Crystalline forms of glucopyranosyl derivatives and their uses

Abstract

The present invention relates to a crystalline form of a glucopyranosyl derivative and its use. In particular, the present invention relates to a crystalline form of N-(2-dimethylaminoethyl)-1-[4-[4-[[5-[(2S,3R,4S,5S,6R)-6-ethyl-3,4,5-trihydroxy-tetrahydropyran-2-yl]-2-methyl-phenyl]methyl]phenyl]butyrylamino]cyclohexylformamide and a pharmaceutical composition comprising the crystalline form, and further to the use of the crystalline form and the pharmaceutical composition in the preparation of a sodium-dependent glucose transporter (SGLT) inhibitor.

Description

[Technical Field]

[0001] The present invention relates to crystalline forms of glucopyranosyl derivatives and pharmaceutical compositions comprising the crystalline forms of the invention, as well as their use in the preparation of sodium-dependent glucose transporter (SGLT) inhibitors. [Background technology]

[0002] SGLT inhibitors can be used to treat diabetes-related complications, such as retinopathy, neuropathy, kidney disease, insulin resistance caused by glucose metabolism disorders, hyperinsulinemia, hyperlipidemia, obesity, etc. Meanwhile, SGLT inhibitors can also be used in combination with current treatment regimens, such as sulfonamides, thiazolidinediones, metformin, and insulin, which can reduce the dose without affecting the efficacy of the medication, thereby avoiding or reducing side effects and improving patient compliance. Currently, SGLT inhibitors on the market include canagliflozin and dapagliflozin, which are mainly used for the treatment of type II diabetes and its complications.

[0003] Patent application WO2021004498A1 discloses a class of glucopyranosyl derivatives as SGLT inhibitors, in particular N-(2-dimethylaminoethyl)-1-[4-[4-[[5-[(2S,3R,4S,5S,6R)-6-ethyl-3,4,5-trihydroxy-tetrahydropyran-2-yl]-2-methylphenyl]methyl]phenyl]butanoylamino]cyclohexylformamide (i.e., the compound shown in formula (I) of the present application), which has significant inhibitory activity against SGLT. The product obtained by the preparation method described in this patent application is amorphous, has insufficient stability, and does not meet the requirements for storage and formulation.

[0004] [ka] [Prior art documents] [License]

[0005] [License 1] WO2021004498A1 [Non-licensed literature]

[0006] [Non-licensed Document 1] Handbook of Chemistry and Physics, 75th Edition, 1994 [Non-licensed Document 2] "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999 [Non-licensed Document 3] "March's Advanced Organic Chemistry", by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007 [Non-licensed Document 4] U.S. National Drug Administration Prescription #23, National Medical Drug Collection #18, pp. 1843~1844, 1995 [Non-licensed Document 5] Chinese Pharmaceutical Administration (2015 Edition) General Rule 0402 "Infrared Spectrophotometry" [Non-licensed Document 6] Johannsson et al., J. Clin. Endocrinol. Metab., 1997;82, 727~734 [Non-licensed Document 7] Remington: The Science and Practice of Pharmacy, 21st Edition, 2005, edited by DB Troy, published by Lippincott Williams & Wilkins, Philadelphia [Non-licensed Document 8] Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York [Non-Patent Document 9] Zhang, S. et al., Drug Discovery Today, 12(9 / 10), 373~381, 2007 [Non-Patent Document 10] Solid-State Chemistry of Drugs, S.R. Byrn, R.R. Pfeiffer, and J.G. Stowell, 2nd ed., SSCI, West Lafayette, Indiana (1999) [Non-Patent Document 11] "Programmed Cooling Batch Crystallizers", J.W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971, 26, 369-377. [Non-Patent Document 12] Sheldrick, G.M. SHELXTL-97, Program for Crystal Structure Solution and Refinement; University of Gottingen: Gottingen, Germany, 1997 [Non-Patent Document 13] "Chinese Pharmacopoeia" (2015 Edition) Part 4 "Guidelines for Drug Hygroscopicity Test" [Non-Patent Document 14] Guidelines for Hygroscopicity Testing of Drugs, General Rule 9103, Chinese Pharmacopoeia 2015 Edition Summary of the Invention [Means for solving the problem]

[0007] The present invention specifically relates to crystalline forms of N-(2-dimethylaminoethyl)-1-[4-[4-[[5-[(2S,3R,4S,5S,6R)-6-ethyl-3,4,5-trihydroxy-tetrahydropyran-2-yl]-2-methylphenyl]methyl]phenyl]butanoylamino]cyclohexylformamide, specifically crystalline forms including crystalline form I and crystalline form II. The crystalline form prepared by the present invention can be identified and distinguished from other crystalline forms using its characteristic powder X-ray diffraction (XRPD) pattern, differential scanning calorimetry (DSC) curve, thermogravimetric analysis (TGA) curve, Raman spectrum, and Fourier transform infrared (FT-IR) spectrum. Crystalline form I described in the present invention has suitable solubility, good stability, and low hygroscopicity, and therefore has excellent development prospects.

[0008] In one aspect, the present invention provides a compound of formula (I);

[0009] [ka]

[0010] The present invention provides a crystalline form of the compound shown in

[0011] In some embodiments, the crystalline form of the compound of formula (I) in the present invention is crystalline form I or II.

[0012] In some embodiments, the powder X-ray diffraction pattern of crystalline Form I described in this invention comprises diffraction peaks at the following 2θ angles: 5.02°±0.2°, 9.99°±0.2°, 12.67°±0.2°, 14.96°±0.2°, 15.55°±0.2°, 20.64°±0.2°.

[0013] In another embodiment, the powder X-ray diffraction pattern of crystalline Form I described in the present invention comprises diffraction peaks at the following 2θ angles: 5.02°±0.2°, 9.06°±0.2°, 9.99°±0.2°, 12.67°±0.2°, 13.47°±0.2°, 14.96°±0.2°, 15.55°±0.2°, 16.16°±0.2°, 18.19°±0.2°, 20.64°±0.2°, 25.02°±0.2°.

[0014] In another embodiment, the powder X-ray diffraction pattern of crystalline Form I described in this invention is at the following 2θ angles: 5.02°±0.2°, 5.72°±0.2°, 7.16°±0.2°, 9.06°±0.2°, 9.99°±0.2°, 10.27°±0.2°, 11.36°±0.2°, 12.67°±0.2°, 13.47°±0.2°, 14.27°±0.2°, 15.02°±0.2°, 16.02°±0.2°, 17.02°±0.2°, 18.02°±0.2°, 19.02°±0.2°, 20.02°±0.2°, 21.02°±0.2°, 22.02°±0.2°, 23.02°±0.2°, 24.02°±0.2°, 25.02°±0.2°, 26.02°±0.2°, 27.02°±0.2°, 28.02°±0.2°, 29.02°±0.2°, 30.02°±0.2°, 31.02°±0.2°, 32.02°±0.2°, 33.02°±0.2°, 34.02°±0.2°, 35.02°±0.2°, 36.02°±0.2°, 37.02°±0.2°, 38.02°±0.2°, 39.02°±0.2°, 40.02°±0.2°, 41.02°±0.2°, 42.02 4.29°±0.2°, 14.96°±0.2°, 15.55°±0.2°, 16.16°±0.2°, 16.84°±0.2°, 16.96°±0.2°, 17.68°±0.2°, 18.19°±0.2°, 18.36°±0.2°, 18.52°±0.2°, 18.94°±0.2°, 19.78°±0.2°, 20.6 4°±0.2°, 21.10°±0.2°, 21.44°±0.2°, 21.85°±0.2°, 22.22°±0.2°, 22.48°±0.2°, 23.08°±0.2°, 23.69°±0.2°, 23.80°±0.2°, 25.02°±0.2°, 25.43°±0.2°, 25.70°±0.2°, 26.38° The diffraction peaks are at 26.74°±0.2°, 26.74°±0.2°, 27.18°±0.2°, 27.68°±0.2°, 28.62°±0.2°, 29.53°±0.2°, 30.01°±0.2°, 30.52°±0.2°, 31.08°±0.2°, 31.53°±0.2°, 32.01°±0.2°, and 32.60°±0.2°.

[0015] In another embodiment, the powder X-ray diffraction pattern of crystalline Form I of the present invention is obtained by diffracting crystalline Form I at the following angles 2θ: 5.02°±0.2°, 5.72°±0.2°, 7.16°±0.2°, 9.06°±0.2°, 9.99°±0.2°, 10.27°±0.2°, 10.55°±0.2°, 11.36°±0.2°, 12.67°±0.2°, 13.47°±0.2°, 14.29°±0.2°, 14.96°±0.2°, 15.55°±0.2° , 16.16°±0.2°, 16.84°±0.2°, 16.96°±0.2°, 17.68°±0.2°, 18.19°±0.2°, 18.36°±0.2°, 18.52°±0.2°, 18.94°±0.2°, 19.78°±0.2°, 20.64°±0.2°, 21.10°±0.2°, 21.44°±0.2°, 21.85°±0.2°, 22.22°±0.2°, 22.48°±0.2°, 23.08° ±0.2°, 23.69°±0.2°, 23.80°±0.2°, 25.02°±0.2°, 25.43°±0.2°, 25.70°±0.2°, 26.38°±0.2°, 26.74°±0.2°, 27.18°±0.2°, 27.68°±0.2°, 28.62°±0.2°, 29.53°±0.2°, 30.01°±0.2°, 30.52°±0.2°, 31.08°±0.2°, 31.53°±0.2°, 3 Diffraction peaks include those at 2.01°±0.2°, 32.60°±0.2°, 33.34°±0.2°, 33.92°±0.2°, 34.28°±0.2°, 34.57°±0.2°, 35.31°±0.2°, 35.73°±0.2°, 36.25°±0.2°, 36.90°±0.2°, 37.37°±0.2°, 37.86°±0.2°, 38.43°±0.2°, 38.92°±0.2°, and 39.46°±0.2°.

[0016] In another embodiment, the powder X-ray diffraction pattern of crystalline Form I of the present invention has the following diffraction patterns at the following 2θ angles: 5.02°±0.2°, 5.72°±0.2°, 7.16°±0.2°, 9.06°±0.2°, 9.99°±0.2°, 10.27°±0.2°, 10.55°±0.2°, 11.36°±0.2°, 12.67°±0.2°, 13.47°±0.2°, 14.29°±0.2°, 14.96°±0.2°, 15.55°±0.2°, 16.16°±0.2°, 16.84°±0.2°, 16.96°±0.2°, 17.68°±0.2°, 18.72°±0.2°, 19.72°±0.2°, 20.72°±0.2°, 21.72°±0.2°, 22.72°±0.2°, 23.72°±0.2°, 24.72°±0.2°, 25.72°±0.2°, 26.72°±0.2°, 27.72°±0.2°, 28.72°±0.2°, 29.72°±0.2°, 30.72°±0.2°, 31.72°±0.2°, 32.72°±0.2°, 33.72°±0.2°, 34.72°±0.2°, 35.72°±0.2°, 36.72°±0.2°, 37.72°±0.2°, 3 .19°±0.2°, 18.36°±0.2°, 18.52°±0.2°, 18.94°±0.2°, 19.78°±0.2°, 20.64°±0.2°, 21.10°±0.2°, 21.44°±0.2°, 21.85°±0.2°, 22.22°±0.2°, 22.48°±0.2°, 23.08°±0.2°, 23.69°±0.2°, 23.80°±0.2°, 25.02°±0.2°, 25.43°±0.2°, 25.70°±0.2°, 26.38°±0.2°, 26.74°±0.2°, 27.18°±0.2°, 27.68°±0.2°, 28.62°±0.2°, 29.53°±0.2°, 30.01°±0.2°, 30.52°±0.2°, 31.08°±0.2°, 31.53°±0.2°, 32.01°±0.2°, 32.60°±0.2°, 33.34°±0.2°, 33.92°±0.2°, 34.28°±0.2°, 34.57°±0.2°, 35.31°±0.2°, 35.73°±0.2°, 36.25°±0.2°, 36.90°±0.2°, 37.37°±0.2°, 37.86°±0.2°, 38.43°±0.2 The diffraction peaks are at 38.92°±0.2°, 39.46°±0.2°, 40.00°±0.2°, 40.94°±0.2°, 41.54°±0.2°, 41.92°±0.2°, 42.39°±0.2°, 42.99°±0.2°, 43.48°±0.2°, 44.08°±0.2°, 44.72°±0.2°, 46.41°±0.2°, 47.24°±0.2°, 48.64°±0.2°, 50.41°±0.2°, 51.52°±0.2°, 53.19°±0.2°, 53.99°±0.2°, and 58.28°±0.2°.

[0017] In some embodiments, the compound of formula (I) described in the present invention is in crystalline form II.

[0018] In some embodiments, the powder X-ray diffraction pattern of crystalline Form II described in this invention comprises diffraction peaks at the following 2θ angles: 4.90°±0.2°, 14.77°±0.2°, 15.89°±0.2°, 16.29°±0.2°, 17.89°±0.2°, 18.51°±0.2°.

[0019] In another embodiment, the powder X-ray diffraction pattern of crystalline Form II described in the present invention comprises diffraction peaks at the following 2θ angles: 4.90°±0.2°, 9.82°±0.2°, 12.46°±0.2°, 14.77°±0.2°, 15.89°±0.2°, 16.29°±0.2°, 17.89°±0.2°, 18.51°±0.2°, 18.92°±0.2°, 20.31°±0.2°, 20.77°±0.2°.

[0020] In another embodiment, the powder X-ray diffraction pattern of crystalline Form II described in the present invention is obtained from the following 2θ angles: 4.90°±0.2°, 5.56°±0.2°, 7.00°±0.2°, 8.90°±0.2°, 9.82°±0.2°, 10.04°±0.2°, 10.33°±0.2°, 11.16°±0.2°, 12.46°±0.2°, 13.28°±0.2°, 14.06°±0.2°, 14.77°±0.2°, 15.28°±0.2°, 16.06°±0.2°, 17.06°±0.2°, 18.06°±0.2°, 19.06°±0.2°, 20.06°±0.2°, 21.06°±0.2°, 22.06°±0.2°, 23.06°±0.2°, 24.06°±0.2°, 25.06°±0.2°, 26.06°±0.2°, 27.06°±0.2°, 28.06°±0.2°, 29.06°±0.2°, 30.06°±0.2°, 31.06°±0.2°, 32.06°±0.2°, 33.06°±0.2°, 34.06°±0.2°, 35.06°±0.2°, 36.06°±0.2°, 37.06°±0.2°, 38.06°±0.2°, 39.06°±0.2°, 40. ±0.2°, 15.89°±0.2°, 16.29°±0.2°, 16.80°±0.2°, 16.99°±0.2°, 17.89°±0.2°, 18.31°±0.2°, 18.51°±0.2°, 18.92°±0.2°, 19.70°±0.2°, 20.31°±0.2°, 20.77°±0.2°, 21.17°±0.2°, 21.71°±0.2°, 21.91°±0.2°, 22.15°±0.2°, 22. 80°±0.2°, 23.08°±0.2°, 23.65°±0.2°, 24.75°±0.2°, 25.07°±0.2°, 25.57°±0.2°, 25.86°±0.2°, 26.39°±0.2°, 27.07°±0.2°, 27.30°±0.2°, 27.59°±0.2°, 28.24°±0.2°, 29.13°±0.2°, 29.77°±0.2°, 30.14°±0.2°, 30.15°±0.2°, Diffraction peaks include those at 30.47°±0.2°, 31.00°±0.2°, 31.17°±0.2°, 31.38°±0.2°, 31.85°±0.2°, 32.41°±0.2°, 33.00°±0.2°, 33.57°±0.2°, 34.08°±0.2°, 34.93°±0.2°, 36.00°±0.2°, 36.32°±0.2°, 37.60°±0.2°, 38.68°±0.2°, and 39.20°±0.2°.

[0021] In some embodiments, in the crystalline form I of the compound of formula (I) of the present invention, the crystalline form I has the following unit cell parameters: unit cell dimensions: a=5.81961 Å, b=17.21305 Å, c=35.51838 Å, α=90°, β=90°, γ=90°; Space group: rectangular system, P212121; Unit cell volume: 3557.99Å 3 ; Number of asymmetric units in the unit cell Z: 4 It has.

[0022] In some embodiments, in crystalline form I of the compound of formula (I) of the present invention, the differential scanning calorimetry diagram of crystalline form I comprises an endothermic peak at 129.31°C ± 3°C.

[0023] In some embodiments, in crystalline form I of the compound of formula (I) of the present invention, crystalline form I has a powder X-ray diffraction pattern substantially as shown in FIG.

[0024] In some embodiments, in crystalline form I of the compound of formula (I) of the present invention, crystalline form I has a differential scanning calorimetry diagram substantially as shown in FIG.

[0025] In some embodiments, in crystalline form I of the compound of formula (I) of the present invention, crystalline form I has a thermogravimetric analysis chart substantially as shown in FIG.

[0026] In some embodiments, in the crystalline form II of the compound of formula (I) of the present invention, the crystalline form II has a powder X-ray diffraction pattern substantially as shown in FIG.

[0027] In some embodiments, in the amorphous form of the compound of Formula (I) of the present invention, the amorphous form has a powder X-ray diffraction pattern substantially as shown in FIG.

[0028] In some embodiments, the method for preparing crystalline Form I of the compound of Formula (I) in the present invention involves heating the compound of Formula (I) and L-proline in an organic solvent, stirring, cooling, precipitating, and filtering to obtain a co-crystal of the compound of Formula (I) and L-proline. Then, adding a mixed solvent, heating, precipitating, filtering, and drying the filter cake to obtain crystalline Form I of the compound of Formula (I).

[0029] In some embodiments, the method for preparing crystalline Form I of the compound of Formula (I) in the present invention comprises heating the compound of Formula (I) and L-proline in ethanol to 60°C, stirring, cooling to room temperature, precipitating crystals, filtering, and drying the filter cake to obtain a co-crystal of the compound of Formula (I) and L-proline. Then, a mixed solvent of ethanol and water is added, heating to 40°C, precipitating crystals, stirring, filtering, and drying the filter cake to obtain crystalline Form I of the compound of Formula (I).

[0030] In another embodiment, in the method for preparing crystalline Form I of compound of formula (I) of the present invention, the organic solvent is selected from methanol, ethanol, isopropanol, or n-propanol, and the mixed solvent is selected from mixed solvents of methanol and water, ethanol and water, isopropanol and water, or n-propanol and water.

[0031] In some embodiments, in the method for preparing crystalline form I of the compound of formula (I) of the present invention, the co-crystal of L-proline may be any co-crystal formed by the compound of formula (I) and L-proline, including, but not limited to, crystalline form B.

[0032] In some embodiments, in the method for preparing crystalline form I of the compound of formula (I) of the present invention, the L-proline cocrystal may be cocrystal B of the compound of formula (I) with L-proline, and its powder X-ray diffraction pattern is obtained at the following 2θ angles: 4.17°±0.2°, 5.50°±0.2°, 8.25°±0.2°, 10.46°±0.2°, 10.88°±0.2°. .2°, 11.20°±0.2°, 11.48°±0.2°, 12.30°±0.2°, 12.80°±0.2°, 13.79°±0.2°, 14.95°±0.2°, 15.55°±0.2°, 16.06°±0.2°, 16.53°±0.2°, 16.75°±0.2°, 17.22°±0.2°, 17.63°±0.2°, 18.04°±0.2°. 2°, 18.71°±0.2°, 19.00°±0.2°, 19.37°±0.2°, 19.61°±0.2°, 19.87°±0.2°, 20.12°±0.2°, 20.48°±0.2°, 21.58°±0.2°, 22.06°±0.2°, 22.27°±0.2°, 22.62°±0.2°, 23.44°±0.2°, 23.89°±0.2° The diffraction peaks are at 24.48°±0.2°, 24.92°±0.2°, 25.77°±0.2°, 26.19°±0.2°, 26.94°±0.2°, 30.73°±0.2°, 31.26°±0.2°, 31.88°±0.2°, 35.21°±0.2°, 39.84°±0.2°, 41.06°±0.2°, and 42.33°±0.2°.

[0033] In some embodiments, the co-crystal of the compound of Formula (I) and L-proline of the present invention is co-crystal form B, and crystalline form B of the co-crystal has a powder X-ray diffraction pattern substantially as shown in FIG. 10.

[0034] In some embodiments, the pharmaceutical compositions of the present invention comprising any of the crystalline forms of the present invention further comprise a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle, or a combination thereof.

[0035] In some embodiments, the pharmaceutical compositions of the present invention further comprise one or more additional therapeutic agents, wherein the additional therapeutic agents are selected from an antidiabetic agent, an antihyperglycemic agent, an antiobesity agent, an antihypertensive agent, an appetite suppressant, a lipid-lowering agent, or a combination thereof.

[0036] In some embodiments, the antidiabetic and antihyperglycemic agents of the present invention are independently selected from an SGLT2 inhibitor, a biguanide, a sulfonylurea, a glucosidase inhibitor, a PPAR agonist, an αP2 inhibitor, a PPARα / γ dual activator, a dipeptidyl peptidase IV inhibitor, a glinide, insulin, a glucagon-like peptide-1 inhibitor, a PTP1B inhibitor, a glycogen phosphorylase inhibitor, a glucose-6-phosphatase inhibitor, or a combination thereof. The antiobesity agent is selected from a centrally acting antiobesity agent, an MCH receptor antagonist, a neuropeptide Y receptor antagonist, a cannabinoid receptor antagonist, a brain-gut peptide antagonist, a lipase inhibitor, a β3 agonist, an 11β-HSD1 inhibitor, a DGAT-1 inhibitor, a peptide appetite suppressant, a cholecystokinin agonist, an appetite suppressant, or a combination thereof. The lipid-lowering drug is selected from an MTP inhibitor, an HMG-CoA reductase inhibitor, a squalene synthase inhibitor, a betaine lipid-lowering drug, an ACAT inhibitor, a lipoxygenase inhibitor, a cholesterol absorption inhibitor, an ileal sodium / bile acid cotransporter inhibitor, an LDL receptor activity upregulator, a niacin lipid-lowering drug, a bile acid chelator, or a combination thereof. The lipid-lowering drug is selected from pravastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, pitavastatin, rosuvastatin, or a combination thereof.

[0037] In one aspect, the present invention relates to crystalline Form I of the compound of formula (I) as described herein, or a pharmaceutical composition thereof, for use in the preparation of a medicament, the medicament being used to inhibit SGLT1.

[0038] In another aspect, the present invention relates to crystalline Form I of the compound of formula (I) as described in the present invention, or a pharmaceutical composition thereof, for use in the preparation of a medicament, the medicament being used for the prevention or treatment of a disease, alleviating the symptoms of a disease, or delaying the progression or onset of a disease.

[0039] In some embodiments, the disease described in the present invention is diabetes, a diabetic complication, insulin resistance, hyperglycemia, hyperinsulinemia, hyperlipidemia, obesity, Syndrome X, atherosclerosis, cardiovascular disease, congestive heart failure, hypomagnesemia, hyponatremia, renal failure, a hemoconcentration-related disorder, constipation, or hypertension; the diabetic complication is diabetic retinopathy, diabetic neuropathy, or diabetic nephropathy; and the hyperlipidemia is hypertriglyceridemia.

[0040] The foregoing merely summarizes certain aspects disclosed herein and is not intended to be limiting in nature. These and other aspects and embodiments are described in more detail below. DETAILED DESCRIPTION OF THE INVENTION

[0041] The present invention relates to a crystalline form of the compound N-(2-dimethylaminoethyl)-1-[4-[4-[[5-[(2S,3R,4S,5S,6R)-6-ethyl-3,4,5-trihydroxy-tetrahydropyran-2-yl]-2-methylphenyl]methyl]phenyl]butanoylamino]cyclohexylformamide, and to a process for preparing said crystalline form. It also relates to pharmaceutical compositions containing said crystalline form and the application of said crystalline form and pharmaceutical compositions in medicine.

[0042] It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in the present invention. In the present invention, the crystalline form of the compound represented by formula (I) may contain a certain amount of water or solvent. A crystalline form containing a certain amount of water or other solvent is considered to be within the scope of the present invention as long as it retains some of the properties of crystalline form I or crystalline form II described in the present invention. After reading the following detailed description, those skilled in the art will be able to more easily understand the features and advantages of the present invention. It should be understood that, for clarity, certain features of the present invention that are described above and below in the context of separate embodiments may also be combined to form a single embodiment. Conversely, for brevity, different features of the present invention that are described in the context of a single embodiment may also be combined to form subcombinations thereof.

[0043] Definitions and General Terms Unless otherwise specified, terms used in the specification and claims of this invention have the following definitions.

[0044] Reference will now be made in detail to certain specific embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. The present invention is intended to encompass all alternatives, modifications, and equivalents that may be included within the scope of the present invention, as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which may also be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs or contradicts with this application (including, but not limited to, defined terms, term usage, described techniques, etc.), this application shall control.

[0045] It will be further understood that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0046] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referenced herein are incorporated by reference in their entirety.

[0047] As used herein, the following definitions shall apply unless otherwise indicated: For purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, and the Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0048] The grammatical articles "a," "an," and "the," as used herein, are intended to include "at least one" or "one or more," unless otherwise indicated herein or clearly contradicted by context. Thus, the articles are used herein to refer to one or to more than one (i.e., at least one) of the grammatical object of the article. By way of example, "a component" means one or more components, and thus, in some cases, more than one component is contemplated and may be used or may be used in the practice of the described embodiments.

[0049] As used herein, the term "cocrystal" or "co-crystal" refers to a specific crystalline structure formed by molecular recognition between an active ingredient and a suitable co-crystal former (also known as a ligand) without disrupting the chemical bonds of the active ingredient itself. This is achieved through intermolecular forces, such as non-covalent hydrogen bonds, halogen bonds, π-stacking interactions, and van der Waals forces. A definite stoichiometry exists between the components in a cocrystal. Cocrystals are multicomponent crystals, including binary cocrystals formed between two neutral solids and multicomponent cocrystals formed between a neutral solid and a salt or solvate. For active pharmaceutical ingredients, the crystalline form affects many physicochemical properties, which can directly affect the ability to process and / or prepare a drug and its corresponding final dosage form. For example, cocrystals can improve the solubility, hygroscopicity, and stability of a drug substance, as well as its manufacturability (such as compressibility, flowability, and filterability), and can also affect the stability, dissolution rate, and bioavailability of a drug. Cocrystals can affect the quality, safety, and efficacy of drugs.

[0050] As used herein, the term "subject" refers to an animal. Typically, an animal is a mammal. A subject also refers to, for example, a primate (e.g., a human, male or female), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, etc. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[0051] As used herein, the terms "subject" and "patient" are used interchangeably. The terms "subject" and "patient" refer to animals (e.g., birds such as chickens, quails, or turkeys, or mammals), particularly "mammals," including non-primate animals (e.g., cows, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primates (e.g., monkeys, chimpanzees, and humans), and more particularly humans. In one embodiment, the subject is a non-human animal, such as a livestock animal (e.g., a horse, cow, pig, or sheep) or a pet (e.g., a dog, cat, guinea pig, or rabbit). In other embodiments, "patient" refers to a human.

[0052] The term "equivalent" number used in this invention is based on the equivalence relationship of a chemical reaction using a base material as the basis (1 equivalent) and an equivalent of the other material required in each step.

[0053] The terms "comprise" or "include" as used herein are open-ended expressions, meaning that they include the content disclosed herein but do not exclude other content.

[0054] In the present invention, crystalline forms can be considered to be characterized by graphical data "drawn" on charts. These data include, for example, single crystal X-ray diffraction patterns, powder X-ray diffraction patterns, Raman spectra, Fourier transform-infrared spectra, DSC curves, and solid-state NMR spectra. Those skilled in the art will understand that graphical representations of such data may be subject to slight variations (such as relative peak intensities and peak positions) due to factors such as variations in instrument response and variations in sample concentration and purity, which are known to those skilled in the art. Nevertheless, a technician can compare the graphical data in the figures of the present invention with graphical data generated for an unknown crystalline form and determine whether the two sets of graphical data characterize the same crystalline form.

[0055] "XRD" refers to X-ray diffraction.

[0056] As used herein, the terms "amorphous" or "amorphous form" are intended to mean that the substance, component, or product lacks a characteristic crystalline shape or structure, is substantially not crystalline, e.g., as determined by XRPD, or that the substance, component, or product may not be birefringent or three-dimensional when viewed, e.g., using a polarized light microscope, or may not have sharp peaks in its X-ray powder diffraction pattern. In certain embodiments, a sample comprising an amorphous form of a substance may be substantially free of other amorphous and / or crystalline forms.

[0057] The term "polymorph" or "polymorphism" as used herein is defined as the possibility of having at least two different crystalline arrangements for the same chemical molecule.

[0058] Polymorphic substances can be detected, identified, classified, and qualified using techniques well known to those skilled in the art. These techniques include, but are not limited to, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), powder X-ray diffraction (XRPD), single crystal X-ray diffraction, vibrational spectroscopy, solution calorimetry, solid-state nuclear magnetic resonance (SSNMR), Fourier transform infrared spectroscopy (FT-IR spectroscopy), Raman spectroscopy, hot-stage optical microscopy, scanning electron microscopy (SEM), electron crystallography, as well as quantitative analysis, particle size analysis (PSA), surface area analysis, solubility, and dissolution rate. Polymorphism can be described as the ability of a particular compound to crystallize in different crystalline forms while maintaining the same chemical structure. Polymorphs of a given substance are chemically equivalent and contain the same atoms bonded in the same manner, but differ in their crystalline form, which may affect one or more physical properties, such as dissolution rate, melting point, bulk density, stability, flowability, etc.

[0059] Unless otherwise indicated, when the present invention refers to spectra or data presented in graphical form (e.g., XRPD, FT-IR, Raman, and NMR spectra), the term "peak" refers to a peak that is not caused by background noise or other special feature that one of ordinary skill in the art can discern. The term "valid peak" refers to a peak that is at least intermediate in size (e.g., height) to the other peaks in the spectrum or data, or that is at least 1.5, 2, or 2.5 times the intermediate size of the other peaks in the spectrum or data.

[0060] "Water of crystallization," also known as "water of hydration," is a specific number of water molecules that combine with ions or molecules in a crystal structure in the form of neutral water molecules and occupy specific positions in the crystal structure. For example, there are five water molecules of crystallization in a crystal of copper(II) sulfate pentahydrate (CuSO4·5H2O).

[0061] "Substantially identical" in the context of powder X-ray diffraction, DSC curve, Raman spectrum, and Fourier transform-infrared spectrum means that 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 99% of the peaks are displayed in the powder X-ray diffraction pattern, DSC curve, Raman spectrum, and Fourier transform-infrared spectrum, respectively.

[0062] As is well known in the field of powder X-ray diffraction (XRPD), for any given crystalline form, the equipment used, humidity, temperature, powder crystal orientation, and other parameters can cause some variability in the appearance, intensity, and position of peaks in the diffraction pattern. See, e.g., U.S. Pharmacopeia #23, National Formulary #18, pp. 1843-1844, 1995. In the present context, a variability of ±0.2° 2θ in peak positions accounts for these possible variations without precluding unambiguous identification of the indicated crystalline form. Identification of a crystalline form can be based on any distinctive difference peak (measured in °2θ) or a combination thereof, typically the more prominent peaks. Thus, in some embodiments, the crystalline compounds of the present invention are characterized by an XRPD pattern with certain peak positions that exhibit substantially identical characteristics to the XRPD patterns provided in the drawings of the present invention. According to the instrumental conditions used in this study, the diffraction peaks have an error tolerance of ±0.2°. For example, a powder X-ray diffraction pattern "substantially identical" to that provided in Figure 1 of the present invention refers to an XRPD pattern that a person skilled in the art would consider to have the same crystalline form as the compound in the XRPD pattern of Figure 1. That is, the XRPD pattern of a crystalline form may be the same as the XRPD pattern in the figure, or, more likely, it may be slightly different. Such XRPD patterns may not necessarily display all of the peaks presented in the diffraction patterns herein and / or may exhibit slight variations in the appearance, intensity, or displacement of peaks due to differences in the conditions involved in data acquisition. One skilled in the art can determine whether a sample of a crystalline compound has the same or a different crystalline form as that disclosed in the present invention by comparing its XRPD patterns. Similarly, one skilled in the art can determine whether the diffraction angles (expressed in °2θ) obtained from a given XRPD pattern are at substantially the same positions as the values ​​presented in the present invention. In the context of the present invention, the 2θ values ​​in a powder X-ray diffraction pattern are in degrees (°).

[0063] Similarly, as is well known in the field of differential scanning calorimetry (DSC), the melting peak height in a DSC curve depends on many relevant factors, such as sample preparation and instrument conditions, while the peak position is relatively insensitive to experimental details. Thus, in some embodiments, the crystalline compounds of the present invention are characterized by DSC thermograms with characteristic peak positions and exhibiting properties substantially identical to those of the DSC thermograms provided in the figures herein. According to the instrument conditions used in this test, the melting peaks have an error margin of ±3°C, ±4°C, or ±5°C. For example, a DSC curve that is "substantially identical" to Figure 2 provided herein refers to a DSC curve that a person skilled in the art would recognize as corresponding to a compound having the same crystalline form as that represented by the DSC curve in Figure 2. That is, the DSC curve may be identical to the DSC curve shown in the figure, but more likely, it may exhibit slight variations. The melting peaks of such DSC curves need not exactly match those shown in the DSC curves presented herein and / or may exhibit minor variations in peak morphology, melting enthalpy, or melting temperature resulting from differences in experimental conditions during data acquisition.

[0064] As is well understood in the field of Raman spectroscopy, the position and shape of spectral bands in a Raman spectrum depend on the frequency of scattered light resulting from the interaction between sample molecules and incident radiation. Thus, in some embodiments, the crystalline compounds of the present invention are characterized by Raman spectra that exhibit the positions and shapes of characteristic spectral bands having substantially the same properties as those of the Raman spectra provided in the figures herein. According to the instrumental conditions used in this study, the absorption peaks are within ±0.1 cm. -1 The error tolerance is .

[0065] As is well known in the field of Fourier transform infrared (FT-IR) spectroscopy, the position and shape of absorption bands in an infrared spectrum depend on the energy level transitions of covalent vibrations within the sample molecules. Thus, in some embodiments, the crystalline compounds of the present invention are characterized by FT-IR spectra that exhibit characteristic absorption band positions and shapes with properties substantially identical to those of the FT-IR spectra provided in the figures herein. According to the Chinese Pharmacopoeia (2015 Edition) General Rule 0402 "Infrared Spectrophotometry" and the experimental equipment used herein, the acceptable limits for absorption band positions are 3000 cm -1 ±5cm in the vicinity -1 , 1000cm -1 ±2cm in the vicinity -1 is.

[0066] The term "combination" refers to a crystalline form containing that tautomer, wherein the purity of the crystalline form with respect to that tautomer is at least 60%, or at least 70%, or at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%; or a crystalline form containing one or more other crystalline forms, wherein the purity of the crystalline form with respect to the other crystalline forms is at least 60%, or at least 70%, or at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%; or a crystalline form that contains other crystalline forms, where the percentage of other crystalline forms by total volume or mass is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.

[0067] "Relative intensity" means the ratio of the intensity of other peaks to the intensity of the first intense peak among all diffraction peaks in a powder X-ray diffraction pattern (XRD), when the intensity of the first intense peak is 100%.

[0068] Whenever a number having a value of N is disclosed, any number having a value of N±0.01, N±0.02, N±0.03, N±0.05, N±0.07, N±0.08, N±0.1, N±0.15, N±0.2, N±1, N±2, N±1.5, N±3, N±4, N±5, N±6, N±7, N±8, N±9, or N±10 is expressly disclosed, where "±" means plus or minus. Whenever a numerical range disclosing a lower limit, R L and an upper limit, R U , is disclosed, every number within that disclosed range is expressly disclosed.

[0069] Crystalline form C of the compound of formula (I) according to the present invention exists in a substantially pure crystalline state.

[0070] The term "substantially pure" refers to both chemical purity and polymorphic purity, and specifically refers to a crystalline form being substantially free of one or more other polymorphic forms, i.e., the purity of the crystalline form is at least 60%, or at least 70%, or at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, or the crystalline form contains other crystalline forms. The percentage of other crystals in the total volume or mass of the crystalline form is less than 30%, or less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.

[0071] The purity of the crystals of the present invention can be determined by known methods, such as powder X-ray diffraction, thermal analysis, etc. The purity of the crystals or mixed crystals of the present invention does not need to be 100% but may be at least 70%, preferably at least 80%, more preferably at least 90%, even more preferably at least 95%, and most preferably at least 98%. A purity within this range is preferred to ensure quality.

[0072] As used herein, the terms "about" and "approximately" generally refer to a deviation of ±10%, suitably ±5%, and particularly ±1% from the stated value or range. Alternatively, to those skilled in the art, the terms "about" and "approximately" mean within an accepted standard error of the mean.

[0073] As used herein, the term "solution" refers to a mixture comprising at least one solvent and at least one compound, wherein the compound is at least partially dissolved in the solvent.

[0074] As used herein, the term "solvate" refers to a solvent present on the surface, in the lattice, or on and within the surface and lattice. The solvent may be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, t-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, 1-methyl-2-pyrrolidone, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran, toluene, xylene, a mixture thereof, or the like. A specific example of a solvate is a hydrate in which the solvent on the surface, in the lattice, or on and within the surface and lattice of the material is water. The hydrate may or may not have any solvent other than water present on the surface, in the lattice, or on and within the surface and lattice of the material.

[0075] Unless otherwise specified, percentages stated throughout this specification are weight / weight (w / w) percentages.

[0076] The term "pharmaceutical composition" refers to a mixture of one or more of the compounds described herein, or physiologically / pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, such as physiologically / pharmaceutically acceptable carriers, excipients, diluents, adjuvants, vehicles, and other additional therapeutic agents, such as antidiabetic agents, antihyperglycemic agents, antilipemic agents, antihypertensive agents, antiplatelet agents, antiatherosclerotic agents, lipid-lowering agents, etc. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.

[0077] The term "Syndrome X" is also known as the metabolic syndrome condition, disease, and the disorders are described in detail in Johannsson et al., J. Clin. Endocrinol. Metab., 1997;82, 727-734, which is incorporated herein by reference.

[0078] As used herein, the terms "treat," "treating," or "treatment" of any disease or disorder, in some embodiments, refer to ameliorating the disease or disorder (i.e., delaying, preventing, or reducing the onset of the disease or at least one of its clinical symptoms). In another embodiment, "treat," "treating," or "treatment" refers to alleviating or ameliorating at least one physical parameter, including those that may not be discernible by the patient. In yet another embodiment, "treat," "treating," or "treatment" refers to physically modulating the disease or disorder (e.g., stabilizing a discernible symptom), physiologically modulating the disease or disorder (e.g., stabilizing a physical parameter), or both. In yet another embodiment, "treat," "treating," or "treatment" refers to preventing or delaying the onset or development or progression of the disease or disorder.

[0079] Pharmaceutical compositions, formulations, and methods of administration comprising the crystalline forms described in the present invention or combinations thereof. As described herein, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable adjuvant. These adjuvants include, but are not limited to, any solvent, solid excipient, adjuvant, binder, disintegrant, or other liquid excipient, dispersant, flavoring or suspending agent, surfactant, isotonicity agent, thickener, emulsifier, preservative, solid binder, or lubricant suitable for a particular target dosage form, as exemplified herein. As described below, Remington: The Science and Practice of Pharmacy, 21st Edition, 2005, edited by DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York (all of which are incorporated herein by reference in their entirety) disclose various carriers used in formulating pharmaceutically acceptable compositions and known techniques for their preparation. Except to the extent that any conventional adjuvant is incompatible with the compounds disclosed herein, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component of the pharmaceutically acceptable compositions, its use is contemplated as being within the scope of the present invention.

[0080] Some non-limiting examples of materials that can be used as pharmaceutically acceptable adjuvants include ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances, such as phosphates; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene-block polymers; wool fat; sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as calcium carbonate. sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; corn; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents; release agents; coating agents; sweeteners; flavorings; fragrances; preservatives and antioxidants.

[0081] The crystalline forms or combinations or pharmaceutical compositions disclosed herein can be administered as the sole pharmaceutical agent or in combination with one or more other additional therapeutic (pharmaceutical) agents, provided that the combination does not cause unacceptable adverse effects. This may be particularly suitable for the treatment of diabetes, diabetic complications, and other related diseases. Some non-limiting examples of these diseases include type I diabetes mellitus, type II diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications, atherosclerosis, and hypertension. As used herein, additional therapeutic agents include antidiabetic agents other than SGLT-2 inhibitors, antihyperglycemic agents, antilipid drugs, antihypertensive agents, antiplatelet agents, antiatherosclerotic agents, lipid-lowering agents, anti-inflammatory agents, or combinations thereof.

[0082] Here, examples of antidiabetic agents other than SGLT-2 inhibitors include biguanides (e.g., phenformin and metformin), sulfonylureas (e.g., acetohexamide, chlorpropamide, glibenclamide, glipizide, gliclazide, glimepiride, glipentide, gliquidone, tolazamide and tolbutamide, meglitinides), glinides (e.g., repaglinide and nateglinide), α-glucoside hydrolase inhibitors (e.g., acarbose), α-glucosidase inhibitors (e.g., adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin and salbostatin), PPAR agonists (e.g., balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone, and troglitazone), PPARα / γ dual agonists (such as CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767, and SB-219994), DPP-IV inhibitors (such as sitagliptin, vildagliptin, alogliptin, linagliptin, and saxagliptin), glucagon-like peptide-1 (GLP-1) agonists (such as exendin-3 and exendin-4), protein tyrosine phosphatase-1B (PTP-1B) inhibitors (such as trodusquemine, hiruthiosal, extracts, and Zhang, Drug Discovery Today, 12(9 / 10), 373-381, 2007), insulin, insulin analogs, glycogen phosphorylase inhibitors, VPAC2 receptor agonists, glucokinase activators, glycogen phosphorylase inhibitors or glucose-6-phosphatase inhibitors, αP2 inhibitors, acetyl-CoA carboxylase-2 (ACC-2) inhibitors, phosphodiesterase (PDE)-10 inhibitors, diacylglycerol acyltransferase (DGAT) 1 or 2 inhibitors, glucose transporter 4 (GLUT4) modulators, and glutamine-fructose-6-phosphate amidotransferase (GFAT) inhibitors.

[0083] Here, examples of the antihyperglycemic agent include biguanides (e.g., phenformin and metformin), sulfonylureas (e.g., acetohexamide, chlorpropamide, glibenclamide, glipizide, gliclazide, glimepiride, glipentide, gliquidone, tolazamide and tolbutamide, meglitinides), glinides (e.g., repaglinide and nateglinide), α-glucoside hydrolase inhibitors (e.g., acarbose), α-glucosidase inhibitors (e.g., adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin and salbostatin), PPAR agonists (e.g., balaglitazone, ciglitazone, darglitazone, englitazone), , isaglitazone, pioglitazone, rosiglitazone, and troglitazone), PPARα / γ dual agonists (such as CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767, and SB-219994), DPP-IV inhibitors (such as sitagliptin, vildagliptin, alogliptin, linagliptin, and saxagliptin), glucagon-like peptide-1 (GLP-1) agonists (such as exendin-3 and exendin-4), protein tyrosine phosphatase-1B (PTP-1B) inhibitors (such as trodusquemine, hiruthiosal, extracts, and Zhang, Drug Discovery Today, 12(9 / 10), 373-381, 2007), insulin, insulin analogs, glycogen phosphorylase inhibitors, VPAC2 receptor agonists, glucokinase activators, glycogen phosphorylase inhibitors or glucose-6-phosphatase inhibitors, αP2 inhibitors, acetyl-CoA carboxylase-2 (ACC-2) inhibitors, phosphodiesterase (PDE)-10 inhibitors, diacylglycerol acyltransferase (DGAT) 1 or 2 inhibitors, glucose transporter 4 (GLUT4) modulators, and glutamine-fructose-6-phosphate amidotransferase (GFAT) inhibitors.

[0084] Herein, the lipid-lowering drugs described in the present invention include, but are not limited to, MTP inhibitors, HMG CoA reductase inhibitors (hydroxymethylglutaryl-CoA reductase inhibitors), squalene synthase inhibitors, fibrates (fibric acid derivatives), ACAT inhibitors (acyl-coenzyme A cholesterol acyltransferase inhibitors), lipoxygenase inhibitors, cholesterol absorption inhibitors, ileal sodium / bile acid cotransporter inhibitors, LDL receptor activity upregulators, bile acid sequestrants, or nicotinic acid derivatives. In some embodiments, the lipid-lowering drug is selected from pravastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, atavastatin, and rosuvastatin. Here, the anti-obesity drug is a CB-1 antagonist (rimonabant, taranabant, surinabant, otenabant, SLV319, AVE1625, etc.), a gut-selective MTP inhibitor (dirlotapide, mitratapide, implitapide, etc.), a CCKa agonist, a 5-HT 2c Agonists (lorcaserin, etc.), MCR4 agonists, lipase inhibitors (cetilistat, etc.), PYY 336 , opioid antagonists (such as naltrexone), oleoyl-estrone, obinepitide, pramlintide, tesofensine, leptin, liraglutide, bromocriptine, orlistat, exenatide, AOD-9604, and sibutramine.

[0085] Suitable anti-inflammatory agents include those for the prevention and treatment of reproductive / urinary tract infections. Exemplary agents include cranberry (Vaccinium macrocarpon) and cranberry derivatives, such as cranberry juice, cranberry extract, or cranberry flavonols. Other suitable anti-inflammatory agents include, but are not limited to, aspirin, nonsteroidal anti-inflammatory drugs, glucocorticosteroids, sulfasalazine, and selective cyclooxygenase-2 inhibitors.

[0086] The compositions disclosed herein may be administered orally, parenterally, topically, bucally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intraocular, intrahepatic, intralesional, and intracranial injection and infusion techniques. The compositions are preferably administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions disclosed herein include aqueous and oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.

[0087] The pharmaceutically acceptable composition of the present invention may be orally administered in any acceptable oral dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions.For oral use of tablets, carriers generally include lactose and corn starch.Lubricants, such as magnesium stearate, are typically added.For oral administration of capsules, suitable diluents include lactose and dried corn starch.For oral administration as an aqueous suspension, the active ingredient is comprised of emulsifiers and suspending agents.If desired, certain sweeteners, flavors or coloring agents may also be added to these dosage forms.

[0088] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may contain known common inert diluents, such as water or other solvents, solubilizing and emulsifying agents, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoic acid (especially cottonseed, peanut, corn, peanut, olive, castor, and sesame oils), glycerol, 2-tetrahydrofuran, methanol, polyethylene glycol, diethylene glycol, 1,3-butanediol, dimethylformamide, sorbitan fatty acid esters, and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifying or suspending agents, sweeteners, flavoring agents, and perfumes.

[0089] Injectable solutions, such as sterile injectable solutions or oily suspensions, may be formulated according to techniques known in the art and formulations using suitable dispersing or wetting agents and suspending agents. Sterile injectable solutions may be non-toxic sterile injectable solutions, suspensions, or emulsions made with an acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents include water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland, fixed oil, including synthetic mono- or diglycerides, can be used in the preparation of injectable solutions, including natural pharmaceutically acceptable oils such as oleic acid, olive oil, or castor oil, especially its polyoxyethylene derivatives. These oily solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose, or similar dispersants commonly used in formulating pharmaceutically acceptable dosage forms, including emulsifying and suspending agents. Other commonly used surfactants, such as Tween, Span and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

[0090] Injectable solutions may be sterilized, for example, filtered through a bacterial filter, or in the form of a sterile solid composition, and the sterilizing agent may be dissolved or dispersed in sterile water or other sterile injectable medium. To prolong the effect of the compound of the present invention, it is generally necessary to delay the absorption of the compound by subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension to overcome the problem of poor aqueous solubility of crystalline or amorphous materials. The absorption rate of a compound depends on its dissolution rate, which in turn depends on particle size and crystalline form. In addition, delayed absorption of a compound injection can be achieved by dissolving or dispersing the compound in an oil vehicle.

[0091] Injectable depot forms are achieved by microencapsulation matrices composed of biodegradable polymers, such as poly(lactic-co-glycolic acid). The controlled release rate of the compound depends on the compound to polymer ratio and the nature of the particular polymer. Other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot forms can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0092] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these dosage forms, the active compound is combined with at least one pharmaceutically acceptable inert excipient or carrier, such as sodium citrate or calcium phosphate, and / or a) fillers, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) blocking solutions, such as paraffin; f) absorption enhancers, such as quaternary amines; g) wetting agents, such as cetyl alcohol and glyceryl monostearate; h) absorbents, such as kaolin and bentonite; i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also incorporate buffering agents.

[0093] Solid dosage forms can be prepared using coatings or capsules, such as enteric coatings, controlled-release coatings, and other well-known pharmaceutical formulation methods for producing tablets, troches, capsules, pills, and granules. In these solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms may also contain additives other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose, as is commonly used. They may optionally contain emulsifiers and may optionally have compositions that release the active ingredient in a delayed manner, or preferably in a specific part of the intestine. Examples of embedding compositions that can be used include polymeric substances and waxes. For capsules, tablets, and pills, these dosage forms may also contain buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard gelatin capsules, utilizing excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0094] The compound of the present invention or its composition is preferably formulated in a dosage form suitable for dosage reduction and dosage uniformity.The term "dosage unit form" herein refers to a physically separate unit in which a patient receives appropriate treatment.However, it should be understood that the daily general use of the compound or composition of the present invention is determined by the attending physician based on reliable medical range judgment.The specific effective dose level for any specific patient or organism depends on several factors, including the severity of the disease and condition being treated, the activity of the specific compound, the specific composition used, the patient's age, weight, health condition, sex and dietary habits, the administration time, administration route and excretion rate of the specific compound used, the duration of treatment, the use of drugs in combination or in combination with the specific compound, and other well-known factors in the field of pharmacy.

[0095] An "effective amount," "therapeutically effective amount," or "effective dose" of a crystalline compound or pharmaceutically acceptable composition is an amount that is effective in treating or reducing the severity of one or more of the aforementioned disorders. The crystalline compound and pharmaceutically acceptable composition are effective when administered over a fairly wide dosage range. For example, daily doses range from about 0.1 mg to 1000 mg per person, and can be administered in a single dose or in divided doses several times daily. The crystalline compounds and compositions according to the methods disclosed herein may be administered in any amount and using any route of administration that is effective in treating or reducing the severity of a disorder or disease. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the specific drug, its mode of administration, etc. The compound or pharmaceutical composition can also be administered with one or more other therapeutic agents as described above.

[0096] Uses of the Crystalline Forms and Pharmaceutical Compositions of the Invention The amount of the crystalline compound or crystalline compound in the pharmaceutical composition disclosed herein is an effective and detectable amount for inhibiting sodium-dependent glucose transporter (SGLT) activity, particularly SGLT-1 activity. SGLT-1 is involved in the reabsorption of D-glucose from the kidney spherule filtrate, which inhibits glucose reabsorption into blood vessels, which is beneficial for reducing blood glucose levels. Therefore, the compounds of the present invention are used for the prevention and treatment of diabetes and related diseases or for ameliorating the symptoms of these diseases.

[0097] The crystalline compounds disclosed herein are useful for preventing or treating, or alleviating, or delaying the progression or onset of diabetes or a related disorder, or increasing HDL levels in a patient, by administering an effective amount of a compound or composition disclosed herein to the patient, including, but not limited to, diabetes, particularly type 2 diabetes, and conditions such as insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia, e.g., hypertriglyceridemia, obesity, hypertriglyceridemia, Syndrome X, diabetic complications, e.g., diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, atherosclerosis, and hypertension.

[0098] Furthermore, the crystalline compounds or pharmaceutical compositions disclosed herein are also suitable for the prevention or treatment of damage in the later stages of diabetes, such as nephropathy, retinopathy, neuropathy, myocardial infarction, peripheral arterial disease, thrombosis, arteriosclerosis, inflammation, immunological diseases, autoimmune diseases such as AIDS, asthma, osteoporosis, cancer, psoriasis, Alzheimer's disease, schizophrenia and infectious diseases.

[0099] In addition to being useful for human treatment, these crystalline compounds are also useful for veterinary treatment of animals, such as companion animals, exotic animals, and farm animals, including mammals, rodents, etc. In other embodiments, animals disclosed herein include horses, dogs, and cats. As used herein, the compounds disclosed herein include pharmaceutically acceptable derivatives thereof. [Brief explanation of the drawings]

[0100] [Figure 1] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of crystalline form I of the compound represented by formula (I). [Figure 2] FIG. 1 shows a differential scanning calorimetry (DSC) curve of crystalline form I of the compound represented by formula (I). [Figure 3]FIG. 1 shows the thermogravimetric analysis (TGA) profile of crystalline form I of the compound represented by formula (I). [Figure 4] FIG. 1 shows the powder X-ray diffraction (XRPD) pattern of crystalline form II of the compound represented by formula (I). [Figure 5] FIG. 1 shows a variable temperature X-ray powder diffraction (XRPD) pattern of crystalline form I of the compound represented by formula (I). [Figure 6] FIG. 1 shows an X-ray powder diffraction (XRPD) pattern of an amorphous form of the compound represented by formula (I). [Figure 7] FIG. 1 shows a thermogravimetric analysis (TGA) profile of an amorphous form of the compound represented by formula (I). [Figure 8] FIG. 1 shows the dynamic vapor sorption (DVS) isotherm of crystalline form I of the compound represented by formula (I). [Figure 9] FIG. 1 shows a dynamic vapor sorption (DVS) isotherm of the amorphous form of the compound represented by formula (I). [Figure 10] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of the co-crystalline form B of the compound represented by formula (I) and L-proline.

[0101] General Preparation and Identification Methods The present invention will now be further illustrated by examples, which are not intended to limit the scope of the present invention.

[0102] Those skilled in the art can learn from this section how to appropriately improve experimental parameters to carry out the preparation method. It should be noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in the scope of the present invention. Those skilled in the art can clearly realize and apply the techniques disclosed herein by making some changes, appropriate modifications or combinations to the method without departing from the spirit, principle and scope of the present disclosure.

[0103] General Preparation Method The structure of the compound can be determined by nuclear magnetic resonance (e.g., 1 H-NMR and 13 The identity was determined by C-NMR. 1 H-NMR and 13 C-NMR chemical shifts (δ) were reported in parts per million (ppm). 1 H-NMR and 13 C-NMR was performed on a Bruker Ultrashield-400 spectrometer and a Bruker Avance III HD 600 spectrometer. The appropriate solvents were deuterated chloroform (CDCl), deuterated methanol (CDOD), or deuterated dimethyl sulfoxide (DMSO-d). TMS (0 ppm) or chloroform (7.25 ppm) was used as the reference standard. When peak multiplicities were reported, the following abbreviations were used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), and dt (doublet of triplets). Coupling constants, J, where indicated, were reported in hertz (Hz).

[0104] MS spectra were determined on an Agilent 6120 quadrupole LC / MS mass spectrometer.

[0105] The thin layer silica gel used was Yantai Huanghai HSGF254 silica gel plate.

[0106] The silica gel used in column chromatography was generally Qingdao Ocean Chemical Factory 300-400 mesh silica gel.

[0107] The starting materials of the present invention are known or can be purchased from Shanghai Accela Company, Energy Company, J&K Company, Chengdu Aiertai Company, Alfa Company, etc., or they can be prepared by conventional synthetic methods in the prior art.

[0108] Unless otherwise stated, reactions disclosed herein were carried out in a nitrogen atmosphere.

[0109] The term "nitrogen atmosphere" refers to an atmosphere in which the reaction flask is fitted with a balloon or stainless steel autoclave filled with approximately 1 L of nitrogen.

[0110] The term "hydrogen atmosphere" refers to the atmosphere in which the reaction flask is fitted with a balloon or stainless steel autoclave filled with approximately 1 L of hydrogen.

[0111] Unless otherwise stated, the solutions used in the examples disclosed herein were aqueous solutions.

[0112] Unless specifically indicated in the examples, reaction temperatures are room temperature, which is 20° C. to 30° C. unless otherwise specified.

[0113] The reaction temperatures and drying temperatures in the examples are the temperatures displayed by the monitoring equipment, with a tolerance of ±5°C.

[0114] Crystalline forms can be prepared by a variety of methods, including, but not limited to, crystallization or recrystallization from a suitable solvent mixture, sublimation, conversion from another solid phase, crystallization from a supercritical fluid, and atomization. Techniques for crystallizing or recrystallizing crystalline forms from a solvent mixture include, but are not limited to, solvent evaporation, lowering the temperature of the solvent mixture, seeding a supersaturated solvent mixture of the compound and / or its salt with crystals (crystal seeding), lyophilizing the solvent mixture, and adding an antisolvent to the solvent mixture. Crystalline forms can be prepared using high-yield crystallization techniques, including polycrystallization.

[0115] Crystalline forms of drugs (including polymorphs), methods of preparation, and characterization of drug crystalline forms are described in Solid-State Chemistry of Drugs, S.R. Byrn, R.R. Pfeiffer, and J.G. Stowell, 2nd ed., SSCI, West Lafayette, Indiana (1999).

[0116] In the crystallization technique using solvent, solvent is generally selected based on one or more factors, including but not limited to, the solubility of compound, the crystallization technique used, and the vapor pressure of solvent.A combination of solvents can be used, for example, compound can be solubilized in a first solvent to obtain a solution, and then anti-solvent is added to reduce the solubility of compound in the solution, and crystal-forming substance is precipitated.Anti-solvent is the solvent in which compound has low solubility.

[0117] Seed crystals can be added to any crystallization mixture to promote crystallization. Seeding can be used to control the growth of a particular polymorph and / or to control the particle size distribution of the crystalline product. Therefore, calculating the required amount of seed crystals depends on the size of the available seed crystals and the desired average diameter of the product particles, as described in "Programmed Cooling Batch Crystallizers," J. W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971, 26, 369-377. Generally, small seed crystals are required to effectively control crystal growth in a material. Small seed crystals can be produced by sieving, grinding, or pulverizing larger crystals or by microcrystallization of a solution. Care should be taken when grinding or pulverizing crystals to avoid altering the crystallinity from the desired crystalline form (i.e., becoming amorphous or another polymorph).

[0118] The cooled crystalline mixture can be filtered under vacuum, and the separated solid product can be washed with a suitable solvent (e.g., cold recrystallization solvent). After washing, the product can be dried under a nitrogen purge to obtain the desired crystalline form. The product can be analyzed using appropriate spectroscopic or analytical techniques, including, but not limited to, single crystal X-ray diffraction analysis, powder X-ray diffraction (XRPD) analysis, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FT-IR) analysis, and Raman spectroscopy, to ensure that a crystalline form of the compound has formed.

[0119] The following abbreviations are used throughout this specification: g grams; mL, ml milliliter; mmol millimole; V volume; RT room temperature 25℃±5℃; DMSO dimethyl sulfoxide.

[0120] The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the present disclosure to the specific steps described therein.

[0121] For a better understanding of the present invention, the invention is described in detail below by way of examples. [Example]

[0122] A specific synthesis method for the compound N-(2-dimethylaminoethyl)-1-[4-[4-[[5-[(2S,3R,4S,5S,6R)-6-ethyl-3,4,5-trihydroxy-tetrahydropyran-2-yl]-2-methyl-phenyl]methyl]phenyl]butanoylamino]cyclohexylformamide represented by formula (I) can be obtained by referring to Example 1 (i.e., amorphous) of International Application WO2021004498A1.

[0123] Example 1 Crystalline Form I of the compound of formula (I) 1. Preparation of Crystalline Form I During the research process, the inventors have tried various methods to prepare crystalline forms of Compound (I), such as anti-solvent addition, solvent evaporation, and slow cooling, to carry out extensive experimental studies. However, the inventors have found that crystalline forms of the free base, including crystalline Form I, cannot be obtained by conventional experimental methods, and can only be prepared by the following method:

[0124] Step 1: Preparation of L-proline co-crystal form B A compound of N-(2-dimethylaminoethyl)-1-[4-[4-[[5-[(2S,3R,4S,5S,6R)-6-ethyl-3,4,5-trihydroxy-tetrahydropyran-2-yl]-2-methyl-phenyl]methyl]phenyl]butyramido]cyclohexylformamide (50.00 g, 77.22 mmol) and L-proline (9.20 g, 78.3 mmol) was added to ethanol (150.0 mL), heated to 60°C to obtain a clear solution, and stirred for 30 minutes. The heating was stopped, and the reaction was allowed to cool to room temperature, allowing a solid to precipitate, and stirring was continued overnight. A mixed solvent of ethanol and n-heptane (100.0 mL, V エタノール :V n-ヘプタン The reaction mixture was diluted with a mixture of ethanol and n-heptane (50.0 mL x 2, V エタノール :V n-ヘプタン =1:4) and dried under vacuum at 50°C to obtain an off-white solid (40.89 g, 70.70%), which is crystalline form B of the co-crystal of the compound of formula (I) and L-proline.

[0125] The off-white solid was characterized by Empyrean powder X-ray diffraction (XRPD) analysis using Cu-Kα radiation at the following 2θ angles: 4.17°, 5.50°, 8.25°, 10.46°, 10.88°, 11.20°, 11.48°, 12.30°, 12.80°, 13.79°, 14.95°, 15.55°, 16.06°, 16.53°, 16.75°, 17.22°, 17.63°, 18.04°, 18.14°. Characteristic peaks were observed at 71°, 19.00°, 19.37°, 19.61°, 19.87°, 20.12°, 20.48°, 21.58°, 22.06°, 22.27°, 22.62°, 23.44°, 23.89°, 24.48°, 24.92°, 25.77°, 26.19°, 26.94°, 30.73°, 31.26°, 31.88°, 35.21°, 39.84°, 41.06°, and 42.33°. There is a ±0.2° margin of error.

[0126] Step 2: Preparation of Crystalline Form I of Compound of Formula (I) The L-proline cocrystal B (5.0 g, 6.77 mmol) obtained in step 1 was dissolved in a mixed solvent of ethanol and water (25.0 mL, V エタノール :V 水 The mixture was added to a 1:1 mixture of ethanol and water and heated to 40°C. A clear liquid was obtained first, and then a large amount of solid rapidly precipitated. The mixture was kept warm and stirred for 1 hour. The heating was stopped, and the reaction mixture was allowed to cool to room temperature. The filter cake was diluted with a mixed solvent of ethanol and water (5.00 mL x 2, V エタノール :V 水 =1:2) and dried in vacuo at 40°C for 60 hours to obtain a gray-white solid (3.47g, yield 82.16%).

[0127] 2. Identification of Crystalline Form I (1) Analysis and identification by Empyrean X-ray powder diffraction (XRPD) using Cu-Kα radiation showed the following characteristic peaks at angles of 2θ: 5.02°, 5.72°, 7.16°, 9.06°, 9.99°, 10.27°, 10.55°, 11.36°, 12.67°, 13.47°, 14.29°, 14.96°, 15.55° °, 16.16°, 16.84°, 16.96°, 17.68°, 18.19°, 18.36°, 18.52°, 18.94°, 19.78°, 20.64°, 21.10°, 21.44°, 21.85°, 22.22°, 22.48°, 23.08°, 23.69°, 23.80°, 25.02°, 25.43°, 25.70°, 26.38°, 26.74°, 27.18°, 27.68°, 28.62°, 29.53°, 30.01°, 30.52°, 31.08°, 31.53°, 32.01°, 32.60°, 33.34°, 33.92°, 34.28°, 34.57°, 35.31°, 35.73°, 36.25°, 36.90°, 37.37°, 37 0.86°, 38.43°, 38.92°, 39.46°, 40.00°, 40.94°, 41.54°, 41.92°, 42.39°, 42.99°, 43.48°, 44.08°, 44.72°, 46.41°, 47.24°, 48.64°, 50.41°, 51.52°, 53.19°, 53.99° and 58.28°. There is an error tolerance of ±0.2°.

[0128] (2) Analysis and identification by TA Q2000 differential scanning calorimetry: the scanning speed was 10°C / min, and the resulting DSC curve is shown in Figure 2, containing an endothermic peak at 129.31°C. There is an error tolerance of ±3°C.

[0129] (3) Analysis and identification by TA Q500 thermogravimetric analysis: The heating rate was 10°C / min, and the resulting TGA curve is shown in Figure 3. The mass loss at 150°C was 2.106%, with an error range of ±0.1%.

[0130] Example 2 Crystalline Form II of the Compound of Formula (I) 1. Preparation of Crystalline Form II Crystalline Form I of the compound of Formula (I) was placed on a sample stage for XRD variable temperature detection at 30°C, 60°C, 80°C, 100°C, 110°C, and 120°C at a heating rate of 10°C / min (each held for 3 minutes). The system was then cooled to 30°C, and XRD detection was performed at each isothermal stage. During the heating process from 60 to 120°C, Crystalline Form II was obtained. As the temperature decreased, Crystalline Form II gradually and spontaneously reverted to Crystalline Form I. The obtained variable temperature powder X-ray diffraction (VT-XRPD) pattern was essentially as shown in Figure 5. This indicates that Crystalline Form II can only exist at high temperatures and is not stable under room temperature conditions.

[0131] 2. Identification of Crystalline Form II (1) Analysis and identification by Empyrean X-ray powder diffraction (XRPD) using Cu-Kα radiation showed the following characteristic peaks at angles of 2θ: 4.90°, 5.56°, 7.00°, 8.90°, 9.82°, 10.04°, 10.33°, 11.16°, 12.46°, 13.28°, 14.06°, 14.77°, 15.28°, 15.89°, 16.29°, 16.80°, 16.99°, 17.89°, 18.31°, 18.51°, 18.92°, 19.70°, 20.31°, 20.77°, 21.17°, 21.7 1°, 21.91°, 22.15°, 22.80°, 23.08°, 23.65°, 24.75°, 25.07°, 25.57°, 25.86°, 26.39°, 27.07°, 27.30°, 27.59°, 28.24°, 29.13°, 29.77°, 30.14°, 30.15°, 30.47°, 31.00°, 31.17°, 31.38°, 31.85°, 32.41°, 33.00°, 33.57°, 34.08°, 34.93°, 36.00°, 36.32°, 37.60°, 38.68° and 39.20°. There is an error tolerance of ±0.2°.

[0132] Example 3 Amorphous Form of the Compound of Formula (I) The amorphous form can be prepared by referring to Example 1 of WO2021004498A1, and can also be obtained by the following preparation method:

[0133] Form I of the compound of formula (I) (100 mg, 0.16 mmol) was added to dichloromethane (3.0 mL) and sonicated until the sample dissolved. The filtrate was then added to a 25 mL single-neck bottle, and the solvent was removed in vacuo on a rotary evaporator at 40°C, followed by drying in vacuo at room temperature for 2 hours to give a foamy off-white solid (79 mg, 79.15% yield).

[0134] 1. Identification of Amorphous Form (1) Analysis and identification by Empyrean X-ray powder diffraction (XRPD) using Cu-Kα radiation, the resulting X-ray powder diffraction (XRPD) pattern is essentially as shown in FIG.

[0135] (2) Analysis and identification by TA Q500 thermogravimetric analysis: The heating rate was 10°C / min, and the resulting TGA curve is shown in Figure 7. The mass loss was 3.388%, with an error range of ±0.1%.

[0136] Single crystal X-ray diffraction study of crystalline form I of the compound of formula (I) Data were collected on an Agilent Technologies Gemini A Ultra diffractometer using Cu Kα radiation (λ = 1.5418 Å). The measured intensity data were indexed and processed using the CrysAlis PRO program. The unit cell parameters were determined by preliminary experiments, and a data collection strategy was developed based on the unit cell parameters.

[0137] The structure solution and refinement were carried out using the SHELX-97 program (Sheldrick, GM SHELXTL-97, Program for Crystal Structure Solution and Refinement; University of Gottingen: Gottingen, Germany, 1997), and the solution was carried out by direct methods. The derived atomic parameters (coordinates and temperature factors) were corrected by full matrix least-squares. The function to be minimized in the correction was Σ w(|F o |-|F c |) 2 R is Σ||F o |-|F c || / Σ|F o R is defined as | w =[Σ w (|F o |-|F c |) 2 / Σ w |F o |2] 1 / 2 where w is a suitable weighting function based on the observed intensity error. Difference maps were checked at every stage of refinement. The positions of the hydrogen atoms H1N and H2N were determined from the difference Fourier maps, while the positions of the other hydrogen atoms were obtained by theoretical calculations. Simulated powder X-ray diffraction patterns were calculated using Mercury software.

[0138] A single crystal of appropriate size (Crystal Form I prepared in Preparation Example 1) was selected for single crystal diffraction analysis. The selected crystal was fixed to a thin glass fiber with a small amount of petrolatum and mounted in an Agilent Technologies Gemini A Ultra diffractometer. The diffractometer was operated at a temperature of approximately 150 K, and the unit cell parameters listed in Table 1 were obtained.

[0139] [Table 1]

[0140] Stability test of the crystalline form of the present invention An appropriate amount of crystalline Form I or amorphous sample of the compound of formula (I) of the present invention was taken and spread flat on a clean Petri dish to form a thin layer with a thickness of ≦5 mm, and tested under the following conditions:

[0141] High temperature test Take an appropriate amount of test sample, place it in a flat weighing bottle, and spread it into a thin layer with a thickness of ≦5 mm. Condition the sample at 60°C and 75% relative humidity (RH) for 30 days. On the 30th day, collect the sample and test it according to the stability main investigation item. The purity of the sample was detected by HPLC and is as shown in Table 2.

[0142] High humidity test Take an appropriate amount of test sample, place it in a flat weighing bottle, and spread it into a thin layer with a thickness of ≦5 mm. Condition the sample at 25°C and 92.5% relative humidity (RH) for 30 days. On the 30th day, collect the sample and perform the test according to the stability main investigation item.

[0143] Light exposure test Take an appropriate amount of test sample, place it in a flat weighing bottle, and spread it into a thin layer with a thickness of ≦5 mm. Leave the bottle uncapped and place it in a UV-equipped light chamber under the following conditions: illuminance: 4500±500 lx, UV intensity: ≧0.7 W / m 2 , temperature: 25°C, relative humidity (RH): 60%. The samples are exposed for 15 or 30 days. On the 15th or 30th day, samples are collected and analyzed according to the key stability parameters.

[0144] Under the above experimental conditions, the collected samples were analyzed for impurity content using HPLC chromatograph by peak area normalization method. The analysis conditions are as follows:

[0145] HPLC was determined on an Agilent 1200DAD high pressure liquid chromatography spectrometer (Zorbax Eclipse Plus C18 150 × 4.6 mm chromatography column).

[0146] HPLC test conditions: run time: 30 min; column temperature: 35°C; detection wavelength: 210 nm and 225 nm; mobile phase: phase C: acetonitrile, phase D: ultrapure water; flow rate: 1.0 mL / min; gradient elution, elution ratio as shown in Table A (Table 2).

[0147] [Table 2]

[0148] [Table 3]

[0149] The test results show that under high temperature, high humidity and light exposure conditions, the amorphous form of compound of formula (I) of the present invention shows a significant increase in impurities, and the increase is particularly significant under high temperature and light exposure conditions.In contrast, Form I maintains a relatively stable chemical purity under these conditions and does not show any significant changes, thereby indicating its excellent stability and suitability for pharmaceutical use.

[0150] Moisture absorption test Test method: According to the test method specified in Part 4, "Guidelines for Drug Hygroscopicity Test," of the "Chinese Pharmacopoeia" (2015 Edition): Prepare a dry stoppered glass weighing bottle (outer diameter 50 mm, height 15 mm) and place it in a suitable constant temperature dryer (containing saturated ammonium chloride or ammonium sulfate solution at the bottom) at 25°C ± 1°C the day before the test. Using a Mettler XP205DR analytical balance, accurately weigh the empty stoppered weighing bottle and record the mass as m1. Take an appropriate amount of sample, spread it evenly in the above weighing bottle with an overall sample thickness of approximately 1 mm, accurately weigh it, and record the mass as m2. Leave the weighing bottle open and place it with the lid under the above constant temperature and humidity conditions for 24 hours. Cover the weighing bottle with the lid and accurately weigh it. Record the mass as m3. Then calculate the percentage (%) of mass increase.

[0151]

number

[0152] An appropriate amount of test sample is taken and tested for moisture absorption by a dynamic moisture sorption apparatus.

[0153] Among them, the hygroscopicity experiment DVS graphs of the crystalline form I and the amorphous form of the present invention are basically as shown in Figures 8 and 9, and the specific experimental results are shown in Table 3.

[0154] [Table 4]

[0155] According to the description of hygroscopic properties and the standard of hygroscopic mass increase (Guidelines for Hygroscopicity Testing of Drugs, General Rule 9103, Chinese Pharmacopoeia 2015 Edition, see Table 4 for details).

[0156] [Table 5]

[0157] Experimental results show that the crystalline form I of the present invention exhibits little mass gain and slight hygroscopicity.

[0158] Crystallinity experiments of the compounds of formula (I) described in this invention 1. Suspension and stirring method 50mg of compound of formula (I) was placed in a glass bottle, and a certain amount of solvent was added to each.The resulting suspension was stirred at room temperature, 50℃ and 60℃ for a certain period, and then the solid was filtered and subjected to powder X-ray diffraction test.The results are shown in the following table.No new crystal forms were obtained in all suspension stirring tests.

[0159] [Table 6]

[0160] 2. Antisolvent addition method – binary solvent system A certain amount of the compound of formula (I) was placed in a glass bottle, and a certain amount of a good solvent was added to dissolve it at a certain temperature. A certain amount of an anti-solvent, such as water, n-heptane, methyl tert-butyl ether, etc., was added dropwise. After a certain period of time, the solid was filtered and subjected to powder X-ray diffraction testing. The results are shown in the table below. No new crystalline forms were obtained in any of the experiments.

[0161] [Table 7]

[0162] 3. Antisolvent addition method - ternary solvent system crystallization method A certain amount of the compound of formula (I) was placed in a glass bottle, a certain amount of a good solvent was added, heated to a certain temperature, and stirred, and then a certain amount of a hydrotropic agent was added for dissolution. After clarification, a certain amount of an anti-solvent was added dropwise, and then cooled to room temperature or -20°C, etc. After a certain period of time, the solid was filtered and subjected to powder X-ray diffraction testing. The results are shown in the table below, and no new crystalline forms were obtained in any of the experiments.

[0163] [Table 8]

[0164] 4. Cooling crystallization method A certain amount of the compound of formula (I) was placed in a glass bottle, and a certain amount of a good solvent was added, and the mixture was heated to 77 ° C to dissolve. After cooling and crystallization, the solid was filtered out after a certain period of time and subjected to powder X-ray diffraction test. The results are shown in the table below, and no new crystalline form was obtained.

[0165] [Table 9]

[0166] 5. Melting and Cooling Method A certain amount of the compound of formula (I) is heated to 130 ° C under vacuum to melt, and is maintained at this temperature for a certain period of time, and then cooled to room temperature.After a certain period of time, the solid is collected and subjected to powder X-ray diffraction test.The results are shown in the table below, and no new crystalline form is obtained.

[0167] [Table 10]

[0168] 6. Solvent Evaporation Method A certain amount of the compound of formula (I) is dissolved in a certain solvent, and the solvent is evaporated in vacuum at 60 ° C. After a certain period of time, the solid is collected and subjected to powder X-ray diffraction test. The results are shown in the following table, and no new crystalline form is obtained.

[0169] [Table 11]

[0170] 7. Gas-solid permeation method 30 mg of the compound of formula (I) was placed in a 5 mL vial, and about 3 mL of solvent was added to another 30 mL vial. The 5 mL vial was opened and placed in a 30 mL vial. After sealing, the vial was left at room temperature for 5 days. The solid was collected and subjected to powder X-ray diffraction testing. The results are shown in the table below. No new crystalline forms were obtained in the gas-solid permeation test.

[0171] [Table 12]

[0172] 8. Polymer Derivatization Method A certain amount of the compound of formula (I) is heated and dissolved in ethyl acetate, a certain amount of polymer is added, the temperature is maintained, and after stirring for a certain period, it is cooled to room temperature.After a certain period, solid is collected and subjected to powder X-ray diffraction test.The result is shown in the following table, and no new crystalline form is obtained.

[0173] [Table 13]

[0174] The above results demonstrate that it is difficult to obtain a crystalline form of the free base of formula (I) through the numerous conventional experiments described above.

[0175] Throughout this specification, references to "one embodiment," "some embodiments," "one embodiment," "another example," "an example," "specific example," or "some examples" mean that a particular feature, structure, material, or characteristic described in connection with an embodiment or example is included in at least one embodiment or example of the present disclosure. Thus, the appearance of phrases such as "in some embodiments," "in one embodiment," "in an embodiment," "in another example," "in an example," "specific example," or "in some examples" in various places throughout this specification do not necessarily refer to the same embodiment or example of the present disclosure. Furthermore, particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments or examples. In addition, one of ordinary skill in the art may integrate and combine different embodiments, examples, or features thereof, as long as they are not mutually inconsistent.

[0176] While illustrative embodiments have been shown and described, the above embodiments cannot be construed as limiting the present disclosure, and it will be understood by those skilled in the art that changes, substitutions, and modifications can be made to the embodiments without departing from the spirit, principle, and scope of the present disclosure. All publications or patents cited herein are incorporated herein by reference.

Claims

1. The crystalline form I of formula (I) 【Chemistry 1】 The crystalline form of the compound.

2. 2. The crystalline form of claim 1, characterized by a powder X-ray diffraction pattern comprising peaks expressed as 2θ at 5.02°±0.2°, 9.99°±0.2°, 12.67°±0.2°, 14.96°±0.2°, 15.55°±0.2°, and 20.64°±0.2°.

3. 3. The crystalline form of claim 1, characterized by a powder X-ray diffraction pattern comprising peaks expressed as 2θ at 5.02°±0.2°, 9.06°±0.2°, 9.99°±0.2°, 12.67°±0.2°, 13.47°±0.2°, 14.96°±0.2°, 15.55°±0.2°, 16.16°±0.2°, 18.19°±0.2°, 20.64°±0.2°, and 25.02°±0.2°.

4. 5.02°±0.2°, 5.72°±0.2°, 7.16°±0.2°, 9.06°±0.2°, 9.99°±0.2°, 10.27°±0.2°, 10.55°±0.2°, 11.36°±0.2°, 12.67°±0.2°, 13.47°±0.2°, 14.29°±0.2°, 14.96°±0.2°, 15.55°±0.2°, 16.16°±0.2°, 16.84°±0.2°, 16.96°±0.2°, 17.68°±0.2°, 18.19°±0.2°, 18.36°±0.2°, 18.52°±0.2°, 18.94° ±0.2°, 19.78°±0.2°, 20.64°±0.2°, 21.10°±0.2°, 21.44°±0.2°, 21.85°±0.2°, 22.22°±0.2°, 22.48°±0.2°, 23.08°±0.2°, 23.69°±0.2°, 23.80°±0.2°, 25.02°±0.2°, 25.43°±0.2°, 25.70°±0.2°, 26.38°±0.2°, 26.74°±0.2°, 27.18°±0.2°, 27.68°±0.2°, 28.62°±0.2°, 29.53°±0.2°, 30.01°±0.2° .2°, 30.52°±0.2°, 31.08°±0.2°, 31.53°±0.2°, 32.01°±0.2°, 32.60°±0.2°, 33.34°±0.2°, 33.92°±0.2°, 34.28°±0.2°, 34.57°±0.2°, 35.31°±0.2°, 35.73°±0.2°, 36.25°±0.2°, 36.90°±0.2°, 37.37°±0.2°, 37.86°±0.2°, 38.43°±0.2°, 38.92°±0.2°, 39.46°±0.2°, 40.00°±0.2°, 40.94°±0.

4. The crystalline form of claim 1, characterized by an X-ray powder diffraction pattern comprising peaks expressed as 2θ at: 41.54°±0.2°, 41.92°±0.2°, 42.39°±0.2°, 42.99°±0.2°, 43.48°±0.2°, 44.08°±0.2°, 44.72°±0.2°, 46.41°±0.2°, 47.24°±0.2°, 48.64°±0.2°, 50.41°±0.2°, 51.52°±0.2°, 53.19°±0.2°, 53.99°±0.2°, and 58.28°±0.2°.

5. 5. The crystalline form of any one of claims 1 to 4, characterized by a powder X-ray diffraction pattern substantially as shown in Figure 1.

6. 6. The crystalline form of any one of claims 1 to 5, characterized by a differential scanning calorimetry thermogram comprising an endothermic peak at 129.31°C ± 3°C.

7. 7. The crystalline form of any one of claims 1 to 6, characterized by differential scanning calorimetry substantially as set out in Figure 2.

8. The following unit cell parameters for crystalline form I: Unit cell dimensions: a=5.81961Å, b=17.21305Å, c=35.51838Å, α=90°, β=90°, γ=90°; Space group: Histogram, P2 1 2 1 2 1 ; Unit cell volume: 3557.99Å 3 ; Number of asymmetric units in the unit cell Z: 4 8. The crystalline form of any one of claims 1 to 7, characterized by:

9. 8. A process for preparing crystalline Form I of the compound of formula (I) according to claim 1, comprising heating the compound of formula (I) and L-proline in an organic solvent, stirring, cooling, precipitating, and filtering to obtain a co-crystal of the compound of formula (I) and L-proline, followed by adding a mixed solvent, heating, precipitating, filtering, and drying the filter cake to obtain crystalline Form I of the compound of formula (I).

10. 10. The method of claim 9, wherein the organic solvent is selected from methanol, ethanol, isopropanol, or n-propanol, and the mixed solvent is selected from a mixed solvent of methanol and water, ethanol and water, isopropanol and water, or n-propanol and water.

11. 10. A pharmaceutical composition comprising the crystalline form of any one of claims 1 to 9, and optionally further comprising a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle, or combination thereof.

12. further comprising one or more additional therapeutic agents, wherein the additional therapeutic agents are selected from an antidiabetic agent, an antihyperglycemic agent, an antiobesity agent, an antihypertensive agent, an appetite suppressant, a lipid-lowering agent, or a combination thereof; The antidiabetic drug and antihyperglycemic drug of the present invention are independently selected from an SGLT2 inhibitor, a biguanide, a sulfonylurea, a glucosidase inhibitor, a PPAR agonist, an αP2 inhibitor, a PPARα / γ dual activator, a dipeptidyl peptidase IV inhibitor, a glinide, insulin, a glucagon-like peptide-1 inhibitor, a PTP1B inhibitor, a glycogen phosphorylase inhibitor, a glucose-6-phosphatase inhibitor, or a combination thereof, and the antiobesity drug is a central antiobesity drug, an MCH receptor antagonist, a neuropeptide Y receptor antagonist, a cannabinoid receptor antagonist, a brain-gut peptide antagonist, a lipase inhibitor, a β3 agonist, an 11β-HSD1 inhibitor, a DGAT- 12. The pharmaceutical composition of claim 11, wherein the lipid-lowering drug is selected from an MTP inhibitor, an HMG-CoA reductase inhibitor, a squalene synthase inhibitor, a betaine lipid-lowering drug, an ACAT inhibitor, a lipoxygenase inhibitor, a cholesterol absorption inhibitor, an ileal sodium / bile acid cotransporter inhibitor, an LDL receptor activity upregulator, a niacin lipid-lowering drug, a bile acid chelator, or a combination thereof; and the lipid-lowering drug is selected from pravastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, pitavastatin, rosuvastatin, or a combination thereof.

13. 13. Use of the crystalline form of any one of claims 1 to 9 or the pharmaceutical composition of claim 11 or 12 in the manufacture of a medicament, wherein the medicament is used for inhibiting SGLT1; or for improving intestinal environment; or for preventing or treating a disease, alleviating disease symptoms, or delaying progression or onset of a disease, and the disease is diabetes, diabetic complications, insulin resistance, hyperglycemia, hyperinsulinemia, hyperlipidemia, obesity, syndrome X, atherosclerosis, cardiovascular disease, congestive heart failure, hypomagnesemia, hyponatremia, renal failure, disorders related to hemoconcentration, constipation, or hypertension, The diabetic complication is diabetic retinopathy, diabetic neuropathy, or diabetic nephropathy, and the hyperlipidemia is hypertriglyceridemia.

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