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Alpha-aminoamide derivative and application thereof

An alkyl and hydroxyl technology, applied in the direction of drug combinations, active ingredients of heterocyclic compounds, medical preparations containing active ingredients, etc., can solve problems that cannot delay disease progression, dyskinesias, motor fluctuations, and mental symptoms, and achieve good results. Effect of pharmacodynamic and pharmacokinetic properties, good safety profile, good metabolic stability

Inactive Publication Date: 2019-01-22
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, surgical deep brain stimulation (deep brain stimulation, DBS), long-acting dopamine receptor agonists can reduce the occurrence of these complications to some extent (SCHAPIRAAHV, EMREBM, 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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  • Alpha-aminoamide derivative and application thereof
  • Alpha-aminoamide derivative and application thereof
  • Alpha-aminoamide derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0244] Embodiment 1 (S)-2-((4-(4-(methylsulfonyl) methyl) benzyloxy group) benzyl amino) the synthesis of propanamide

[0245]

[0246] Step 1) Synthesis of 4-(4-(bromomethyl)benzyloxy)benzaldehyde

[0247] 4-Hydroxybenzaldehyde (1.0g, 8.19mmol), 1,4-bis(bromomethyl)benzene (4.3g, 16.38mmol), potassium carbonate (4.5g, 32.76mmol) and acetone (50mL) were added to In a 100mL single-necked round bottom flask, react at 60°C for 5h, cool to room temperature, filter, collect the filtrate, and then directly mix the sample for column chromatography purification (petroleum ether / ethyl acetate (v / v)=5 / 1) to obtain the title compound As a white solid (1.35 g, 54.0%).

[0248] MS(ESI,pos.ion)m / z:305.0[M+H] + ;

[0249] 1 H NMR (400MHz, CDCl 3 )δ(ppm)9.89(s,1H),7.92-7.75(m,2H),7.46-7.39(m,4H),7.07(d,J=8.7Hz,2H),5.15-5.14(m,2H) ,4.50(s,2H).

[0250] Step 2) Synthesis of 4-(4-((methylsulfonyl)methyl)benzyloxy)benzaldehyde

[0251] 4-(4-(Bromomethyl)benzyloxy)benzaldehyde (0.78...

Embodiment 2

[0259] Synthesis of Example 2 (S)-2-(4-(4-((methylsulfonyl)methyl)benzyloxy)benzyl)(propyl-2-yn-1-yl)amino)propionamide

[0260]

[0261] (S)-2-((4-(4-(Methylsulfonyl)methyl)benzyloxy)benzylamino)propanamide (0.16g, 0.43mmol), DIPEA (0.34mL, 2.04mmol), DMF (5mL) and 3-bromopropyne (0.29mL, 3.44mmol) were successively added into a 100mL single-necked round bottom flask, heated to 80°C for 15h, stopped the reaction, cooled to room temperature, added water (20mL) and washed with ethyl acetate (20mL ×2) extraction, washing with water (20mL×3), collecting the ethyl acetate layer, and then concentrating and purifying by column chromatography (petroleum ether / ethyl acetate (v / v)=1 / 5) to obtain the title compound as a white solid (0.05g ,28.4%).

[0262] MS(ESI,pos.ion)m / z:415.2[M+H] + ;

[0263] 1 H NMR (400MHz, CDCl 3 )δ (ppm) 7.45 (dd, J = 19.4, 7.8Hz, 4H), 7.24 (d, J = 8.2Hz, 2H), 6.93 (d, J = 8.3Hz, 2H), 5.07 (s, 2H), 4.26(s,2H),3.63(dd,J=75.3,13.1Hz,2H),3.42(dd,J=13.7,6...

Embodiment 3

[0265] Embodiment 3 (S)-2-(4-(2,2,3,3-tetrafluoropropoxy) benzylamino) propionamide synthesis

[0266]

[0267] Step 1) Synthesis of 4-(2,2,3,3-tetrafluoropropoxy)benzaldehyde

[0268] Tetrafluoropropyl 4-methylbenzenesulfonate (4.0g, 13.97mmol), 4-hydroxybenzaldehyde (3.4g, 27.95mmol), potassium carbonate (3.86g, 27.95mmol) and DMF (20mL) were added to In a 100mL single-necked round-bottom flask, heat to 100°C for 13h, stop the reaction, cool to room temperature, add water (40mL) and extract with ethyl acetate (50mL×2), wash with water (50mL×3), collect the ethyl acetate layer, and then Purification by concentration column chromatography (petroleum ether / ethyl acetate (v / v)=10 / 1) gave the title compound as a light yellow oil (3.10 g, 94.0%).

[0269] MS(ESI,pos.ion)m / z:237.1[M+H] + ;

[0270] 1 H NMR (400MHz, CDCl 3 )δ (ppm) 9.92 (s, 1H), 7.88 (d, J = 8.8Hz, 2H), 7.05 (d, J = 8.7Hz, 2H), 6.06 (tt, J = 53.1, 4.6Hz, 1H), 4.44(t,J=11.8Hz,2H).

[0271] Step 2) Synth...

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Abstract

The invention discloses an alpha-aminoamide derivative and application thereof. Specifically, the invention relates to a novel alpha-aminoamide derivative and a pharmaceutical composition containing the compound. The invention also relates to a method for preparation of the compound and pharmaceutical composition, and application of the compound and pharmaceutical composition in preparation of drugs treating MAO-B (monoamine oxidase B) inhibitor regulated diseases 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 alpha-aminoamide 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 distu...

Claims

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Application Information

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IPC IPC(8): C07C317/18C07C237/06C07D213/65C07D295/13A61K31/44A61K31/5375A61K31/165A61P25/28A61P25/18A61P35/00A61P25/16A61P9/10A61P25/14A61P35/02A61P25/22A61P27/02A61P27/06
CPCA61P9/10A61P25/14A61P25/16A61P25/18A61P25/22A61P25/28A61P27/02A61P27/06A61P35/00A61P35/02C07B2200/07C07C237/06C07C317/18C07D213/65C07D295/13
Inventor 陈康智金传飞张英俊
Owner SUNSHINE LAKE PHARM CO LTD
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