Indoline-2-ketone D3 receptor ligand and preparation method and application thereof

A kind of indoline and receptor technology, applied in the field of indoline-2-one D3 receptor ligand and preparation thereof

Active Publication Date: 2016-04-06
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the main method for the treatment of drug addiction at home and abroad is to detoxify or control the symptoms of drug withdrawal, and non-drug treatment is rarely used

Method used

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  • Indoline-2-ketone D3 receptor ligand and preparation method and application thereof
  • Indoline-2-ketone D3 receptor ligand and preparation method and application thereof
  • Indoline-2-ketone D3 receptor ligand and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 14-(2-((3-(4-phenylpiperazin-1-yl) propyl) (propyl) amino) ethyl) preparation of indolin-2-one (3a) one, Preparation of 1-(3-chloropropyl)-4-phenylpiperazine (1a)

[0045] (1) Preparation of two (2-chloroethyl) amine hydrochloride (5)

[0046] Thionyl chloride (128 mL, 1.76 mol) was added into 80 mL of chloroform, stirred, and 68 mL of chloroform-diluted diethanolamine (40 mL, 0.417 mol) was slowly added dropwise within 1 h. After dropping, react at room temperature for 2-5 hours, slowly raise the temperature to 70° C., and end the reaction after reflux for 0.5-1 hour. Cool, filter with suction, wash the filter cake twice with dichloromethane, and dry to obtain 66 g of a white solid with a yield of 89% and a melting point of 214-215°C (207-209°C in literature).

[0047] (2) Preparation of 1-phenylpiperazine hydrochloride (7)

[0048] Compound 5 (30 g, 0.168 mol) was added to 150 mL of n-butanol, stirred, and aniline (14.25 g, 0.153 mol) diluted with 10 mL of n-...

Embodiment 2

[0076] Example 23-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-10-methoxymethyl-2,3,4,4a,5,6-hexahydro -1H-

[0077] Preparation of pyrazino[1,2-a]quinoline (3b)

[0078] Referring to the preparation method of compound 3a, compound 1b was prepared, and intermediate 2 (0.70 g, 3.21 mmol) was put in. After the reaction, 0.93 g of brown viscous compound was obtained, with a yield of 67%.

[0079] 1 HNMR (300MHz, CDCl 3 ),δ H ,ppm:0.88(t,J=7.2Hz,3H),1.41-1.53(m,2H),1.63-1.73(m,2H),2.26(s,3H),2.39(t,J=7.4Hz,2H ),2.46(t,J=7.5Hz,2H),2.54(t,J=7.3Hz,2H),2.60(s,4H),2.67(s,4H),3.15(s,4H),3.47(s ,2H),6.71(d,J=7.7Hz,1H),6.84(d,J=7.9Hz,3H),7.06(d,J=8.0Hz,2H),7.13(t,J=7.7Hz,1H ),9.28(s,1H); 13 C-NMR (300MHz, CDCl 3 ), δ: 11.9, 20.3, 20.3, 24.5, 30.9, 35.1, 49.6, 52.1, 53.2, 54.3, 56.1, 56.6, 107.5, 116.3, 122.7, 124.0, 127.9, 129.1, 129.5, 137.1, 142.5, 147.6, 17; IR(KBr,cm -1 ):3368,2954,2815,1687,1610,1577,1511,1459,1451,1237,811,720,651; MS:435.3[M+H] + .

Embodiment 3

[0080] Example 34-(2-((3-(4-(2,3-dimethylphenyl)piperazin-1-yl)propyl)(propyl)amino)ethyl)indoline-2 - Preparation of ketones (3c)

[0081] Referring to the preparation method of compound 3a, compound 1c was prepared, and intermediate 2 (0.70 g, 3.21 mmol) was added. After the reaction, 0.89 g of brown viscous compound was obtained, with a yield of 62%.

[0082] 1 HNMR (300MHz, CDCl 3 ),δ H ,ppm:0.89(t,J=7.3Hz,3H),1.43-1.55(m,2H),1.65-1.75(m,2H),2.22(s,3H),2.27(s,3H),2.39-2.49 (m,4H),2.53-2.69(m,10H),2.91-2.94(m,4H),3.48(s,2H),6.72(d,J=7.7Hz,1H),6.83-6.93(m,3H ), 7.07(t, J=7.7Hz, 1H), 7.15(t, J=7.7Hz, 1H), 9.08(s, 1H); 13 C-NMR (300MHz, CDCl 3 ), δ: 11.9, 13.9, 20.2, 20.5, 24.5, 30.8, 35.1, 52.0, 52.1, 53.7, 54.2, 56.0, 56.7, 107.5, 116.6, 122.7, 124.0, 124.8, 125.7, 127.9, 131.1, 137.1, 137 142.5, 151.5, 177.6; IR (KBr, cm -1 ):3440,3067,3025,2952,2872,1679,1619,1606,1581,1475,1460,1452,1376,1243,1145,1082,779,721,651; MS:449.4[M+H] + .

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Abstract

The invention discloses an indoline-2-ketone D3 receptor ligand, which is a compound as shown in the formula I or pharmaceutical salt thereof, wherein n=2 or 3; R represents H, 4-CH3, 2,3-diCH3, 2-CH3, 4-OCF3, 3-OCH3, 3,4-diCH3 or 4-Cl. In comparison with the prior art, the compound has a strong activity to a dopamine D3 receptor, is used in treating or preventing central nervous and metal diseases such as schizophrenia, Parkinson's disease, drug dependence and relapse, etc., can be used in neuroprotection, and is used as a tool drug for researching D3 receptor structure, function and diseases related to D3 receptor dysfunction.

Description

technical field [0001] The invention relates to an indolin-2-one D3 receptor ligand, a preparation method and application thereof, and belongs to the technical field of drug synthesis. Background technique [0002] Dopamine is an important neurotransmitter in the central nervous system, which is related to Parkinson's disease (PD), Huntington's disease, schizophrenia (SCZD) and other diseases. Dopamine receptors are divided into five different receptor subtypes, D1, D2, D3, D4 and D5, which have a high degree of amino acid sequence homology in the transmembrane region, making it possible to develop dopamine receptors with both high affinity and high selectivity Ligands are extremely important. However, the high degree of sequence identity between dopamine D3 and the D2 receptor transmembrane single loop, especially the near identity of the residues in these receptors that are inferred to form the binding site, makes it possible to develop D3 receptors with drug-like physico...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/34A61K31/496A61P25/16A61P25/18A61P25/30A61P25/14A61P25/22A61P25/20A61P15/10
CPCC07D209/34
Inventor 蔡进吉民周本华
Owner SOUTHEAST UNIV
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