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5-HT2A receptor antagonist, and application thereof in treating central nervous system diseases

A solvate, selected technology, applied in the field of medicine, can solve the problems of type 2 diabetes, abnormal motor function and the like

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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  • 5-HT2A receptor antagonist, and application thereof in treating central nervous system diseases
  • 5-HT2A receptor antagonist, and application thereof in treating central nervous system diseases
  • 5-HT2A receptor antagonist, and application thereof in treating central nervous system diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0173] Example 1: Synthesis of 1-(4-fluoro-benzyl)-3-(4-isobutoxy-benzyl)-1-(9-methyl-3-oxa-9-aza- Bicyclo[3.3.1]non-7-yl)-urea (Compound#1), ER10048

[0174]

[0175] (4-fluoro-benzyl)-(9-methyl-3-oxa-9-za-bicyclo[3,3,1]non-7-yl)amine (1-1): at room temperature, 4-Fluorobenzene Methylamine (151mg, 1.21mmol), then sodium triacetoxyborohydride (341mg, 1.61mmol), and 0.1ml of acetic acid were added slowly in portions. The mixture was stirred overnight at room temperature. Ice water (10 ml) was added, and the mixture was extracted with 10% (v / v) isopropanol / chloroform (30 ml×2). Organic Phase Na 2 SO 4 Drying, filtration and concentration under vacuum gave Intermediate (1-1) (181 mg, 85% yield) as a colorless oil. LCMS: [M+1] + 265.2.

[0176]

[0177] 4-Isobutoxybenzonitrile (1-2): In acetone (150 mL), potassium carbonate (58.0 g, 420 mmol) was added to 4-hydroxybenzonitrile (25.0 g, 210 mmol) and 1-bromo -2-Methylpropane (34.5g, 252mmol) in a mixture. Stir at 60...

Embodiment 2

[0184] Example 2: Synthesis of 1-(3-(azetidin-1-yl)-propyl)-1-(4-fluoro-benzyl)-3-(4-isobutoxy-benzyl) - Urea (Compound #12), ER10053

[0185]

[0186] (3-(azetidin-1)-yl-propyl)-(4-fluoro-benzyl)-amine (12-1): The synthesis method is similar to intermediate (1-1). Using 0.88 mmol of 3-(azetidin-1-yl)-propylamine and 4-fluorobenzaldehyde, compound (12-1) (155 mg, 80% yield) was obtained as a brown oil. LCMS: [M+1] + 223.3.

[0187]

[0188] 1-(3-(azetidin-1-yl)-propyl)-1-(4-fluoro-benzyl)-3-(4-isobutoxy-benzyl)-urea (Compound# 12) The synthesis method is similar to compound#1. With 0.70mmol (3-(azetidin-1)-yl-propyl)-(4-fluoro-benzyl)-amine (12-1), and 1-isobutoxy-4-(isocyanate Acidomethyl)benzene (1-4) was reacted to give compound #12 (100 mg. 33% yield) as a white solid. 1 H NMR (300MHz, CDCl3): δ7.31(d, J=6.4Hz, 4H), 7.01(t, J=8.7Hz, 2H), 6.93-6.84(m, 2H), 4.48(s, 2H), 4.41(s, 2H), 3.73(d, J=6.5Hz, 2H), 3.245(s, 2Hz), 3.02-2.91(m, 4H), 2.36(d, J=5.9Hz, 2H), 2.0...

Embodiment 3

[0189] Example 3: Synthesis of 1-(4-fluoro-benzyl)-3-(4-isobutoxy-benzyl)-1-(1-methyl-pyrrolidin-3-ylmethyl)- Urea (compound#10), ER10054

[0190]

[0191] (4-Fluoro-benzyl)-(1-methyl-pyrrolidin-3-ylmethyl)-amine (10-1): The synthesis method is similar to intermediate (1-1). (1-Methyl-pyrrolidin-3-yl)-methanamine (100 mg, 0.87 mmol) was reacted with 4-fluorobenzaldehyde to give product (10-1) (155 mg, 80% yield) as yellow oil. LCMS: [M+1] + 223.4.

[0192]

[0193] 1-(4-Fluoro-benzyl)-3-(4-isobutoxy-benzyl)-1-(1-methyl-pyrrolidin-3-ylmethyl)-urea (compound#10 ) synthesis method is similar to compound#1. With (4-fluoro-benzyl)-(1-methyl-pyrrolidin-3-ylmethyl)-amine (10-1) 0.69mmol and 1-isobutoxy-4-(isocyanato Methyl)benzene (1-4) was reacted to give compound #10 (140 mg, 47% yield) as a yellow solid. 1 H NMR (300MHz, CDCl 3 ): δ7.29-7.17(m, 4H), 7.02(dd, J=9.8, 7.5Hz, 2H), 6.86(dd, J=9.1, 2.4Hz, 2H), 6.37(s, 1H), 4.70- 4.58(m, 2H), 4.44-4.32(m, 2H), 3.80(s, 2H), ...

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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 some mental diseases (such as depression, anxiety, psychosis, schizophrenia, insomnia, autism) and central nervous system degenerative diseases (such as Alzheimer's disease, Parkinson's disease) , Huntington's disease, dementia with Lewy bodies) related or concurrent psychiatric 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 plays a role in regulating various behaviors such as sleep, diet, activity, learning and memory, body temperature, blood pressure, and pathological states (such as anxiety, r...

Claims

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Application Information

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IPC IPC(8): C07D498/08C07D205/04C07D207/09C07D471/04C07D498/04C07D295/13C07D233/64C07D211/26C07D405/12A61K31/397A61K31/5386A61K31/40A61K31/445A61K31/4375A61K31/5383A61K31/417A61K31/4453A61K31/4525A61K31/4025A61P25/24A61P25/22A61P25/18A61P25/20A61P25/00A61P25/28A61P25/16A61P25/14
CPCC07D498/08C07D205/04C07D207/09C07D471/04C07D498/04C07D295/13C07D233/64C07D211/26C07D405/12A61P25/24A61P25/22A61P25/18A61P25/20A61P25/00A61P25/28A61P25/16A61P25/14C07B2200/07
Inventor 邢洪涛
Owner HAN YUAN MEDI PHARM CO LTD
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