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Novel enantiomer of tetra hydrogen isoquinoline derivative and officinal salt, preparation and pharmaceutical composition thereof

A technology of tetrahydroisoquinoline and derivatives, applied in the field of new enantiomers, can solve problems such as toxicity

Inactive Publication Date: 2005-06-22
尹崔惠淑 +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] As mentioned above, there is a problem with the use of racemic mixtures without resolution, that is, although one of its enantiomers has excellent pharmaceutical action and is non-toxic, the other enantiomer is toxic

Method used

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  • Novel enantiomer of tetra hydrogen isoquinoline derivative and officinal salt, preparation and pharmaceutical composition thereof
  • Novel enantiomer of tetra hydrogen isoquinoline derivative and officinal salt, preparation and pharmaceutical composition thereof
  • Novel enantiomer of tetra hydrogen isoquinoline derivative and officinal salt, preparation and pharmaceutical composition thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0201] Two-μ-chloro-bis[(η 6 - p-cymene) ruthenium (II) chloride]

[0202] [Reaction Scheme 1]

[0203]

[0204] In a flask, the RuCl 3 h 2 O (514 mg, 1.97 mmol) was dissolved in ethanol (25 ml), to which α-phellandrene (3.51 mL, 21.6 mmol) was added dropwise. Then, the flask equipped with a reflux condenser was filled with nitrogen. Using a thermostat, the temperature of the reaction solution was adjusted to 79° C., followed by reflux for 4 hours. The reaction mixture was cooled to room temperature. After this time, the precipitated solid was filtered through a Buchner funnel. The brown solid thus obtained was washed once with methanol (40 ml), and the solvent was removed under reduced pressure. The brown solid (340 mg) was recrystallized from methanol (3 mL) to provide the desired compound, di-μ-chloro-bis[(η 6 - p-cymene) ruthenium (II) chloride] (211 mg, 35%) as a brown solid.

[0205] 1 H-NMR (300MHz, DMSO-d 6 ): δ5.77(q, 4H), 2.8(m, 1H), 2.1(s, 3H), 1.2(d, ...

preparation Embodiment 2

[0206] Synthesis of RuCl[TsDPEN] (p-cymene) catalyst

[0207] [Reaction Route 2]

[0208]

[0209] In a flask, di-μ-chloro-bis[(η 6 - p-cymene) ruthenium (II) chloride] (211 mg, 345 μmol) was dissolved in 2-propanol (10 mL), to which was added triethylamine (TEA) (0.192 mL, 1.38 mmol), then dropwise Add (1S,2S)-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (253 mg, 689 μmol). Then, the flask equipped with a reflux condenser was filled with nitrogen. Using a thermostat, the temperature of the reaction solution was adjusted to 80° C., followed by reflux for 1.5 hours. Reaction completion was checked by thin layer chromatography. The reaction mixture was cooled to room temperature and concentrated in vacuo to afford a very viscous liquid residue. The residue was dissolved in methanol (1 ml) with gentle heating, and allowed to stand for 1 day and night. A dark red solid precipitated and only the dark brown supernatant was discarded. The residue of the dark red solid p...

Embodiment 1

[0212] Synthesis of (R)-6,7-dihydroxy-1-(p-hydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline hydrobromide

[0213] (Step 1): Synthesis of N-(3,4-dimethoxyphenethyl)(p-methoxyphenyl)acetamide

[0214] [Reaction Route 3]

[0215]

[0216] To p-methoxyphenylacetic acid (50.4 g, 0.303 mol) in a 50 ml round bottom flask was added 3,4-dimethoxyphenethylamine (51.2 mL, 0.303 mol) dropwise. Then, the flask equipped with a reflux condenser was filled with nitrogen. Using a thermostat, the temperature of the reaction solution was adjusted to 198-200° C. and heated for 4 hours. Reaction completion was checked by thin layer chromatography. The reaction mixture was cooled to room temperature, and chloroform (500 mL) was added thereto to dissolve the synthesized precipitate. Continuously with 1N HCl, 1N NaHCO 3 The chloroform solution was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered through a glass filter. The filtrate was concentrated in vacuo to...

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PUM

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Abstract

The present disclosure relates to new enantiomers of tetrahydroisoquinoline derivatives and pharmaceutically acceptable salts thereof, their formulations and pharmaceutical compositions. Enantiomers of tetrahydroisoquinoline derivatives are provided for heart rate stimulating and blood pressure lowering activity, inhibitory activity on platelet aggregation, and inhibition of inducible NO synthase activity. The enantiomers of tetrahydroisoquinoline derivatives and their pharmaceutically acceptable salts are useful in the treatment of congestive heart failure, hypertension, thrombosis, inflammation, sepsis, cardiac insufficiency, and disseminated intravascular coagulation.

Description

technical field [0001] The present invention generally relates to new enantiomers of tetrahydroisoquinoline derivatives and pharmaceutically acceptable salts thereof, preparations and uses thereof. More specifically, the present invention relates to novel tetrahydroisoquinoline-based enantiomers and pharmaceutically acceptable salts thereof, processes for their preparation and their pharmaceutical use, characterized in that the enantiomer-based R, S-configuration The S-configuration is superior to the R-configuration in inducing vasodilation, positive inotropic and chronotropic effects, and inhibiting the expression of inducible NO synthase (abbreviated as "iNOS" hereinafter) and platelet aggregation. On the other hand, although the effect is not as potent as that of the S-configuration enantiomer, the R-configuration enantiomer is selectively potent in inducing vasodilation, inhibiting platelet aggregation and inhibiting iNOS, and has only minimal cardiotonic effects . Bac...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/04A61K31/472A61P7/02A61P9/04A61P9/10A61P9/12C07D217/08C07D217/16C07D217/18C07D217/20C07D401/06C07D401/10C07D401/12C07D413/10
CPCC07D217/18C07D217/20C07D401/06C07D401/10C07D401/12C07D413/10A61P29/00A61P7/02A61P9/00A61P9/04A61P9/10A61P9/12C07D217/16
Inventor 尹崔惠淑张基哲李德衡
Owner 尹崔惠淑
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