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Dopamine D1 receptor agonist compounds

A receptor stimulant, dopamine technology, applied in the direction of active ingredients of heterocyclic compounds, organic chemistry, drug combination, etc., can solve problems such as abnormalities

Inactive Publication Date: 2004-03-24
SHIRE PHARMA DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, L-DOPA can cause serious side effects such as nausea, vomiting, cardiac arrhythmias, and low blood pressure

Method used

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  • Dopamine D1 receptor agonist compounds
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  • Dopamine D1 receptor agonist compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] a) 1-(benzofuran-7-yl)-2-[2-(2-chloro-3,4-dimethoxyphenyl)ethylamino]ethanol

[0025] A solution of 2-chloro-3,4-dimethoxyphenylethylamine (6.35g, 0.0296mol) and (7-benzofuryl)oxirane (4.29g, 0.0268mol) in 15ml of acetonitrile Reflux for 16 hours. The reaction mixture was cooled to 0°C (ice bath). Filtration and recrystallization of the crude product from hot acetonitrile afforded the title compound (3.52 g, 35%) as a white crystalline solid. 1 H-NMR (CDCl 3 )[δ, ppm]: 2.86-3.16 (m, 6H); 3.85 (s, 6H); 5.26 (dd, 1H); 6.73-6.77 (m, 2H); 6.91 (d, 1H); m, 1H); 7.39(d, 1H); 7.51(d, 1H); 7.61(d, 1H).

[0026] b) 1-(benzofuran-7-yl)-6-chloro-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

[0027] 1-(benzofuran-7-yl)-2-[2-(2-chloro-3,4-dimethoxyphenyl) in 70ml trifluoroacetic acid was treated with concentrated sulfuric acid (0.71ml, 0.0135mol) ) ethylamino]ethanol (2.20 g, 5.85 mmol), and stirred at room temperature for 90 minutes. The solution was evaporated in vacuo...

Embodiment 2

[0033] a) 1-(Benzo[b]thiophen-7-yl)-2-[2-(2-chloro-3,4-dimethoxyphenyl)ethylamino]ethanol

[0034] A mixture of 2-chloro-3,4-dimethoxyphenylethylamine (7.00g, 32.5mmol) and 7-benzo[b]thienyloxirane (5.30g, 30.1mmol) in 20ml of acetonitrile The solution was refluxed for 72 hours. The reaction mixture was cooled to 0°C (ice bath), filtered and the crude product recrystallized from hot acetonitrile to afford the title compound (5.57 g, 47%) as a white crystalline solid. 1 H-NMR (CDCl 3 )[δ, ppm]: 2.83-3.08(m, 6H); 3.84(s, 3H); 3.85(s, 3H); 5.06(m, 1H); 6.73(d, 1H); 6.88(d, 1H) ; 7.35 (m, 3H); 7.43 (d, 1H); 7.73 (m, 1H).

[0035] b) 1-(Benzo[b]thiophen-7-yl)-6-chloro-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

[0036] 1-(Benzo[b]thiophen-7-yl)-2-[2-(2-chloro-3 , 4-dimethoxyphenyl)ethylamino]ethanol (3.90 g, 10 mmol), and the solution was heated to reflux for 18 hours. The solution was evaporated in vacuo and the residue was dissolved in dichloromethane (100ml), the re...

Embodiment 3

[0041] a) 2-(2-chloro-3,4-dimethoxyphenyl)ethylamino]-1-indan-5-yl-ethanol

[0042] To a solution of 2-indan-5-yloxirane (3.38 g, 21.1 mmol) in anhydrous acetonitrile (20 ml) was added 2-(2-chloro-3,4-dimethoxyphenyl) Ethylamine (2.0 g, 23.2 mmol), and the solution was refluxed for 20 hours. Upon cooling a white precipitate formed which was collected by filtration and washed with diethyl ether to give the title compound as a white solid (2.85 g, 36%).

[0043] 1 H NMR (400 MHz, DMSO-d6): δ (ppm) 1.96-2.03 (2H, m, CH 2 -CH 2 -CH 2 ), 2.50-2.84 (10H, m, 5xCH 2 ), 3.72 (3H, s, CH 3 O), 3.80 (3H, s, CH 3 O), 4.56 (1H, t, J 6.04, H-1), 5.14 (1H, broad, NH) and 6.94-7.14 (5H, m, Ar-H). This material was used in the next reaction without further purification.

[0044] b) 1-indan-5-yl-6-chloro-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

[0045] 2-[(2-Chloro-3,4-dimethoxyphenyl)ethylamino]-1-indan-5-yl-ethanol (2.7g, 7.18mmol) was dissolved in trifluoroacetic acid (50m...

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Abstract

The invention provides 2,3,4,5-tetrahydro-1H-3-benzazepines of general formula (I) wherein: R<1> is hydrogen, halogen, C1-C4 alkyl, or CF3; R<2> is hydrogen, methyl, or lower alkenyl of 3-5 carbon atoms; R<3> and R<4> together form a furan, dihydrofuran, thiophene, dihydrothiophene, cyclopentane or cyclohexane ring and R<5> is hydrogen or R<4> and R<5> together form a furan, dihydrofuran, thiophene, dihydrothiophene, cyclopentane or cyclohexane ring and R<3> is hydrogen; R<6> is hydrogen, halogen, CF3, CN, NO2 or NH2; R<7> is hydrogen, halogen, CF3, CN, NO2 or NH2. The specific combination of substituents: R1 = H, R2 = H and R4 and R5 together forming a cyclohexane ring is excluded, namely 1-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,3,4,5-tetrahydro-1H-benzol[d]azepine-7,8-diol. The compounds of the invention provide therapeutic agents that selectively interact positively with postsynaptic dopamine D1 receptors in the striatum, directly or in-directly (termed dopamine D1 agonists) and are particularly valuable as anti-Parkinsonian agents.

Description

technical field [0001] The present invention relates to a dopamine D1 receptor stimulant compound, a preparation method and use of the compound. Background technique [0002] GB 1 599 705 discloses 1-thienyl and 1-furyl-2,3,4,5-tetrahydro-1H-3-benzazepines suitable for use as cardiovascular drugs. Certain benzoacridines have been disclosed as dopamine D1 receptor agonists. For example, 1-phenyl-3-benzazepine is disclosed in EP 0 230 755-A, and 6-chloro-7,8-dihydroxy-1-( Carbamate of 4'-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine. [0003] The present invention provides compounds that are potent and selective ligands for the dopamine D1 receptor. The compounds are useful in the treatment of neurodegenerative diseases, particularly, but not limited to, Parkinson's disease. Parkinson's disease is a progressive neurodegenerative disease characterized by the progressive death of postsynaptic dopamine neurons in the substantia nigra innervating postsynaptic striatal neu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/55A61P25/16A61P25/28C07D223/16C07D405/04C07D409/04
CPCC07D223/16C07D409/04C07D405/04A61P25/16A61P25/28
Inventor G·蒂尔布洛克
Owner SHIRE PHARMA DEV
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