Salts of pyrrolizine compounds and uses thereof

Abstract

The application provides a salt of a compound shown in formula I, a solid form, a crystalline form and a crystal form of the salt, a pharmaceutical composition containing the salt and the use of the salt, preferably the salt is convenient for purification and separation, the crystal form has good crystallinity, stability and solubility, and meets the requirements of hygroscopicity, and has good drug-making potential.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to salts of pyrrolidine compounds, their crystal forms, pharmaceutical compositions containing them, and their uses. Background Technology

[0002] Dipeptidyl peptidase IV (DPP-4) is a type II transmembrane glycoprotein with serine protease activity. It degrades proline or glycine residues at the second residue of the N-terminus of a peptide chain to produce an N-terminal dipeptide. DPP-4 plays a role in glucose metabolism by degrading and inactivating the N-terminus of glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP). DPP-4 inhibitors reduce the inactivation of GLP-1 in vivo by inhibiting DPP-4, thereby increasing insulin secretion in a glucose concentration-dependent manner and inhibiting glucagon secretion.

[0003] Compound I (structural formula below) is a DPP-4 inhibitor that can be used to treat type II diabetes. Patent CN101970402B discloses a series of pyrrolidine compounds (including compound I) and their preparation methods, and describes the pharmaceutically acceptable salts of pyrrolidine compounds; Jiang Guoyou et al. [Chinese Journal of New Drugs, 2016, Vol. 25, No. 13, pp. 1531-1534] explored a new synthetic route for compound I, and the salt form of compound I has not been disclosed in the prior art.

[0004] Summary of the Invention

[0005] The inventors of this invention conducted the first study on the salt of compound I and discovered a salt form that can be used as an active pharmaceutical ingredient and for subsequent formulation processing.

[0006] On the one hand, the present invention provides salts of the compounds shown in Formula I,

[0007]

[0008] The salt is selected from hydrobromide, p-toluenesulfonate, fumarate and hydrochloride; preferably hydrobromide, p-toluenesulfonate and fumarate; more preferably hydrobromide and p-toluenesulfonate; and even more preferably p-toluenesulfonate.

[0009] In some embodiments of the present invention, in the salt of the compound represented by Formula I, the chemical ratio of the compound represented by Formula I to the acid molecule is 1:m, wherein m is selected from 0.5-4 (integer or half-integer); preferably, m is selected from 0.5, 1, 1.5, 2, 2.5 or 3; more preferably, m is 1.

[0010] Secondly, the present invention provides a compound represented by Formula II.

[0011]

[0012] Wherein, X is an acid selected from p-toluenesulfonic acid, hydrobromic acid, fumaric acid, and hydrochloric acid; preferably hydrobromic acid, p-toluenesulfonic acid, or fumaric acid; more preferably hydrobromic acid or p-toluenesulfonic acid; and even more preferably p-toluenesulfonic acid.

[0013] n is an integer or half-integer from 1 / 2 to 4; more preferably 0.5, 1, 1.5, 2, 2.5 or 3; more preferably 1.

[0014] In some embodiments of the present invention, the salt of the compound represented by Formula I or the compound represented by Formula II is in solid form.

[0015] In some embodiments of the present invention, the salt of the compound represented by Formula I or the compound represented by Formula II is in crystalline form.

[0016] In some embodiments of the present invention, the compound represented by Formula II, wherein X is p-toluenesulfonic acid, and n is 0.5, 1, 1.5, 2, 2.5 or 3; preferably 1.

[0017] In some embodiments of the present invention, the compound represented by Formula II is a compound represented by Formula II-1:

[0018]

[0019] In some embodiments of the present invention, the compound represented by Formula II-1 is in solid form.

[0020] In some embodiments of the present invention, the compound represented by Formula II-1 is in crystalline form.

[0021] In some embodiments of the present invention, the crystalline form of the compound represented by Formula II-1, which is crystal form A, has a characteristic diffraction peak (±0.2°) at the following 2θ angles when subjected to Cu-Kα radiation: 6.7, 17.5, 21.2.

[0022] In some embodiments of the present invention, the crystal form A, using Cu-Kα radiation, has an X-ray powder diffraction pattern with characteristic diffraction peaks (±0.2°) at the following 2θ angles: 6.7, 17.5, 18.2, 19.5, 21.2.

[0023] In some embodiments of the present invention, the crystal form A, using Cu-Kα radiation, has an X-ray powder diffraction pattern with characteristic diffraction peaks (±0.2°) at the following 2θ angles: 6.7, 8.5, 13.4, 17.5, 18.2, 19.5, 21.2.

[0024] In some embodiments of the present invention, the crystal form A, using Cu-Kα radiation, has an X-ray powder diffraction pattern with characteristic diffraction peaks (±0.2°) at the following 2θ angles: 6.7, 8.5, 9.2, 11.6, 13.4, 17.5, 18.2, 19.5, 21.2.

[0025] In some embodiments of the present invention, the crystal form A, using Cu-Kα radiation, has an X-ray powder diffraction pattern with characteristic diffraction peaks (±0.2°) at the following 2θ angles: 6.7, 8.5, 9.2, 11.6, 13.4, 17.5, 18.2, 19.5, 21.2, 22.5, 24.3.

[0026] In some embodiments of the present invention, the crystal form A, using Cu-Kα radiation, has an X-ray powder diffraction pattern with characteristic diffraction peaks (±0.2°) at the following 2θ angles: 6.7, 8.5, 9.2, 11.6, 13.4, 17.5, 18.2, 18.6, 19.5, 21.2, 22.5, 24.3.

[0027] In some embodiments of the present invention, crystal form A, using Cu-Kα radiation, has substantially the following properties: Figure 1 The X-ray powder diffraction pattern shown is shown.

[0028] In some embodiments of the present invention, the differential scanning calorimetry curve of crystal form A has an endothermic peak at 203±5℃.

[0029] In some embodiments of the present invention, crystal form A has substantially the following characteristics: Figure 2 The DSC spectrum shown.

[0030] In some embodiments of the present invention, the thermogravimetric analysis curve of crystal form A shows that it begins to lose weight at 210±5℃.

[0031] In some embodiments of the present invention, crystal form A has substantially the following characteristics: Figure 2 The TGA spectrum shown.

[0032] In some embodiments of the present invention, the compound represented by Formula II, wherein X is hydrobromic acid, and n is 0.5, 1, 1.5, 2, 2.5 or 3; more preferably 1.

[0033] In some embodiments of the present invention, the compound represented by Formula II is a compound represented by Formula II-2:

[0034]

[0035] In some embodiments of the present invention, the compound represented by Formula II-2 is in solid form.

[0036] In some embodiments of the present invention, the compound represented by Formula II-2 is in crystalline form.

[0037] In some embodiments of the present invention, the crystalline form of the compound represented by formula II-2, which is crystal form 1, has a characteristic diffraction peak (±0.2°) at the following 2θ angles when subjected to Cu-Kα radiation: 5.3, 14.2, 16.2, 21.7, 24.5.

[0038] In some embodiments of the present invention, the crystal form 1, using Cu-Kα radiation, has an X-ray powder diffraction pattern with characteristic diffraction peaks (±0.2°) at the following 2θ angles: 5.3, 14.2, 16.2, 21.7, 24.5, 27.2.

[0039] In some embodiments of the present invention, the crystal form 1, using Cu-Kα radiation, has an X-ray powder diffraction pattern with characteristic diffraction peaks (±0.2°) at the following 2θ angles: 5.3, 8.1, 14.2, 16.2, 21.7, 24.5, 25.1, 27.2.

[0040] In some embodiments of the present invention, the crystal form 1, using Cu-Kα radiation, has an X-ray powder diffraction pattern with characteristic diffraction peaks (±0.2°) at the following 2θ angles: 5.3, 8.1, 14.2, 16.2, 16.6, 17.7, 21.7, 24.5, 25.1, 27.2.

[0041] In some embodiments of the present invention, the crystal form 1, using Cu-Kα radiation, has an X-ray powder diffraction pattern with characteristic diffraction peaks (±0.2°) at the following 2θ angles: 5.3, 8.1, 14.2, 16.2, 16.6, 17.7, 18.9, 21.7, 24.5, 25.1, 26.1, 27.2.

[0042] In some embodiments of the present invention, the crystal form 1, using Cu-Kα radiation, has an X-ray powder diffraction pattern with characteristic diffraction peaks (±0.2°) at the following 2θ angles: 5.3, 8.1, 14.2, 16.2, 16.6, 17.7, 18.9, 21.7, 22.5, 24.5, 25.1, 26.1, 27.2, 28.6.

[0043] In some embodiments of the present invention, the crystal form 1, using Cu-Kα radiation, has an X-ray powder diffraction pattern with characteristic diffraction peaks (±0.2°) at the following 2θ angles: 5.3, 8.1, 14.2, 15.1, 16.2, 16.6, 17.7, 18.9, 21.7, 22.5, 24.5, 25.1, 26.1, 27.2, 28.6.

[0044] In some embodiments of the present invention, the crystal form 1, using Cu-Kα radiation, has an X-ray powder diffraction pattern with characteristic diffraction peaks (±0.2°) at the following 2θ angles: 5.3, 8.1, 14.2, 15.1, 16.2, 16.6, 17.7, 18.5, 18.9, 21.3, 21.7, 22.5, 24.5, 25.1, 26.1, 27.2, 28.6.

[0045] In some embodiments of the present invention, the crystal form 1, using Cu-Kα radiation, has an X-ray powder diffraction pattern with characteristic diffraction peaks (±0.2°) at the following 2θ angles: 5.3, 8.1, 14.2, 15.1, 16.2, 16.6, 17.7, 18.5, 18.9, 21.3, 21.7, 22.5, 24.5, 25.1, 26.1, 27.2, 28.6, 38.5.

[0046] In some embodiments of the present invention, crystal form 1, using Cu-Kα radiation, has substantially the following properties: Figure 3 The X-ray powder diffraction pattern shown is shown.

[0047] In some embodiments of the present invention, the differential scanning calorimetry curve of crystal form 1 has an endothermic peak at 146±5℃.

[0048] In some embodiments of the present invention, the differential scanning calorimetry curve of crystal form 1 has an endothermic peak at 209.2±5℃.

[0049] In some embodiments of the present invention, the differential scanning calorimetry curve of crystal form 1 has endothermic peaks at 76±5℃ and 209.2±5℃.

[0050] In some embodiments of the present invention, the differential scanning calorimetry (DSC) curve of crystal form 1 exhibits endothermic peaks at 76±5℃, 96±5℃, 146±5℃, and 206±5℃. In some embodiments of the present invention, the thermogravimetric analysis (TGA) curve of crystal form 1 shows a weight loss of 11.1% ± 0.2% between room temperature and 100±5℃.

[0051] In some embodiments of the present invention, the thermogravimetric analysis curve of crystal form 1 shows that it begins to lose weight at 215±5℃.

[0052] In some embodiments of the present invention, the compound represented by Formula II, wherein X is a fumarate and n is 0.5, 1, 1.5, 2, 2.5 or 3; more preferably 1.

[0053] In some embodiments of the present invention, the compound represented by Formula II is a compound represented by Formula II-3:

[0054]

[0055] In some embodiments of the present invention, the compound represented by formula II-3 is in solid form.

[0056] In some embodiments of the present invention, the compound represented by Formula II-3 is in crystalline form.

[0057] In some embodiments of the present invention, the crystalline form of the compound of formula II-3, which is crystal form A, has a characteristic diffraction peak (±0.2°) at the following 2θ angles when subjected to Cu-Kα radiation: 8.3, 16.6, 19.1, 25.9.

[0058] In some embodiments of the present invention, the crystal form A of the compound shown in Formula II-3, when subjected to Cu-Kα radiation, has a characteristic diffraction peak (±0.2°) at the following 2θ angles in its X-ray powder diffraction pattern: 8.3, 15.1, 16.6, 19.1, 24.4, 25.9.

[0059] In some embodiments of the present invention, the crystal form A of the compound shown in Formula II-3, when subjected to Cu-Kα radiation, has a characteristic diffraction peak (±0.2°) at the following 2θ angles in its X-ray powder diffraction pattern: 8.3, 15.1, 16.6, 18.6, 19.1, 21.8, 24.4, 25.9.

[0060] In some embodiments of the present invention, the crystal form A of the compound shown in Formula II-3, when subjected to Cu-Kα radiation, has a characteristic diffraction peak (±0.2°) at the following 2θ angles in its X-ray powder diffraction pattern: 8.3, 15.1, 15.6, 16.6, 18.6, 19.1, 21.8, 24.4, 25.0, 25.9.

[0061] In some embodiments of the present invention, the crystal form A of the compound represented by Formula II-3, when subjected to Cu-Kα radiation, has a characteristic diffraction peak (±0.2°) at the following 2θ angles in its X-ray powder diffraction pattern: 8.3, 12.9, 15.1, 15.6, 16.6, 18.6, 19.1, 21.8, 22.4, 22.7, 24.4, 25.0, 25.9.

[0062] In some embodiments of the present invention, the crystal form A of the compound represented by Formula II-3, when subjected to Cu-Kα radiation, has a characteristic diffraction peak (±0.2°) at the following 2θ angles in its X-ray powder diffraction pattern: 4.7, 8.3, 12.9, 15.1, 15.6, 16.6, 18.6, 19.1, 19.9, 21.8, 22.4, 22.7, 24.4, 25.0, 25.9.

[0063] In some embodiments of the present invention, the crystal form A of the compound represented by formula II-3, when subjected to Cu-Kα irradiation, has substantially the following properties: Figure 4 The X-ray powder diffraction pattern shown is shown.

[0064] In some embodiments of the present invention, the crystal form A of the compound represented by Formula II-3 has an endothermic peak at 119±5℃ in its differential scanning calorimetry curve.

[0065] In some embodiments of the present invention, the crystal form A of the compound represented by Formula II-3 has endothermic peaks at 72±5℃ and 119±5℃ in its differential scanning calorimetry curve.

[0066] In some embodiments of the present invention, the crystal form A of the compound represented by Formula II-3 has a thermogravimetric analysis curve showing a weight loss of 6.8% ± 0.2% between room temperature and 150 ± 5 °C.

[0067] In some embodiments of the present invention, the crystal form A of the compound represented by Formula II-3 shows that its thermogravimetric analysis curve begins to lose weight at 170±5℃.

[0068] In some embodiments of the present invention, the compound represented by Formula II, wherein X is hydrochloric acid, and n is 0.5, 1, 1.5, 2, 2.5 or 3; more preferably 1.

[0069] In some embodiments of the present invention, the compound represented by Formula II is a compound represented by Formula II-4:

[0070]

[0071] In some embodiments of the present invention, the compound represented by formula II-4 is in solid form.

[0072] In some embodiments of the present invention, the compound represented by Formula II-4 is in crystalline form.

[0073] In some embodiments of the present invention, the crystalline form of the compound of formula II-4, which is crystal form 1, has a characteristic diffraction peak (±0.2°) at the following 2θ angles when subjected to Cu-Kα radiation: 14.3, 16.3, 24.5.

[0074] In some embodiments of the present invention, the crystal form 1 of the compound shown in Formula II-4, when subjected to Cu-Kα radiation, has a characteristic diffraction peak (±0.2°) at the following 2θ angles in its X-ray powder diffraction pattern: 8.1, 14.3, 16.3, 19.1, 24.5.

[0075] In some embodiments of the present invention, the crystal form 1 of the compound shown in Formula II-4, when subjected to Cu-Kα radiation, has a characteristic diffraction peak (±0.2°) at the following 2θ angles in its X-ray powder diffraction pattern: 8.1, 10.9, 14.3, 16.3, 19.1, 24.5, 26.4.

[0076] In some embodiments of the present invention, the crystal form 1 of the compound shown in Formula II-4, when subjected to Cu-Kα radiation, has a characteristic diffraction peak (±0.2°) at the following 2θ angles in its X-ray powder diffraction pattern: 8.1, 10.9, 14.3, 16.3, 19.1, 22.8, 24.5, 26.4, 28.9.

[0077] In some embodiments of the present invention, the crystal form 1 of the compound shown in Formula II-4, when subjected to Cu-Kα radiation, has a characteristic diffraction peak (±0.2°) at the following 2θ angles in its X-ray powder diffraction pattern: 8.1, 10.9, 14.3, 16.3, 19.1, 21.4, 21.9, 22.8, 24.5, 26.4, 28.9.

[0078] In some embodiments of the present invention, the crystal form 1 of the compound shown in Formula II-4, when subjected to Cu-Kα irradiation, has substantially the following properties: Figure 5 The X-ray powder diffraction pattern shown is shown.

[0079] In some embodiments of the present invention, the crystal form 1 of the compound shown in Formula II-4 has an endothermic peak at 77±5℃ in its differential scanning calorimetry curve.

[0080] In some embodiments of the present invention, the crystal form 1 of the compound shown in Formula II-4 has a thermogravimetric analysis curve showing a weight loss of 11.6% ± 0.2% between room temperature and 100 ± 5 °C.

[0081] In some embodiments of the present invention, the crystal form 1 of the compound shown in Formula II-4 begins to lose weight at 200±5℃ according to its thermogravimetric analysis curve.

[0082] Thirdly, the present invention provides a crystalline composition comprising crystal form A of the compound shown in Formula II-1 above.

[0083] Fourthly, the present invention provides a crystalline composition comprising crystal form 1 of the compound shown in Formula II-2 above.

[0084] Fifthly, the present invention provides a crystalline composition comprising crystal form A of the compound shown in Formula II-3 above.

[0085] In a sixth aspect, the present invention provides a crystalline composition comprising crystal form 1 of the compound shown in Formula II-4 above.

[0086] In a seventh aspect, the present invention provides a pharmaceutical composition comprising a salt of the compound shown in Formula I, a compound shown in Formula II, a compound shown in Formula II-1, a compound shown in Formula II-2, a compound shown in Formula II-3, or a compound shown in Formula II-4. Optionally, the pharmaceutical composition further comprises other therapeutic components, which are other active ingredients or drugs for diabetes, such as insulin, metformin or pharmaceutically acceptable salts thereof, sulfonylureas, and / or thiazolidinediones, preferably metformin or pharmaceutically acceptable salts thereof, more preferably metformin hydrochloride. Preferably, the other therapeutic components are synergistic with the compound shown in Formula I. Optionally, the salt of the compound shown in Formula I or the compound shown in Formula II is administered in a single formulation or a combination formulation with other therapeutic components.

[0087] In an eighth aspect, the present invention provides a pharmaceutical composition comprising a salt of a compound of Formula I, in solid or crystalline form thereof, or a compound of Formula II, in solid or crystalline form thereof, optionally further comprising one or more pharmaceutically acceptable carriers.

[0088] In some embodiments of the present invention, the pharmaceutical composition comprises the compound shown in Formula II-1, its solid form, its crystalline form or its crystal form A, or the aforementioned (third aspect) crystalline composition, optionally further comprising one or more pharmaceutically acceptable carriers.

[0089] In some embodiments of the present invention, the pharmaceutical composition comprises the compound shown in Formula II-2, its solid form, its crystalline form or its crystal form 1, or the aforementioned (fourth aspect) crystalline composition, optionally further comprising one or more pharmaceutically acceptable carriers.

[0090] In some embodiments of the present invention, the pharmaceutical composition comprises the compound shown in Formula II-3 above, its solid form, its crystalline form or its crystal form A, or the aforementioned (fifth aspect) crystalline composition, optionally further comprising one or more pharmaceutically acceptable carriers.

[0091] In some embodiments of the present invention, the pharmaceutical composition comprises the compound represented by Formula II-4, its solid form, its crystalline form or its crystal form 1, or the aforementioned (sixth aspect) crystalline composition, optionally further comprising one or more pharmaceutically acceptable carriers.

[0092] In some embodiments of the present invention, the pharmaceutical compositions described above (seventh aspect, eighth aspect) are formulated into clinically acceptable preparations, such as oral preparations, injectable preparations, topical preparations, and excipient preparations. The oral preparations are preferably solid preparations, such as tablets, capsules, granules, etc. These preparations can be prepared using excipients including fillers, lubricants, disintegrants, binders, coating materials, etc., employing conventional pharmaceutical preparation techniques. For example, the pharmaceutical carrier may include fillers, disintegrants, and lubricants, and optionally, further include a binder; the pharmaceutical composition can be formulated into tablets or capsules. The filler comprises one or more of microcrystalline cellulose, lactose, calcium salts (e.g., calcium carbonate, calcium sulfate, calcium phosphate, calcium hydrogen phosphate, etc.), starches (e.g., pregelatinized starch, dry starch, etc.), powdered sugar, or dextrin; the lubricant comprises one or more of stearic acid, magnesium stearate, calcium stearate, hydrogenated vegetable oil, talc, colloidal silica, silica, sodium stearoyl fumarate, magnesium stearoyl fumarate, or polyethylene glycol; the disintegrant comprises celluloses (e.g., carboxymethyl cellulose, packaged cellulose, methyl cellulose). The adhesive comprises one or more of the following: low-substituted hydroxypropyl cellulose, potassium polacolin, sodium alginate, sodium starch glycolate, polyvinylpyrrolidone, corn starch, pregelatinized starch, crospovidone, sodium carboxymethyl starch, or sodium crospovidone carboxymethyl cellulose; the adhesive comprises one or more of the following: starch paste, copovidone, cellulose derivatives (e.g., methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethylcellulose, or sodium carboxymethyl cellulose), powdered sugar, syrup, polyvinylpyrrolidone, glue, polyethylene glycol 4000, and dextrin.

[0093] In some embodiments of the present invention, the pharmaceutical composition or clinically accepted formulation comprises 0.01 to 1000 mg, preferably 0.1 to 800 mg, preferably 1 to 500 mg, preferably 5 to 300 mg, preferably 25 to 200 mg, more preferably 50 to 100 mg of a salt of a compound of formula I or a compound of formula II, based on the compound of formula I.

[0094] In a ninth aspect, the present invention provides the use of the salt of the compound shown in Formula I, and the solid or crystalline form thereof, the compound shown in Formula II, and the solid or crystalline form thereof, the compound shown in Formula II-1, the solid form, the crystalline form thereof and its crystal form A, the compound shown in Formula II-2, the solid form, the crystalline form thereof and its crystal form 1, the compound shown in Formula II-3, the solid form, the crystalline form thereof and its crystal form A, the compound shown in Formula II-4, the solid form, the crystalline form thereof and its crystal form 1, the aforementioned (third, fourth, fifth, and sixth aspects) crystalline compositions or the aforementioned (seventh and eighth aspects) pharmaceutical compositions as pharmaceuticals or in the preparation of pharmaceuticals.

[0095] In some embodiments of the present invention, the drug is used to treat and / or prevent diabetes, preferably type II diabetes.

[0096] In a tenth aspect, the present invention also provides salts of compounds of formula I, and their solid or crystalline forms; compounds of formula II, and their solid or crystalline forms; compounds of formula II-1, their solid or crystalline forms and crystal form A; compounds of formula II-2, their solid or crystalline forms and crystal form 1; compounds of formula II-3, their solid or crystalline forms and crystal form A; compounds of formula II-4, their solid or crystalline forms and crystal form 1; the aforementioned (third, fourth, fifth, and sixth aspects) crystalline compositions or the aforementioned (seventh and eighth aspects) pharmaceutical compositions, for the treatment and / or prevention of diabetes, preferably type II diabetes.

[0097] In some embodiments of the present invention, the above-described application is wherein the therapeutically effective amount of the salt of the compound shown in Formula I or the compound shown in Formula II is 1 to 500 mg, preferably 10 to 300 mg, preferably 25 to 200 mg, preferably 50 to 150 mg, more preferably 100 mg, based on the compound shown in Formula I.

[0098] Eleventhly, the present invention provides a method for preparing the compound of formula II, comprising reacting the compound of formula I with an acid in a solvent to separate and obtain the compound of formula II:

[0099]

[0100] in,

[0101] X is an acid; preferably p-toluenesulfonic acid, hydrobromic acid, fumaric acid, hydrochloric acid, maleic acid, phosphoric acid, L-camphorsulfonic acid, succinic acid, citric acid, glycolic acid, sulfuric acid, methanesulfonic acid, L-malic acid, or oxalic acid; more preferably p-toluenesulfonic acid, hydrobromic acid, fumaric acid, hydrochloric acid, maleic acid, sulfuric acid, methanesulfonic acid, L-malic acid, or oxalic acid; further preferably p-toluenesulfonic acid, hydrobromic acid, fumaric acid, or hydrochloric acid; further preferably hydrobromic acid, p-toluenesulfonic acid, or fumaric acid; further preferably hydrobromic acid and p-toluenesulfonic acid; even more preferably p-toluenesulfonic acid;

[0102] n is an integer or half-integer from 1 / 2 to 4; more preferably 0.5, 1, 1.5, 2, 2.5 or 3; more preferably 1.

[0103] According to the preparation method of the present invention, the molar ratio of the compound represented by Formula I to the acid is 1-4:0.5-4, preferably 1-2:0.5-2, and more preferably 1:0.6-1.1.

[0104] According to the preparation method of the present invention, the reaction temperature is 0-70℃, preferably 5-60℃, and more preferably room temperature-50℃.

[0105] According to the preparation method of the present invention, the reaction solvent is selected from one or a combination of two of alcohols, esters, nitriles, ketones, water, ethers, or heterocyclic alkane solvents; preferably, it is selected from one or a combination of two of ROH, RCOOR1, RCN, RCOOR1, R(OR1)2, ROR1, water, or heterocyclic alkane solvents, wherein R and R1 are each independently selected from C 1-6 Straight-chain or branched alkyl groups; preferably, R and R1 are each independently selected from C1. 1-4 The reaction solvent is a straight-chain or branched alkyl group; preferably, the reaction solvent is selected from one or a combination of two of methanol, ethanol, isopropanol, ethyl acetate, acetone, butanone, 4-methyl-2-pentanone, ethylene glycol dimethyl ether, acetonitrile, water or tetrahydrofuran; when it is a mixed solvent composed of two solvents, the volume ratio of the two solvents is 1-10:10-1, preferably 1-5:5-1, and more preferably 1-3:3-1.

[0106] According to the preparation method of the present invention, the reaction time is 0.1 h to 5 days; preferably 0.5 h to 4 days; more preferably 0.5 h to 2 days; more preferably 1 h to 2 days; and more preferably 1 day to 2 days.

[0107] According to the preparation method of the present invention, after the reaction is completed, crystallization is carried out at -20 to 30°C for 0.5 to 48 hours. The solid is separated, dried, and the compound represented by Formula II is obtained. Preferably, the crystallization temperature is -15 to 30°C. Preferably, the crystallization temperature is 0 to 30°C. Preferably, the crystallization temperature is room temperature, and the crystallization time is 1 to 24 hours.

[0108] According to the preparation method of the present invention, after the reaction is completed, the temperature is lowered to 0-30°C, and the mixture is allowed to stand for crystallization for 0.5-48 hours. The solid is then separated, dried, and the compound represented by Formula II is obtained. Preferably, the crystallization temperature is room temperature, and the crystallization time is 1-24 hours.

[0109] According to the preparation method of the present invention, the separation step includes using suitable methods such as vacuum filtration, filtration, and centrifugation to separate the compound represented by Formula II from the crystallization liquid.

[0110] According to the preparation method of the present invention, the drying method can be any suitable known method, preferably drying at room temperature to 80°C, more preferably drying at room temperature to 50°C. Specific drying conditions include, for example, a drying time preferably of 1 to 50 hours, more preferably 3 to 24 hours, and even more preferably 5 to 18 hours. Regardless of the drying method used, it is preferable that the residual solvent content in the resulting product meets the quality standards.

[0111] Definitions and Explanations

[0112] Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense.

[0113] The terms "salt of the compound shown in Formula I in solid form or compound shown in Formula II in solid form", "compound shown in Formula II-1 in solid form" or "compound shown in Formula II-2 in solid form" mentioned in this invention refer to salts of the compound shown in Formula I in solid form, compounds shown in Formula II in solid form, etc., including crystalline or amorphous forms of salts of the compound shown in Formula I, compounds shown in Formula II, etc.

[0114] The terms "salt of the compound shown in Formula I or compound shown in Formula II in crystalline form", "compound shown in Formula II-1 in crystalline form", or "compound shown in Formula II-2 in crystalline form" mentioned in this invention refer to salts of the compound shown in Formula I and compounds shown in Formula II that are crystalline in form after characterization (e.g., polarized light microscopy characterization or X-ray powder diffraction characterization), including anhydrous and solvent-free forms, hydrate forms, solvate forms and eutectic forms of salts of the compound shown in Formula I and compounds shown in Formula II.

[0115] The term "solvent" or "solvent compound" refers to an assemblage formed by stoichiometric or non-stoichiometric solvent molecules with a salt of the compound shown in Formula I, the compound shown in Formula II, the compound shown in Formula II-1, the compound shown in Formula II-2, etc. of the present invention, including assemblages containing both water molecules and one or more other solvent molecules, and assemblages containing only one or more other solvent molecules.

[0116] The term "hydrate" refers to an assemblage formed by stoichiometric or non-stoichiometric water molecules with salts of compounds of Formula I, compounds of Formula II, compounds of Formula II-1, compounds of Formula II-2, etc.

[0117] The term "anhydrous and solvent-free form" refers to a form that does not contain water or solvent molecules, or where water or solvent molecules coexist with the salt of the compound shown in Formula I, the compound shown in Formula II, the compound shown in Formula II-1, the compound shown in Formula II-2, etc., in a manner not bound by intermolecular forces, such as through adsorption.

[0118] The term "crystalline composition" refers to a solid form comprising one or more specific crystal forms of the compounds mentioned in this invention (salts of compounds represented by Formula I, compounds represented by Formula II, compounds represented by Formula II-1, compounds represented by Formula II-2, etc.). For example, in one embodiment of this invention, it comprises crystal form A of the compound represented by Formula II-1 mentioned in this invention. Furthermore, in addition to the crystal forms of this invention, the crystalline composition may optionally contain other crystalline forms, other crystal forms, or other amorphous forms of the compound of Formula II-1, or impurities other than these substances. Those skilled in the art will understand that the sum of the contents of all components in the crystalline composition should be 100%.

[0119] The "room temperature" referred to here is the room temperature in the conventional sense of the art, generally 10 to 35°C, preferably 10 to 30°C, and more preferably 25°C ± 5°C.

[0120] In the context of this invention, the 2θ values ​​in X-ray powder diffraction patterns are all in degrees (°).

[0121] In X-ray powder diffraction (XRD) patterns, the term "substantially" or "substantially as shown" refers to a substantially pure crystalline form whose powder XRD pattern shows at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% of the peaks. Furthermore, as the content of a crystalline form in a product gradually decreases, some diffraction peaks attributable to that crystalline form in the XRD pattern may decrease due to factors such as instrument detection sensitivity. In addition, for any given crystalline form, the peak positions may have slight errors, which is well known in the field of crystallography. For example, due to temperature variations during sample analysis, sample movement, or instrument calibration, the peak positions can shift, and the determination error of the 2θ value is typically about ±0.2°. Therefore, this error should be taken into account when determining each crystal structure, and the terms "substantially" or "substantially as shown in the figure" are also intended to cover such differences in diffraction peak positions.

[0122] In DSC or TGA spectra, the terms "substantially" or "substantially as shown" refer to the fact that, for the same crystal form of the same compound, the error in thermal transition onset temperature, endothermic peak peak temperature, exothermic peak peak temperature, melting point, weight loss temperature, decomposition temperature, weight loss onset temperature, or weight loss endpoint temperature, etc., is typically within about 5°C, and usually within about 3°C, in continuous analysis. When describing a compound as having a given thermal transition onset temperature, endothermic peak peak temperature, exothermic peak peak temperature, melting point, decomposition temperature, weight loss temperature, weight loss onset temperature, or weight loss endpoint temperature, it refers to that temperature ±5°C.

[0123] As used herein, the term "prevention" means that, when used for a disease or condition (e.g., diabetes), the compound or drug reduces the frequency of symptoms of the medical condition or delays the onset of the condition in a subject compared to a subject who has not been given the compound or drug (e.g., a pharmaceutical composition claimed in this invention or a preparation made from a pharmaceutical composition).

[0124] As used in this article, the term “treatment” means to reduce, alleviate or improve the symptoms of a disease or condition, improve underlying metabolic symptoms, suppress a disease or condition, such as preventing the development of a disease or condition, alleviating a disease or condition, causing the remission of a disease or condition, relieving the condition caused by a disease or condition, or preventing the symptoms of a disease or condition.

[0125] The terms "pharmaceutical-grade carrier" or "pharmaceuticalally acceptable excipient" refer to carriers or excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound.

[0126] The compound represented by Formula I of the present invention can be prepared by various synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining it with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention. For example, it can be prepared using the method described in CN101970402B.

[0127] The chemical reactions in the specific embodiments of this invention are carried out in a suitable solvent, which must be suitable for the chemical changes of this invention and the reagents and materials required therefor. To obtain the compounds of this invention, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction flow based on existing embodiments.

[0128] The present invention will be described in detail below through embodiments, which are not intended to limit the present invention in any way.

[0129] All solvents used in this invention are commercially available and can be used without further purification.

[0130] Technical effect

[0131] The salts, solid forms, crystalline forms, or crystal forms of the compounds represented by Formula I provided by this invention have one or more of the following characteristics.

[0132] Beneficial effects:

[0133] (1) The salts of the compounds shown in Formula I are easy to purify and separate.

[0134] (2) Salts of compounds in the crystal form of Formula I have good crystallinity, for example, crystal form A of the compound in Formula II-1, crystal form 1 of the compound in Formula II-2, crystal form A of the compound in Formula II-3 and crystal form 1 of the compound in Formula II-4.

[0135] (3) Preferred salts (e.g., p-toluenesulfonate, hydrobromide) and / or their crystal forms (e.g., p-toluenesulfonate crystal form A) have high thermal stability.

[0136] (4) Preferred salts (e.g., p-toluenesulfonate, hydrobromide) and their crystal forms are non-hygroscopic or slightly hygroscopic, which is beneficial for storage and subsequent formulation processes.

[0137] (5) Preferred salts (e.g., p-toluenesulfonate, hydrobromide, fumarate) and their crystal forms have good physical stability and good pharmaceutical prospects.

[0138] (6) Preferred salts (e.g., p-toluenesulfonate, hydrobromide, fumarate) and their crystal forms have suitable solubility in water, acidic buffer media and biological media of different pH, which meets the requirements for the development of pharmaceutical formulations.

[0139] (7) Preferred salts (e.g., p-toluenesulfonate, hydrobromide, fumarate) and their crystal forms are rapidly soluble in water, buffer solutions of different pH, or biological media solutions of different pH.

[0140] (8) Preferred salts (e.g., p-toluenesulfonate) and their crystal forms are stable in different solvents.

[0141] (9) Preferred salts (e.g., p-toluenesulfonate) and their crystal forms have good long-term stability (e.g., physical and chemical stability).

[0142] (10) Preferred salts (e.g., p-toluenesulfonate) and their crystal forms have regular morphology and the crystal particles can be uniformly dispersed without adhesion.

[0143] (11) When a preferred salt (e.g., p-toluenesulfonate) and its crystal form are used as active ingredients to form an oral solid dosage form, the effect of rapid dissolution can be achieved and the active ingredient has good stability.

[0144] (12) Preferred salts (e.g., p-toluenesulfonate, hydrobromide) and their crystal forms can be obtained in high yields and / or with high purity.

[0145] Furthermore, if the active pharmaceutical ingredient (API) contains a primary or secondary amine and the formulation excipients contain reducing sugars (e.g., glucose, lactose), a Maillard reaction may occur. Using an amine salt (blocking the free primary or secondary amino group) as the API may relax the restrictions on the selection of excipients in the formulation, which can help reduce costs and better control product quality (e.g., storage conditions). Attached Figure Description

[0146] Figure 1 X-ray powder diffraction pattern of crystal form A of p-toluenesulfonate in Example 1.

[0147] Figure 2 DSC-TGA spectrum of crystal form A of p-toluenesulfonate in Example 1.

[0148] Figure 3 X-ray powder diffraction pattern of crystal form 1 of hydrobromide in Example 2.

[0149] Figure 4 X-ray powder diffraction pattern of crystal form A of fumarate in Example 3.

[0150] Figure 5 X-ray powder diffraction pattern of crystal form 1 of the hydrochloride in Example 4. Detailed Implementation

[0151] 1. X-ray powder diffractometer (XRPD)

[0152] Instrument Model: Bruker D8 Advance X-ray Powder Diffractometer

[0153] Test method: Approximately 5–10 mg of sample is used for XRPD detection.

[0154] The detailed XRPD parameters are as follows:

[0155] X-ray generator: Cu, Kα,

[0156] Phototube voltage: 40kV, Phototube current: 40mA

[0157] Scan range: 3°-45° (2θ)

[0158] Scan step size: 0.02°

[0159] Sample tray: Zero background sample tray.

[0160] 2. Differential Scanning Calorimeter (DSC)

[0161] Instrument Model: TADiscovery 2500 Differential Scanning Calorimeter

[0162] Test method: Place the sample in a perforated aluminum crucible, and heat the sample to the final temperature at a heating rate of 10℃ / min after equilibration at 25℃.

[0163] Type of gas flow: Nitrogen

[0164] Flow rate: 50 mL / min

[0165] Heating start temperature: 25℃

[0166] Termination temperature: 300℃.

[0167] 3. Thermogravimetric Analysis (TGA)

[0168] Instrument Model: TADiscovery 55 Thermogravimetric Analyzer (TA, US)

[0169] Test method: Place the sample in a balanced open aluminum sample pan. After the sample mass is automatically weighed in the TGA heating furnace, heat the sample to the final temperature at a rate of 10℃ / min.

[0170] Sample amount: 2-5 mg

[0171] Type of gas flow: Nitrogen

[0172] Sample chamber airflow rate: 60 mL / min

[0173] Heating start temperature: room temperature

[0174] Termination temperature: 300℃.

[0175] 4. Dynamic moisture adsorption-desorption analysis (DVS)

[0176] Dynamic moisture adsorption-desorption analysis was performed using DVS Intrinsic (SMS, UK) at 25°C. The sample amount for each test was approximately 15-20 mg.

[0177] (1) Simplified DVS Test (Example 4)

[0178] A simplified DVS test was conducted using a gradient mode with humidity variations of 30%-50%-80%-95% RH, with each humidity gradient held for one hour. The sample mass at 30% RH was used as the mass reference point. After the test, XRPD analysis was performed on the samples to confirm whether the solid morphology had changed.

[0179] (2) Conventional DVS Test (Examples 1-3)

[0180] The standard DVS test uses a gradient mode with humidity changes ranging from 50% to 95% to 0% to 50%. Within the 0% to 90% range, each gradient represents a 10% change in humidity. The gradient endpoint is determined using the dm / dt method, with a dm / dt value less than 0.002% maintained for 10 minutes as the endpoint. After the test, XRPD analysis is performed on the sample to confirm whether the solid morphology has changed.

[0181] 5. High-performance liquid chromatography (HPLC)

[0182] Instrument Model: Waters Acquity Arc (Waters, US)

[0183] Chromatographic column: Waters CORTECS C18, 4.6 × 150 mm, 2.7 μm

[0184] Test conditions: wavelength 205nm; column temperature 30℃

[0185] Flow rate: 0.8 mL / min.

[0186] 6. Nuclear Magnetic Resonance Spectroscopy (NMRS)

[0187] Instrument model: Bruker AVANCE III (Bruker, GER)

[0188] Contents and test solvents: 1 H-NMR, the test solvent was DMSO-d6.

[0189] 7. Solubility test of biological media

[0190] The preparation process of the biological medium is shown in the table below:

[0191]

[0192]

[0193] The solubility was calculated based on the standard curve of the compound shown in Formula I.

[0194] 8. Weight gain test at 60% RH

[0195] Weigh approximately 20 mg of sample into a weighing bottle and place it open at 25°C / 60% RH. Take samples at 2, 4, 6, 15, and 24 hours for XRPD characterization. The percentage weight gain was collected using DVS at 60% RH.

[0196] 9. Polarizing Microscopy (PLM) Analysis

[0197] The polarizing microscope used was a Nikon Ci-POL (Nikon, Japan). A small amount of sample was placed on a glass slide, and a suitable lens was selected to observe the sample morphology.

[0198] 10. Ion chromatography (IC)

[0199] Instrument Model: ICS 5000 (Thermo Fisher, US)

[0200] Column: Dionex IonPac™ AS11-HC Analytical (4×250mm)

[0201] 11. Karl Fischer (KF) water titration

[0202] Instrument model: 870KF Titrino Plus (Metrohm, Swiss)

[0203] Test method: The precisely weighed sample is added to a pre-equilibrated methanol solvent, and the instrument automatically titrates to the endpoint and calculates the water content of the sample.

[0204] To better understand the content of this invention, further explanation is provided below with reference to specific embodiments. However, the specific implementation methods are not intended to limit the scope of this invention. Test methods not specifying specific conditions in the following embodiments, comparative examples, or test examples should be performed according to conventional methods and conditions, or as selected in the product manual.

[0205] Example 1: Preparation of p-toluenesulfonate of the compound shown in Formula I (compound shown in Formula II-1)

[0206] Weigh 396.5 mg of the compound sample shown in Formula I into a reaction flask, add p-toluenesulfonic acid (1.1 equivalents) and isopropanol (8 mL), stir at room temperature for 2 days, filter, and dry the resulting solid under vacuum at 40 °C for 1 day to obtain a solid (531.0 mg). Analysis confirmed that it had formed a salt with a base / acid ratio of 1:1.

[0207] X-ray powder diffraction of the sample revealed it to be a crystalline solid (crystal form A) with good crystallinity; the spectrum is shown below. Figure 1The XRPD diffraction peak data are shown in Table 1. DSC-TGA tests were performed on the sample. The DSC plot showed an endothermic peak at 202.8℃, and the TGA plot showed that the sample began to lose weight around 210℃. Figure 2 .

[0208] Table 1 shows the XRPD diffraction peak data of crystal form A of p-toluenesulfonate as shown in Formula II-1.

[0209] 6.669 48.3 17.514 100.0 21.191 77.7 8.455 22.4 17.635 5.6 22.505 13.0 9.235 14.9 18.215 40.6 23.838 6.6 11.629 21.8 18.596 9.8 24.322 10.3 13.432 24.6 19.492 34.0 26.773 6.1

[0210] Note: Peaks with a relative peak intensity > 5.0% are listed in the table.

[0211] Example 2: Preparation of the hydrobromide salt of the compound shown in Formula I (the compound shown in Formula II-2)

[0212] Weigh 356.9 mg of the compound sample shown in Formula I into a reaction flask, add hydrobromic acid (1.1 equivalents, 1 M, diluted with ethanol) and 10 mL of 4-methyl-2-pentanone, stir at room temperature for 2 days, filter, and dry the resulting solid under vacuum at room temperature for 1 day to obtain a solid (296.3 mg). Analysis confirmed that it had formed a salt with a base / acid ratio of 1:1.

[0213] X-ray powder diffraction of the sample revealed it to be a crystalline solid (crystal form 1) with good crystallinity; the spectrum is shown below. Figure 3 The XRPD diffraction peak data are shown in Table 2. DSC-TGA tests were performed on the sample. The DSC plot showed endothermic peaks at 76.4℃, 96.5℃, 146.2℃, and 209.2℃, with the endothermic peak at 209.2℃ originating at 206.2℃. The TGA plot showed an 11.1% weight loss between room temperature and 100℃, with weight loss beginning around 215℃. KF moisture titration results showed that the water content of hydrobromide crystal form 1 was 11.1%, consistent with the TGA weight loss.

[0214] Table 2 shows the XRPD diffraction peak data of crystal form 1 of hydrobromide as shown in Formula II-2.

[0215] 5.346 50.1 19.337 16.4 27.215 65.8 8.067 35.9 20.529 7.8 28.283 9.1 10.122 9.8 21.308 27.9 28.640 25.1 12.775 11.0 21.722 69.5 30.851 12.0 14.177 61.4 22.482 30.2 31.266 11.5 15.071 25.6 22.549 24.5 31.898 7.5 15.825 11.3 24.273 40.6 32.257 12.9 16.228 71.8 24.483 100.0 32.867 17.4 16.555 40.0 25.123 31.8 33.532 14.8 17.668 31.0 25.764 30.4 34.827 10.6 18.543 32.1 26.064 43.1 35.161 13.2 18.750 26.5 26.462 12.9 38.486 33.4 18.931 40.6 27.013 15.9 41.454 10.6

[0216] Note: Peaks with a relative peak intensity > 6.0% are listed in the table.

[0217] Example 3: Preparation of fumarate of the compound shown in Formula I (compound shown in Formula II-3)

[0218] Weigh 454.4 mg of the compound sample shown in Formula I into a reaction flask, add fumaric acid (1.5 equivalents) and ethanol (5 mL), stir at room temperature for 2 days, add n-heptane (20 mL), continue stirring at room temperature for 2 days, filter, and dry the resulting solid under vacuum at 40 °C for 1 day to obtain a solid (470 mg). Analysis confirmed that it had formed a salt with a base / acid ratio of 1:1.

[0219] X-ray powder diffraction of the sample revealed it to be a crystalline solid (crystal form A) with good crystallinity; the spectrum is shown below. Figure 4 The XRPD diffraction peak data are shown in Table 3. The sample was subjected to DSC-TGA testing. The DSC plot showed endothermic peaks at 69.2℃ and 126.5℃. The TGA plot showed a 5.9% weight loss between room temperature and 70℃, a 3.3% weight loss between 70℃ and 130℃, and weight loss beginning near 170℃.

[0220] Table 3 shows the XRPD diffraction peak data of crystal form A of the fumarate of the compound shown in Formula I.

[0221] 4.682 17.6 18.658 41.6 25.094 34.3 8.320 67.9 19.193 54.2 25.583 22.5 9.312 13.6 19.908 16.1 25.894 64.1 9.866 11.2 21.790 25.7 27.532 9.1 13.008 25.4 22.442 30.1 33.704 12.8 15.115 36.3 22.685 32.7 34.404 12.2 15.610 30.9 22.923 26.7 16.666 100.0 24.422 31.5

[0222] Note: Peaks with a relative peak intensity > 9.0% are listed in the table.

[0223] Example 4: Preparation of the hydrochloride salt of the compound shown in Formula I (the compound shown in Formula II-4)

[0224] Weigh 26 mg of the compound sample shown in Formula I and add 1 mL of 4-methyl-2-pentanone. Add hydrochloric acid (1.1 equivalents, 6 M, diluted with anhydrous ethanol) dropwise. Stir at room temperature for 2 days. Place the solution in a -15°C freezer to allow crystallization for approximately 18 hours. Filter the solution and dry the resulting solid under vacuum at room temperature. Testing confirmed that a salt had formed, with a base / acid ratio of 1:1.

[0225] X-ray powder diffraction of the sample revealed it to be a crystalline solid (crystal form 1) with good crystallinity; the spectrum is shown below. Figure 5 The XRPD diffraction peak data are shown in Table 4. The sample was subjected to DSC-TGA testing. The DSC plot showed endothermic peaks at 77.1℃ and near 140℃. The TGA plot showed that the sample experienced an 11.6% weight loss between room temperature and 100℃, with weight loss beginning near 200℃.

[0226] Table 4 shows the XRPD diffraction peak data of crystal form 1 of the hydrochloride salt of the compound shown in Formula I.

[0227] 8.076 31.3 19.088 28.6 25.316 10.3 10.884 21.3 21.375 16.8 26.448 19.1 14.304 69.5 21.929 16.6 26.451 18.9 15.184 11.5 22.773 20.8 27.534 12.3 16.275 100.0 24.536 62.7 28.910 20.9

[0228] Note: Peaks with a relative peak intensity >10.0% are listed in the table.

[0229] Example 5: Preparation of p-toluenesulfonate of the compound shown in Formula I (compound shown in Formula II-1)

[0230] Following the method of Example 1, other solvents were used to obtain p-toluenesulfonate. X-ray powder diffraction analysis showed that all of them were p-toluenesulfonate crystal form A. The results are shown in the table below.

[0231]

[0232] Comparative Example 1: Preparation of maleate salt of the compound shown in Formula I

[0233] Weigh 454.8 mg of the compound sample shown in Formula I into a reaction flask, add maleic acid (1.1 equivalents) and ethylene glycol dimethyl ether (8 mL), stir at room temperature for 2 days, add n-heptane (20 mL), continue stirring at room temperature for 2 days, filter, and dry the resulting solid under vacuum at 40 °C for 1 day to obtain a solid (260 mg). Analysis confirmed that it had formed a salt with a base / acid ratio of 1:1.

[0234] X-ray powder diffraction of the sample revealed it to be a crystalline solid (crystal form A) with good crystallinity. XRPD diffraction peak data are shown in Table 5. DSC-TGA analysis of the sample showed an endothermic peak at 112.4℃, while the TGA analysis showed a 4.6% weight loss between room temperature and 150℃, with weight loss beginning around 175℃.

[0235] Table 5 shows the XRPD diffraction peak data of crystal form A of the maleate of the compound shown in Formula I.

[0236] 8.192 22.4 18.035 88.5 24.091 10.9 8.481 100.0 18.260 59.7 24.883 11.8 9.080 48.7 18.801 10.7 25.206 51.2 12.250 20.5 19.329 21.4 25.742 27.9 15.712 59.5 19.536 25.2 26.475 30.1 15.958 25.3 20.062 26.2 26.871 14.3 16.410 68.0 20.743 62.5 27.826 11.8 16.536 61.6 21.452 14.7 33.511 13.3 17.021 84.2 22.387 17.1 17.814 44.1 22.546 18.9

[0237] Note: Peaks with a relative peak intensity >10.0% are listed in the table.

[0238] Comparative Example 2: Preparation of other salts of compound I

[0239] Weigh approximately 26 mg of the compound sample shown in Formula I and the corresponding acid (1.1 equivalents, see table below), add them to the solvents shown in the table below (1 mL), stir at room temperature for 2 days, centrifuge the suspension, and dry the solid under vacuum at room temperature for approximately 18 hours. If the solution is clear, place it in a -15°C freezer to cool and crystallize. Centrifuge the solution with precipitated solid and dry the solid under vacuum at room temperature for approximately 18 hours. If no solid precipitates, add the antisolvent n-heptane dropwise until solid precipitates. Centrifuge the solution with precipitated solid and dry the solid under vacuum at room temperature for approximately 18 hours.

[0240] Preparation of other salts of compound I in Table 6

[0241]

[0242]

[0243] Note: "*" represents the result after the solution is placed at -15℃, and "**" represents the result after adding the antisolvent.

[0244] Results: After the above-mentioned acids (Table 6) reacted with the compounds shown in Formula I, except for a few that were separated into free bases, the others all yielded solids (amorphous), gels or oils, and no crystalline solids were obtained.

[0245] Comparative Example 3: Preparation of other salts of compound I

[0246] Following the same preparation method as Comparative Example 2, the salts shown in the table below were prepared.

[0247] Preparation of other salts of compound I in Table 7

[0248]

[0249] Note: "*" represents the result after the solution was placed at -15℃, and "**" represents the result after adding antisolvent; hygroscopic oil formation: After X-ray powder diffraction test, the sample was oily, which may be due to the high hygroscopicity or deliquescence of several comparative samples.

[0250] Results: When the above-mentioned acids (Table 7) reacted with the compounds shown in Formula I, they all yielded amorphous, oily, gel-like or unstable crystalline forms.

[0251] Test Example 1: Hygroscopicity test of different salts of the compound shown in Formula I

[0252] The samples from Examples 1-3 and Comparative Example 1 were subjected to routine DVS testing, and the results are shown in the table below.

[0253] Table 8. Hygroscopicity test results of Examples 1-3 and Comparative Example 1

[0254]

[0255] Results: Tests showed that the p-toluenesulfonate crystal form A obtained in Example 1 was slightly hygroscopic, the hydrobromide crystal form 1 obtained in Example 2 was hygroscopic or almost hygroscopic, and the fumarate crystal form A obtained in Example 3 was hygroscopic. The crystal forms of the three crystal forms did not change after testing. The maleate crystal form A obtained in Comparative Example 1 may have undergone a crystal form change first when the humidity gradually increased, and then showed slight hygroscopicity. After the test was completed, the crystal form change was detected.

[0256] Test Example 2: Stability Test under Fixed Humidity Conditions

[0257] The stability of samples from Examples 1-3 was studied by placing them open for 24 hours at 25℃ / 60%RH. Samples were taken at 2h, 4h, 6h, 15h and 24h for XRPD characterization. At the same time, DVS was used to test the 24-hour increment at 60%RH. The results are shown in the table below.

[0258] Table 9. Results of the stability study

[0259]

[0260]

[0261] Note: / indicates no weight gain.

[0262] Results: Under 60% RH conditions, no crystal form transformation occurred in the p-toluenesulfonate crystal form A obtained in Example 1, the hydrobromide crystal form 1 obtained in Example 2, and the fumarate crystal form A obtained in Example 3, nor was there any significant increase in weight due to moisture absorption.

[0263] Test Example 3: Hygroscopicity test of crystal form 1 of the hydrochloride salt of the compound shown in Formula I

[0264] The sample obtained in Example 4 was used to perform a simple DVS test, and the results are shown in the table below.

[0265] Table 10. Hygroscopicity test results of Example 4

[0266]

[0267] Results: The hydrochloride crystal form 1 obtained in Example 4 is hygroscopic, and the crystal form did not change after testing.

[0268] Test Example 4: Stability Study

[0269] Weigh appropriate amounts of samples from Example 1 (p-toluenesulfonate crystal form A), Example 2 (hydrobromide crystal form 1), Example 3 (fumarate crystal form A), and Comparative Example 1 into vials. Place them under high temperature (60°C, open), light irradiation (25°C / 4500Lux, open), and accelerated conditions (40°C / 75%RH, open) for 7 days and 15 days, respectively. Take samples for X-ray powder diffraction to investigate the stability of different samples under different conditions. The results are shown in the table below.

[0270] Table 11 Results of Solid Stability Experiment

[0271]

[0272] Note: *After XRPD testing, it was observed that the sample absorbed moisture and turned into oil.

[0273] Results: Examples 1 (p-toluenesulfonate crystal form A), 2 (hydrobromide crystal form 1), and 3 (fumarate crystal form A) all maintained crystal form stability in the solid stability test; the sample obtained in Comparative Example 1 underwent crystal form transformation or decreased crystallinity under different conditions.

[0274] Test Example 5: Solubility Test of Biological Media

[0275] The solubility of samples from Examples 1-3 was determined in three biological media (FaSSIF, FeSSIF, and FaSSGF), and the results are shown in the table below.

[0276] Table 12 Results of biological media solubility test

[0277]

[0278] Note: ① Solubility is calculated based on compound I; ②> indicates that the sample has dissolved completely, and the actual solubility is greater than the solubility measured at this time.

[0279] Results: The p-toluenesulfonate crystal form A obtained in Example 1, the hydrobromide crystal form 1 obtained in Example 2, and the fumarate crystal form A obtained in Example 3 all showed good solubility in three different biological media with different pH values, especially in acidic media (FaSSGF).

[0280] Although the foregoing invention has been described in considerable detail by way of illustration and example for the purpose of clear understanding, it will be apparent from the teachings of the invention that those skilled in the art may make certain changes and modifications thereto without departing from the spirit or scope of the appended claims.

Claims

1. A compound, wherein, The compound is the compound shown in Formula II-1. ； The compound is of crystal form A, as shown in Formula II-1. When subjected to Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.7°±0.2°, 8.5°±0.2°, 13.4°±0.2°, 17.5°±0.2°, 18.2°±0.2°, 19.5°±0.2°, and 21.2°±0.2°.

2. The compound according to claim 1, wherein, The compound is of crystal form A, as shown in Formula II-1. Its X-ray powder diffraction pattern, obtained using Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ angles: 6.7°±0.2°, 8.5°±0.2°, 9.2°±0.2°, 11.6°±0.2°, 13.4°±0.2°, 17.5°±0.2°, 18.2°±0.2°, 19.5°±0.2°, and 21.2°±0.2°.

3. The compound according to claim 1, wherein, The compound is the compound of formula II-1 in crystal form A. Its X-ray powder diffraction pattern, obtained using Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ angles: 6.7°±0.2°, 8.5°±0.2°, 9.2°±0.2°, 11.6°±0.2°, 13.4°±0.2°, 17.5°±0.2°, 18.2°±0.2°, 19.5°±0.2°, 21.2°±0.2°, 22.5°±0.2°, and 24.3°±0.2°.

4. The compound according to claim 1, wherein, The compound is of crystal form A, as shown in Formula II-1. Its X-ray powder diffraction pattern, obtained using Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ angles: 6.7°±0.2°, 8.5°±0.2°, 9.2°±0.2°, 11.6°±0.2°, 13.4°±0.2°, 17.5°±0.2°, 18.2°±0.2°, 18.6°±0.2°, 19.5°±0.2°, 21.2°±0.2°, 22.5°±0.2°, and 24.3°±0.2°.

5. The compound according to claim 1, wherein, The compound is the compound of formula II-1 in crystal form A, and it has the X-ray powder diffraction pattern shown in Figure 1 when irradiated with Cu-Kα.

6. A pharmaceutical composition comprising the compound of any one of claims 1-5, optionally further comprising one or more pharmaceutically acceptable carriers.

7. Use of the compound according to any one of claims 1-5 or the pharmaceutical composition according to claim 6 in the preparation of a medicament for treating diabetes.

8. The application according to claim 7, wherein, The diabetes is type II diabetes.

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