Tegorasan monoethyl fumarate, preparation method thereof, pharmaceutical composition and application of tegorasan monoethyl fumarate

Abstract

The invention provides tegorasan monoethyl fumarate as well as a preparation method, a pharmaceutical composition and an application of the tegorasan monoethyl fumarate. The tegorac monoethyl fumarate provided by the invention is relatively good in solubility and good in stability, the bioavailability of a medicine is increased by improving the solubility of the medicine, and the tegorac monoethyl fumarate is suitable for industrial production and has a good market prospect.

Description

[0001] This application claims priority to the prior art of the applicant's earlier patent application filed on May 10, 2024, with the China National Intellectual Property Administration, application number 202410572924.2, entitled "Tegorashen monoethyl fumarate, preparation method thereof, pharmaceutical composition and application thereof". The entire contents of the aforementioned earlier patent application are incorporated herein by reference. Technical Field

[0002] This invention relates to tegogastric monoethyl fumarate, its preparation method, pharmaceutical composition and application, and belongs to the field of chemical pharmaceuticals. Background Technology

[0003] Tegoprazan, also known as tegoprazan, was originally developed by Pfizer. In 2008, it was licensed to RaQualiaPharma for collaborative development. In 2014, RaQualiaPharma licensed it to CJ HealthCare, which ultimately developed it successfully in South Korea. In July 2018, it was approved for marketing by the Korean Ministry of Food and Drug Safety (MFDS) for the treatment of gastroesophageal reflux disease and erosive esophagitis.

[0004]

[0005] For drugs absorbed from the intestine, the dissolution process or membrane permeation process is a rate-determined step. In cases of poor drug solubility, the dissolution process is usually a rate-determined step, and the goal is to increase the bioavailability of the drug by improving the solubility.

[0006] Drugs are known to exist in single crystal form, hydrates, polymorphic solvates, or different salt forms, each possessing distinct physicochemical properties, including solubility, melting point, and stability. These properties are often difficult to predict. Therefore, obtaining drug crystal or salt forms that are conducive to maintaining stable drug quality is crucial for quality control during drug production and storage.

[0007] Currently, the publicly reported crystal form of tegorasens is crystal form A (see patent CN107207478B). Although crystal form A is the most thermodynamically stable crystal form and is also the currently marketed pharmaceutical crystal form of this drug, this crystal form results in poor drug solubility and a relatively slow absorption process in the body.

[0008] Tigorafenib has very low water solubility. While acidic conditions can slightly increase solubility, the effect is minimal, and degradation products increase under acidic conditions, resulting in poor stability of the compound. Furthermore, using solubilizers (such as surfactants) to improve solubility requires excessive amounts of excipients, making production difficult.

[0009] Domestic patent CN109769392B discloses an acid addition salt form of ticoraxan, thus forming a new modified amorphous drug (pyruvate and malate), which can be used as a thermodynamically very stable injectable drug component. This compound has good water solubility and stability. However, because this drug uses pyruvate and malate, there are certain potential safety risks associated with in vivo administration of the injectable form.

[0010] Therefore, developing a pharmaceutical form of tigorafenib with good solubility, high bioavailability in vivo, stable safety properties, and suitable for industrial production is a pressing technical problem that needs to be solved. Summary of the Invention

[0011] The technical problem this invention aims to solve is to overcome the relatively poor solubility of the existing ticoraxan free base, which affects bioavailability. This invention provides ticoraxan monoethyl fumarate, its preparation method, pharmaceutical compositions containing it, and its applications. The ticoraxan monoethyl fumarate provided by this invention has relatively good solubility and stability. By improving drug solubility, it increases drug bioavailability, making it suitable for industrial production and possessing excellent market prospects.

[0012] This invention provides tigorasine monoethyl fumarate, the structural formula of which is shown below:

[0013]

[0014] Where X ranges from 0.1 to 10.0.

[0015] According to an embodiment of the present invention, the ticoraxan monoethyl fumarate is formed by salt formation of 7-[[(4S)-5,7-difluoro-3,4-dihydro-2H-1-benzopyran-4-yl]oxy]-N,N,2-trimethyl-1H-benzimidazole-5-carboxamide (i.e., ticoraxan) and monoethyl fumarate.

[0016] According to an embodiment of the present invention, the X in the tegorazone monoethyl fumarate can be 0.5 to 5.0, for example 1.0.

[0017] According to embodiments of the present invention, the tegoranoic acid monoethyl fumarate can be in crystalline or amorphous form. For example, the tegoranoic acid monoethyl fumarate can be in crystalline, polycrystalline, or amorphous form.

[0018] According to an embodiment of the present invention, the tegorazine monoethyl fumarate can be anhydrous, hydrated, or solvate.

[0019] According to an embodiment of the present invention, when present, the molar ratio of the salt to water molecules or solvent molecules in its solid form can vary in the range of 1:0.5 to 1:5 (e.g., 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, 1:3), and this molar ratio can also be detected by methods known to those skilled in the art.

[0020] This invention also provides the amorphous form of the ticoraxan monoethyl fumarate, the X-ray powder diffraction (XRPD) pattern of which is substantially as follows: Figure 1 , Figure 3 , Figure 4 , Figure 5 or Figure 6 As shown.

[0021] According to an embodiment of the present invention, the melting point of the tegorazine monoethyl fumarate is about 230.41±3.0℃, for example 230.41±1.5℃.

[0022] According to an embodiment of the present invention, the differential scanning calorimetry (DSC) spectrum of ticoraxan monoethyl fumarate is basically as follows: Figure 2 As shown.

[0023] The present invention also provides a method for preparing ticoraxan monoethyl fumarate, which includes the following steps: forming a solution with ticoraxan, monoethyl fumarate and a solvent, then adding a poor solvent, crystallizing, and obtaining ticoraxan monoethyl fumarate.

[0024] According to an embodiment of the present invention, the solvent is preferably an alcohol solvent, and the alcohol solvent is preferably methanol and / or ethanol;

[0025] According to an embodiment of the present invention, the molar ratio of the monoethyl fumarate to the tegorazine can be 0.1 to 10.0, or 0.5 to 5.0, for example 1.0.

[0026] According to an embodiment of the present invention, the solution formed by ticoraxan, monoethyl fumarate and solvent is preferably obtained by stirring and dissolving; the stirring and dissolving temperature is preferably 20°C to 30°C.

[0027] According to an embodiment of the present invention, the non-benign solvent is preferably an ester solvent, and the ester solvent is preferably ethyl acetate and / or isopropyl acetate.

[0028] According to an embodiment of the present invention, the crystallization temperature is preferably 20°C to 30°C.

[0029] According to an embodiment of the present invention, the crystallization time is preferably 4 to 10 hours.

[0030] According to an embodiment of the present invention, the method for preparing ticoraxan monoethyl fumarate preferably includes the following post-processing steps: after the reaction is completed, the mixture is filtered and dried to obtain the ticoraxan monoethyl fumarate.

[0031] According to an embodiment of the present invention, the drying temperature is preferably 45°C to 55°C.

[0032] According to an embodiment of the present invention, the drying time is preferably 8 to 20 hours.

[0033] The present invention also provides a pharmaceutical composition comprising the tigorashen monoethyl fumarate.

[0034] According to embodiments of the present invention, the pharmaceutical composition may further include pharmaceutically acceptable excipients.

[0035] According to an embodiment of the present invention, the pharmaceutical composition comprises a therapeutically effective amount of the ticoraxan monoethyl fumarate and pharmaceutically acceptable excipients.

[0036] According to embodiments of the present invention, the weight percentage content of ticoraxan monoethyl fumarate in the pharmaceutical or pharmaceutical composition is greater than the content of other salt forms or crystalline forms of ticoraxan, based on the total weight of ticoraxan monoethyl fumarate in the composition. For example, the weight percentage content of ticoraxan monoethyl fumarate in the composition is 80% or more, preferably 90% or more, more preferably 95% or 99% or more.

[0037] According to embodiments of the present invention, the purpose of the pharmaceutical composition is to facilitate the administration of the compound to organisms such as humans or other mammals.

[0038] The present invention also provides the use of the ticoraxan monoethyl fumarate in medicaments for the treatment and / or prevention of diseases mediated by acid pump antagonistic activity.

[0039] The present invention also provides a method for treating and / or preventing diseases mediated by acid pump antagonism, which provides a therapeutically effective amount of the ticoraxan monoethyl fumarate or the pharmaceutical composition thereof to a patient in need.

[0040] According to an embodiment of the present invention, the disease mediated by the acid pump antagonistic activity can be a digestive tract disease, such as a gastroesophageal disease.

[0041] According to embodiments of the present invention, the diseases mediated by the acid pump antagonistic activity include, but are not limited to: gastroesophageal reflux disease (GERD), peptic ulcer, gastric ulcer, duodenal ulcer, NSAID-induced ulcer, gastritis, Helicobacter pylori infection, dyspepsia, Zollinger-Ellison syndrome, non-erosive reflux disease (NERD), visceral pain, heartburn, nausea, esophagitis (e.g., erosive esophagitis), dysphagia, drooling, airway lesions, and asthma.

[0042] According to an embodiment of the present invention, the indigestion may be functional dyspepsia.

[0043] Terminology Explanation and Description

[0044] In this invention, the term "polycrystalline" refers to different crystalline forms and other solid molecular forms of the same compound, such as solids containing two or more crystalline forms and / or amorphous forms of the ticoraxan monoethyl fumarate described above.

[0045] In this invention, the ticoraxan monoethyl fumarate includes a solvate formed therefrom with a solvent. The solvate includes a hydrate of ticoraxan monoethyl fumarate and a solvate formed therefrom with an organic solvent. The "organic solvent" in the "solvate formed therefrom with an organic solvent" includes, but is not limited to, ethanol, acetone, and dimethyl sulfoxide.

[0046] In this invention, the term "solvate" refers to a molecular complex of a drug and one or more solvent molecules (such as ethanol) in stoichiometric or non-stoichiometric amounts. When the solvent is tightly bound to the drug, the resulting complex has a well-defined stoichiometry independent of humidity. However, when the solvent is weakly bound to the drug, as in channel solvates and hygroscopic compounds, the solvent content depends on humidity and drying conditions. In such cases, the complex is typically non-stoichiometric.

[0047] In this invention, the term "hydrate" describes a solvate comprising a drug and a stoichiometric or non-stoichiometric amount of water. The term "relative humidity" refers to the ratio, expressed as a percentage, of the amount of water vapor at a specified temperature to the maximum amount of water vapor that can be retained at that temperature and pressure.

[0048] It should be understood that those skilled in the art can adjust the amounts of raw materials and reagents used in the method of the present invention based on their knowledge and experience, including proportionally increasing or decreasing the amount of raw materials, adjusting the ratio of raw materials, reagents, and solvents, and changing the temperature of the present invention. These adjustments are also included in the method of the present invention.

[0049] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0050] The reagents and raw materials used in this invention are all commercially available.

[0051] In this invention, room temperature refers to an ambient temperature of 10℃ to 35℃.

[0052] The positive and progressive effects of this invention are as follows: Tigorafenib monoethyl fumarate of this invention has relatively good solubility and stability. By improving the solubility of the drug, the bioavailability of the drug is increased, which is beneficial to its use in processing and pharmaceutical compositions. It is suitable for industrial production and has good market prospects. Attached Figure Description

[0053] Figure 1 The XRPD pattern of tegogastric monoethyl fumarate obtained in Example 1 of this invention;

[0054] Figure 2 The DSC spectrum of tegogastric monoethyl fumarate obtained in Example 1 of this invention;

[0055] Figure 3 The crystal form XRPD image for day 0 in Table 4 of Example 2;

[0056] Figure 4 The XRPD diagram of the crystal form after 6 months of accelerated condition investigation is shown in Table 4 of Example 2.

[0057] Figure 5 The XRPD diagram of the crystal form after 6 months of long-term stability testing is shown in Table 4 of Example 2.

[0058] Figure 6 The XRPD diagram of the crystal form after 6 months of observation under intermediate conditions is shown in Table 4 of Example 2.

[0059] Figure 7 The image shown is an XRPD diagram of the crystal form A of the self-made ticoraxol in the example. Detailed Implementation

[0060] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0061] In the following examples, the instruments and conditions for XRPD chromatogram detection were as follows: The determination was performed according to Method 2 of General Chapter 0451, Part IV of the 2020 edition of the Chinese Pharmacopoeia. Test conditions: Cu target; 40kV, 40mA.

[0062] The instruments and conditions for DSC spectrum detection were as follows: Detection was performed according to General Chapter 0661 of Part IV of the 2020 edition of the Chinese Pharmacopoeia. Test conditions: DSC: 30℃~300℃, heating rate 10℃ / min;

[0063] The solubility test was conducted in accordance with the solubility test method and definition in the General Rules of Part II of the 2020 edition of the Chinese Pharmacopoeia.

[0064] The raw material for ticoraxate is self-made, with a purity of 99.86%.

[0065] Tigrasean fumarate, oxalate, citrate, L-tartrate, pyrrolidone, malate, and tigrasean crystal form A were prepared in-house; their purities are detailed in Table 5. The XRPD plot of tigrasean crystal form A is shown in [reference needed]. Figure 7 .

[0066] All other reagents were chemically pure.

[0067] Example 1: Preparation of ticoraxan monoethyl fumarate

[0068] 10 g (1 eq) of ticoraxan and 3.92 g (1.05 eq) of monoethyl fumarate were added to 50 mL of methanol solvent and stirred at 20-30 °C for 2 h until the solution was clear. Then, 200 mL of ethyl acetate was slowly added to the reaction solution, allowing for slow crystallization. After the addition was complete, the mixture was stirred at 20-30 °C for 8 h. After stirring, the mixture was filtered and dried to obtain 13.32 g of solid ticoraxan monoethyl fumarate, with a yield of 97% and an HPLC purity of 99.91%. The XPRD chromatogram is shown below. Figure 1 DSC spectrum Figure 2 .

[0069] 1 H-NMR (400MHz, deuterated DMSO): δ: 7.10 (1H, s), 6.84 (1H, s), 6.74 (1H, t), 6.6 (3H, m), 5.95 (1H, s), 4 .33(1H,dd), 4.25(3H,m), 2.85(6H,s), 2.45(3H,s), 2.21(1H,dd), 2.08(1H,m), 1.19(3H,t).

[0070] In the tegorazine monoethyl fumarate prepared in this embodiment, the molar ratio of tegorazine to monoethyl fumarate is 1:1.

[0071] Example 2: Properties of ticoraxan monoethyl fumarate

[0072] Further research revealed that the tegorazane monoethyl fumarate of the present invention remains stable under high temperature, high humidity, and light conditions. The stability of the tegorazane monoethyl fumarate is consistent with that of the existing tegorazane crystal form A. In addition, the compound has relatively good solubility and superior bioavailability in vivo.

[0073] In summary, the tegorazine monoethyl fumarate of the present invention is superior to the existing tegorazine crystal form A, as well as tegorazine pyruvate and malate.

[0074] The results of the above studies are shown in Table 1 for the influencing factors, Table 2 for the acceleration experiment, and Table 3 for the solubility experiment data.

[0075] Table 1. Experimental data on influencing factors

[0076]

[0077]

[0078]

[0079]

[0080] Table 2 Accelerated Experiment Data Table

[0081]

[0082] Table 3 Solubility Data

[0083] solvent Tigorafenib monoethyl fumarate Tigora methanol Very soluble Easily soluble Anhydrous ethanol Very soluble Easily soluble dichloromethane Very soluble Easily soluble Acetonitrile Very soluble Easily soluble water Slightly soluble Almost insoluble

[0084] Table 4 Crystal form diagram during the stability period

[0085] condition Crystal form XRPD diagram 0 days amorphous Figure 3 Accelerated (25℃±2℃ / 60%RH±5%RH) for 6 months amorphous Figure 4 Long-term (2~8℃ / 60%RH±5%RH) for 6 months amorphous Figure 5 Intermediate conditions (20℃±2℃ / 60%RH±5%RH) for 6 months amorphous Figure 6

[0086] Table 5 Comparison with other salt forms and ticorazine crystal form A during stability period

[0087]

[0088] The embodiments of the technical solution of the present invention have been described above by way of example. It should be understood that the protection scope of the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art within the spirit and principles of the present invention should be included within the protection scope of the claims of this application.

Claims

1. A tigorasine monoethyl fumarate, characterized in that... The structural formula is shown below: Where X ranges from 0.1 to 10.

0.

2. The tigorasine monoethyl fumarate as described in claim 1, characterized in that: The ticoraxan monoethyl fumarate is formed by salting 7-[[(4S)-5,7-difluoro-3,4-dihydro-2H-1-benzopyran-4-yl]oxy]-N,N,2-trimethyl-1H-benzimidazole-5-carboxamide and monoethyl fumarate. Preferably, X is 0.5 to 5.0, for example 1.

0.

3. The tigorasine monoethyl fumarate as described in claim 1, characterized in that: The tegoraphen monoethyl fumarate is in crystalline or amorphous form; for example, it can be crystalline, polycrystalline, or amorphous. And / or, The tegorazine monoethyl fumarate is an anhydrous form, a hydrate, or a solvate.

4. The tigorasine monoethyl fumarate as described in claim 1, characterized in that: The amorphous form of ticoraxan monoethyl fumarate; Preferably, the X-ray powder diffraction pattern of the amorphous form of ticoraxan monoethyl fumarate is basically as shown in Figure 1, Figure 3, Figure 4, Figure 5 or Figure 6.

5. The tigorafenib monoethyl fumarate as described in claim 1, characterized in that: The melting point of the tegorazine monoethyl fumarate is approximately 230.41℃ ± 3.0℃.

6. The tigorasine monoethyl fumarate as described in claim 1, characterized in that: The differential scanning calorimetry (DSC) chromatogram of ticoraxan monoethyl fumarate is basically shown in Figure 2.

7. The method for preparing ticoraxan monoethyl fumarate according to any one of claims 1 to 6, characterized in that... Includes the following steps: Tigorasan, monoethyl fumarate, and a solvent are mixed to form a solution. Then, a poor solvent is added, and crystals are precipitated to obtain tigorasan monoethyl fumarate.

8. The preparation method according to claim 7, characterized in that: The solvent is an alcohol solvent, preferably methanol and / or ethanol; And / or, The molar ratio of the monoethyl fumarate to the tegopragene is 0.1 to 10.0, or it can be 0.5 to 5.0, for example, 1.0; And / or, The solution formed by ticoraxan, monoethyl fumarate and solvent is obtained by stirring and dissolving; the preferred temperature for stirring and dissolving is 20℃~30℃; And / or, The non-benign solvent is an ester solvent; the preferred ester solvents are ethyl acetate and / or isopropyl acetate. And / or, The crystallization temperature is 20℃~30℃; And / or, The crystallization time is 4 to 10 hours; And / or, The method for preparing ticoraxan monoethyl fumarate includes the following post-processing steps: after the reaction is completed, the mixture is filtered and dried to obtain the ticoraxan monoethyl fumarate; the drying temperature is preferably 45℃~55℃; and the drying time is preferably 8 hours~20 hours.

9. A pharmaceutical composition, characterized in that: The pharmaceutical composition comprises tigorashen monoethyl fumarate as described in any one of claims 1 to 6.

10. The use of tigorashen monoethyl fumarate according to any one of claims 1 to 6 in a medicament for treating and / or preventing diseases mediated by acid pump antagonistic activity; The diseases mediated by the acid pump antagonistic activity can be digestive tract diseases, such as gastroesophageal diseases; Preferably, the diseases mediated by the acid pump antagonistic activity include, but are not limited to: gastroesophageal reflux disease, peptic ulcer, gastric ulcer, duodenal ulcer, NSAID-induced ulcer, gastritis, Helicobacter pylori infection, dyspepsia, Zollinger-Ellison syndrome, non-erosive reflux disease, visceral pain, heartburn, nausea, esophagitis, dysphagia, drooling, airway lesions, and asthma.

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