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Nitrogen-containing heterocyclic amide derivative and use thereof

A compound and heteroaryl technology, applied in the field of compounds for the treatment of Parkinson's disease, can solve the problems of inability to delay disease progression, dyskinesia, motor fluctuations and mental symptoms, and achieve good pharmacodynamics and pharmacokinetic properties, The effect of good safety and good metabolic stability

Active Publication Date: 2018-11-30
SUNSHINE LAKE PHARM CO LTD
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  • 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 stimulation of DA neurons, deep brain stimulation (deep brain stimuli, DBS) through surgery, and long-acting dopamine receptor agonists can reduce the occurrence of these complications to some extent (SCHAPIRAAH V, EMREB M, JENNERP, et al.Levodopa in 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

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  • Nitrogen-containing heterocyclic amide derivative and use thereof
  • Nitrogen-containing heterocyclic amide derivative and use thereof
  • Nitrogen-containing heterocyclic amide derivative and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0255] Example 1 Synthesis of 1-(4-((3-fluorobenzyloxy)benzyl)azetidine-3-formamide

[0256]

[0257] Step 1) Synthesis of 4-(3-fluorobenzyloxy)benzaldehyde

[0258] 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, 94.4 %).

[0259] MS(ESI,pos.ion)m / z:231.1[M+H] + ;

[0260] 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).

[0261] Step 2) Synthesis of 1-(4-(3-fluorobenzyloxy)benzyl)azetidine-3-carboxamide

[0262] 4-(3-fluo...

Embodiment 2

[0266] Example 2 Synthesis of 1-(4-(3-fluorobenzyloxy)-2-methylbenzyl)azetidine-3-carboxamide

[0267]

[0268] Step 1) Synthesis of 4-(3-fluorobenzyloxy)-2-methylbenzaldehyde

[0269] 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 (0.48mL, 3.90mmol), 4-hydroxy-2-methylbenzaldehyde (0.50g, 3.67mmol), carbonic acid Potassium (2.03g, 14.70mmol) and acetone (35mL) were sequentially added to a 100mL single-necked round bottom flask for reaction preparation, and then concentrated and mixed with column chromatography for purification (petroleum ether / ethyl acetate (v / v)=9 / 1) The title compound was obtained as a white solid (0.78 g, 87.0%).

[0270] MS(ESI,pos.ion)m / z:245.1[M+H] + ;

[0271] 1 H NMR (400MHz, CDCl 3 )δ (ppm) 10.14 (s, 1H), 7.77 (d, J = 8.6Hz, 1H), 7.37 (tt, J = 13.3, 6.7Hz, 1H), 7.19 (dd, J = 18.1, 8.6Hz, 2H ),7.05(td,J=8.4,2.2Hz,1H),6.96–6.87(m,1H),6.87–6.80(m,1H),5....

Embodiment 3

[0277] Example 3 Synthesis of 1-(2-fluoro-4-(3-fluorobenzyloxy)benzyl)azetidine-3-carboxamide

[0278]

[0279] Step 1) Synthesis of 2-fluoro-4-(3-fluorobenzyloxy)benzaldehyde

[0280] 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 (0.46mL, 3.75mmol), 2-fluoro-4-hydroxybenzaldehyde (0.50g, 3.57mmol), potassium carbonate (1.97g, 14.28mmol) 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 white solid (0.73 g, 81.8%).

[0281] MS(ESI,pos.ion)m / z:249.1[M+H] + ;

[0282] 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, J=8.8, 2.2...

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Abstract

The present invention discloses a nitrogen-containing heterocyclic amide derivative and use thereof, and in particular, the present invention relates to a novel class of nitrogen-containing heterocyclic amide derivatives and pharmaceutical compositions comprising the same. The invention also relates to methods of preparing the compounds and pharmaceutical compositions, and use of the compounds andpharmaceutical compositions in manufacture of medicaments for treatment of diseases modulated by MAO-B inhibitors, including neurodegenerative diseases, particularly 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 nitrogen-containing heterocyclic amide 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 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D205/04A61K31/397A61P25/28A61P25/18A61P35/00A61P25/16A61P9/10A61P25/00A61P25/14A61P35/02A61P25/22
CPCA61P9/10A61P25/00A61P25/14A61P25/16A61P25/18A61P25/22A61P25/28A61P35/00A61P35/02C07D205/04
Inventor 金传飞陈康智
Owner SUNSHINE LAKE PHARM CO LTD