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Tetrahydroisoquinoline derivative as well as preparation method and medical application thereof

A technology of medicinal salts and compounds, applied in the field of NHE3 inhibitors, can solve the problems of less NHE inhibitors and the like

Pending Publication Date: 2021-04-20
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, so far there are very few studies on NHE inhibitors that are not absorbed (i.e., not systemic) and target the gastrointestinal tract

Method used

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  • Tetrahydroisoquinoline derivative as well as preparation method and medical application thereof
  • Tetrahydroisoquinoline derivative as well as preparation method and medical application thereof
  • Tetrahydroisoquinoline derivative as well as preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0219] N 1 ,N 4 -Di(2-(2-(2-(2-(3-(8-chloro-2,6-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl) Sulfonylamino)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide1

[0220]

[0221]

[0222] first step

[0223] 1-(3-bromophenyl)-2-((2-chloro-4-methylbenzyl)methylamino)ethanone 1b

[0224] Dissolve 2-bromo-1-(3-bromophenyl)ethanone 1a (8.22g, 29.59mmol) in 50mL of dichloromethane, cool down to 0°C, add triethylamine (5.98g, 59.18mmol) and 1 -(2-Chloro-4-methylphenyl)-N-methylmethylamine (5g, 29.59mmol), stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title product 1b (7 g), yield: 64.8%.

[0225] MS m / z(ESI):368.1[M+1]

[0226] second step

[0227] 1-(3-Bromophenyl)-2-((2-chloro-4-methylbenzyl)methylamino)ethanol 1c

[0228] Compound 1b (1.25 g, 3.41 mmol) was dissolved in 10 mL of methanol, cooled to 0° C., sodium b...

Embodiment 2

[0268] N 1 ,N 4 -Di(2-(2-(2-(2-(3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl Sulfonylamino)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide2

[0269]

[0270] first step

[0271] 1-(3-bromophenyl)-2-((4-chloro-2-methylbenzyl)methylamino)ethanone 2a

[0272] Dissolve 2-bromo-1-(3-bromophenyl)ethanone 1a (1.84g, 6.61mmol) in 20mL of dichloromethane, cool to 0°C, add triethylamine (1.34g, 13.22mmol) and 1 -(4-Chloro-2-methylphenyl)-N-methylmethylamine (1.20g, 6.95mmol), stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title product 2a (2.42 g), which was directly subjected to the next reaction without purification.

[0273] MS m / z(ESI):366.1[M-1]

[0274] second step

[0275] 1-(3-Bromophenyl)-2-((4-chloro-2-methylbenzyl)methylamino)ethanol 2b

[0276] Crude product 2a (2.40 g, 6.61 mmol) was dissolved in 15 mL of methanol, cooled to 0°C, sodium borohydride (503 mg, 13.22 mmol) was added, a...

Embodiment 3

[0303] N 1 ,N 4 -Di(2-(2-(2-(2-(3-(2,6,8-trimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonyl Amino)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide3

[0304]

[0305]

[0306] first step

[0307] 1-(3-Bromophenyl)-2-((2,4-dimethylbenzyl)methylamino)ethanone 3a

[0308] Dissolve 2-bromo-1-(3-bromophenyl)ethanone 1a (2.60g, 9.35mmol) in 20mL of dichloromethane, cool down to 0°C, add triethylamine (1.90g, 18.70mmol) and 1 -(2,4-Xylyl)-N-methylmethylamine (1.46g, 9.82mmol), stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title product 3a (4.50 g), which was directly subjected to the next reaction without purification.

[0309] MS m / z(ESI):348.1[M+1]

[0310] second step

[0311] 1-(3-Bromophenyl)-2-((2,4-dimethylbenzyl)methylamino)ethanol 3b

[0312] Crude product 3a (3.24g, 9.35mmol) was dissolved in 15mL of methanol, cooled to 0°C, sodium borohydride (711mg, 18.70mmol) was added, and the reaction wa...

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Abstract

The invention relates to a tetrahydroisoquinoline derivative, a preparation method thereof and medical application of the tetrahydroisoquinoline derivative. Specifically, the invention relates to a tetrahydroisoquinoline derivative as shown in a general formula (I) and a medicinal salt thereof, a preparation method of the tetrahydroisoquinoline derivative and the medicinal salt thereof, and application of the tetrahydroisoquinoline derivative and the medicinal salt thereof as NHE3 inhibitors, particularly as a therapeutic agent for diseases related to body fluid retention or salt overload or gastrointestinal diseases. Wherein the definition of each substituent in the general formula (I) is the same as the definition in the specification.

Description

technical field [0001] The disclosure belongs to the field of medicine, and relates to a tetrahydroisoquinoline derivative represented by general formula (I), its preparation method and a pharmaceutical composition containing the derivative, and its use as an NHE3 inhibitor, especially as a Use of a therapeutic agent for a condition related to fluid retention or salt overload or a condition of the gastrointestinal tract. Background technique [0002] The clinical syndrome of CHF (congestive heart failure) occurs when cardiac insufficiency prevents proper perfusion of surrounding tissues. In CHF patients, neurohumoral compensatory mechanisms are activated in an attempt to maintain normal circulation. As blood volume in the heart increases, cardiac output increases proportionally, to the point where the heart cannot relax further. In a failing heart, contractility is reduced, allowing the heart to operate at higher volumes and higher filling pressures to maintain output. In...

Claims

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Application Information

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IPC IPC(8): C07D217/18A61K31/472A61P29/00A61P9/12A61P1/00A61P13/12A61P1/10A61P9/10A61P25/16A61P9/04A61P25/00A61P25/24A61P5/14
Inventor 杨方龙陈刚王伟民
Owner JIANGSU HENGRUI MEDICINE CO LTD
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