CN116947819A - A dabigatran etexilate pamoate compound and its preparation and use - Google Patents

Abstract

The invention discloses a dabigatran etexilate pamoate compound and preparation and application thereof, and belongs to the technical field of medicines. The invention provides a novel salt compound of dabigatran etexilate shown in a formula (I), which can effectively improve the solubility and the stability under influencing factors after salifying dabigatran etexilate and pamoic acid, is beneficial to further researching the medicinal way and the administration mode of dabigatran etexilate in future, improves the pharmacological effect and reduces the adverse reaction of medicaments.

Description

A dabigatran etexilate pamoate compound and its preparation and use

Technical field

The invention belongs to the field of medical technology, and specifically relates to a dabigatran etexilate pamoate compound and its preparation and use.

Background technique

Dabigatran etexilate mesylate was developed by Boehringer-Ingelheim. It was first approved by the European Medicines Agency (EMA) for marketing in Germany and the United Kingdom on March 18, 2008; it was launched on October 19, 2010. It was approved for marketing by the U.S. Food and Drug Administration (FDA) on January 21, 2011; it was approved for marketing by Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) on January 21, 2011; it is marketed in various places by Boehringer Ingelheim under the trade name

Dabigatran etexilate and its acyl glucuronide are competitive direct thrombin inhibitors. The active ingredients inhibit free and clot-bound thrombin, as well as thrombin-induced platelet aggregation. Its indications are:

To reduce the risk of stroke and systemic embolism in adults with non-valvular atrial fibrillation; for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) in adults receiving parenteral anticoagulants for 5 to 10 days; to reduce the risk of stroke and systemic embolism in adults receiving parenteral anticoagulants for 5 to 10 days; Risk of recurrence of DVT and PE in previously treated adult patients; for the prevention of DVT and PE in adult patients undergoing hip replacement surgery; for the treatment of pediatric patients 8 years to less than 18 years of age who have been treated with parenteral anticoagulants for at least 5 days of venous thromboembolic events (VTE); reduces the risk of recurrence of VTE in previously treated pediatric patients aged 8 to less than 18 years.

Dabigatran etexilate is used in the form of mesylate, which has certain shortcomings: 1. The stability of dabigatran etexilate itself is acceptable, but after being salted with the strong acid methanesulfonic acid, dabigatran etexilate becomes salty. The stability of galtran etexilate is relatively poor, which poses challenges to its stability during storage, transportation and preparation production processes; 2. Due to the use of methanesulfonic acid, genotoxic mesylate is likely to be produced during the production and preparation process. compounds, there are potential risks.

Contents of the invention

In response to the above situation, the present invention provides a new salt compound of dabigatran etexilate. After forming a salt of dabigatran etexilate and pamoic acid, the solubility and stability under influencing factors can be effectively improved, which is beneficial to In the future, we will further study the medicinal routes and administration methods of dabigatran etexilate to improve its pharmacological effects and reduce adverse drug reactions.

The object of the present invention is to provide a dabigatran etexilate pamoate compound having a structure shown in formula (I):

Among them, n is 1 or 0.5.

Another object of the present invention is to provide a method for preparing the above-mentioned dabigatran etexilate pamoate compound. The compound of formula (II) is added to the solvent. After the compound is completely dissolved, the compound of formula (III) is added to form a salt and crystallize. The dabigatran etexilate pamoate compound represented by formula (I) is obtained; the reaction route of the method is as follows:

In one embodiment of the present invention, the solvent is any one or a combination of acetone, water, methanol, ethanol, acetonitrile, DMF, DMSO, ethyl acetate, tetrahydrofuran, and methyl tert-butyl ether.

In one embodiment of the present invention, the molar ratio of the compound of formula (II) to the compound of formula (III) is 1: (0.5-1.5).

In one embodiment of the present invention, the process of salt formation and crystallization includes: adding the compound of formula (III), maintaining the temperature at 40-60°C for 20-30 minutes, then lowering the temperature to crystallize, and stirring for 0.5-14 hours.

In one embodiment of the present invention, the temperature is lowered to 10-15°C and stirring is continued for 12-14 hours.

In one embodiment of the present invention, the dabigatran etexilate pamoate compound of the present invention has better stability and solubility than dabigatran etexilate mesylate or its salt compound.

In one embodiment of the present invention, the dabigatran etexilate pamoate salt compound further includes its solvent compound and crystal water compound.

The present invention also provides the application of the above-mentioned dabigatran etexilate pamoate compound or its solvent compound and crystal water compound in preparing drugs for preventing or treating stroke and systemic embolism (SEE) in patients with non-valvular atrial fibrillation.

The present invention also provides the application of the above-mentioned dabigatran etexilate pamoate compound or its solvent compound and crystal water compound in preparing drugs for treating the formation and recurrence of deep vein thrombosis (DVT).

The present invention also provides the use of the above-mentioned dabigatran etexilate pamoate compound or its solvent compound and crystal water compound in the preparation of drugs for the treatment of pulmonary embolism (PE) and recurrence.

The present invention also provides the application of the above-mentioned dabigatran etexilate pamoate compound or its solvent compound and crystal water compound in the preparation of drugs for preventing deep vein thrombosis DVT and pulmonary embolism PE.

Beneficial effects:

The invention provides a new salt compound of dabigatran etexilate. After salting dabigatran etexilate and pamoic acid, the solubility and stability under influencing factors can be effectively improved. The dabigatran etexilate pamoate salt of the present invention is superior to dabigatran etexilate mesylate in terms of stability, solubility, etc., and at the same time avoids the use of methanesulfonic acid, which is beneficial to the medication safety and improves pharmacology. Reduces adverse drug reactions.

Detailed ways

The compound dabigatran etexilate shown in the formula (II) and dabigatran etexilate mesylate involved in the present invention are both self-made and obtained with reference to CN1972919A; the compound pamoic acid shown in the formula (III) is a commonly used chemical and can be purchased from From Shanghai Aladdin Biochemical Technology Co., Ltd.

Example 1

Synthesis of dabigatran etexilate pamoate:

Add 251g of dabigatran etexilate (399.8mmol) into the reaction bottle, add 4500g of acetone, heat to 50°C to completely dissolve; then add 156g of pamoic acid (401.7mmol), keep warm and stir for about 20min; cool naturally to 10 ℃, continue stirring for about 12 hours; filter, collect the solid, and dry it; obtain 393g of yellow solid. Yield: 96.7%.

¹ H-NMR (300MHz, DMSO-d ₆ +D ₂ O): 0.84～0.88ppm(t,3H); 1.10～1.14ppm(t,3H); 1.26～1.38ppm(m,6H); 1.59～1.68 ppm(m,2H); 2.66～2.70ppm(t,2H); 3.77ppm(s,3H); 3.94～4.01ppm(q,2H); 4.14～4.18ppm(t,2H); 4.21～4.26ppm( t,2H);4.65pm(s,2H);4.77pm(s,2H);6.82～6.85ppm(d,3H);6.88～6.91ppm(d,1H);7.10～7.18ppm(m,4H) ;7.28～7.33ppm(t,2H);7.39～7.42ppm(d,1H);7.48ppm(s,1H);7.52～7.57ppm(t,1H);7.69～7.72ppm(d,2H);7.80 ~7.82ppm(d,2H); 8.13~8.16ppm(d,2H); 8.37~8.40ppm(m,1H); 9.89ppm(s,1H). Because the hydrogen spectrum solvent is DMSO-d ₆ +D ₂ O , dabigatran etexilate pamoate contains a total of 7 active hydrogens that are not reflected in the hydrogen spectrum. The total number of hydrogens in this structure is 57. After removing 7 active hydrogens, the remaining 50 hydrogens are all reasonably reflected in the hydrogen spectrum.

Example 2

Synthesis of dabigatran etexilate hempamoate:

Add 251g dabigatran etexilate (399.8mmol) into the reaction bottle, add 3000g acetone, heat to 50°C to completely dissolve; then add 77.5g pamoic acid (199.5mmol), keep warm and stir for about 20 minutes; cool naturally to 10°C, continue stirring for about 12 hours; filter, collect the solid, and dry it; obtain 311g of light yellow solid. Yield: 94.8%.

¹ H-NMR (300MHz, DMSO-d ₆ +D ₂ O): 0.84～0.89ppm(t,3H); 1.10～1.14ppm(t,3H); 1.26～1.37ppm(m,6H); 1.58～1.66 ppm(m,2H); 2.66～2.70ppm(t,2H); 3.77ppm(s,3H); 3.94～4.01ppm(q,2H); 4.08～4.13ppm(t,2H); 4.20～4.25ppm( t,2H);4.64pm(s,2H);4.75pm(s,1H);6.80～6.83ppm(d,2H);6.88～6.91ppm(d,1H);7.10～7.17ppm(m,3H) ;7.24～7.28ppm(t,1H);7.39～7.42ppm(d,1H);7.48ppm(s,1H);7.52～7.57ppm(t,1H);7.72～7.75ppm(d,2H);7.75 ~7.78ppm(d,1H); 8.14~8.17ppm(d,1H); 8.34ppm(s,1H); 8.38~8.39ppm(d,1H). Because the hydrogen spectrum solvent is DMSO-d6+D ₂ O, Dabigatran etexilate hemipamoate contains a total of 5 active hydrogens that are not reflected in the hydrogen spectrum. The total number of hydrogens in this structure is 49. After removing 5 active hydrogens, the remaining 44 hydrogens are all reasonably reflected in the hydrogen spectrum.

Comparative example 1

Stability comparison experiment between dabigatran etexilate mesylate and dabigatran pamoate:

Dabigatran etexilate mesylate and dabigatran pamoate samples obtained in Example 1 were used in a double-layer pharmaceutical low-density polyethylene bag plus a desiccant and a polyester/aluminum/polyethylene composite film for pharmaceutical packaging. Bag crystal packaging (this packaging is a common medicinal packaging, medicinal low-density polyethylene, which can be purchased from Shijiazhuang Yucai Medicinal Packaging Materials Co., Ltd.), inspection conditions: temperature 25℃±2℃, relative humidity RH60%± 5% for stability storage comparison. The detection method is: using octadecylsilane bonded silica gel as filler (GL Sciences Inertsil ODS-2, 4.0mm×125mm, 5μm or a chromatographic column with equivalent performance); using 0.2% ammonium acetate solution (adjusting the pH with glacial acetic acid value to 4.4) is the mobile phase A, and acetonitrile is the mobile phase B; the flow rate is 2.0 ml per minute for elution; the column temperature is 40°C for detection. The results are shown in Table 1.

Table 1

According to the results in the above table, it can be seen that the oxidative impurities of dabigatran etexilate mesylate increased significantly during the stability stakeout process, while the dabigatran etexilate pamoate was only Slight growth.

The structure of oxidized impurities is as follows:

Comparative example 2

Comparative experiment on solubility of dabigatran etexilate mesylate and dabigatran pamoate:

The test and judgment were carried out according to the solubility test method in the four general regulations of the Chinese Pharmacopoeia 2020 edition. The detailed experimental results are shown in Table 2.

Table 2

Solvent Dabigatran etexilate mesylate dabigatran etexilate pamoate Methanol Soluble Soluble Anhydrous ethanol slightly soluble slightly soluble DMSO Soluble Soluble Acetonitrile Almost insoluble Almost insoluble water Almost insoluble Slightly soluble (2mg/mL)

Through a simple solubility comparison experiment, it was found that the solubility is basically the same, but when dissolved in purified water, there is a significant difference in the dissolution speed of the two, so we further studied it. It was found that the solubility of dabigatran etexilate mesylate in water is almost insoluble, while the solubility of dabigatran etexilate pamoate in water is about 2mg/mL, which is a significant difference. The follow-up will be based on the stability and Solubility-related experiments will further study whether relevant parameters in the formulation process can be improved to further improve bioavailability.

Comparative example 3

The salt of dabigatran etexilate is replaced with caffeic acid, vanillic acid, or methanesulfonic acid to obtain the corresponding salt compound.

Corresponding stability and solubility tests were conducted on different salt compounds, and the results are shown in Table 3.

table 3

According to the results in the table above, compared with caffeic acid, vanillic acid, and methanesulfonic acid, pamoic acid has significantly improved stability and water solubility.

The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details of the above embodiments. Within the scope of the technical concept of the present invention, a variety of simple modifications can be made to the technical solution of the present invention. These modifications are It belongs to the protection scope of the present invention. Some of the specific technical features described in the above specific embodiments are not detailed, such as solvent, molar ratio, salt formation of dabigatran etexilate mesylate and pamoic acid after desalting. If there is no contradiction, they can be combined by any preparation method. In order to avoid unnecessary repetition, various possible combination methods are not described separately in the present invention.

Claims (10)

1. A dabigatran etexilate pamoate compound having a structure represented by formula (I): Among them, n is 1 or 0.5. 2. The dabigatran etexilate pamoate compound according to claim 1, further comprising its solvent compound and crystal water compound. 3. The preparation method of dabigatran etexilate pamoate compound according to claim 1, characterized in that it includes the following process: adding the compound of formula (II) to the solvent, and adding the compound of formula (III) after complete dissolution , salt formation and crystallization are obtained to obtain the dabigatran etexilate pamoate salt compound represented by formula (I); the reaction route of the method is as follows: 4. The method according to claim 3, wherein the solvent is any one of acetone, water, methanol, ethanol, acetonitrile, DMF, DMSO, ethyl acetate, tetrahydrofuran, and methyl tert-butyl ether. or multiple combinations. 5. The method according to claim 3, characterized in that the molar ratio of the compound of formula (II) to the compound of formula (III) is 1: (0.5-1.5). 6. The method according to claim 3, characterized in that the process of salt formation and crystallization includes: adding the compound of formula (III), maintaining the temperature at 40-60°C for 20-30 minutes, then lowering the temperature to crystallize, and stirring for 0.5-14 hours. . 7. The dabigatran etexilate pamoate compound according to claim 1, or its solvent compound and crystal water compound according to claim 2, for use in the preparation, prevention or treatment of reducing stroke and systemic embolism in patients with non-valvular atrial fibrillation. Applications in SEE drugs. 8. The dabigatran etexilate pamoate compound according to claim 1, or the use of its solvent compound and crystal water compound according to claim 2 in the preparation of drugs for the treatment of deep vein thrombosis DVT formation and recurrence. 9. Application of the dabigatran etexilate pamoate compound according to claim 1, or its solvent compound and crystal water compound according to claim 2 in the preparation of drugs for the treatment of PE and recurrence of pulmonary embolism. 10. Application of the dabigatran etexilate pamoate compound according to claim 1, or its solvent compound and crystal water compound according to claim 2 in the preparation of medicines for preventing deep vein thrombosis (DVT) and pulmonary embolism (PE).