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Piperidine amino derivative and application thereof in fighting schizophrenia

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

Active Publication Date: 2018-03-13
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0068] Aiming at the above-mentioned shortcomings in the prior art, the present invention discloses a piperidine amino derivative to overcome the side effects of existing drugs such as obesity, elevated blood sugar and other metabolic side effects, arrhythmia, EPS (such as catalepsy) and other side effects. Negative symptoms, poor efficacy of cognitive impairment and other defects to meet the needs of clinical medication

Method used

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  • Piperidine amino derivative and application thereof in fighting schizophrenia
  • Piperidine amino derivative and application thereof in fighting schizophrenia
  • Piperidine amino derivative and application thereof in fighting schizophrenia

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0217] Example 1: N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)acetyl Preparation of amine (compound I-1) and its salt

[0218] 4-(2-(4-(Benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)piperidin-1-amine (9) (prepared according to General Method 1) (2.0 g, 5.8mmol), triethylamine (8.7mmol) were added to dichloromethane (20mL), a solution of acetyl chloride (0.5g, 6.4mmol) in dichloromethane (10mL) was added dropwise, reacted for 3h, followed by water ( 40mL×2), washed with saturated brine (20mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to give a white solid, which was crystallized from 95% ethanol solution to give 2.02g of a white solid with a yield of 90%.

[0219] 1 HNMR (CDCl 3 ,δ:ppm):1.20-1.23(m,1H,A-H),1.35-1.38(m,2H,A-H),1.47-1.51(m,2H,A-H),1.54-1.57(m,2H,A-H), 2.10(s,3H,A-H),2.42-2.44(m,2H,A-H),2.50(t,2H,J=8.0Hz,N-CH 2 ),2.66(brs,4H,A-H),3.18-3.20(m,2H,A-H),3.54(brs,4H,A-H),7.12-7.14(m,1H,Ar-H),7.24-7.28(m, 2H,A...

Embodiment 2

[0234] Example 2: N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)butyryl Preparation of amine (compound I-2) and its salt

[0235] Using intermediate 9 (5.6 mmol) and butyryl chloride (6.2 mmol) as raw materials, according to the preparation method of compound I-1, 2.12 g of the target compound I-2 was obtained as a white solid, with a yield of 91%.

[0236] 1 HNMR (CDCl 3 ,δ:ppm):0.88(t,3H,J=6.8Hz,A-H),1.21-1.24(m,1H,A-H),1.36-1.39(m,2H,A-H),1.48-1.52(m,2H, A-H),1.55-1.58(m,2H,A-H),1.64-1.66(m,2H,A-H),2.32(t,2H,J=7.2Hz,A-H),2.43-2.45(m,2H,A-H), 2.50(t, 2H, J=8.0Hz, N-CH 2 ),2.66(brs,4H,A-H),3.18-3.20(m,2H,A-H),3.54(brs,4H,A-H),7.10-7.12(m,1H,Ar-H),7.22-7.26(m, 2H,Ar-H),7.31-7.32(m,1H,Ar-H).

[0237] ESI-MS:416[M+H + ].

[0238] The preparation of compound 1-2 hydrobromic acid salt

[0239] Using compound I-2 (4.0 mmol) and 5% hydrobromic acid aqueous solution (4.1 mmol) as raw materials, the preparation method of compound I-1 hydrobromide ...

Embodiment 3

[0241] Example 3: N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-methyl Preparation of oxyacetamide (compound I-3) and its salt

[0242] Using intermediate 9 (5.6 mmol) and 2-methoxyacetyl chloride (6.2 mmol) as raw materials, according to the preparation method of compound I-1, 2.06 g of target compound I-3 was obtained as a white solid, with a yield of 88%.

[0243] 1 HNMR (CDCl 3 ,δ:ppm):1.23-1.26(m,1H,A-H),1.38-1.41(m,2H,A-H),1.50-1.54(m,2H,A-H),1.57-1.60(m,2H,A-H), 2.45-2.47(m,2H,A-H),2.52(t,2H,J=7.8Hz,N-CH 2 ),2.68(brs,4H,A-H),3.20-3.22(m,2H,A-H),3.48(s,3H,A-H),3.55(brs,4H,A-H),4.44(s,2H,A-H),7.12 -7.14(m,1H,Ar-H),7.24-7.28(m,2H,Ar-H),7.32-7.34(m,1H,Ar-H).

[0244] ESI-MS:418[M+H + ].

[0245] Preparation of Compound I-3 Fumarate

[0246] Using compound I-3 (4.0 mmol) and fumaric acid (4.1 mmol) as raw materials, the preparation method of compound I-1 hydrobromide was used to obtain 1.73 g of white solid with a yield of 81%.

[024...

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Abstract

The invention discloses a piperidine amino compound and an application thereof in fighting schizophrenia. Pharmacological experiment results show that the piperidine amino compound related to by the invention has good water solubility, has high affinity with dopamine D<2>, D<3>, 5-HT<1A>, and 5-HT<2A> receptors, and has good selectivity on D<3> / D<2> receptors. In-vivo test results show that a preferable compound has a good anti-schizophrenia effect, is relatively low in acute toxicity, high in safety and good in pharmacokinetic characteristic, and has a development value as a high-efficiency low-toxicity novel anti-schizophrenia new drug. The piperidine amino compounds are compounds represented as a structural general formula (I), or salts of the compounds, or hydrates of the salts.

Description

technical field [0001] The present invention relates to a piperidine amino derivative having anti-schizophrenia activity or a pharmaceutically acceptable hydrate, a salt or a hydrate of a salt thereof, a hydrate comprising the compound or a pharmaceutically acceptable hydrate, a salt or a salt thereof A hydrated pharmaceutical composition, a kit, 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 cognitiv...

Claims

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Application Information

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IPC IPC(8): C07D417/12C07D413/14A61K31/496A61K31/4545A61P25/18
CPCC07D413/14C07D417/12
Inventor 李建其陈晓文李林孙媛媛阮乐军
Owner SHANGHAI INST OF PHARMA IND
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