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Dabigatran etexilate derivative and preparation method and application thereof

A technology of dabigatran etexilate and its derivatives, which is applied in the field of medicine and can solve the problems of low oral bioavailability of dabigatran etexilate

Active Publication Date: 2012-11-07
BEIJING PRELUDE PHARM SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, studies have shown that the oral bioavailability of dabigatran etexilate is still relatively low

Method used

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  • Dabigatran etexilate derivative and preparation method and application thereof
  • Dabigatran etexilate derivative and preparation method and application thereof
  • Dabigatran etexilate derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Embodiment 1: the preparation of compound I2 of the present invention

[0058]

[0059] step 1):

[0060]

[0061] To a stirred solution of Formula III (2.0 g, 4.15 mmol) in EtOH (50 mL) was added hydroxylamine hydrochloride (1.72 g, 24.9 mmol) and DIPEA (4.36 mL, 24.9 mmol). The mixture was stirred at 90°C for 16 hours. The solution was cooled to room temperature, then the solvent was removed under reduced pressure. The residue was partitioned between EA (50 mL) and water (20 mL), and the organic layer was separated. The aqueous phase was further extracted with EA (2 x 30 mL) and the combined organic extracts. Dry over NaSO4, filter and concentrate. The crude product (550 mg, 25.7%) was purified on a silica gel column MW1207.

[0062] 1H NMR(DMSO-d6,400MHz)δ9.24(s,1H),8.38-8.39(m,1H),7.37-7.56(m,5H),7.09-7.15(m,2H),6.88(d,J =8.0Hz,1H),6.69(d,J=8.8Hz,2H),6.44(t,J=5.2Hz,1H),5.56(br s,2H),4.51(d,J=5.6Hz,2H) ,4.22(t,J=7.2Hz,2H),3.97(q,J=7.2Hz,2H),3.76(s,3H),...

Embodiment 3

[0078] Embodiment 3: in vitro stability test

[0079] In this example, the in vitro hepatic microsomal stability of the compound of formula I1 and compound of formula I2 of the present invention was tested, wherein the formation of dabigatran was detected and compared with the known compound of formula I5.

[0080] Test compound: compound of formula I1, compound of formula I2 and compound of formula I5;

[0081] Control compound: verapamil.

[0082] Microsomes: Human liver microsomes and rat liver microsomes were purchased from CellzDirect (Invitrogen); store at –80°C until use.

[0083] method:

[0084] 1) Prepare the mother solution as shown in Table 1, and then add the test compound or control compound, so that the final concentration of these compounds in the reaction system is 2 μM. Then preheat the mixed solution at 37 °C for 2 min.

[0085] Table 1. Preparation of mother liquors

[0086]

[0087] 2) NADPH was added to the mixed solution to make the final conce...

Embodiment 4

[0110] Embodiment 4: Pharmacokinetic test in vivo

[0111] In this embodiment, the in vivo pharmacokinetics of compounds I1, I2 and I6 of the present invention and the known dabigatran etexilate (formula I5) were detected.

[0112] method:

[0113] Compounds I1, I2, I5 and I6 were dissolved in the blank solution (30% PEG-400 and saline) at a concentration of 1 g / L, respectively.

[0114] The experimental animals were male SD rats, aged 6 to 8 weeks, weighing 190-215 grams, purchased from Beijing Weili Tonghua Experimental Animal Technology Co., Ltd. SD rats were randomly divided into 4 groups based on body weight, with 3 animals in each group. See Table 4 for the dosage and route of each group of rats.

[0115] Table 4. Grouping and administration of pharmacokinetic tests

[0116]

[0117] Before the pharmacokinetic test, SD rats were fasted for 16 hours. A single dose of compound or blank solution was then administered intravenously (1 mg / kg) or orally (10 mg / kg) as...

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PUM

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Abstract

The invention provides a dabigatran etexilate derivative shown as a formula I, or pharmaceutically acceptable salt, a solvate, a polymorph, an antipode or a racemic mixture thereof. In the formula I, R1 is hydrogen or C1 to C5 alkyl, R2 is shown in the specifications, R3 and R4 are independently hydrogen or C1 to C5 alkyl, n is 0 or 1, and R5 is C1 to C8 alkyl or optionally substituted C1 to C8 alkyl. The compound has the activity of a thrombin inhibitor. The invention also provides a preparation method for the compound, a compound-containing medical composition, and application of the compound and the medicinal composition to preparation of thrombin inhibitor medicines and treatment of related diseases.

Description

technical field [0001] The invention belongs to the field of medicine, in particular, the invention relates to a dabigatran ester derivative having thrombin inhibitor activity, a preparation method of the derivative, a pharmaceutical composition containing the derivative, and the Use of derivatives and pharmaceutical compositions in preparing thrombin inhibitor drugs and treating related diseases. Background technique [0002] Dabigatran (Dabigatran, see formula I6 below) is a selective and highly effective thrombin inhibitor, but due to its strong basic amidine group, it cannot be absorbed orally: [0003] [0004] In order to improve the bioavailability of dabigatran, the free carboxyl in the dabigatran molecule has been converted into ethyl ester respectively, and the amidine group has been converted into hexyl carbamate to obtain its diester prodrug dabigatran etexilate ( Dabigatran Etexilate, Formula I5): [0005] [0006] Dabigatran etexilate (hereinafter refer...

Claims

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Application Information

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IPC IPC(8): C07D401/12A61K31/4439A61P7/02
Inventor 王志岩
Owner BEIJING PRELUDE PHARM SCI & TECH
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