Salt form of tigorazan, preparation method thereof, composition containing salt form of tigorazan and application of salt form of tigorazan

Abstract

The invention discloses a salt form of tigorasan, a preparation method of the salt form, a composition containing the salt form and application of the composition. The invention provides an acid addition salt of tigorasan, wherein the acid is N-acetyl-trans-4-hydroxy-L-proline, N-acetyl-L-proline, N-acetyl-L-cysteine or (R)-2-oxothiazolidine-4-carboxylic acid, and the acid addition salt of tigorasan is a salt of tigorasan, a salt of tigorasan, a salt of tigorasan, a salt of tigorasan and a salt of tigorasan. The four new salt forms of the tigorasone, provided by the invention, have excellent solubility and better light stability.

Description

Technical Field

[0001] The present invention relates to a salt form of tigolaxan, a preparation method thereof, a composition containing the salt form and an application thereof. Background Art

[0002] Tegoprazan is a new potassium ion competitive acid blocker that competitively blocks H + / K + -K on ATPase + Tigorapen binds to the α-binding site, inhibiting gastric acid secretion. Tigorapen oral tablets were approved for marketing in South Korea in 2018 for the treatment of gastroesophageal reflux disease, gastric ulcers, and in combination with antibiotics for the eradication of Helicobacter pylori in patients with peptic ulcers and / or chronic atrophic gastritis. In 2022, they were approved in China for the treatment of reflux esophagitis and duodenal ulcers.

[0003]

[0004] Tigraxan has a low solubility (0.02 mg / mL, pH 6.8) and is currently produced only as an oral tablet. If it could be formulated as an injectable form, the dosage would be significantly reduced and its pharmacological effects would be exerted more rapidly. Therefore, the development of technologies to improve the solubility of Tigraxan is crucial.

[0005] Salt formation is a common method to increase the solubility of a compound. However, studies have found that although the solubility of tigolaxant is slightly increased under acidic conditions (0.7 mg / mL, pH 3.0), its ether bond is easily broken under acidic conditions, resulting in an increase in degradation products (degradation product B and degradation product C). Therefore, it is very necessary to select a suitable acid.

[0006]

[0007] CN109769392A discloses several amorphous forms of acid addition salts of ticagrelor, among which fumarate, oxalate, citrate, L-pyroglutamate (also known as pyridoxalate), L-malate and L-fumarate show a solubility of> 50 mg / mL, but only L-pyroglutamate has better stability, and the other salt forms are unstable. CN109769392A also discloses that ticagrelor is formed into salts / eutectics with natural amino acids to improve solubility, but the 12 amino acids tested all show little improvement in solubility, among which L-alaninate solubility is 4 mg / mL, L-phenylalaninate solubility is 0.5 mg / mL, L-alaninate solubility is 3 mg / mL, and the most soluble L-isoleucine salt is only 13 mg / mL. Therefore, it is difficult to use natural amino acids and ticagrelor to form salts to improve the solubility of ticagrelor.

[0008] While the L-pyroglutamate salts disclosed in the prior art have excellent solubility, the inventors discovered that tigolasan L-pyroglutamate is susceptible to degradation under light conditions, which can affect drug quality and increase transportation and storage costs. Therefore, the development of an acid addition salt of tigolasan with superior solubility and increased stability is highly desirable. Summary of the Invention

[0009] The technical problem to be solved by the present invention is to overcome the shortcomings of prior art ticlopidine acid addition salts, such as poor solubility and / or poor stability, by providing a salt form of ticlopidine, a preparation method thereof, and its use. The ticlopidine acid addition salt prepared by the present invention has high solubility and good stability, and has improved processing capabilities into preparations, making it particularly suitable for the development of injectable preparations. This has significant significance for the industrial production of ticlopidine preparations.

[0010] The present invention solves the above technical problems through the following technical solutions:

[0011] In a first aspect, the present invention provides an acid addition salt of tegrassen, wherein the acid is N-acetyl-trans-4-hydroxy-L-proline, N-acetyl-L-proline, N-acetyl-L-cysteine or (R)-2-oxothiazolidine-4-carboxylic acid.

[0012] In some embodiments, in the acid addition salt of tegrassen, the acid is N-acetyl-trans-4-hydroxy-L-proline.

[0013] In some embodiments, the acid addition salt of ticlopidine is ticlopidine N-acetyl-trans-4-hydroxy-L-proline salt.

[0014] In some embodiments, the molar ratio of ticagrelor to N-acetyl-trans-4-hydroxy-L-proline is 1:1.

[0015] In some embodiments, the N-acetyl-trans-4-hydroxy-L-proline salt of ticlopidine is:

[0016]

[0017] In some embodiments, the ticaglasan N-acetyl-trans-4-hydroxy-L-proline salt is in crystalline form.

[0018] In some embodiments, the N-acetyl-trans-4-hydroxy-L-proline salt of ticlopidine is in an amorphous form.

[0019] In some embodiments, the amorphous form of ticoplasmin N-acetyl-trans-4-hydroxy-L-proline salt is an anhydrous form or a non-solvated form.

[0020] In some embodiments, the XRPD pattern of the amorphous form of the N-acetyl-trans-4-hydroxy-L-proline salt of ticlopidine is substantially the same as Figure 1 consistent.

[0021] In some embodiments, the differential scanning calorimetry (DSC) spectrum of the amorphous form of the N-acetyl-trans-4-hydroxy-L-proline salt of ticlopidine shows an endothermic peak at 74.07±5°C.

[0022] In some embodiments, the DSC spectrum of the amorphous form of the N-acetyl-trans-4-hydroxy-L-proline salt of ticlopidine is substantially the same as Figure 2 consistent.

[0023] In some embodiments, the amorphous form of ticoplasmin N-acetyl-trans-4-hydroxy-L-proline salt exhibits a glass transition temperature (Tg) of less than 100° C. as measured by modulated differential scanning calorimetry (MDSC).

[0024] In some embodiments, the amorphous form of ticoplasmin N-acetyl-trans-4-hydroxy-L-proline salt exhibits a glass transition temperature (Tg) of 80.90±5° C. as measured by modulated differential scanning calorimetry (MDSC).

[0025] In some embodiments, the modulated differential scanning calorimetry (MDSC) spectrum of the amorphous form of the N-acetyl-trans-4-hydroxy-L-proline salt of ticlopidine is substantially the same as Figure 3 consistent.

[0026] In some embodiments, the TGA spectrum of the amorphous form of the N-acetyl-trans-4-hydroxy-L-proline salt of ticlopidine is substantially the same as Figure 4 consistent.

[0027] In some embodiments, in the acid addition salt of tegrasane, the acid is N-acetyl-L-proline.

[0028] In some embodiments, the acid addition salt of ticlopidine is ticlopidine N-acetyl-L-proline salt.

[0029] In some embodiments, in the N-acetyl-L-proline salt of ticlopidine, the molar ratio of ticlopidine to N-acetyl-L-proline is 1:1.

[0030] In some embodiments, the N-acetyl-L-proline salt of ticlopidine is:

[0031]

[0032] In some embodiments, the N-acetyl-L-proline salt of ticlopidine is in crystalline form.

[0033] In some embodiments, the N-acetyl-L-proline salt of ticlopidine is in an amorphous form.

[0034] In some embodiments, the amorphous form of ticoplasma N-acetyl-L-proline salt is an anhydrous form or a non-solvated form.

[0035] In some embodiments, the XRPD pattern of the amorphous form of the N-acetyl-L-proline salt of ticlopidine is substantially the same as Figure 5 consistent.

[0036] In some embodiments, the differential scanning calorimetry (DSC) spectrum of the amorphous form of the N-acetyl-L-proline salt of ticlopidine shows an endothermic peak at 65.93±5°C.

[0037] In some embodiments, the DSC spectrum of the amorphous form of the N-acetyl-L-proline salt of ticlopidine is substantially the same as Figure 6 consistent.

[0038] In some embodiments, the amorphous form of the N-acetyl-L-proline salt of ticoplasma exhibits a glass transition temperature (Tg) of less than 60° C. as measured by modulated differential scanning calorimetry (MDSC).

[0039] In some embodiments, the amorphous form of the N-acetyl-L-proline salt of ticoplasma exhibits a glass transition temperature (Tg) of 43.28±5° C. as measured by modulated differential scanning calorimetry (MDSC).

[0040] In some embodiments, the modulated differential scanning calorimetry (MDSC) spectrum of the amorphous form of the N-acetyl-L-proline salt of ticlopidine is substantially the same as Figure 7 consistent.

[0041] In some embodiments, the TGA spectrum of the amorphous form of the N-acetyl-L-proline salt of ticlopidine is substantially the same as Figure 8 consistent.

[0042] In some embodiments, in the acid addition salt of tegrasane, the acid is N-acetyl-L-cysteine.

[0043] In some embodiments, the acid addition salt of ticlopidine is ticlopidine N-acetyl-L-cysteine salt.

[0044] In some embodiments, in the ticlopidine N-acetyl-L-cysteine salt, the molar ratio of ticlopidine to N-acetyl-L-cysteine is 1:1.

[0045] In some embodiments, the ticaglasan N-acetyl-L-cysteine salt is:

[0046]

[0047] In some embodiments, the ticaglasan N-acetyl-L-cysteine salt is in crystalline form.

[0048] In some embodiments, the ticaglasan N-acetyl-L-cysteine salt is in an amorphous form.

[0049] In some embodiments, the amorphous form of ticoplasma N-acetyl-L-cysteine salt is an anhydrous form or a non-solvated form.

[0050] In some embodiments, the XRPD pattern of the amorphous form of the N-acetyl-L-cysteine salt of ticlopidine is substantially the same as Figure 9 consistent.

[0051] In some embodiments, the differential scanning calorimetry (DSC) spectrum of the amorphous form of ticoplasma N-acetyl-L-cysteine salt shows an endothermic peak at 66.16±5°C.

[0052] In some embodiments, the DSC spectrum of the amorphous form of ticlopidine N-acetyl-L-cysteine salt is substantially the same as Figure 10 consistent.

[0053] In some embodiments, the amorphous form of ticoplasmin N-acetyl-L-cysteine salt exhibits a glass transition temperature (Tg) of less than 80° C. as measured by modulated differential scanning calorimetry (MDSC).

[0054] In some embodiments, the amorphous form of ticoplasmin N-acetyl-L-cysteine salt exhibits a glass transition temperature (Tg) of 63.25±5° C. as measured by modulated differential scanning calorimetry (MDSC).

[0055] In some embodiments, the modulated differential scanning calorimetry (MDSC) spectrum of the amorphous form of ticoplasm N-acetyl-L-cysteine salt is substantially the same as Figure 11 consistent.

[0056] In some embodiments, the TGA spectrum of the amorphous form of ticlopidine N-acetyl-L-cysteine salt is substantially the same as Figure 12 consistent.

[0057] In some embodiments, in the acid addition salt of tegrasane, the acid is (R)-2-oxothiazolidine-4-carboxylic acid.

[0058] In some embodiments, the acid addition salt of tegrassen is tegrassen (R)-2-oxothiazolidine-4-carboxylate.

[0059] In some embodiments, in the (R)-2-oxothiazolidine-4-carboxylate salt of tigolaxan, the molar ratio of tigolaxan to (R)-2-oxothiazolidine-4-carboxylic acid is 1:1.

[0060] In some embodiments, the teigolan (R)-2-oxothiazolidine-4-carboxylate is:

[0061]

[0062] In some embodiments, the (R)-2-oxothiazolidine-4-carboxylate salt of tigolaxan is in crystalline form.

[0063] In some embodiments, the (R)-2-oxothiazolidine-4-carboxylate salt of tigolaxan is in amorphous form.

[0064] In some embodiments, the amorphous form of ticoplasmin (R)-2-oxothiazolidine-4-carboxylate is an anhydrous form or a non-solvated form.

[0065] In some embodiments, the XRPD pattern of the amorphous form of the (R)-2-oxothiazolidine-4-carboxylate of ticoplasm is substantially the same as Figure 13 consistent.

[0066] In some embodiments, the differential scanning calorimetry (DSC) spectrum of the amorphous form of (R)-2-oxothiazolidine-4-carboxylate of ticoplasma shows an endothermic peak at 79.12±5°C.

[0067] In some embodiments, the differential scanning calorimetry (DSC) spectrum of the amorphous form of (R)-2-oxothiazolidine-4-carboxylate of ticoplasmin shows endothermic peaks at 79.12±5°C and 183.64±5°C.

[0068] In some embodiments, the DSC spectrum of the amorphous form of (R)-2-oxothiazolidine-4-carboxylate of ticoplasm is substantially the same as Figure 14 consistent.

[0069] In some embodiments, the amorphous form of (R)-2-oxothiazolidine-4-carboxylate of ticoplasmin exhibits a glass transition temperature (Tg) of less than 100° C. as measured by modulated differential scanning calorimetry (MDSC).

[0070] In some embodiments, the amorphous form of ticoplasmin (R)-2-oxothiazolidine-4-carboxylate exhibits a glass transition temperature (Tg) of 83.44±5° C. as measured by modulated differential scanning calorimetry (MDSC).

[0071] In some embodiments, the modulated differential scanning calorimetry (MDSC) spectrum of the amorphous form of (R)-2-oxothiazolidine-4-carboxylate of ticoplasmin is substantially the same as Figure 15 consistent.

[0072] In some embodiments, the TGA spectrum of the amorphous form of ticlopidine (R)-2-oxothiazolidine-4-carboxylate is substantially the same as Figure 16 consistent.

[0073] In a second aspect, the present invention provides a method for preparing the acid addition salt of ticagrelor as described in any of the above schemes, the preparation method comprising the following steps:

[0074] (a) dissolving ticlopidine and an acid in an organic solvent at a certain temperature; the acid is one of N-acetyl-trans-4-hydroxy-L-proline, N-acetyl-L-proline, N-acetyl-L-cysteine, or (R)-2-oxothiazolidine-4-carboxylic acid;

[0075] (b) concentrating the solution obtained in step (a) to remove the organic solvent, and then adding a slurrying solvent and stirring the resultant;

[0076] and (c) isolating and drying the precipitated solid.

[0077] In some embodiments, in step (a), tigolaxant and acid are mixed with an organic solvent simultaneously and stirred until completely dissolved.

[0078] In some embodiments, in step (a), after tigolaxant is mixed with an organic solvent, an acid is added and stirred until completely dissolved.

[0079] In some embodiments, in step (a), tigolaxant is first dissolved in an organic solvent under stirring, and then the acid is added, and stirring is continued until the acid is completely dissolved.

[0080] In some embodiments, in step (a), the temperature is 10°C to 40°C, preferably 15°C to 35°C, more preferably 20°C to 30°C, and further preferably 20°C to 25°C.

[0081] In some embodiments, in step (a), the organic solvent is selected from one or more of alcohols, ketones and nitriles, preferably alcohols, more preferably C1-C4 lower straight-chain alcohols or branched alcohols, further preferably selected from one or more of methanol, ethanol and isopropanol, and even more preferably methanol.

[0082] In some embodiments, in step (a), the volume-to-weight ratio of the organic solvent to tegrassen is 5 mL / g to 25 mL / g, preferably 8 mL / g to 20 mL / g, more preferably 10 mL / g to 15 mL / g, and even more preferably 10 mL / g.

[0083] In some embodiments, in step (b), the concentration is atmospheric distillation and reduced pressure distillation, preferably reduced pressure distillation.

[0084] In some embodiments, in step (b), the temperature during the concentration is 30°C to 55°C, preferably 35°C to 50°C, more preferably 40°C to 45°C, and further preferably 40°C.

[0085] In some embodiments, in step (b), the removing of the organic solvent is the removal of all or substantially all of the organic solvent.

[0086] In some embodiments, in step (b), the pulping solvent is selected from one or more of ethers, esters and alkanes, preferably ethers, more preferably C1-C4 lower alkyl ethers, further preferably one or more of diethyl ether, methyl tert-butyl ether and isopropyl ether, and further preferably methyl tert-butyl ether.

[0087] In some embodiments, in step (b), the volume-to-weight ratio of the slurry solvent to ticlopidine is 2 mL / g to 15 mL / g, preferably 3 mL / g to 10 mL / g, more preferably 4 mL / g to 6 mL / g, and even more preferably 4 mL / g.

[0088] In some embodiments, in step (b), the temperature during the beating is 10°C to 40°C, preferably 15°C to 35°C, more preferably 20°C to 30°C, and further preferably 20°C to 25°C.

[0089] In some embodiments, in step (c), the separation is performed by filtration under reduced pressure or suction filtration, preferably filtration under reduced pressure.

[0090] In some embodiments, in step (c), the drying is oven drying or drying under reduced pressure, preferably drying under reduced pressure.

[0091] In some embodiments, in step (c), the drying temperature is 30°C to 50°C, preferably 35°C to 45°C, more preferably 40°C to 45°C, and further preferably 40°C.

[0092] In a third aspect, the present invention provides a pharmaceutical composition comprising the acid addition salt of ticlopidine as described in any of the previous embodiments, and a pharmaceutically acceptable carrier.

[0093] In some embodiments, the pharmaceutical compositions of the present invention are prepared by combining the compounds of the present invention with pharmaceutically acceptable solid or liquid carriers, and optionally with pharmaceutically acceptable adjuvants and excipients, using standard and conventional techniques to prepare usable dosage forms.

[0094] In a fourth aspect, the present invention provides use of the acid addition salt or pharmaceutical composition of ticoplasm in the preparation of a medicament for preventing and / or treating diseases mediated by acid pump antagonistic activity.

[0095] In some embodiments, the disease mediated by acid pump antagonist activity is gastroesophageal disease, gastroesophageal reflux disease (GERD), peptic ulcer, gastric ulcer, duodenal ulcer, nonsteroidal anti-inflammatory drug (NSAID)-induced ulcer, gastritis, Helicobacter pylori infection, dyspepsia, functional dyspepsia, Zollinger-Ellison syndrome, non-erosive reflux disease (NERD), heartburn, nausea, esophagitis, dysphagia, drooling, airway obstruction, or asthma.

[0096] In some embodiments, the disease mediated by acid pump antagonist activity is gastroesophageal reflux disease (GERD), peptic ulcer, gastric ulcer, duodenal ulcer, or Helicobacter pylori infection.

[0097] The positive progress effect of the present invention is:

[0098] 1) The four new salt forms of ticagrelor of the present invention have excellent solubility:

[0099] The solubility of the ticaglasan N-acetyl-L-proline salt, N-acetyl-trans-4-hydroxy-L-proline salt, N-acetyl-L-cysteine salt and (R)-2-oxothiazolidine-4-carboxylate salt of the present invention is greater than 200 mg / mL, which is much greater than the solubility of the ticaglasan amino acid salt / cocrystal disclosed in the prior art CN109769392A, and is comparable to the solubility of the preferred salt form ticaglasan L-pyroglutamate in CN109769392A.

[0100] 2) The four new salt forms of tegrasen of the present invention have better photostability

[0101] The liquid phase stability and solid state stability of the ticoplasmin N-acetyl-L-proline salt, N-acetyl-trans-4-hydroxy-L-proline salt, N-acetyl-L-cysteine salt and (R)-2-oxothiazolidine-4-carboxylate salt of the present invention are comparable to those of ticoplasmin L-pyroglutamate, but the photostability is significantly better than that of ticoplasmin L-pyroglutamate. BRIEF DESCRIPTION OF THE DRAWINGS

[0102] Figure 1 The XRPD pattern of the amorphous form of ticaglasen N-acetyl-trans-4-hydroxy-L-proline salt is shown below:

[0103] Figure 2 This is the DSC spectrum of the amorphous form of ticaglasen N-acetyl-trans-4-hydroxy-L-proline salt;

[0104] Figure 3 MDSC profile of the amorphous form of ticaglasen N-acetyl-trans-4-hydroxy-L-proline salt;

[0105] Figure 4 This is the TGA spectrum of the amorphous form of ticaglasen N-acetyl-trans-4-hydroxy-L-proline salt;

[0106] Figure 5 This is the XRPD pattern of the amorphous form of ticaglasen N-acetyl-L-proline salt;

[0107] Figure 6 This is the DSC spectrum of the amorphous form of ticaglasen N-acetyl-L-proline salt;

[0108] Figure 7 MDSC profile of the amorphous form of ticaglasan N-acetyl-L-proline salt;

[0109] Figure 8 This is the TGA spectrum of the amorphous form of ticaglasen N-acetyl-L-proline salt;

[0110] Figure 9 This is the XRPD pattern of the amorphous form of ticaglasen N-acetyl-L-cysteine salt;

[0111] Figure 10 This is the DSC spectrum of the amorphous form of ticaglasen N-acetyl-L-cysteine salt;

[0112] Figure 11 MDSC profile of the amorphous form of ticaglasan N-acetyl-L-cysteine salt;

[0113] Figure 12 This is the TGA spectrum of the amorphous form of ticaglasen N-acetyl-L-cysteine salt;

[0114] Figure 13 The XRPD pattern of the amorphous form of (R)-2-oxothiazolidine-4-carboxylate of tigolasen is shown below:

[0115] Figure 14 This is the DSC spectrum of the amorphous form of tigolasen (R)-2-oxothiazolidine-4-carboxylate;

[0116] Figure 15 This is the MDSC profile of the amorphous form of tigolasen (R)-2-oxothiazolidine-4-carboxylate;

[0117] Figure 16 This is the TGA spectrum of the amorphous form of tigolasen (R)-2-oxothiazolidine-4-carboxylate;

[0118] Figure 17 This is the XRPD pattern of ticaglasen N-acetyl-trans-4-hydroxy-L-proline salt after being stored under accelerated conditions for 1 month and under light conditions for 10 days;

[0119] Figure 18 This is the XRPD pattern of ticagrelor N-acetyl-L-proline salt after being stored under accelerated conditions for 1 month and under light conditions for 10 days;

[0120] Figure 19 This is the XRPD pattern of ticaglasen N-acetyl-L-cysteine salt after being stored under accelerated conditions for 1 month and under light conditions for 10 days;

[0121] Figure 20 This is the XRPD pattern of tigolasen (R)-2-oxothiazolidine-4-carboxylate after being placed under accelerated conditions for 1 month and under light conditions for 10 days. DETAILED DESCRIPTION

[0122] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples.

[0123] The abbreviations used in the present invention are explained as follows:

[0124] XRPD: X-ray powder diffraction

[0125] DSC: Differential Scanning Calorimetry

[0126] MDSC: Modulated Differential Scanning Calorimetry

[0127] TGA: Thermogravimetric analysis

[0128] The experimental method used in the embodiment of the present invention is as follows:

[0129] X-ray powder diffraction (XRPD):

[0130] Instrument model: Bruker D8 Advance X-ray powder diffractometer; measurement conditions: Cu-Kα 40 kV 40 mA, divergence slit 1.0 mm, continuous scanning, LynxEye detector, step size: 0.02°, scanning speed: 6° / min, scanning range: 3-50°.

[0131] Thermogravimetric analysis (TGA):

[0132] A TGA Q500 thermogravimetric analyzer was used with a heating rate of 10°C / min over a temperature range from room temperature to 350°C. Nitrogen was used as the protective gas and the purge gas.

[0133] Differential Scanning Calorimetry (DSC):

[0134] A TA Instruments DSC Q2000 differential scanning calorimeter was used, with a standard crucible with a lid, a heating rate of 10°C / min, a temperature range of 30-300°C, and nitrogen as the protective gas and the purge gas.

[0135] Modulated Differential Scanning Calorimetry (MDSC):

[0136] A PerkinElmer DSC8000 differential scanning calorimeter was used with a standard crucible with a lid, a heating rate of 2°C / min, a modulation amplitude of ±1°C, a modulation period of 60s, a temperature range of 10-110°C, and nitrogen as the protective gas and purge gas.

[0137] Solubility test method:

[0138] Preparation of reference solution: Take an appropriate amount of ticagrelor, dissolve it with 50% acetonitrile solution by ultrasonication and quantitatively dilute it to prepare a 5 μg / mL solution as the reference solution.

[0139] Preparation of test solution: Weigh an appropriate amount of different ticagrelor acid addition salt samples, put them into a 10 mL centrifuge tube, add an appropriate amount of water, mix well, centrifuge (10000 rpm, 10 min), take the supernatant and dilute it with water, and take the diluted solution as the test solution.

[0140] Accurately measure 10 μL of each reference solution and test solution, inject into a HPLC instrument, and record the peak area. Calculate the solubility of the acid addition salt of tigolasen in water using the external standard method based on the tigolasen peak area.

[0141] High Performance Liquid Chromatography (HPLC):

[0142] Instrument model: Thermo UltiMate 3000; chromatographic column: Agilent ZORBAX Eclipse XDB-C18 (150 mm × 4.6 mm, 5 μm); flow rate: 0.8 mL / min; column temperature: 30°C; detection wavelength: 220 nm; gradient elution: mobile phase A: 0.01 M ammonium acetate solution-acetonitrile (95:5), mobile phase B: acetonitrile; elution gradient: 0 min, 95% A / 5% B→2 min, 95% A / 5% B→15 min, 50% A / 50% B→22 min, 20% A / 80% B→25 min, 5% A / 95% B→27 min, 5% A / 95% B→27.1 min, 95% A / 5% B→37 min, 95% A / 5% B, for a total of 37 minutes.

[0143] Example

[0144] The present invention is further illustrated by the following examples, but the invention is not limited to the scope of the examples. Experimental methods in the following examples, where specific conditions are not specified, were performed according to conventional methods and conditions, or according to the product specifications. Reagents and instruments used, where the manufacturer is not specified, are commercially available conventional products.

[0145] Tegolasen L-pyroglutamate was prepared according to the method disclosed in Example 1 of patent CN109769392A.

[0146] Preparation Example 1: Preparation method of tegrasen acid addition salt

[0147] 4 g of tegrasin free base was dissolved in 40 mL of methanol at room temperature, and acid (1.05 eq) was added thereto. The mixture was stirred at 20°C to 25°C for 0.5 to 1 hour until the reaction solution became clear. The reaction solution was then removed from all solvents under reduced pressure at 40°C. 16 mL of methyl tert-butyl ether was added to the concentrate at 20°C to 25°C, followed by slurrying at 20°C to 25°C for 0.5 to 1 hour. The mixture was then filtered under reduced pressure, and the filter cake was washed with 8 mL of methyl tert-butyl ether. The resulting solid was dried under vacuum at 40°C for 16 hours to obtain the acid addition salt of tegrasin.

[0148] (a) Tigolasen N-acetyl-trans-4-hydroxy-L-proline salt:

[0149]

[0150] 5.58 g of a white solid was obtained, which was in amorphous form. The X-ray powder diffraction (XRPD) spectrum was as follows: Figure 1 As shown, the DSC spectrum is Figure 2As shown, the MDSC spectrum is as follows Figure 3 As shown in the TGA spectrum Figure 4 As shown. Figure 2-3 It can be seen that the sample shows a sharp endothermic peak at about 74.07℃ on the DSC spectrum, and its glass transition temperature (Tg) is about 80.90℃. Figure 4 , about 1.3% weight loss was observed at 30-100 °C. 1 H NMR detection showed that in the N-acetyl-trans-4-hydroxy-L-proline salt of ticlopidine, the molar ratio of ticlopidine to N-acetyl-trans-4-hydroxy-L-proline was 1:1.

[0151] 1 H NMR (400MHz, D2O): δ7.26(d,1H),7.12(d,J=4.0Hz,1H),6.40-6.36(m,2H),5.60(s,1H),4.43(d,J=24.0Hz,1H),4.35-4.25(m,1H),4.16-4.1 3(d,J=4.0Hz,1H),3.73(s,1H),3.70-3.46(m,2H),3.04(s,3H),2.93( s,3H),2.55(s,3H),2.37-2.17(m,2H),2.12-1.97(m,4H),1.91(s,1H).

[0152] (b) Tigolasen N-acetyl-L-proline salt:

[0153]

[0154] 5.35 g of white powder was obtained, which was in amorphous form. The X-ray powder diffraction (XRPD) spectrum was as follows: Figure 5 Its DSC spectrum is shown as Figure 6 As shown in FIG, a sharp endothermic peak is shown at about 65.93°C, and the MDSC curve shows that the glass transition temperature (Tg) is about 43.28°C (as shown in FIG. Figure 7 The TGA spectrum of the amorphous form is shown as Figure 8 As shown, about 0.52% weight loss was observed at 30-50°C, about 0.64% weight loss was observed at 60-100°C, and about 0.69% weight loss was observed at 110-140°C. 1 H NMR detection showed that in the N-acetyl-L-proline salt of ticlopidine, the molar ratio of ticlopidine to N-acetyl-L-proline was 1:1.

[0155] 1H NMR (400MHz, D2O): δ7.24(s,1H),7.09(s,1H),6.37-6.33(t,2H),5.57(s,1H),4.25-4.20(m,1H),4.10(s,1H),3.77-3.74(d,1H),3.55-3.3 7(m,2H),3.04(s,3H),2.93(s,3H),2.52(d,J=4.0Hz,3H),2.24-2.15(t,2H),2.01(s,2H),1.95(s,1H),1.88(s,3H),1.79(d,J=4.0Hz,1H).

[0156] (c) Tigolasen N-acetyl-L-cysteine salt:

[0157]

[0158] 5.50 g of a white solid was obtained, which was in amorphous form. The X-ray powder diffraction (XRPD) spectrum was as follows: Figure 9 As shown, the DSC spectrum is Figure 10 As shown, the MDSC spectrum is as follows Figure 11 As shown in the TGA spectrum Figure 12 As shown. Figure 10-11 The sample shows a sharp endothermic peak at about 66.16°C on the DSC spectrum, and its glass transition temperature (Tg) is about 63.25°C. Figure 12 , about 1.0% weight loss was observed at 60-90°C. 1 H NMR detection showed that in the ticlopidine N-acetyl-L-cysteine salt, the molar ratio of ticlopidine to N-acetyl-L-cysteine was 1:1.

[0159] 1 H NMR (400MHz, D2O): δ7.24(s,1H),7.09(s,1H),6.32(s,2H),5.55(s,1H),4.33(t,J=8.0Hz,1H),4.11(d,J=8.0Hz,1H),3.80(s,1H), 3.03(s,3H),2.92(s,3H),2.83-2.82(d,J=4.0Hz,2H),2.53-2.52(d,J=4.0Hz,3H),2.18-2.15(d,J=12.0Hz,1H),1.97-1.94(m,4H).

[0160] (d) Tigoradine (R)-2-oxothiazolidine-4-carboxylate:

[0161]

[0162] 5.36 g of white solid was obtained, which was in amorphous form. The X-ray powder diffraction (XRPD) spectrum was as follows: Figure 13 As shown, the DSC spectrum is Figure 14 As shown, the MDSC spectrum is as follows Figure 15 As shown in the TGA spectrum Figure 16 As shown. Figure 14 The sample shows a sharp endothermic peak at about 79.12℃ and another endothermic peak at about 183.64℃. Figure 15 , its glass transition temperature (Tg) is about 83.44℃. Figure 16 , a weight loss of about 1.24% was observed at 30-100 °C. 1 H NMR detection showed that in the tigolasen (R)-2-oxothiazolidine-4-carboxylate, the molar ratio of tigolasen to (R)-2-oxothiazolidine-4-carboxylic acid was 1:1.

[0163] 1 H NMR (400MHz, D2O): δ7.28(d,J=4.0Hz,1H),7.14(s,1H),6.37-6.35(d,2H),5.62(s,1H),4.33-4.30(m,1H),4.16(s,1H),3.90( s,1H),3.67-3.65(t,1H),3.41-3.38(t,1H),3.04(s,3H),2.93(d,J=4.0Hz,3H),2.59-2.56(t,3H),2.18(s,1H),1.99(s,1H).

[0164] Preparation Comparative Example 1:

[0165] Tigolasan L-proline salt, tigolasan N-acetyl-L-valine salt, tigolasan N-acetyl-L-alanine salt and tigolasan N-acetyl-L-phenylalanine salt were prepared using the same method as the above preparation method.

[0166] Effect test example 1: solubility test

[0167] The solubility of the acid addition salts prepared in Preparation Example 1 and Comparative Example 1 was tested, and the results are shown in Table 1.

[0168] Table 1: Solubility of Tegolazen Acid Addition Salt

[0169]

[0170] As shown in Table 1, the solubility of ticagrelor was significantly improved when N-acetyl-L-proline was used to form an acid addition salt with ticagrelor compared to L-proline. Acid addition salts formed with other acetylated amino acids also significantly improved the solubility of ticagrelor. Among them, N-acetyl-L-proline salt, N-acetyl-trans-4-hydroxy-L-proline salt, and N-acetyl-L-cysteine salt all showed solubility >200 mg / mL, which is comparable to the solubility of L-pyroglutamate salt. (R)-2-oxothiazolidine-4-carboxylate also showed excellent solubility, which was also comparable to the solubility of L-pyroglutamate salt.

[0171] Effect test example 2: Liquid phase stability experiment

[0172] Five acid addition salts of ticlopidine (L-pyroglutamate, N-acetyl-L-proline, N-acetyl-trans-4-hydroxy-L-proline, N-acetyl-L-cysteine, and (R)-2-oxothiazolidine-4-carboxylate) were dissolved in purified water to a concentration of 20 mg / mL. The resulting solution was then shaken in a water bath shaker (37°C, 150 rpm) for 24 hours. The amount of degradation products produced was determined by HPLC at the initial stage and after 24 hours. The results are shown in Table 2.

[0173] Table 2: Liquid phase stability test results of tigolazine acid addition salt

[0174]

[0175]

[0176] The results of the liquid phase stability experiment showed that after storage at 37°C for 24 hours, the L-pyroglutamate, N-acetyl-L-proline, N-acetyl-trans-4-hydroxy-L-proline, N-acetyl-L-cysteine and (R)-2-oxothiazolidine-4-carboxylate salts of tigrasen maintained a homogeneous liquid phase state and had excellent stability. The content of degradation product B increased slightly, but was less than 0.3%; the content of degradation product C remained essentially unchanged.

[0177] Effect test example 3: solid phase stability experiment

[0178] The following stability tests were conducted on the acid addition salt of ticlopidine: (a) Accelerated stability: Samples of the acid addition salt of ticlopidine were placed in a double-layer PE bag, then sealed with an aluminum foil bag, and stored at 40±2°C / 75±5% RH for one month. (b) High-temperature stability: Samples of the acid addition salt of ticlopidine were placed in a sealed brown glass bottle and stored at 60°C for one month. (c) High-humidity stability: Samples of the acid addition salt of ticlopidine were placed in a transparent glass bottle and stored at 25°C and 90±5% RH for one month. The amount of degradation products produced in the samples was determined by HPLC at the initial stage and after one month.

[0179] Table 3: Solid phase stability test results of tigolazine acid addition salt

[0180]

[0181]

[0182] Note: “ND” means not detected.

[0183] The results showed that the stability of N-acetyl-L-proline and N-acetyl-trans-4-hydroxy-L-proline salts of tigrasen was superior to that of L-pyroglutamate, and they exhibited excellent stability under accelerated testing and high temperature and humidity conditions. L-pyroglutamate, N-acetyl-L-cysteine, and (R)-2-oxothiazolidine-4-carboxylate showed a slight increase in degradation product B under high temperature conditions, but still met the stability requirements.

[0184] Effect test example 4: photostability experiment

[0185] The sample of ticagrelor acid addition salt was placed in a PE bag, opened and placed in a light box equipped with a fluorescent lamp, and the light intensity was 5000 Lux under white light and 90 μw / cm 2 Under the conditions (total illumination is not less than 1.2×10 6 Lux·hr and 200W·hr / m 2 ) for 10 days, and the amount of degradation products produced by the samples at the beginning and after 10 days was determined by HPLC. The results are shown in Table 4.

[0186] Table 4: Results of photostability test of ticagrelor acid addition salt

[0187]

[0188] Note: “ND” means not detected.

[0189] The results showed that the L-pyroglutamate salt of ticagrelor had poor photostability. After 10 days of exposure to light, the content of ticagrelor decreased significantly, and an impurity (named Impurity A) greater than 1.0% appeared at RRT 0.96. Impurity A may be formed by N-demethylation of the amide bond of ticagrelor. However, the photostability of the N-acetyl-L-proline salt, N-acetyl-trans-4-hydroxy-L-proline salt, N-acetyl-L-cysteine salt, and (R)-2-oxothiazolidine-4-carboxylate salt of ticagrelor was significantly better than that of L-pyroglutamate.

[0190] Effect Test Example 5: Crystal Stability

[0191] X-ray powder diffraction (XRPD) analysis was performed on the acid addition salt of tigolaxan after being placed under accelerated test conditions (40±2°C / 75±5%RH) for one month and under light conditions for 10 days. The spectra are shown in FIG. Figures 17 to 20 As shown, the results showed that N-acetyl-L-proline salt, N-acetyl-trans-4-hydroxy-L-proline salt, N-acetyl-L-cysteine salt and (R)-2-oxothiazolidine-4-carboxylate salt of ticlopidine all maintained an amorphous form.

Claims

1. An acid addition salt of tegrassen, wherein the acid is N-acetyl-trans-4-hydroxy-L-proline, N-acetyl-L-proline, N-acetyl-L-cysteine or (R)-2-oxothiazolidine-4-carboxylic acid.

2. The acid addition salt of tegrasane according to claim 1, characterized in that It meets one of the following conditions: 1) The acid addition salt of ticlopidine is ticlopidine N-acetyl-trans-4-hydroxy-L-proline salt; 2) The acid addition salt of ticlopidine is ticlopidine N-acetyl-L-proline salt; 3) The acid addition salt of ticlopidine is ticlopidine N-acetyl-L-cysteine salt; 4) The acid addition salt of tegrassen is tegrassen (R)-2-oxothiazolidine-4-carboxylate.

3. The acid addition salt of tegrasane according to claim 2, characterized in that It meets one of the following conditions: 1) The N-acetyl-trans-4-hydroxy-L-proline salt of ticlopidine is: 2) The N-acetyl-L-proline salt of ticlopidine is: 3) The ticaglasane N-acetyl-L-cysteine salt is: 4) The (R)-2-oxothiazolidine-4-carboxylate of tigolasen is:

4. The acid addition salt of tegrasane according to claim 2, characterized in that It meets one of the following conditions: 1) The N-acetyl-trans-4-hydroxy-L-proline salt of ticlopidine is in a crystalline form; 2) the N-acetyl-L-proline salt of ticlopidine is in crystalline form; 3) the ticagrelsen N-acetyl-L-cysteine salt is in crystalline form; 4) the teigolan (R)-2-oxothiazolidine-4-carboxylate is in crystalline form; Or, it meets one of the following conditions: 1) The N-acetyl-trans-4-hydroxy-L-proline salt of ticlopidine is in an amorphous form; 2) the N-acetyl-L-proline salt of ticlopidine is in an amorphous form; 3) the N-acetyl-L-cysteine salt of ticlopidine is in an amorphous form; 4) The (R)-2-oxothiazolidine-4-carboxylate of tigolasen is in an amorphous form.

5. The acid addition salt of tegrasane according to claim 4, characterized in that It meets one or more of the following conditions: 1) The differential scanning calorimetry spectrum of the amorphous form of the N-acetyl-trans-4-hydroxy-L-proline salt of tigrasen shows an endothermic peak at 74.07±5° C.; 2) the amorphous form of the N-acetyl-trans-4-hydroxy-L-proline salt of ticlopidine exhibits a glass transition temperature of less than 100° C. as measured by modulated differential scanning calorimetry; for example, a glass transition temperature of 80.90±5° C.; 3) The differential scanning calorimetry spectrum of the amorphous form of the N-acetyl-L-proline salt of ticlopidine showed an endothermic peak at 65.93±5°C; 4) The amorphous form of the N-acetyl-L-proline salt of ticlopidine exhibits a glass transition temperature of less than 60° C. as measured by modulated differential scanning calorimetry; for example, a glass transition temperature of 43.28±5° C.; 5) The differential scanning calorimetry spectrum of the amorphous form of ticlopidine N-acetyl-L-cysteine salt shows an endothermic peak at 66.16±5°C; 6) The amorphous form of ticlopidine N-acetyl-L-cysteine salt exhibits a glass transition temperature of less than 80° C. as measured by modulated differential scanning calorimetry; for example, a glass transition temperature of 63.25±5° C.; 7) The differential scanning calorimetry spectrum of the amorphous form of the (R)-2-oxothiazolidine-4-carboxylate of tigolasen shows an endothermic peak at 79.12±5°C; for example, the differential scanning calorimetry spectrum of the (R)-2-oxothiazolidine-4-carboxylate of tigolasen shows endothermic peaks at 79.12±5°C and 183.64±5°C; 8) The amorphous form of ticoplasmin (R)-2-oxothiazolidine-4-carboxylate exhibits a glass transition temperature of less than 100°C as measured by modulated differential scanning calorimetry; for example, a glass transition temperature of 83.44±5°C.

6. The acid addition salt of tegrasane according to claim 4, characterized in that It meets one or more of the following conditions: 1) The XRPD spectrum of the amorphous form of ticagrelor N-acetyl-trans-4-hydroxy-L-proline salt is substantially consistent with FIG1 ; 2) The DSC spectrum of the amorphous form of ticagrelor N-acetyl-trans-4-hydroxy-L-proline salt is substantially consistent with FIG2 ; 3) The modulated differential scanning calorimetry analysis spectrum of the amorphous form of tigrasen N-acetyl-trans-4-hydroxy-L-proline salt is substantially consistent with FIG3 ; 4) The XRPD spectrum of the amorphous form of ticagrelor N-acetyl-L-proline salt is substantially consistent with FIG5 ; 5) The DSC spectrum of the amorphous form of ticaglasane N-acetyl-L-proline salt is substantially consistent with FIG6 ; 6) The modulated differential scanning calorimetry analysis spectrum of the amorphous form of ticlopidine N-acetyl-L-proline salt is substantially consistent with FIG7 ; 7) The XRPD spectrum of the amorphous form of ticagrelor N-acetyl-L-cysteine salt is substantially consistent with that shown in FIG9 ; 8) The DSC spectrum of the amorphous form of ticagrelor N-acetyl-L-cysteine salt is substantially consistent with FIG10 ; 9) The modulated differential scanning calorimetry analysis spectrum of the amorphous form of ticoplasmin N-acetyl-L-cysteine salt is substantially consistent with FIG11 ; 10) The XRPD spectrum of the amorphous form of (R)-2-oxothiazolidine-4-carboxylate of tigolasen is substantially consistent with that in FIG13 ; 11) The DSC spectrum of the amorphous form of (R)-2-oxothiazolidine-4-carboxylate of tigolasen is substantially consistent with that in FIG14 ; 12) The modulated differential scanning calorimetry spectrum of the amorphous form of ticoplasmin (R)-2-oxothiazolidine-4-carboxylate is substantially consistent with that in FIG15 .

7. A method for preparing the acid addition salt of ticaglassen according to any one of claims 1 to 6, comprising the following steps: (a) dissolving ticlopidine and an acid in an organic solvent at a certain temperature; the acid is one of N-acetyl-trans-4-hydroxy-L-proline, N-acetyl-L-proline, N-acetyl-L-cysteine, or (R)-2-oxothiazolidine-4-carboxylic acid; (b) concentrating the solution obtained in step (a) to remove the organic solvent, and then adding a slurrying solvent and stirring the resultant; and (c) isolating and drying the precipitated solid.

8. The method for preparing the acid addition salt of ticagrelor according to claim 7, wherein: It meets one or more of the following conditions: 1) In step (a), tigolaxan and an acid are mixed simultaneously with an organic solvent and stirred until completely dissolved, or tigolaxan is mixed with the organic solvent and then an acid is added and stirred until completely dissolved; 2) In step (a), the temperature is 10°C to 40°C, preferably 15°C to 35°C, more preferably 20°C to 30°C, and further preferably 20°C to 25°C; 3) In step (a), the organic solvent is selected from one or more of alcohols, ketones and nitriles, preferably alcohols, more preferably C1-C4 lower linear alcohols or branched alcohols, further preferably selected from one or more of methanol, ethanol and isopropanol, and further preferably methanol; 4) In step (a), the volume-to-weight ratio of the organic solvent to ticlopidine is 5 mL / g to 25 mL / g, preferably 8 mL / g to 20 mL / g, more preferably 10 mL / g to 15 mL / g, and even more preferably 10 mL / g; 5) In step (b), the concentration is atmospheric distillation and reduced pressure distillation, preferably reduced pressure distillation; 6) In step (b), the temperature during the concentration is 30°C to 55°C, preferably 35°C to 50°C, more preferably 40°C to 45°C, and further preferably 40°C; 7) In step (b), the removal of the organic solvent is to remove all or substantially all of the organic solvent; 8) In step (b), the pulping solvent is selected from one or more of ethers, esters and alkanes, preferably ethers, more preferably C1-C4 lower alkyl ethers, further preferably one or more of diethyl ether, methyl tert-butyl ether and isopropyl ether, further preferably methyl tert-butyl ether; 9) In step (b), the volume-to-weight ratio of the slurry solvent to ticlopidine is 2 mL / g to 15 mL / g, preferably 3 mL / g to 10 mL / g, more preferably 4 mL / g to 6 mL / g, and even more preferably 4 mL / g; 10) In step (b), the temperature during beating is 10°C to 40°C, preferably 15°C to 35°C, more preferably 20°C to 30°C, and further preferably 20°C to 25°C; 11) In step (c), the separation is performed by vacuum filtration or suction filtration, preferably vacuum filtration; 12) In step (c), the drying is oven drying or drying under reduced pressure, preferably drying under reduced pressure; 13) In step (c), the drying temperature is 30°C to 50°C, preferably 35°C to 45°C, more preferably 40°C to 45°C, and further preferably 40°C.

9. A pharmaceutical composition comprising the acid addition salt of tegrassen according to any one of claims 1 to 6, and a pharmaceutically acceptable carrier.

10. Use of the acid addition salt of ticlopidine according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 9 in the preparation of a medicament for preventing and / or treating a disease mediated by acid pump antagonist activity; the disease mediated by acid pump antagonist activity is gastroesophageal disease, gastroesophageal reflux disease, peptic ulcer, gastric ulcer, duodenal ulcer, nonsteroidal anti-inflammatory drug-induced ulcer, gastritis, Helicobacter pylori infection, dyspepsia, functional dyspepsia, Zollinger-Ellison syndrome, non-erosive reflux disease, heartburn, nausea, esophagitis, dysphagia, drooling, airway obstruction or asthma; for example, gastroesophageal reflux disease, peptic ulcer, gastric ulcer, duodenal ulcer or Helicobacter pylori infection.

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