5HT2A receptor antagonist, and preparation and application thereof

A R1OCH2-, solvate technology, applied in the field of medicine, can solve problems such as abnormal motor function and type 2 diabetes

Active Publication Date: 2021-08-06
HAN YUAN MEDI PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the second-generation antipsychotic drugs all have broad-spectrum receptor activity, and these compounds act as agonists, competitive antagonists or inverse agonists to regulate various monoaminergic receptors such as 5-HTergic, dopaminergic, Adrenergic, muscarinic, or histaminergic receptors, this broad-spectrum modulation is likely responsible for side effects such as abnormal sedation, abnormal motor function, and type 2 diabetes

Method used

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  • 5HT2A receptor antagonist, and preparation and application thereof
  • 5HT2A receptor antagonist, and preparation and application thereof
  • 5HT2A receptor antagonist, and preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0134] Example 1: 3-(4-isopropoxymethylbenzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea (III-1 ) Preparation (ER10067)

[0135]

[0136] To a solution of trimeric phosgene (49.7 mg, 0.167 mmol, 1.0 equiv.) in dichloromethane was added dropwise 4-isopropoxymethyl-1-benzylamine (I-1) (30 mg, 0.167 mmol , 1.0 equiv.) in tetrahydrofuran (1.0 mL). A solution of triethylamine (0.070 mL, 3.0 equiv.) in dichloromethane (2.0 mL) was then added dropwise. After precipitation, the residue was redissolved in dichloromethane (3.0 mL), and (4-fluoro-benzyl)-(1-methylpiperidin-4-yl)-amine (II-1) was added ( 39.6 mg, 1.0 equiv.) in tetrahydrofuran (2.0 mL). The mixture was stirred at room temperature for 2 hours. After precipitation, the crude product was purified by silica gel column to give the final product.

Embodiment 2

[0137] Example 2: 3-((4-isopropoxymethyl)benzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl ) Preparation of urea (III-2) (ER10235)

[0138]

[0139] 3-((4-isopropoxymethyl)benzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)urea (III -2) is prepared analogously to 3-(4-isopropoxymethylbenzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea ( III-1) Preparation: Using 4-isopropoxymethyl-1-benzylamine (I-1) (30 mg, 0.167 mmol, 1.0 equiv.) and N-(4-fluorobenzyl)- 1-(1-methylpiperidin-4-yl)methanamine (II-2) (39.6 mg, 0.167 mmol, 1.0 equiv.), silica gel column purification gave the final product (13 mg, yield 18%). LCMS: M+1] + 442.8.

Embodiment 3

[0140] Example 3: 3-((4-isopropoxymethyl)benzyl)-1-(4-fluorobenzyl)-1-(((R)-1-(1-methylpyrrolidine Preparation of -3-yl))methyl)urea (III-3) (ER10236)

[0141]

[0142] 3-((4-isopropoxymethyl)benzyl)-1-(4-fluorobenzyl)-1-(((R)-1-(1-methylpyrrolidin-3-yl )) methyl) urea (III-3) is prepared analogously to 3-(4-isopropoxymethylbenzyl)-1-(4-fluorobenzyl)-1-(1-methylpiper Preparation of pyridin-4-yl)urea (III-1): Using 4-isopropoxymethyl-1-benzylamine (I-1) (30 mg, 0.167 mmol, 1.0 equiv.) and (S) -N-(4-fluorobenzyl)-1-(1-methylpyrrolidin-3-yl)methanamine (II-3) (37.2 mg, 0.167 mmol, 1.0 equiv.), purification on silica gel column gave Final product (5.3 mg, yield 7.0%). LCMS: [M+1] + 428.8.

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Abstract

The invention provides a compound with a central nervous system disease treatment effect and a structure shown in a formula I. The compound has 5-HT2A receptor antagonist or inverse agonist activity, and has the advantages of high selectivity to 5-HT2A receptors, low cardiotoxicity, good metabolic stability, and no toxic or side effect. The compound can be used for treating certain mental diseases (such as depression, anxiety, psychosis, schizophrenia, insomnia and autism) and mental disorder symptoms related to or concurrent with central nervous system degenerative diseases (such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Lewy small body dementia).

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a 5-HT2A receptor antagonist or inverse agonist with therapeutic effect on central nervous system diseases and application thereof. Said compound can be used for the treatment of certain mental illnesses (such as depression, anxiety, psychosis, schizophrenia, insomnia, autism, etc.) and degenerative diseases of the central nervous system (such as Alzheimer's disease, Parkinson's disease, Huntington's disease, dementia with Lewy bodies, etc.) related or concurrent mental disorder symptoms. Background technique [0002] Serotonin or 5-hydroxytryptamine (5-HT) plays an extremely important role in the physiological functions of the human body. In the central nervous system, 5-HT is an important neurotransmitter and neuromodulator, which regulates various behaviors such as sleep, diet, activity, learning and memory, body temperature, blood pressure and pathological states (such as anx...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/58C07D211/26C07D207/09A61K31/4468A61K31/445A61K31/40A61P25/00A61P25/18A61P25/22A61P25/24A61P25/20A61P25/28A61P25/16A61P25/14
CPCC07D211/58C07D211/26C07D207/09A61P25/00A61P25/18A61P25/22A61P25/24A61P25/20A61P25/28A61P25/16A61P25/14C07B2200/07
Inventor 邢洪涛
Owner HAN YUAN MEDI PHARM CO LTD
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