the treatment of pain. Background technique [0002] The heterocyclic derivatives of the present invention are sodium channel blockers and are useful in various therapeutic applications, especially in the treatment of pain. More specifically, the heterocyclic derivatives of the present invention are modulators of Nav1.7 and Nav1.8 channels. In the discussion that follows, the invention is illustrated by reference to the inhibition of Nav1.7 and Nav1.8 channels. The heterocyclic derivatives showed significantly higher affinity to Nav1.7 and Nav1.8 channels than to Nav1.5 channels. Compared with Nav1.5 channel, the heterocyclic derivative of the present invention shows good selectivity to Nav1.7 and Nav1.8 channels. [0003] Voltage-gated sodium channels (VGSC, Nav1.x) play a key role in the in...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4427A61K31/4439A61K31/4545A61K31/4709A61K31/506A61P25/00C07D401/12C07D401/14C07D403/12
CPCA61P25/00C07D401/12C07D401/14C07D403/12A61K45/06A61K31/444A61K31/506A61P29/00A61K31/395A61K31/435
Inventor 山岸龙也川村清肉户祐二山口龙一森田干雄我谢德一
Owner RAQUALIA PHARMA INC
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