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Arylethyl piperidinyl derivatives and their application in the treatment of schizophrenia

A technology of arylethylpiperidine and derivatives, which is applied in the field of hydrate, salt or salt hydrate, and can solve problems such as cognitive impairment and poor curative effect

Active Publication Date: 2021-06-04
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0069] Aiming at the above-mentioned shortcomings in the prior art, the present invention discloses an arylethylpiperidinyl derivative to overcome metabolic side effects such as obesity, elevated blood sugar, cardiac arrhythmia, EPS (such as catalepsy), etc. Side effects and poor curative effect on negative symptoms and cognitive impairment, so as to meet the needs of clinical medication

Method used

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  • Arylethyl piperidinyl derivatives and their application in the treatment of schizophrenia
  • Arylethyl piperidinyl derivatives and their application in the treatment of schizophrenia
  • Arylethyl piperidinyl derivatives and their application in the treatment of schizophrenia

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0221] Embodiment 1: N-(4-(2-(4-(2,3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) acetamide (compound Preparation of material 1-1) and salt thereof

[0222] 4-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)piperidin-1-amine (9) (prepared according to General Method 1) (1.0g, 2.8 mmol), triethylamine (4.2mmol) were added to dichloromethane (10mL), and a solution of acetyl chloride (0.24g, 3.1mmol) in dichloromethane (5mL) was added dropwise, and reacted for 3h, followed by water (20mL×2 ), washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a white solid, which was crystallized from 95% ethanol solution to obtain 1.1 g of a white solid with a yield of 95%.

[0223] 1 HNMR (CDCl 3 ,δ:ppm):1.19-1.36(m,2H,A-H),1.44-1.53(m,4H,A-H),1.71-1.74(m,1H,A-H),2.15(s,3H,A-H),2.29- 2.35(m,2H,A-H),2.40(t,2H,J=8.0Hz,N-CH 2 ),2.61(brs,4H,A-H),3.03(brs,4H,A-H),3.10-3.12(m,2H,A-H),6.92-6.95(m,1H,Ar-H),7.08-7.13(m, 2H,A...

Embodiment 2

[0238] Embodiment 2: N-(4-(2-(4-(2,3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) butanamide (compound The preparation of thing 1-2) and salt thereof

[0239] Using intermediate 9 (2.8 mmol) and butyryl chloride (3.1 mmol) as raw materials, according to the preparation method of compound I-1, 1.14 g of the target compound I-2 was obtained as a white solid with a yield of 95%.

[0240] 1 HNMR (CDCl 3 ,δ:ppm):0.95(t,3H,J=6.8Hz,A-H),1.17-1.34(m,2H,A-H),1.43-1.52(m,4H,A-H),1.68-1.71(m,3H, A-H),2.28-2.34(m,2H,A-H),2.36(t,2H,J=7.2Hz,A-H),2.39(t,2H,J=8.0Hz,N-CH 2 ),2.59(brs,4H,A-H),3.01(brs,4H,A-H),3.09-3.10(m,2H,A-H),6.90-6.93(m,1H,Ar-H),7.06-7.12(m, 2H,Ar-H).

[0241] ESI-MS:427[M+H + ].

[0242] The preparation of compound 1-2 hydrobromic acid salt

[0243] Using compound I-2 (2.0 mmol) and 5% hydrobromic acid aqueous solution (2.1 mmol) as raw materials, the preparation method of compound I-1 hydrobromide was used to obtain 0.9 g of white solid with a yield o...

Embodiment 3

[0245] Example 3: N-(4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-methoxyethyl Preparation of amides (compound I-3) and their salts

[0246] Using intermediate 9 (2.8 mmol) and 2-methoxyacetyl chloride (3.1 mmol) as raw materials, according to the preparation method of compound I-1, 1.1 g of the target compound I-3 was obtained as a white solid with a yield of 92%.

[0247] 1 HNMR (CDCl 3 ,δ:ppm):1.18-1.36(m,2H,A-H),1.44-1.70(m,5H,A-H),2.32-2.38(m,2H,A-H),2.43(t,2H,J=8.0Hz, N-CH 2 ),2.63(brs,4H,A-H),3.06(brs,4H,A-H),3.12-3.14(m,2H,A-H),3.32(s,3H,A-H),4.30(s,2H,A-H),6.93 -6.97(m,1H,Ar-H),7.10-7.16(m,2H,Ar-H).

[0248] ESI-MS:429[M+H + ].

[0249] Preparation of Compound I-3 Fumarate

[0250] Using compound I-3 (2.3 mmol) and fumaric acid (2.4 mmol) as raw materials, the preparation method of compound I-1 hydrobromide was used to obtain 1.0 g of white solid with a yield of 72%.

[0251] Elemental Analysis: C 20 h 30 Cl 2 N 4 O·C 4 h 4 o 4...

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Abstract

The invention discloses an arylethyl piperidinyl derivative and its application in anti-schizophrenia. The results of pharmacological experiments show that the arylethylpiperidine compounds involved in the present invention, to dopamine D 2 、D 3 , 5‑HT 1A , 5‑HT 2A The receptor has a higher affinity for D 3 / D 2 Receptor selectivity is good. The results of in vivo experiments show that the preferred compound has good anti-schizophrenia effect, low acute toxicity, high safety, good pharmacokinetic properties, and has development value as a new antipsychotic and neurological disease drug with high efficiency and low toxicity. The arylethylpiperidine compound is a compound having the general structural formula (I) or its salt or a hydrate of the salt:

Description

technical field [0001] The present invention relates to arylethyl piperidinyl derivatives having anti-schizophrenia activity or pharmaceutically acceptable hydrates, salts or hydrates of salts, including said compounds or pharmaceutically acceptable hydrates and salts thereof A pharmaceutical composition, a kit, or a hydrate of a salt, and an application thereof for treating schizophrenia. Background technique [0002] Schizophrenia is a chronic and persistent disease. It is the most serious and harmful mental disease, affecting the normal life of about 1% of the world's population. The number of patients in my country exceeds 10,000,000, and it is the seventh largest disease of social burden. The symptoms of schizophrenia are complex, and the symptoms often vary with the course of the disease. The symptoms of schizophrenia mainly include positive symptoms, such as delusions and hallucinations; negative symptoms, such as social withdrawal and apathy; and cognitive dysfuncti...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/98C07D401/12C07D405/12C07D409/12A61K31/496A61K31/5377A61P25/18
CPCC07D211/98C07D401/12C07D405/12C07D409/12
Inventor 李建其陈晓文李林周爱南张怡
Owner SHANGHAI INST OF PHARMA IND CO LTD
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