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Fluorine-containing ticlopidine analogues, and preparation method and application thereof

A technology of ticlopidine and analogs, applied in the field of medicine, can solve the problems of high dosage, many adverse reactions, low activity of ticlopidine, etc., and achieve the effects of inhibiting thrombosis and inhibiting thrombosis.

Active Publication Date: 2013-06-12
TIANJIN HANRUI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] However, the activity of ticlopidine against platelet aggregation is low, and the dosage is large
[0007] At the same time, there are many adverse reactions caused by the blood system including: the most serious and frequent side effects of ticlopidine are in hematology, and blood cytopenia, agranulocytosis, and aplastic anemia have all been reported

Method used

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  • Fluorine-containing ticlopidine analogues, and preparation method and application thereof
  • Fluorine-containing ticlopidine analogues, and preparation method and application thereof
  • Fluorine-containing ticlopidine analogues, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] 2-(Acetoxy)-5-(2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (NO.1)

[0053] Add 5, 6, 7, 7 to the three-necked bottle in turn a - Tetrahydrothieno[3,2-c]pyridone-2 hydrochloride (compound 1) (3.83g, 0.02mol), chloroform (25ml), triethylamine (4.5g), stirred, heated to At 40° C., 2-fluorobenzyl bromide (3.78 g, 0.02 mol) was added to react for 5 hours, then triethylamine (4 g) and acetic anhydride (2.04 g) were added, and the reaction was continued for 2 hours. Add 20 ml of water, stir and let stand, separate the chloroform layer, dry over anhydrous sodium sulfate, recover the light yellow oil after chloroform under reduced pressure, and separate it with a silica gel column, petroleum ether:ethyl acetate=3: 1 is the eluent, the product is collected, and the solvent is recovered under reduced pressure to obtain 2-(acetoxy)-5-(2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2- c] 4.1 g of pyridine, yield 67.2%. MS-ESI: 306.1 [M+H].

[0054] Elemental analysis: C,...

Embodiment 2

[0058] 2-(Acetoxy)-5-(2-fluoro-6-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (NO.4)

[0059] Add 5, 6, 7, 7 to the three-necked bottle in turn a - Tetrahydrothieno[3,2-c]pyridone-2 hydrochloride (compound 1) (3.83g, 0.02mol), dichloromethane (20ml), pyridine (3.2g), stirred, heated to 35°C , 2-fluoro-6-chlorobenzyl chloride (3.58g, 0.02mol) was added to react for 4 hours, then pyridine (3.1g) and acetic anhydride (2.0g) were added, and the reaction was continued for 1.5 hours. Add 22 ml of water, stir and let stand, separate the dichloromethane layer, dry over anhydrous sodium sulfate, recover the colorless oily substance after dichloromethane under reduced pressure, separate it with silica gel column, petroleum ether:ethyl acetate=3: 1 is the eluent, the product is collected, and the solvent is recovered under reduced pressure to obtain 2-(acetoxy)-5-(2-fluoro-6-chlorobenzyl)-4,5,6,7-tetrahydrothieno[ 3,2-c]pyridine 3.6 g, yield 52.8%. MS-ESI: 340.8 [M+H].

[00...

Embodiment 3

[0062] 2-(Acetoxy)-5-(2,4-difluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (NO.5)

[0063] Add 5, 6, 7, 7 to the three-necked bottle in turn a - Tetrahydrothieno[3,2-c]pyridone-2 hydrochloride (compound 1) (3.83g, 0.02mol), tetrahydrofuran (50ml), triethylamine (4.4g), stirred, heated to 38°C , 2,4-difluorobenzyl chloride (3.25g, 0.02mol) was added to react for 4.5 hours, then triethylamine (4.1g) and acetic anhydride (2.0g) were added, and the reaction was continued for 1 hour.

[0064] The colorless oil after tetrahydrofuran was recovered under reduced pressure, separated by silica gel column, petroleum ether: ethyl acetate = 3: 1 was the eluent, the product was collected, and the solvent was recovered under reduced pressure to obtain 2-(acetoxy)-5- (2,4-Difluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine 4.3 g, yield 66.4%. MS-ESI: 324.1 [M+H].

[0065] 2-(Acetoxy)-5-(2,4-difluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (NO.5) 1g was dissolved in 15ml ...

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Abstract

The invention relates to fluorine-containing ticlopidine analogues with a general formula (I), and a preparation method and application thereof. In the general formula (I), R1 is C1-C4 straight-chain or branched-chain alkyl, R2 is halogen or trifluoromethyl, R3 is hydrogen or fluorine, and n is an integer ranging from 0 to 4. The general formula (I) is shown in the specification.

Description

technical field [0001] The invention belongs to the technical field of medicine, and more specifically, relates to a class of fluorine-containing ticlopidine analogs, a preparation method thereof, a pharmaceutical composition containing these analogs, and their use as an antithrombotic drug. Background technique [0002] Cardiovascular and cerebrovascular diseases have now become the main diseases endangering human health. Thrombosis is the main complication and death factor of such diseases and atherosclerosis-related diseases. The research and development of such drugs are quite promising. [0003] Ticlopidine was the first ADP receptor antagonist, and its chemical structure belongs to thienopyridines. It was first listed in foreign countries by the French company Sanofi in 1978, and began to enter the Chinese market in 1989. It has been proved to be an effective antithrombotic drug in the treatment of heart, brain and peripheral vascular and microvascular diseases, and ha...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D495/04A61K31/4365A61P7/02
Inventor 严洁
Owner TIANJIN HANRUI PHARMA
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