Dabigatran etexilate derivative and pharmaceutical use thereof

A pharmacy and prodrug technology, applied in the field of dabigatran etexilate derivatives and their pharmaceutical uses, can solve the problems of short half-life, easy stimulation of the gastrointestinal tract, strong acidity and the like

Active Publication Date: 2019-06-18
SHANGHAI MEIYUE BIOTECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, patients should be informed not to open the capsules and take the particles in them alone (such as dispersed in food or placed in drinks) to avoid the risk of bleeding; , short half-life (quick excretion), the patient needs to take 110mg or 150mg of dabigatran etexilate twice a day; however, thi

Method used

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  • Dabigatran etexilate derivative and pharmaceutical use thereof
  • Dabigatran etexilate derivative and pharmaceutical use thereof
  • Dabigatran etexilate derivative and pharmaceutical use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0139] The synthesis of embodiment 1 compound II-1

[0140] Compound II-1 was synthesized according to the following reaction formula and experimental steps.

[0141]

[0142] Step 1: Synthesis of Compound 1

[0143] At room temperature, (S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanoic acid (1.0g, 3.77mmol), ethylene glycol (935mg, 15.1mmol), DCC (1.0g , 4.9mmol) and DMAP (69mg, 0.56mmol) were added to anhydrous dichloromethane (20mL) solvent, after 12 hours of reaction, water (10mL) was added, extracted with dichloromethane (20mL×3), concentrated under reduced pressure The organic phase was removed, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=10 / 1 to 3 / 1) to obtain compound 1 (900 mg) as a white solid.

[0144] 1 H NMR (300MHz, DMSO-d 6 ):δ7.27-7.16(m,5H),4.19-4.14(m,1H),4.03-3.98(m,2H),3.52(s,2H),3.05-2.80(m,2H),1.98(s ,1H), 1.34(s,9H).

[0145] Step 2: Synthesis of Compound 2

[0146] At room temperature, CDI...

Embodiment 2

[0153] Embodiment 2: the synthesis of compound II-2

[0154] Compound II-2 was synthesized according to the following reaction formula and experimental steps.

[0155]

[0156] Step 1: Synthesis of compound 3

[0157] Pyridine-3-carboxylic acid chloride (1.80 g, 12.5 mmol) and DIPEA (2.20 g, 16.3 mmol) were added to glycerol (500 mg, 5.43 mmol) in DMF (5 mL) at room temperature and stirred for 16 hours. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol=10:1, to obtain compound 3 (510 mg) as a yellow solid.

[0158] 1 H NMR (300MHz, CDCl 3 ): δ9.12(s, 2H), 8.16(d, J=3.6Hz, 2H), 8.33(t, J=4.5Hz, 2H), 7.56(dd, J=7.8, 4.8Hz, 2H), 4.41 -4.39(m,4H),4.25-4.23(m,1H).

[0159] Step 2: Synthesis of compound 4

[0160] At room temperature, CDI (70 mg, 0.437 mmol) was added to a solution of compound 3 (120 mg, 0.40 mmol) in DMF (20 mL), and stirred at 50° C. for 16 hours. After cool...

Embodiment 3

[0165] Embodiment 3: the synthesis of compound II-3

[0166] Compound II-3 was synthesized according to the following reaction formula and experimental steps.

[0167]

[0168] At room temperature, 2-hydroxyethyl-acetate (0.77g, 3.73mmol) was added to DMF (5mL) solution, CDI (0.3g, 1.87mmol) was added, and DIPEA (0.14g, 1.12 mmol) and compound I-4 (0.2g, 0.37mmol), stirred for 12 hours. Concentrated under reduced pressure and purified by HPLC to obtain compound II-3 (120 mg) as a white solid.

[0169] 1 H NMR(400MHz,DMSO-d6):δ9.17(br s,1H),8.72(br s,1H),8.39(s,1H),7.81(d,J=8.8Hz,2H),7.56-7.52 (m,1H),7.47(s,1H),7.40(d,J=8.4Hz,1H),7.16-7.10(m,2H),7.02-6.99(m,1H),6.88(d,J=7.6 Hz,1H),6.76(d,J=8.4Hz,2H),4.59(d,2H),4.31-4.17(m,6H),3.96(q,2H),3.77(s,3H),2.66(t , J=7.2Hz, 2H), 1.97(s, 6H), 1.12(t, J=7.2Hz, 3H).

[0170] LCMS: Rt=3.194min, [M+H] + = 630.3.

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Abstract

The invention discloses a compound shown as formula (II), a hydrate, isomer, solvate, prodrug or a mixture thereof, and pharmaceutically acceptable salts thereof. The invention also discloses a pharmaceutical composition and a combination preparation containing the compounds as active ingredients, and use of the compounds, the pharmaceutical composition and the combination preparation as thrombininhibitors.

Description

technical field [0001] The present invention relates to a kind of dabigatran etexilate derivative and pharmaceutical application thereof, be specifically related to a kind of compound shown in formula (II), its hydrate, isomer, solvate, prodrug or their mixture, and Their pharmaceutically acceptable salts; the present invention also relates to pharmaceutical compositions and joint preparations containing these compounds as active ingredients; and the use of said compounds, pharmaceutical compositions and joint preparations as thrombin inhibitors. Background technique [0002] At present, cardiovascular disease is one of the main causes of human death, and one of its main factors is thrombosis, which is caused by blood coagulation caused by a series of complex reactions. Blood coagulation is a protective mechanism of the organism whereby defects in the vessel wall are quickly and reliably "sealed" so that blood loss is avoided or minimized, maintaining normal hemostasis, the ...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07D401/14A61K31/4439A61K31/444A61K45/06A61P7/02A61P11/00A61P9/00A61P9/10
CPCA61K31/4439A61K31/444A61K31/497A61K45/06A61P7/02A61P9/00A61P9/10A61P11/00C07D401/12C07D401/14
Inventor 胡治隆余尚海李世强王小林冯焱王朝东
Owner SHANGHAI MEIYUE BIOTECH DEV
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