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Dibenzyl tetrahydroisoquinoline derivative as well as preparation method and application thereof

A technology of alkynyl group and compound, applied in the field of bisbenzyl tetrahydroisoquinoline derivatives and preparation thereof, can solve problems such as not yet seen

Active Publication Date: 2014-05-07
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, no structurally modified derivatives of bisbenzyltetrahydroisoquinoline have been used for anti-hepatic fibrosis

Method used

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  • Dibenzyl tetrahydroisoquinoline derivative as well as preparation method and application thereof
  • Dibenzyl tetrahydroisoquinoline derivative as well as preparation method and application thereof
  • Dibenzyl tetrahydroisoquinoline derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Example 1: Preparation of 5-(3,3-dimethyl-but-1-ynyl)-tetrandrine

[0051] Weigh 700 mg (1 mmol) of 5-bromo-tetrandrine and dissolve it in 10 ml DMSO, add CsCO 3 651.6mg (2mmol, 2eq), 3,3-dimethyl-1-butyne (CAS: 917-92-0) 164mg (2mmol, 2eq), PdCl 2 (PPh 3 ) 2 21mg (0.03mmol, 0.03eq). Under the protection of nitrogen, the reaction was stirred at 100° C. for 10 hours. After completion of the reaction, filter, add 5ml of ammonia water, then add 30ml of ethyl acetate, wash with saturated brine for 3 times, dry over anhydrous sodium sulfate, perform silica gel column chromatography or ether:methanol (2:1) recrystallization to obtain 5-(3, 3-Dimethyl-but-1-ynyl)-tetrandrine 576 mg. Yield: 82%.

[0052] Properties: Colorless needle crystal.

[0053]

[0054] 5-(3,3-Dimethyl-but-1-ynyl)-tetratridine

[0055] C 44 h 50 N 2 o 6

[0056] MS(ESI):703.35.[M+H] + .

[0057] 1 H NMR (300MHz, CDCl 3 )δ7.32(d, J=8.1Hz, 1H), 7.12(dd, J=8.1, 2.1Hz, 1H), 6.84(m, 2H), 6....

Embodiment 2

[0059] Example 2: Preparation of 5-(hex-1-ynyl)-tetrandrine

[0060] Weigh 700 mg (1 mmol) of 5-bromo-tetrandrine and dissolve it in 10 ml DMSO, add CsCO 3 651.6mg (2mmol, 2eq), 1-hexyne (CAS: 693-02-7) 164mg (2mmol, 2eq), PdCl 2 (PPh 3 ) 2 35mg (0.05mmol, 0.03eq), BINAP20mg (0.03mmol, 0.03eq). Under the protection of nitrogen, the reaction was stirred at 100° C. for 10 hours. After completion of the reaction, filter, add 5ml of ammonia water, then add 30ml of ethyl acetate, wash with saturated brine three times, dry over anhydrous sodium sulfate, perform silica gel column chromatography or ether:methanol (2:1) recrystallization to obtain 5-(hexyl 1-alkynyl)-tetrandrine 527 mg, yield: 75%.

[0061] Properties: white amorphous powder.

[0062]

[0063] 5-(Hex-1-ynyl)-tetrandrine

[0064] C 44 h 50 N 2 o 6

[0065] MS(ESI):703.35.[M+H] + .

[0066] 1 H NMR (300MHz, CDCl 3 )δ7.34(dd, J=8.3, 1.8Hz, 1H), 7.13(dd, J=8.2, 2.5Hz, 1H), 6.86(s, 2H), 6.80(dd, J=8.3, 2....

Embodiment 3

[0068] Example 3: Preparation of 5-(octyl-1,7-diynyl)-tetrandrine

[0069] Weigh 700 mg (1 mmol) of 5-bromo-tetrandrine and dissolve it in 10 ml DMSO, add Ba(OH)2 513mg (3mmol, 2eq), 1,7-octadiyne (CAS: 871-84-1) 212mg (2mmol, 2eq), PdCl 2 (PPh 3 ) 2 35 mg (0.05 mmol, 0.03 eq). Under the protection of nitrogen, the reaction was stirred at 100° C. for 10 hours. After the reaction was completed, filter, add 5ml of ammonia water, then add 30ml of ethyl acetate, wash with saturated brine three times, dry over anhydrous sodium sulfate, perform silica gel column chromatography or ether:methanol (2:1) recrystallization to obtain 5-(octyl- 1,7-diynyl)-tetrandrine 566 mg, yield: 75%.

[0070] Properties: Colorless needle crystal.

[0071]

[0072] 5-(oct-1,7-diynyl)-tetratridine

[0073] C 46 h 50 N 2 o 6

[0074] MS(ESI):727.35.[M+H] + .

[0075] 1 H NMR (300MHz, CDCl 3 )δ7.34(dd, J=8.2, 2.0Hz, 1H), 7.13(dd, J=8.1, 2.5Hz, 1H), 6.85(m, 2H), 6.80(dd, J=8.3, 2.5Hz, 1H ...

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Abstract

The invention discloses a compound shown in the following formula I or pharmaceutically acceptable salt thereof. In the formula I, R1, R2, R3, R4 and R5 are defined in the specification. The invention further discloses a method for preparing the compound which is shown in the formula I. The compound shown in the formula I can be used for inhibiting hepatic stellate cells activated by PDGF (Platelet Derived Growth Factor) so as to reverse hepatic fibrosis.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a class of bisbenzyl tetrahydroisoquinoline derivatives capable of reversing liver fibrosis, a preparation method and a medical application thereof. Background technique [0002] Liver fibrosis is a pathological process in which extracellular matrix (ECM) is deposited excessively in the liver due to various pathogenic factors. my country is a high-incidence area of ​​viral hepatitis. There are 120 million carriers of hepatitis B virus (HBV) alone, of which more than 30 million are chronic hepatitis B patients. There are 350 million chronic HBV infections worldwide, about 25% of chronic hepatitis B patients will eventually develop liver cirrhosis (hepatic cirrhosis), and even liver cancer. Chronic hepatitis C virus (HCV) infection can reach 50%-85%, and 10%-30% develop into Liver cirrhosis, 3%-10% develops into liver cancer. Other diseases such as alcoholic liver di...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/18A61K31/4748A61P1/16
CPCC07D491/18
Inventor 杨义芳赖龙吴春珍胡晓
Owner SHANGHAI INST OF PHARMA IND CO LTD
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