A dabigatran etexilate pamorate compound, its preparation and use

Abstract

The present invention discloses a dabigatran etexilate pamolate compound, its preparation and use, belonging to the field of pharmaceutical technology. The present invention provides a novel salt compound of dabigatran etexilate shown in formula (I). After forming a salt of dabigatran etexilate with pamolic acid, it can effectively improve solubility and stability under influencing factors, which is beneficial to further study the medicinal route and administration method of dabigatran etexilate in the future, improve the pharmacological effect and reduce the adverse reactions of the drug.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicine, and particularly relates to a dabigatran etexilate pamolate compound, its preparation and use. Background Art

[0002] Dabigatran etexilate mesylate was developed by Boehringer-Ingelheim. It was first approved by the European Medicines Agency (EMA) for marketing in Germany and the UK on March 18, 2008; approved by the US Food and Drug Administration (FDA) for marketing on October 19, 2010; approved by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan for marketing on January 21, 2011; and marketed by Boehringer-Ingelheim in various regions under the trade name

[0003] Dabigatran etexilate and its acyl glucuronide are competitive direct thrombin inhibitors. The active component can inhibit free and clot-bound thrombin, as well as thrombin-induced platelet aggregation. Its indications are as follows:

[0004] Reducing the risk of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation; treating deep vein thrombosis (DVT) and pulmonary embolism (PE) in adult patients receiving parenteral anticoagulant therapy for 5 - 10 days; reducing the risk of recurrence of DVT and PE in adult patients who have previously received treatment; preventing DVT and PE in adult patients undergoing hip replacement surgery; treating venous thromboembolism events (VTE) in pediatric patients aged 8 to 18 years receiving parenteral anticoagulant therapy for at least 5 days; reducing the risk of recurrence of VTE in pediatric patients aged 8 to 18 years who have previously received treatment.

[0005] When dabigatran etexilate is administered in the form of mesylate, there are certain deficiencies: First, the stability of dabigatran etexilate itself is acceptable, but the stability of dabigatran etexilate mesylate after salification with strong acid mesylic acid is relatively poor, posing challenges to its stability during storage, transportation, and pharmaceutical production; Second, due to the use of mesylic acid, there is a high probability of generating genotoxic mesylate compounds during the production process, with potential risks. Summary of the Invention

[0006] In view of the above situation, the present invention provides a novel salt compound of dabigatran etexilate. After salifying dabigatran etexilate with pamolic acid, it can effectively improve solubility and stability under stress conditions, which is beneficial for further research on the medicinal route and administration method of dabigatran etexilate in the future, improving the pharmacological effect and reducing the adverse reactions of the drug.

[0007] The object of the present invention is to provide a dabigatran etexilate pamolate compound having the structure shown in formula (I):

[0008]

[0009] Among them, n is 1 or 0.5.

[0010] 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 a solvent, and after complete dissolution, the compound of formula (III) is added, and salt formation and crystallization are carried out to obtain the dabigatran etexilate pamoate compound shown in formula (I); the reaction route of the method is as follows:

[0011]

[0012] 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, methyl tert-butyl ether.

[0013] 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).

[0014] In one embodiment of the present invention, the process of salt formation and crystallization includes: after adding the compound of formula (III), keeping warm at 40 - 60 °C for 20 - 30 min, then cooling for crystallization, and stirring for 0.5 - 14 h.

[0015] In one embodiment of the present invention, it is cooled to 10 - 15 °C and stirring is continued for 12 - 14 h.

[0016] In one embodiment of the present invention, the dabigatran etexilate pamoate compound of the present invention has better stability and solubility compared with dabigatran etexilate mesylate or its salt compound.

[0017] In one embodiment of the present invention, the above-mentioned dabigatran etexilate pamoate compound further includes its solvate compound and hydrate compound.

[0018] The present invention also provides the use of the above-mentioned dabigatran etexilate pamoate compound or its solvate compound and hydrate compound in the preparation of drugs for preventing or treating stroke and systemic embolism (SEE) in patients with non-valvular atrial fibrillation.

[0019] The present invention also provides the use of the above-mentioned dabigatran etexilate pamoate compound or its solvate compound and hydrate compound in the preparation of drugs for treating the formation and recurrence of deep vein thrombosis (DVT).

[0020] The present invention also provides the use of the above-mentioned dabigatran etexilate pamoate compound or its solvate compound and hydrate compound in the preparation of drugs for treating pulmonary embolism (PE) and recurrence.

[0021] The present invention also provides the use of the above-mentioned dabigatran etexilate pamolate compound or its solvate compound or hydrate compound in the preparation of a drug for preventing deep vein thrombosis (DVT) and pulmonary embolism (PE).

[0022] Beneficial effects:

[0023] The present invention provides a novel salt compound of dabigatran etexilate. After forming a salt with pamoic acid, the solubility and stability under influencing factors of dabigatran etexilate can be effectively improved. The dabigatran etexilate pamolate of the present invention is superior to dabigatran etexilate mesylate in terms of stability and solubility, etc. At the same time, the use of methanesulfonic acid is avoided, which is beneficial to the drug use safety, improves the pharmacological effect and reduces the adverse drug reactions. Specific embodiments

[0024] The dabigatran etexilate shown by formula (II) involved in the present invention and dabigatran etexilate mesylate are both prepared by reference to CN1972919A; the pamoic acid shown by formula (III) is a commonly used chemical and is purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.

[0025] Example 1

[0026] Synthesis of dabigatran etexilate pamolate:

[0027]

[0028] Add 251 g (399.8 mmol) of dabigatran etexilate to a reaction flask, add 4500 g of acetone, heat to 50 °C to completely dissolve it; then add 156 g (401.7 mmol) of pamoic acid, keep the temperature and stir for about 20 min; cool naturally to 10 °C, continue to stir for about 12 h; filter, collect the solid, and dry it; 393 g of yellow solid is obtained. Yield: 96.7%.

[0029] 11H-NMR (300 MHz, DMSO-d6 + D2O): 0.84 - 0.88 ppm (t, 3H); 1.10 - 1.14 ppm (t, 3H); 1.26 - 1.38 ppm (m, 6H); 1.59 - 1.68 ppm (m, 2H); 2.66 - 2.70 ppm (t, 2H); 3.77 ppm (s, 3H); 3.94 - 4.01 ppm (q, 2H); 4.14 - 4.18 ppm (t, 2H); 4.21 - 4.26 ppm (t, 2H); 4.65 ppm (s, 2H); 4.77 ppm (s, 2H); 6.82 - 6.85 ppm (d, 3H); 6.88 - 6.91 ppm (d, 1H); 7.10 - 7.18 ppm (m, 4H); 7.28 - 7.33 ppm (t, 2H); 7.39 - 7.42 ppm (d, 1H); 7.48 ppm (s, 1H); 7.52 - 7.57 ppm (t, 1H); 7.69 - 7.72 ppm (d, 2H); 7.80 - 7.82 ppm (d, 2H); 8.13 - 8.16 ppm (d, 2H); 8.37 - 8.40 ppm (m, 1H); 9.89 ppm (s, 1H). Since the solvent for 1H-NMR is DMSO-d6 + D2O, 7 active hydrogens in dabigatran etexilate pamotate are not shown in the 1H-NMR spectrum. The total number of hydrogens in this structure is 57. After removing 7 active hydrogens, the remaining 50 hydrogens are all reasonably shown in the 1H-NMR spectrum.

[0030] Example 2

[0031] Synthesis of dabigatran etexilate hemipamotate:

[0032]

[0033] Add 251 g (399.8 mmol) of dabigatran etexilate to a reaction flask, add 3000 g of acetone, heat to 50 °C to completely dissolve it; then add 77.5 g (199.5 mmol) of pamotic acid, keep the temperature and stir for about 20 min; cool naturally to 10 °C and continue to stir for about 12 h; filter, collect the solid and dry it; obtain 311 g of a light yellow solid. Yield: 94.8%.

[0034] 11H-NMR (300 MHz, DMSO-d6 + D2O): 0.84 - 0.89 ppm (t, 3H); 1.10 - 1.14 ppm (t, 3H); 1.26 - 1.37 ppm (m, 6H); 1.58 - 1.66 ppm (m, 2H); 2.66 - 2.70 ppm (t, 2H); 3.77 ppm (s, 3H); 3.94 - 4.01 ppm (q, 2H); 4.08 - 4.13 ppm (t, 2H); 4.20 - 4.25 ppm (t, 2H); 4.64 ppm (s, 2H); 4.75 ppm (s, 1H); 6.80 - 6.83 ppm (d, 2H); 6.88 - 6.91 ppm (d, 1H); 7.10 - 7.17 ppm (m, 3H); 7.24 - 7.28 ppm (t, 1H); 7.39 - 7.42 ppm (d, 1H); 7.48 ppm (s, 1H); 7.52 - 7.57 ppm (t, 1H); 7.72 - 7.75 ppm (d, 2H); 7.75 - 7.78 ppm (d, 1H); 8.14 - 8.17 ppm (d, 1H); 8.34 ppm (s, 1H); 8.38 - 8.39 ppm (d, 1H). Since the solvent for 1H-NMR is DMSO-d6 + D2O, five active hydrogens in dabigatran etexilate hemiparmoate are not reflected in the 1H-NMR spectrum. The total number of hydrogens in this structure is 49. After removing the five active hydrogens, the remaining 44 hydrogens are all reasonably reflected in the 1H-NMR spectrum.

[0035] Comparative Example 1

[0036] Stability comparison experiment between dabigatran etexilate mesylate and dabigatran parmoate:

[0037] The samples of dabigatran etexilate mesylate and the dabigatran parmoate obtained in Example 1 were packed in a double-layer medicinal low-density polyethylene bag with a desiccant and a polyester / aluminum / polyethylene composite film bag for 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.). The investigation conditions were: temperature 25°C ± 2°C, relative humidity RH60% ± 5%, and a stability storage comparison was carried out. The detection method was: using octadecylsilane-bonded silica gel as the filler (GL Sciences Inertsil ODS-2, 4.0 mm × 125 mm, 5 μm or a chromatographic column with equivalent efficiency); using 0.2% ammonium acetate solution (adjusted to pH 4.4 with glacial acetic acid) as mobile phase A and acetonitrile as mobile phase B; the flow rate was 2.0 ml per minute for elution; the column temperature was 40°C for detection. The results are shown in Table 1.

[0038] Table 1

[0039]

[0040]

[0041] According to the results in the above table, it can be seen that the oxidative impurities of dabigatran etexilate mesylate increase significantly during the stability study, while under the influence of pamidic acid, the oxidative impurities of dabigatran etexilate pamoate only increase slightly.

[0042] The structures of the oxidative impurities are shown as follows:

[0043]

[0044] Comparative Example 2

[0045] Solubility comparison experiment between dabigatran etexilate mesylate and dabigatran etexilate pamoate:

[0046] The test and judgment were carried out according to the solubility test method in the General Principles of the Chinese Pharmacopoeia (2020 Edition), Volume IV. The detailed experimental results are shown in Table 2.

[0047] Table 2

[0048] Solvent Dabigatran etexilate mesylate Dabigatran etexilate pamoate Methanol Freely soluble Freely soluble Absolute ethanol Sparingly soluble Sparingly soluble Dimethyl sulfoxide Freely soluble Freely soluble Acetonitrile Practically insoluble Practically insoluble Water Practically insoluble Slightly soluble (2mg / mL)

[0049] Through a simple solubility comparison experiment, it was found that the solubilities were basically the same, but when dissolved in purified water, there was an obvious difference in the dissolution rates of the two. Further research was carried out. It was found that the solubility of dabigatran etexilate mesylate in water was almost insoluble, while the solubility of dabigatran etexilate pamoate in water was about 2 mg / mL, showing an obvious difference. Subsequently, whether the relevant parameters in the formulation process can be improved to further increase the bioavailability will be further studied based on the relevant experiments on stability and solubility.

[0050] Comparative Example 3

[0051] Replace the salt of dabigatran etexilate with caffeic acid, vanillic acid, or methanesulfonic acid to obtain the corresponding salt compounds.

[0052] The corresponding stability and solubility tests were carried out on different salt compounds respectively, and the results are shown in Table 3.

[0053] Table 3

[0054]

[0055]

[0056] According to the results in the above table, compared with caffeic acid, vanillic acid, and methanesulfonic acid, pamidic acid has a significant improvement in terms of stability and water solubility.

[0057] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept scope of the present invention, various simple modifications can be made to the technical solutions of the present invention, and these modifications all fall within the protection scope of the present invention. In the above specific embodiments, some of the specific technical features described are not refined, such as solvents, molar ratios, the salt formation of dabigatran etexilate after hydrolysis with pamidic acid, etc. In the case of no contradiction, they can be combined by any preparation method. To avoid unnecessary repetition, the present invention does not further describe various possible combination methods.

Claims

1. A dabigatran etexilate pamolate compound having the structure shown in formula (I): Among them, n is 1 or 0.

5.

2. The preparation method of the dabigatran etexilate pamoate compound according to claim 1, characterized in that, It includes the following process: adding the compound of formula (II) into a solvent, and after complete dissolution, adding the compound of formula (III), and performing salting out crystallization to obtain the dabigatran etexilate pamolate compound shown in formula (I); the reaction route of the method is as follows:

3. The method according to claim 2, characterized in that, The solvent is any one or a combination of acetone, water, methanol, ethanol, acetonitrile, DMF, DMSO, ethyl acetate, tetrahydrofuran, methyl tert-butyl ether.

4. The method according to claim 2, wherein The molar ratio of the compound of formula (II) to the compound of formula (III) is 1:(0.5 - 1.5).

5. The method according to claim 2, wherein The process of salting out crystallization includes: after adding the compound of formula (III), keeping warm at 40 - 60 °C for 20 - 30 min, then cooling for crystallization, and stirring for 0.5 - 14 h.

6. Use of the dabigatran etexilate pamolate compound according to claim 1 in the preparation of a drug for preventing or treating stroke and systemic embolism (SEE) in patients with non-valvular atrial fibrillation.

7. Use of the dabigatran etexilate pamolate compound according to claim 1 in the preparation of a drug for treating the formation and recurrence of deep vein thrombosis (DVT).

8. Use of the dabigatran etexilate pamolate compound according to claim 1 in the preparation of a drug for treating pulmonary embolism (PE) and its recurrence.

9. Use of the dabigatran etexilate pamolate compound according to claim 1 in the preparation of a drug for preventing deep vein thrombosis (DVT) and pulmonary embolism (PE).

Images