Unlock instant, AI-driven research and patent intelligence for your innovation.

Morpholine amide derivative and application thereof

A compound and nitrogen oxide technology, applied in the field of compounds for the treatment of Parkinson's disease, can solve the problems of dyskinesia, motor fluctuations and mental symptoms, cannot delay disease progression, etc., and achieve good safety, good pharmacodynamics and pharmacokinetics. Effects of kinetic properties, good bioavailability

Pending Publication Date: 2020-12-01
广东东阳光药业股份有限公司
View PDF8 Cites 1 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although L-dopa can temporarily control the symptoms of PD, long-term use can cause many adverse reactions such as dyskinesias, motor fluctuations and psychiatric symptoms
Although the use of continuous DAergic neuron stimulation, surgical deep brain stimulation (deep brain stimulation, DBS), long-acting dopamine receptor agonists can reduce the occurrence of these complications to some extent (SCHAPIRA A H V, EMREB M, JENNER P, et al.Levodopain the treatment of Parkinson's disease[J].Eur J Neurol,2009,16(9):982-989), but it cannot delay the progress of the disease

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Morpholine amide derivative and application thereof
  • Morpholine amide derivative and application thereof
  • Morpholine amide derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0237] Synthesis of Example 1 (S)-4-(4-((3-fluorobenzyl)oxy)benzyl)morpholine-3-formamide

[0238]

[0239] Step 1) Synthesis of 4-((3-fluorobenzyl)oxy)benzaldehyde

[0240] 4-Hydroxybenzaldehyde (1.0g, 8.19mmol), 3-fluorobenzyl bromide (1.06mL, 8.64mmol), potassium carbonate (4.30g, 32.76mmol) and acetone (50mL) were successively added into a 100mL single-necked round bottom flask , reacted at 60°C for 5h, cooled to room temperature, filtered, collected the filtrate, and purified by direct column chromatography (petroleum ether / ethyl acetate (v / v)=10 / 1) to obtain the title compound as a white solid (1.78g, 94.7 %).

[0241] MS(ESI,pos.ion)m / z:231.1[M+H] + ;

[0242] 1 H NMR (400MHz, CDCl 3 )δ (ppm) 9.89 (s, 1H), 7.85 (d, J = 8.8Hz, 2H), 7.37 (td, J = 7.9, 6.0Hz, 1H), 7.20 (d, J = 7.7Hz, 1H), 7.15 (d, J = 9.4Hz, 1H), 7.08 (s, 1H), 7.06 (s, 1H), 7.03 (dd, J = 8.4, 2.2Hz, 1H), 5.15 (s, 2H).

[0243] Step 2) Synthesis of (4-((3-fluorobenzyl)oxy)phenyl)methanol

[0...

Embodiment 2

[0254] Example 2 Synthesis of (S)-4-(2-fluoro-4-((3-fluorobenzyl)oxy)benzyl)morpholine-3-formamide

[0255]

[0256] Step 1) Synthesis of 2-fluoro-4-((3-fluorobenzyl)oxy)benzaldehyde

[0257]The title compound of this step was prepared by referring to the method described in step 1 of Example 1, that is, 3-fluorobenzyl bromide (0.92mL, 7.50mmol), 2-fluoro-4-hydroxybenzaldehyde (1.00g, 7.14mmol), potassium carbonate (3.94g, 28.56mmol) and acetone (25mL) were sequentially added to a 100mL single-necked round-bottomed flask for reaction preparation, and then concentrated and mixed with column chromatography for purification (petroleum ether / ethyl acetate (v / v)=10 / 1) to obtain The title compound was a light red solid (1.48 g, 83.7%).

[0258] MS(ESI,pos.ion)m / z:249.1[M+H] + ;

[0259] 1 H NMR (400MHz, CDCl 3 )δ (ppm) 10.20 (s, 1H), 7.83 (t, J = 8.4Hz, 1H), 7.37 (td, J = 7.9, 5.9Hz, 1H), 7.18 (d, J = 7.6Hz, 1H), 7.13(d, J=9.4Hz, 1H), 7.05(td, J=8.4, 2.2Hz, 1H), 6.84(dd, ...

Embodiment 3

[0271] Embodiment 3 (S)-4-(4-((3-bromobenzyl) oxygen group) benzyl) morpholine-3-formamide synthesis

[0272]

[0273] Step 1) Synthesis of 4-((3-bromobenzyl)oxy)benzaldehyde

[0274] The title compound of this step was prepared by referring to the method described in step 1 of Example 1, that is, 3-bromobenzyl bromide (0.96mL, 6.00mmol), 4-hydroxybenzaldehyde (0.77g, 6.30mmol), potassium carbonate (0.91g, 6.60mmol) and acetone (25mL) were sequentially added to a 100mL single-necked round-bottomed flask for reaction preparation, and then concentrated and mixed with column chromatography for purification (petroleum ether / ethyl acetate (v / v)=10 / 1) to obtain the title compound as white Solid (1.61 g, 92.2%).

[0275] MS(ESI,pos.ion)m / z:292.0[M+H] + ;

[0276] 1 H NMR (400MHz, CDCl 3 )δ(ppm)9.90(s,1H),7.87(s,1H),7.85(s,1H),7.61(s,1H),7.49(d,J=7.9Hz,1H), 7.36(d,J =7.6Hz, 1H), 7.31–7.26(m, 1H), 7.09(s, 1H), 7.06(s, 1H), 5.12(s, 2H).

[0277] Step 2) Synthesis of (4-((3...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention discloses a morpholine amide derivative and application thereof, and particularly relates to a novel morpholine amide derivative and a pharmaceutical composition containing the compound.The invention also relates to a method for preparing the compound and the pharmaceutical composition, and application of the compound and the pharmaceutical composition in preparation of drugs for treating diseases regulated by MAO-B inhibitors, including neurodegenerative diseases, especially Parkinson's disease.

Description

technical field [0001] The invention belongs to the technical field of medicines, and specifically relates to a compound for treating Parkinson's disease, a pharmaceutical composition containing the compound, and a method and use thereof. In particular, the compounds described in the present invention are morpholine amides derivatives that can act as MAO-B inhibitors. Background technique [0002] Parkinson's disease (Parkinson's disease, PD) is a common chronic degenerative disease of the nervous system. The prevalence of PD in people over 65 years old in my country is about 1.7%. Most Parkinson's disease patients are sporadic cases, and less than 10% of patients have a family history. Parkinson's disease has an insidious onset and slow progression. The first symptom is usually tremor or clumsiness in one extremity, which then involves the opposite extremity. Clinically, the main manifestations are resting tremor, bradykinesia, muscle rigidity, and posture and gait dist...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07D265/30A61K31/5375A61P25/00A61P25/18A61P25/16A61P25/28A61P35/00A61P9/10A61P21/00A61P25/14A61P9/08
CPCC07D265/30A61P25/00A61P25/18A61P25/16A61P25/28A61P35/00A61P9/10A61P21/00A61P25/14A61P9/08
Inventor 金传飞陈康智张英俊
Owner 广东东阳光药业股份有限公司