Salt forms and crystals of Vanin enzyme inhibitors, and their preparation and use

Abstract

The present invention relates to a salt form and crystal of a Vanin enzyme inhibitor represented by formula I, and a method for producing and using the same, the salt form being a salt formed by a compound represented by formula I and an acid, and the crystal being selected from A-type crystal, B-type crystal, C-type crystal, and D-type crystal of the L-tartrate salt of the compound represented by formula I. The salt of the compound represented by formula I of the present invention has high stability and good water solubility, which is beneficial for enhancing oral absorption and improving bioavailability, and the preparation method is simple to operate, easy to control, has good reproducibility, and is suitable for industrial production. The crystal of the present invention has high stability, good solubility, low hygroscopicity, and has good potential for drug discovery. [Formula 1] JPEG2025507207000026.jpg32169

Description

Detailed Description of the Invention

[0001] This application claims priority to Chinese patent application CN202210272562.6, filed March 18, 2022, and Chinese patent application CN202211104893.5, filed September 9, 2022, the entire texts of which are incorporated herein by reference.

[0002] [Technical Field] The present invention relates to the field of medicine, and in particular to salt forms and crystals of Vanin enzyme inhibitors and methods for their preparation, as well as the use of said salt forms and crystals in the manufacture for the prevention and / or treatment of cardiovascular and tumor diseases.

[0003] [Background technology] Vanin-1 (vascular anti-inflammatory molecule-1) is an exonuclease with ubiquitinase activity that primarily catalyzes the hydrolysis of pantetheine to produce pantothenic acid (VB5) and 2-mercaptoethylamine. Coenzyme A (CoA), synthesized by VB5, regulates biotransformations such as fatty acid synthesis and oxidation and energy metabolism. The reversible reaction between 2-mercaptoethylamine and cystamine is an important sensor of oxidative stress. Increasing research has shown that mercaptoethylamine deficiency or reduced levels enhance γ-GCS activity, leading to increased endogenous GSH stores in tissues and preventing or eliminating tissue inflammation. Studies have shown that vanin-1 mRNA is highly expressed in the human colon, duodenum, endometrium, liver, kidney, gallbladder, and small intestine. In patients with ulcerative colitis (UC), vanin-1 expression is highly expressed, diffuse, and restricted to the brush border. Furthermore, colonic Vanin-1 expression levels remained significantly higher than those of control groups during the clinical quiescent phase of UC. In TNBS model experiments, the survival rate of Vanin-1 knockout mice (Vanin-1- / -) was significantly higher than that of model controls, and no significant weight loss was observed. Furthermore, 90% of Vanin-1- / - mice treated with cystamine died within 5 days, indicating that cystamine completely reversed the protective effect of Vanin-1 deficiency against colitis.Furthermore, histopathological analysis of mice revealed that inhibition or knockout of Vanin-1 significantly improved colonic lesions in mice (Berruyer C, et al., Vanin-1- / - mice exhibit a glutathione-mediated tissue resistance to oxidative stress. Mol. Cell Biol. 2004;24:7214-7224; Berruyer C, et al., Vanin-1 licenses inflammatory mediator production by gut epithelial cells and controls colitis by antagonizing peroxisome proliferator-activated receptor γ activity. J. Exp. Med. 2006;203:2817-2827).

[0004] Furthermore, vanin-1 is thought to play a regulatory role in cardiovascular and neoplastic diseases. Studies have demonstrated that vanin-1 regulates smooth muscle cell activation in vitro and the development of neointimal hyperplasia in response to carotid artery ligation in vivo. Polymorphisms in the VNN1 gene are associated with blood pressure and HDL levels. In SF-1 transgenic mice, vanin-1 deficiency prevents the mice from developing adrenal cortical tumors, indicating a role for vanin-1 in certain cancers. Studies in inflammatory diseases have shown that vanin-1 is highly upregulated in psoriatic skin lesions compared with normal individuals. VNN1 gene expression is also upregulated in whole blood from pediatric immune thrombocytopenia (ITP) patients, where overexpression of VNN1 is associated with the progression of chronic ITP. Furthermore, elevated vanin-1 has been detected in the urine of patients with various renal disorders, including systemic lupus erythematosus, nephrotoxicant-induced renal injury, and type 2 diabetes (Rommelaere S, et al. PPARalpha regulates the production of serum vanin-1 by liver. FEBS Lett. 2013 Nov 15;587(22):3742-8).

[0005] Chinese patent application CN2021110954656 (WO2022063197A1) disclosed the structure of formula I below:

[0006] [ka]

[0007] The compound of formula I is an effective Vanin enzyme inhibitor and has a wide range of medical applications. Therefore, to improve the above technical problems, there is a need to research and develop efficient, low-toxicity and / or long-acting pharmaceutically acceptable active ingredients.

[0008] Summary of the Invention To solve the problems present in the prior art, a first aspect of the present invention provides a pharmaceutically acceptable salt of a compound of formula I, wherein said compound of formula I is as shown below:

[0009] [ka]

[0010] The pharmaceutically acceptable salt of the compound represented by formula I is a salt formed from the compound represented by formula I and an acid.

[0011] The acid may be selected from inorganic or organic acids, such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, paracetamol, pectinic acid, persulfates, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxybenzoylbenzoic acid, ... The acidic acid may be dimethylsulfonic acid, diethylsulfonic acid, dimethyl ... Illustratively, the acid may be hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, citric acid, L-tartaric acid, succinic acid, ethanesulfonic acid, L-malic acid, L-glutamic acid, oxalic acid, D-malic acid, pamoic acid. , GiThe acid may be one selected from acetic acid, trifluoroacetic acid, lauric acid, benzoic acid and benzenesulfonic acid.

[0012] In one preferred embodiment, the pharmaceutically acceptable salt of the compound represented by formula I is one selected from the group consisting of hydrochloride, sulfate, phosphate, methanesulfonate, p-toluenesulfonate, fumarate, maleate, citrate, L-tartrate, succinate, ethanesulfonate, L-malate, L-glutamate, oxalate, D-malate, and pamoate.

[0013] In one preferred embodiment, in the pharmaceutically acceptable salt of the compound of formula I, the molar ratio of the compound of formula I to the acid may be selected from 1:1, 2:1 or 3:1, provided that the ions of the compound of formula I in the salt are charge balanced with the ions of the acid. For example, when the number of ionizable hydrogen atoms in the acid (e.g., hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, ethanesulfonic acid) is 1, the molar ratio of the compound represented by Formula I to the acid is 1:1; when the number of ionizable hydrogen atoms in the acid (e.g., sulfuric acid, fumaric acid, maleic acid, citric acid, L-tartaric acid, oxalic acid, succinic acid, malic acid, L-glutamic acid, pamoic acid) is 2, the molar ratio of the compound represented by Formula I to the acid may be 1:1 or 2:1; and when the number of ionizable hydrogen atoms in the acid (e.g., phosphoric acid) is 3, the molar ratio of the compound represented by Formula I to the acid is 1:1, 2:1, or 3:1.

[0014] In a more preferred embodiment, in the pharmaceutically acceptable salt of the compound of formula I, the molar ratio of the compound of formula I to the acid is 1:1, i.e., when the acid is L-tartaric acid, fumaric acid, or malic acid, the pharmaceutically acceptable salt is selected from the monotartrate, monofumarate, and monomalate of the compound of formula I, more preferably the mono-L-tartrate of the compound of formula I.

[0015] A second aspect of the present invention provides a method for preparing a pharmaceutically acceptable salt of a compound represented by formula I, comprising the step of reacting a compound represented by formula I with an acid to prepare a pharmaceutically acceptable salt of the compound represented by formula I.

[0016] According to an embodiment of the present invention, the preparation method includes the steps of dissolving a compound of formula I in an organic solvent A, adding an acid to react, and then adding an organic solvent B to prepare a pharmaceutically acceptable salt of the compound of formula I.

[0017] According to an embodiment of the present invention, the acid has the definition described above. In some embodiments, the acid is first dissolved in an organic solvent C to prepare an acid solution, which is then added to the reaction.

[0018] According to an embodiment of the present invention, the organic solvent A is selected from at least one of an ester, a ketone, and an alcohol. The ester may be selected from an organic carboxylic acid ester, such as methyl formate, ethyl acetate, isobutyl formate, ethyl acetate propyl, isopropyl acetate, or a combination thereof. The ketone may be selected from a ketone having 3 to 10 carbon atoms, such as acetone, butanone, pentanone, methyl ethyl ketone, 4-methyl-2-pentanone, or a combination thereof. The alcohol may be selected from an alcohol having 1 to 8 carbon atoms, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, neopentyl alcohol, or a combination thereof.

[0019] According to an embodiment of the present invention, the organic solvent B is selected from nitriles, esters, ethers, or a combination thereof. The nitriles may be selected from nitriles having 2 to 6 carbon atoms, such as acetonitrile, propionitrile, isopropionitrile, butyronitrile, or a combination thereof. The esters may be selected from organic carboxylic acid esters, such as methyl formate, ethyl acetate, isobutyl formate, ethyl propyl acetate, isopropyl acetate, or a combination thereof. The ethers may be selected from ethers having 2 to 6 carbon atoms, such as ethyl ether, propyl ether, isopropyl ether, tert-butyl ether, methyl tert-butyl ether, or a combination thereof.

[0020] According to an embodiment of the present invention, those skilled in the art should understand that the organic solvent C is selected from any organic solvent that dissolves the acid.

[0021] In some embodiments, when the acid is selected from L-tartaric acid, the organic solvent C is selected from an alcohol, which may be selected from an alcohol having 1 to 8 carbon atoms, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, neopentyl alcohol, or a combination thereof.

[0022] In the production method, the volume ratio of the organic solvent A to the organic solvent B is 1:1 to 1:5, and preferably 1:1.

[0023] In the production method, the molar ratio of the compound represented by formula I to the acid is 1:0.8 to 1:1.5, preferably 1:0.9 to 1:1.3, and more preferably 1:1.0 to 1:1.1.

[0024] According to an embodiment of the present invention, the reaction temperature is 20°C to 80°C, preferably 20°C to 60°C.

[0025] According to an embodiment of the present invention, the preparation method further comprises the step of filtering and / or drying the reaction mixture after completion to prepare and obtain a pharmaceutically acceptable salt of the compound of Formula I.

[0026] In the above production method, the drying temperature may be 30°C to 60°C, and more preferably 40°C to 50°C.

[0027] In the above production method, the drying pressure is 0 to 20 Kpa, preferably 0 to 10 Kpa, and more preferably 5 to 10 KPa.

[0028] The present invention further provides a crystal, preferably a single crystal, of the mono-L-tartrate salt of the compound of formula I, wherein the unit cell parameters of the single crystal are as shown below.

[0029] It is a monoclinic crystal and its space group is P21. a=6.3430(5)Å, b=8.8372(7)Å, β=96.577, c=24.809(2)Å, V=1381.5(2)Å 3 , Z=2.

[0030] The present invention further provides a method for producing crystals of the mono-L-tartrate salt of the compound represented by formula I, particularly a single crystal, comprising the steps of dissolving the mono-L-tartrate salt of the compound represented by formula I in solvent D and diffusing it in an atmosphere of solvent E.

[0031] The solvent D is selected from alcohol solvents, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, neopentyl alcohol, or a combination thereof.

[0032] The solvent E is selected from an ester solvent, an ether solvent, an alkane solvent, or a combination thereof. The ester solvent may be selected from an organic carboxylic acid ester, such as ethyl acetate or isopropyl acetate. The ether solvent may be selected from an ether having 2 to 6 carbon atoms, such as ethyl ether, propyl ether, isopropyl ether, tert-butyl ether, or methyl tert-butyl ether. The alkane solvent may be selected from an alkane having 1 to 8 carbon atoms, such as n-hexane or n-heptane.

[0033] A third aspect of the present invention provides a crystal of a pharmaceutically acceptable salt of the compound represented by formula I above.

[0034] In a preferred embodiment of the present invention, there is provided a crystal of the mono-L-tartrate salt of the compound represented by formula I, which is selected from the following crystal types A, B, C and D.

[0035] In some embodiments, there is provided a Form A crystal of the mono-L-tartrate salt of the compound represented by Formula I. The Form A crystal has characteristic diffraction peaks at 17.06±0.20°, 20.06±0.20°, and 22.58±0.20° in powder X-ray diffraction using Cu-Kα radiation and expressed as 2θ angles.

[0036] Preferably, the A-type crystal has characteristic diffraction peaks at 17.06±0.20°, 18.00±0.20°, 18.80±0.20°, 19.22±0.20°, 20.06±0.20°, 22.58±0.20°, 23.72±0.20°, and 24.38±0.20° in powder X-ray diffraction using Cu-Kα radiation and expressed as 2θ angles.

[0037] Preferably, the A-type crystal has characteristic diffraction peaks at 8.30±0.20°, 14.24±0.20°, 17.06±0.20°, 18.00±0.20°, 18.80±0.20°, 19.22±0.20°, 20.06±0.20°, 20.52±0.20°, 22.58±0.20°, 23.72±0.20°, 24.38±0.20°, and 25.70±0.20° in powder X-ray diffraction using Cu-Kα radiation and expressed as 2θ angles.

[0038] Preferably, the A-type crystal has a powder X-ray diffraction pattern expressed as 2θ angles using Cu-Kα radiation as shown in Table 1, with an error range of ±0.20°.

[0039] [Table 1]

[0040] Preferably, the Form A crystal has a powder X-ray diffraction spectrum essentially as shown in FIG.

[0041] According to an embodiment of the present invention, the Type A crystal is an anhydrous mono-L-tartrate salt of the compound of formula I.

[0042] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the Form A crystals shows that the first endothermic peak appears upon heating to a peak temperature of about 150.14°C.

[0043] Preferably, the type A crystal has a DSC spectrum essentially as shown in FIG.

[0044] According to an embodiment of the present invention, thermogravimetric analysis (TGA) of the A-type crystals shows that the weight loss is about 0.069% in the range of 22.03°C to 120°C.

[0045] Preferably, the Type A crystal has a TGA spectrum essentially as shown in FIG.

[0046] According to an embodiment of the present invention, the A-type crystals are irregularly shaped crystals. Preferably, the particle size of the A-type crystals is less than 10 μm.

[0047] Preferably, the type A crystal has a PLM spectrum essentially as shown in FIG.

[0048] In some embodiments, there is provided a type B crystal of the mono-L-tartrate salt of the compound represented by Formula I. The type B crystal has characteristic diffraction peaks at 19.28±0.20°, 19.94±0.20°, 21.30±0.20°, and 23.72±0.20° in powder X-ray diffraction analysis using Cu-Kα radiation and expressed as 2θ angles.

[0049] Preferably, the B-type crystals have characteristic diffraction peaks at 7.56±0.20°, 17.36±0.20°, 19.28±0.20°, 19.94±0.20°, 21.30±0.20°, 23.72±0.20°, and 26.02±0.20° in powder X-ray diffraction expressed as 2θ angles using Cu-Kα radiation.

[0050] Preferably, the B-type crystals have characteristic diffraction peaks at 7.56±0.20°, 17.36±0.20°, 18.14±0.20°, 19.28±0.20°, 19.94±0.20°, 21.30±0.20°, 23.72±0.20°, 24.52±0.20°, 26.02±0.20°, and 29.52±0.20° in powder X-ray diffraction using Cu-Kα radiation and expressed as 2θ angles.

[0051] Preferably, the B-type crystals have characteristic diffraction peaks at 3.78±0.20°, 7.56±0.20°, 17.36±0.20°, 18.14±0.20°, 19.28±0.20°, 19.94±0.20°, 21.30±0.20°, 23.72±0.20°, 24.52±0.20°, 26.02±0.20°, and 29.52±0.20° in powder X-ray diffraction using Cu-Kα radiation and expressed as 2θ angles.

[0052] Preferably, the B-type crystals have powder X-ray diffraction using Cu-Kα radiation, expressed as 2θ angles, as shown in Table 2, with an error range of ±0.20°.

[0053] [Table 2]

[0054] Preferably, the B-type crystals have a powder X-ray diffraction spectrum essentially as shown in FIG.

[0055] According to an embodiment of the present invention, the B-type crystals are a hydrate of the mono-L-tartrate salt of the compound of formula I.

[0056] According to an embodiment of the present invention, the hydrate contains 0.5 to 1 mol of water.

[0057] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the B-type crystals shows that a first endothermic peak appears upon heating to a peak temperature of about 61.57° C., and a second endothermic peak appears upon heating to a peak temperature of about 152.18° C. The first endothermic peak is a dehydration peak, and the second endothermic peak is a melting peak.

[0058] Preferably, the B-type crystals have a DSC spectrum essentially as shown in FIG.

[0059] According to an embodiment of the present invention, thermogravimetric analysis (TGA) of the B-type crystals shows that the weight loss is about 2.76% in the range of 21.34°C to 120°C.

[0060] Preferably, the B-type crystals have a TGA spectrum essentially as shown in FIG.

[0061] In some embodiments, there is provided a C-type crystal of the mono-L-tartrate salt of the compound represented by Formula I. The C-type crystal has characteristic diffraction peaks at 17.88±0.20°, 19.40±0.20°, and 21.38±0.20° in powder X-ray diffraction analysis using Cu-Kα radiation and expressed as 2θ angles.

[0062] Preferably, the C-type crystal has characteristic diffraction peaks at 7.14±0.20°, 17.88±0.20°, 19.40±0.20°, 20.06±0.20°, 21.38±0.20°, 23.76±0.20°, and 25.92±0.20° in powder X-ray diffraction using Cu-Kα radiation and expressed as 2θ angles.

[0063] Preferably, the C-type crystal has characteristic diffraction peaks at 3.58±0.20°, 7.14±0.20°, 13.96±0.20°, 17.10±0.20°, 17.88±0.20°, 19.40±0.20°, 20.06±0.20°, 21.38±0.20°, 25.92±0.20°, and 29.38±0.20° in powder X-ray diffraction using Cu-Kα radiation and expressed as 2θ angles.

[0064] Preferably, the C-type crystal has a powder X-ray diffraction pattern expressed as 2θ angles using Cu-Kα radiation as shown in Table 3, with an error range of ±0.20°.

[0065] [Table 3]

[0066] Preferably, the C-type crystal has a powder X-ray diffraction spectrum essentially as shown in FIG.

[0067] According to an embodiment of the present invention, the C-type crystals are a mono-L-tartrate solvate of the compound represented by formula I, and preferably an ethanol solvate of the mono-L-tartrate of the compound represented by formula I.

[0068] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the C-type crystals shows that a first endothermic peak appears upon heating to a peak temperature of about 129.45° C., and a second endothermic peak appears upon heating to a peak temperature of about 151.90° C. The first endothermic peak is the desolvation peak, and the second endothermic peak is the melting peak.

[0069] Preferably, the C-type crystal has a DSC spectrum essentially as shown in FIG.

[0070] According to an embodiment of the present invention, thermogravimetric analysis (TGA) of the C-type crystals shows that the weight decreases by about 4.59% in the range of 21.47°C to 150°C.

[0071] Preferably, the C-type crystals have a TGA spectrum essentially as shown in FIG.

[0072] According to an embodiment of the present invention, the C-type crystals are irregularly shaped crystals. Preferably, the particle size of the C-type crystals is less than 10 μm.

[0073] Preferably, the C-type crystal has a PLM spectrum essentially as shown in FIG.

[0074] In some embodiments, there is provided a D-type crystal of the mono-L-tartrate salt of the compound of Formula I, wherein the D-type crystal exhibits characteristic diffraction peaks at 3.50±0.20°, 7.46±0.20°, and 23.04±0.20° in powder X-ray diffraction analysis using Cu-Kα radiation and expressed as 2θ angles.

[0075] Preferably, the D-type crystal has characteristic diffraction peaks at 3.50±0.20°, 6.92±0.20°, 7.46±0.20°, 17.22±0.20°, 18.20±0.20°, 19.88±0.20°, and 23.04±0.20° in powder X-ray diffraction using Cu-Kα radiation and expressed as 2θ angles.

[0076] Preferably, the D-type crystal has characteristic diffraction peaks at 3.50±0.20°, 6.92±0.20°, 7.46±0.20°, 17.22±0.20°, 18.20±0.20°, 19.88±0.20°, 20.76±0.20°, 23.04±0.20°, and 25.62±0.20° in powder X-ray diffraction using Cu-Kα radiation and expressed as 2θ angles.

[0077] Preferably, the D-type crystal has a powder X-ray diffraction pattern expressed as 2θ angles using Cu-Kα radiation as shown in Table 4, with an error range of ±0.20°.

[0078] [Table 4]

[0079] Preferably, the D-type crystal has a powder X-ray diffraction spectrum essentially as shown in FIG.

[0080] According to an embodiment of the present invention, the D-type crystals are a mono-L-tartrate solvate of the compound represented by formula I, and preferably a tetrahydrofuran solvate of the mono-L-tartrate of the compound represented by formula I.

[0081] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the D-type crystals shows that a first endothermic peak appears when heated to a peak temperature of about 94.15° C., a second endothermic peak appears when heated to a peak temperature of about 118.79° C., and a third endothermic peak appears when heated to a peak temperature of about 146.04° C. The first and second endothermic peaks are desolvation peaks, and the third endothermic peak is a melting peak.

[0082] Preferably, the D-type crystal has a DSC spectrum essentially as shown in FIG.

[0083] According to an embodiment of the present invention, thermogravimetric analysis (TGA) of the D-type crystals shows that the weight loss is about 5.25% in the range of 23.19°C to 120°C.

[0084] Preferably, the D-type crystal has a TGA spectrum essentially as shown in FIG.

[0085] A fourth aspect of the present invention provides a method for preparing a crystal of a pharmaceutically acceptable salt of the compound represented by formula I.

[0086] According to a preferred embodiment of the present invention, there is provided a method for producing crystals of the mono-L-tartrate salt of the compound represented by formula I.

[0087] In some embodiments, there is provided a method for producing Form A crystals of the mono-L-tartrate salt of the compound represented by formula I, comprising stirring the mono-L-tartrate salt of the compound represented by formula I in a solvent to obtain the Form A crystals.

[0088] The stirring temperature is 20 to 80°C, and preferably 25 to 55°C.

[0089] The solvent is selected from alcohol-based solvents, ester-based solvents, ketone-based solvents, ether-based solvents, alkane-based solvents, haloalkane-based solvents, and nitrile-based solvents, or a combination thereof.

[0090] The alcohol solvent is one selected from methanol, ethanol and isopropanol.

[0091] The ester solvent is one selected from ethyl acetate, propyl acetate, and isopropyl acetate.

[0092] The ketone solvent is one selected from acetone, 2-butanone, methyl isobutyl ketone, and 4-methyl-2-pentanone.

[0093] The ether solvent is one selected from ethyl ether, propyl ether, isopropyl ether, methyl tert-butyl ether and tetrahydrofuran.

[0094] The alkane solvent is one selected from toluene, n-heptane, and cyclohexane.

[0095] The nitrile solvent is one selected from acetonitrile, phenylacetonitrile, and benzonitrile.

[0096] The mass / volume ratio of the mono-L-tartrate salt of the compound represented by formula I to the solvent is 1 g:(20 to 40) ml, and preferably 1 g:(20 to 30) ml.

[0097] In some embodiments, there is provided a second method for producing Type A crystals of the mono-L-tartrate salt of the compound represented by formula I, the method comprising the steps of adding and dissolving the mono-L-tartrate salt of the compound represented by formula I in an alcoholic solvent, then adding an anti-solvent and stirring to obtain the Type A crystals.

[0098] The alcohol solvent is one selected from methanol, ethanol, propanol and isopropanol.

[0099] The anti-solvent is one or more of an ether-based solvent or an ester-based solvent. The ether-based solvent is one selected from ethyl ether, propyl ether, isopropyl ether, and methyl tert-butyl ether. The ester-based solvent is one selected from ethyl acetate, propyl acetate, and isopropyl acetate.

[0100] The mass / volume ratio of the mono-L-tartrate salt of the compound represented by formula I to the alcoholic solvent and antisolvent is 1 g:(10-30) ml:(80-120) ml, preferably 1 g:(15-25) ml:(90-110) ml.

[0101] According to an embodiment of the present invention, the first or second method for producing type A crystals further includes post-treatment steps such as filtration and drying.

[0102] In some embodiments, there is provided a method for producing Type B crystals of the mono-L-tartrate salt of the compound of Formula I, comprising the step of subjecting the Type A crystals to high humidity conditions to obtain Type B crystals, preferably for 2 days or more, more preferably for 3 days or more.

[0103] The high humidity conditions are 80% to 100% RH, and preferably 90% to 100% RH.

[0104] In some embodiments, there is provided a second method for producing type B crystals of the mono-L-tartrate salt of the compound represented by formula I, the method comprising dissolving the mono-L-tartrate salt of the compound represented by formula I in an alcoholic solvent and evaporating the solvent to obtain type B crystals.

[0105] The alcohol solvent is one selected from methanol, ethanol and isopropanol.

[0106] The dissolution temperature is 15 to 45°C, and preferably 25 to 35°C.

[0107] The mass / volume ratio of the mono-L-tartrate salt of the compound represented by formula I to the alcoholic solvent is 1 g:(10 to 30) ml, and preferably 1 g:(15 to 25) ml.

[0108] In some embodiments, there is provided a method for producing type C crystals of the mono-L-tartrate salt of the compound represented by formula I, comprising dissolving the mono-L-tartrate salt of the compound represented by formula I in an alcoholic solvent and crystallizing the solution to obtain the type C crystals.

[0109] The alcoholic solvent is selected from methanol, ethanol and / or isopropanol, preferably methanol.

[0110] The mass / volume ratio of the mono-L-tartrate salt of the compound represented by formula I to the alcoholic solvent is 1 g:(20 to 40) ml, and preferably 1 g:(20 to 30) ml.

[0111] According to an embodiment of the present invention, the method for producing the C-type crystals further includes post-treatment steps such as filtration and drying.

[0112] In some embodiments, there is provided a method for producing type D crystals of the mono-L-tartrate salt of the compound represented by formula I, comprising the steps of dissolving the mono-L-tartrate salt of the compound represented by formula I in an ethereal solvent, heating and stirring the mixture, cooling the mixture, and then precipitating a solid to obtain the type D crystals.

[0113] The ether solvent is one selected from ethyl ether, tetrahydrofuran, and methyl tert-butyl ether, and is preferably tetrahydrofuran.

[0114] The heating temperature is 30°C to 80°C, and preferably 45°C to 75°C.

[0115] The cooling temperature is 20°C to 30°C.

[0116] The mass / volume ratio of the mono-L-tartrate salt of the compound represented by formula I to the ether solvent is 1 g:(20 to 40) ml, and preferably 1 g:(20 to 30) ml.

[0117] According to an embodiment of the present invention, the method for producing the D-type crystals includes post-treatment steps such as filtration and drying.

[0118] The present invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable salt of the compound represented by formula I or a crystal thereof, and optionally pharmaceutically acceptable pharmaceutical adjuvants. In a preferred embodiment of the present invention, the pharmaceutically acceptable salt is the mono-L-tartrate salt of the compound represented by formula I, and the crystal is selected from Type A, Type B, Type C, and Type D crystal of the mono-L-tartrate salt of the compound represented by formula I. Preferably, the pharmaceutical composition is in the form of a formulation.

[0119] The present invention further provides a formulation comprising the pharmaceutically acceptable salt or a crystal thereof of the compound represented by formula I, and optionally pharmaceutically acceptable pharmaceutical auxiliaries. In a preferred embodiment of the present invention, the pharmaceutically acceptable salt is the mono-L-tartrate salt of the compound represented by formula I, and the crystal is selected from the group consisting of Type A, Type B, Type C, and Type D crystals of the mono-L-tartrate salt of the compound represented by formula I.

[0120] The present invention further provides use of a pharmaceutically acceptable salt of the compound represented by formula I described above or a crystal thereof, or said pharmaceutical composition, in the manufacture of a medicament for preventing and / or treating a disease or condition associated with a Vanin enzyme inhibitor.

[0121] According to an embodiment of the present invention, the diseases or conditions associated with the Vanin enzyme inhibitors include one or more of autoimmune diseases, inflammatory diseases, allergic diseases, metabolic diseases, infectious diseases, fibrotic diseases, cardiovascular diseases, respiratory diseases, kidney diseases, skin diseases, liver diseases, gastrointestinal diseases, oral diseases and hematopoietic diseases, and are, for example, Crohn's disease, inflammatory bowel disease and ulcerative colitis.

[0122] The present invention further provides a method for preventing and / or treating a disease or condition associated with a Vanin enzyme inhibitor, comprising administering to an individual in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of the compound represented by formula I or a crystal thereof, or the pharmaceutical composition.

[0123] According to an embodiment of the present invention, the diseases or conditions associated with the Vanin enzyme inhibitors include one or more of autoimmune diseases, inflammatory diseases, allergic diseases, metabolic diseases, infectious diseases, fibrotic diseases, cardiovascular diseases, respiratory diseases, kidney diseases, skin diseases, liver diseases, gastrointestinal diseases, oral diseases and hematopoietic diseases, and are, for example, Crohn's disease, inflammatory bowel disease and ulcerative colitis.

[0124] The treatment method of the present invention can include administering one, two or more pharmaceutically acceptable salts of the compound represented by formula I of the present invention or crystals thereof alone, and administering one, two or more pharmaceutically acceptable salts of the compound represented by formula I of the present invention or crystals thereof in combination with other chemotherapeutic agents. In the combined administration, different drugs can be administered simultaneously or sequentially.

[0125] Those skilled in the art will understand that the terms "... or combinations thereof" and "one or more of" used herein are equivalent to "one, two or more of" and that either one, two or more combinations of each alternative may be used (i.e., a combination of two alternatives is not excluded).

[0126] Beneficial effects (1) The salts of the compound represented by formula I of the present invention have high stability, and in particular, the mono-L-tartrate salt has high solubility in water, which is beneficial for increasing oral absorption and improving bioavailability.

[0127] (2) The method for producing the salt of the compound of formula I of the present invention is simple in operation, easy to control, has good reproducibility, and is suitable for industrial production.

[0128] (3) The four crystals of the mono-L-tartrate salt of the compound represented by formula I of the present invention have high stability, good solubility, low hygroscopicity, and good potential for drug discovery.

[0129] (4) The preparation methods for the four crystals of the mono-L-tartrate salt of the compound represented by formula I of the present invention are simple, the reaction conditions are mild, and the product yields are high, which is advantageous for industrial production.

[0130] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is an XRPD pattern of crystalline form A of the L-tartrate salt of the compound represented by formula I. [Figure 2] DSC pattern of type A crystals of the L-tartrate salt of the compound represented by formula I. FIG. 3 is a TGA pattern of type A crystals of the L-tartrate salt of the compound of formula I. [Figure 4] PLM pattern of type A crystals of the L-tartrate salt of the compound represented by formula I. [Figure 5] XRPD pattern of type B crystals of the L-tartrate salt of the compound represented by formula I. FIG. 6 is a DSC pattern of type B crystals of the L-tartrate salt of the compound of formula I. FIG. 7 is a TGA pattern of type B crystals of the L-tartrate salt of the compound of formula I. FIG. 8 is an XRPD pattern of crystalline form C of the L-tartrate salt of the compound of formula I. FIG. 9 is a DSC pattern of the C-form crystals of the L-tartrate salt of the compound of formula I. FIG. 10 is a TGA pattern of type C crystals of the L-tartrate salt of the compound of formula I. [Figure 11] PLM pattern of C-type crystals of the L-tartrate salt of the compound represented by formula I. FIG. 12 is an XRPD pattern of crystalline form D of the L-tartrate salt of the compound of formula I. FIG. 13 is a DSC pattern of the D-form crystals of the L-tartrate salt of the compound of formula I. FIG. 14 is a TGA pattern of D-form crystals of the L-tartrate salt of the compound of formula I. FIG. 15 is an XRPD pattern of type A crystals of the L-tartrate salt of the compound represented by formula I in Example 7. FIG. 16 is an XRPD pattern of type B crystals of the L-tartrate salt of the compound of formula I in Example 9. FIG. 17 is an XRPD pattern of crystalline Form A of the L-tartrate salt of compound of Formula I after storage under high temperature and humidity conditions for 3 days. FIG. 18 is an XRPD pattern of crystalline Form A of the L-tartrate salt of compound of Formula I after storage under high temperature and humidity conditions for 2 days. FIG. 19 is a single crystal pattern of the mono-L-tartrate salt of the compound of formula I.

[0131] [Mode for Carrying Out the Invention] The technical solutions of the present invention will be described in more detail below in combination with specific embodiments. It should be understood that the following examples are only for illustrating the present invention and do not limit the scope of the present invention. All technologies realized based on the above content of the present invention belong to the scope of the present invention.

[0132] Unless otherwise specified, all raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0133] 40℃ / 75%RH-open refers to the state when left open under conditions of 40℃ and 75% humidity.

[0134] 60℃-open refers to the state when left open at 60℃.

[0135] 80%RH open refers to the state when left open under 80% humidity conditions.

[0136] What is 92.5%RH-open? 92.5 This refers to the state when the product is left open under humidity conditions of 100%.

[0137] 40℃ / 75%RH-closed-2wks refers to a condition in which the product is left sealed and stored at 40℃ and 75% humidity for two weeks.

[0138] 40℃ / 75%RH-open-2wks refers to a condition in which the product is left open for two weeks under conditions of 40℃ and 75% humidity.

[0139] 60℃-closed-2wks refers to a state in which the product has been left sealed at 60℃ for two weeks.

[0140] STD-1 refers to the control sample.

[0141] Initial refers to the initial state.

[0142] SGF refers to simulated gastric fluid.

[0143] FaSSIF refers to simulated intestinal fluid in a fasting state FeSSIF refers to fed-state simulated intestinal fluid.

[0144] 1d refers to 1 day and 3d refers to 3 days.

[0145] Experimental equipment parameters X-ray powder diffraction (XRPD) The equipment is a Shimadzu XRD-6000 and the sample is scanned according to the following parameters:

[0146] The X-ray source is a CuKα target (1.54056 Å).

[0147] The minimum operating voltage and current of the light tube are 40kV and 30mA respectively. The 2-Theta value of the scanning range of the sample is 2° to 50°, and the scanning speed is 5 deg / min.

[0148] Thermogravimetric analysis (TGA) Approximately 5 mg of sample is weighed into a crucible, protected with nitrogen gas, and heated from 30°C to 300°C at a heating rate of 20°C / min, and maintained at 300°C for 1 min.

[0149] Differential scanning calorimetry (DSC) Approximately 1–5 mg of powder sample was weighed into a sealed aluminum crucible with a hole drilled in the lid. Protected by nitrogen gas, the sample was heated from 30°C to 300°C and maintained at 300°C for 1 min. The heating rate was 20°C / min.

[0150] Polarized Light Microscope (PLM) The sample was dispersed in a medium (silicone oil), and the sample was observed with a 10x eyepiece and a 10x objective lens, and images were recorded using a camera computer system.

[0151] Dynamic Water Sorption (DVS) Approximately 10 mg of sample was weighed and subjected to a relative humidity (RH) cycle of 0% to 95% to 0% at 25°C to carry out a moisture absorption / desorption test, with the parameters as shown below.

[0152] [Table 5]

[0153] Single crystal test equipment and test conditions: Instrument model: D8 Venture Instrument parameters: Light source: Cu target X-ray: Cu-Kα (=1.54Å) Detector: CMOS area detector Resolution: 0.80Å Current voltage: 50 kV, 1.2 mA Exposure time: 50 s Distance from area detector to sample: 40 mm Test temperature: 170(2)K Preparation of Intermediate 1f and Compounds of Formula I (1) Preparation of Intermediate 1f

[0154] [ka]

[0155] 2-Chloropyrimidine-5-carboxylic acid (284 g, 1.78 mol) and 8-oxa-2-azaspiro[4.5]decane hydrochloride (310 g, 1.78 mol) were dissolved in dichloromethane and cooled to -10 °C. T3P (625 g, 1.78 mol) was slowly added dropwise. After the addition was completed, the reaction was continued at the same temperature for 2 hours. After the completion of the reaction was detected by LCMS, water was added, the mixture was stirred, and the solid precipitated, filtered, and dried to obtain compound 1f (350 g, purity 98%).

[0156] 1H NMR (400 MHz, CDCl3):δ8.80 (s, 2H), 3.81-3.57 (m, 7H), 3.36 (s, 1H), 1.93 (td, J = 14.58, 7.25 Hz, 2H), 1.66 (t, J = 5.35 Hz, 2H), 1.58 (dd, J = 11.10, 4.64 Hz, 2H).

[0157] (2) Preparation of Compounds Represented by Formula I

[0158] [ka]

[0159] Step 1 Compound 1b (385 g, 3.18 mol) and tetraethyl titanate (905 g, 3.97 mol) were dissolved in toluene (3 L), stirred, heated to 110 °C, and refluxed. To the reaction solution, a toluene solution (500 mL) of compound 1a (352 g, 2.65 mol) was added dropwise. After the addition was complete, the mixture was heated and refluxed for 1 hour. Upon completion of the reaction, the reaction was stopped, cooled to room temperature, and concentrated to remove the toluene. The residue was quenched with water (400 mL), diluted with ethyl acetate (1000 mL), and filtered through diatomaceous earth. The filtrate was separated, and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to remove the solvent. The residue was stirred with MTBE (100 mL) and petroleum ether (300 mL), filtered, and the filtrate was concentrated to give compound 1c (500 g, 80% yield).

[0160] Step 2 Compound 1c (500 g, 2.1 mol) was dissolved in THF (3000 mL) and cooled to -60 °C. L-tri-sec-butyllithium borohydride (2510 mL, 2.51 mol) was then slowly added dropwise. After the addition was complete, the mixture was stirred at -60 °C. After the reaction was complete, 1000 mL of water was slowly added to quench the reaction. The mixture was concentrated to remove most of the THF. Extraction was performed with ethyl acetate (500 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (200 mL) and dried. The solvent was removed by distillation under reduced pressure, and the crude product 1d was used directly in the next step.

[0161] Step 3 The crude product 1d was dissolved in methanol (500 mL) and HCl / MeOH (200 mL, 4 M) was slowly added. The reaction solution was allowed to react at room temperature for 2 h. After completion of the reaction, the reaction solution was concentrated to give an oil, which was then stirred with ethyl acetate (100 mL) and filtered to give compound 1e as a red solid powder (300 g, ee value 98%, purity 99%).

[0162] Step 4 Compound 1e (284 g, 1.375 mol), compound 1f (350 g, 1.25 mol), and K2CO3 (862.5 g, 6.25 mol) were dissolved in isopropanol (400 mL) and heated to reflux overnight. After completion of the reaction, the mixture was cooled, filtered, and the filtrate was concentrated. The residue was dissolved in water (300 mL), the pH was adjusted to 8-9 with dilute hydrochloric acid (2N), extracted with dichloromethane (200 mL x 3), washed with saturated sodium chloride solution (200 mL x 1), dried, and concentrated to give compound of Formula I (374 g).

[0163] 1H NMR (400 MHz, CD3OD) δ 8.58 (s, 2H), 8.37 (d, J = 5.1 Hz, 1H), 7.77 (s, 1H), 7.26 (d, J = 2.5 Hz, 1H), 5.72 (t, J = 7.7 Hz, 1H), 4.53 (s, 2H), 3.80 - 3.58 (m, 7H), 3.54 (d, J = 18.8 Hz, 2H), 3.15 (ddd, J = 16.9, 9.2, 3.7 Hz, 1H), 3.02 (dt, J = 16.8, 8.5 Hz, 1H), 2.68 (dq, J = 12.8, 4.4 Hz, 1H), 2.14 - 2.02 (m, 1H), 1.93 (q, J = 8.1 Hz, 2H), 1.67 (d, J = 5.8 Hz, 2H), 1.59 (d, J = 5.7 Hz, 2H).

[0164] Example 1 Preparation of the mono-L-tartrate salt of the compound of formula I

[0165] [ka]

[0166] The compound of formula I (1 g) was dissolved in acetone (18 ml), and an ethanol solution (2 mol / L) of L-tartaric acid (1.24 ml) was added, followed by stirring overnight. Isopropyl acetate (18 ml) was then added to obtain a solid, which was filtered and vacuum-dried under reduced pressure to obtain the L-tartrate salt of the compound of formula I (the molar ratio of the compound of formula I to L-tartaric acid was 1:1, i.e., mono-L-tartrate salt was obtained).

[0167] The L-tartrate salt (50 mg) of the compound represented by Formula I was placed in an 8 mL vial, added with 1 mL of methanol, and dissolved by ultrasonication. The resulting solution was filtered, and the filtrate was placed in a new 8 mL vial. The 8 mL vial was then placed in a 40 mL vial with 4 mL of methyl tert-butyl ether added through the opening, and the cap of the 40 mL vial was tightened to allow single crystal cultivation. The single crystal data for the mono-L-tartrate salt of the compound represented by Formula I are shown below.

[0168] [Table 6]

[0169] A single crystal of the mono-L-tartrate salt of the compound of formula I is shown in FIG.

[0170] Example 2 Preparation of the fumarate salt of the compound of formula I The compound of formula I (536 mg) was dissolved in acetone (10 ml), fumaric acid (161.4 mg) was added, and the mixture was stirred overnight. Then, isopropyl acetate (10 ml) was added, and the mixture was stirred to obtain a solid. The solid was filtered and dried under reduced pressure to obtain the fumarate salt of the compound of formula I.

[0171] Example 3 Preparation of the D-Malate Salt of the Compound of Formula I The compound of formula I (517 mg) was dissolved in isopropyl acetate (10 ml), D-malic acid (187.4 mg) was added, and the mixture was stirred until the solution became viscous. Further isopropyl acetate (10 ml) was added to obtain a white viscous solid, which was filtered and dried under vacuum under reduced pressure to obtain the D-malate salt of the compound of formula I.

[0172] Example 4 Stability Test of Mono-L-Tartrate, Mono-Fumarate, and Mono-D-Malate of Compound of Formula I The stability of the mono-L-tartrate, mono-fumarate and mono-D-malate salts of the compounds of formula I obtained in Examples 1 to 3 was tested.

[0173] Stability test conditions: 40℃ / 75%RH-closed, 40℃ / 75%RH-open, 60℃-closed; Stability test contents: changes in related substances and crystals.

[0174] Detection of related substances: Approximately 5 mg of sample was weighed into each 40 mL sample vial, dissolved in 10 mL of 50% acetonitrile aqueous solution, diluted to the mark, and 5 μL was injected. The chromatographic conditions are as shown in Table 5.

[0175] The experimental results of the stability test of the mono-L-tartrate, mono-fumarate and mono-D-malate salts of the compound of formula I are shown in Table 6.

[0176] [Table 7]

[0177] [Table 8]

[0178] From Table 6, it can be seen that the chemical stability of the L-tartrate, fumarate, and D-malate salts of the compound of Formula I, especially the L-tartrate salt of the compound of Formula I, remained good under accelerated high humidity and high temperature conditions.

[0179] Example 5 Solubility Test of the Compound of Formula I and Its L-Tartrate, Fumarate, and D-Malate Salts The compound of formula I and its L-tartrate, fumarate, and D-malate salts were tested for solubility in water, SGF, FaSSIF, and FeSSIF, pH 7.4, at 37°C.

[0180] Experimental method: 30 mg (in water) or 15 mg of sample was weighed into a 4 mL vial, 3 mL of test medium was added, and stirring was continued under 37 °C. 0.5 mL samples were taken at 1 hour and 24 hours, respectively, and centrifuged at 12,000 rpm for 5 minutes. The supernatant was diluted appropriately with 50% acetonitrile and its concentration was measured. The chromatographic conditions for the solubility test are shown in Table 7.

[0181] Control and Linearity: Compound I was not suitable as a control due to its high hygroscopicity and excessive impurities. Therefore, the fumarate salt of compound I (13 mg) was weighed into a 25 mL volumetric flask (approximately 10 mg of the free base, 25 mL volumetric flask), dissolved in 50% acetonitrile, diluted to the mark, and prepared in duplicate. STD-1 was taken and diluted with 50% acetonitrile to 200 μg / mL, 50 μg / mL, and 10 μg / mL, and 5 μL was injected to construct a standard curve.

[0182] The results of the solubility test of the compound of formula I and its L-tartrate, fumarate, and D-malate salts are shown in Table 8.

[0183] [Table 9]

[0184] [Table 10] JPEG0007802955000016.jpg124169

[0185] Table 8 shows that the compound represented by formula I and its mono-L-tartrate, mono-fumarate, and mono-D-malate salts all have good solubility and can be completely dissolved in each medium up to the target concentration of 5 mg / mL or 10 mg / mL calculated as the free base.

[0186] Example 6: Method for producing A-type crystals 400 mg of the mono-L-tartrate salt of the compound of formula I (prepared according to Example 1) was taken, and 10 mL of acetone was added thereto, followed by stirring, centrifuging, and vacuum drying at 40°C under reduced pressure to obtain type A crystals.

[0187] XRPD, DSC, TGA and PLM characterization was carried out on the Form A crystals.

[0188] The A-type crystals were anhydrous. The positions and intensities of the characteristic XRPD peaks are shown in Table 1, and the XRPD spectrum is shown in Figure 1.

[0189] DSC showed that the first endothermic peak appeared upon heating to a peak temperature of 150.14° C., as shown in FIG.

[0190] TGA showed a weight loss of 0.069% in the range from 22.03°C to 120°C, as shown in Figure 3.

[0191] The PLM spectrum shows that the sample is composed of irregularly shaped crystals of less than 10 μm, as shown in FIG.

[0192] The XRPD spectrum of the A-type crystal is a powder X-ray diffraction spectrum expressed in 2θ angles, and the 2θ values ​​are as shown in Table A below.

[0193] [Table 11]

[0194] Example 7 Method for producing A-type crystals 500 mg of the mono-L-tartrate salt of the compound of formula I (prepared according to Example 1) was dissolved in 10 ml of methanol, and then 60 ml of methyl tert-butyl ether was added. The mixture was stirred for 1.5 hours, centrifuged, filtered, and dried to obtain the above-mentioned Type A crystals.

[0195] The XRPD spectrum of the A-type crystal is shown in FIG.

[0196] Example 8: Method for producing B-type crystals 500 mg of type A crystals of the mono-L-tartrate salt of the compound of formula I was exposed to 92.5% RH for 3 days to obtain type B crystals.

[0197] XRPD, DSC, TGA and PLM characterizations were carried out on the B-type crystals.

[0198] The B-type crystals were hydrates containing 0.5 to 1 mol of water. The positions and intensities of the characteristic XRPD peaks are shown in Table B, and the XRPD spectrum is shown in Figure 5.

[0199] DSC showed that the first endothermic peak appeared upon heating to a peak temperature of about 61.57° C. and the second endothermic peak appeared upon heating to a peak temperature of about 152.18° C., as shown in FIG.

[0200] TGA showed a weight loss of 2.76% in the range from 22.03°C to 120°C, as shown in Figure 7.

[0201] The XRPD spectrum of the B-type crystal is a powder X-ray diffraction spectrum expressed in 2θ angles, and the 2θ values ​​are as shown in Table B below.

[0202] [Table 12]

[0203] Example 9: Method for producing B-type crystals 414 mg of the mono-L-tartrate salt of the compound of formula I (prepared according to Example 1) was taken, and 10 mL of methanol was added to completely dissolve it. After that, the solvent was evaporated naturally to obtain a white solid, which was dried under reduced pressure to obtain type B crystals.

[0204] The XRPD spectrum of the B-type crystals is shown in FIG.

[0205] Example 10: Method for producing C-type crystals 410 mg of the mono-L-tartrate salt of the compound of formula I (prepared according to Example 1) was taken, and 16 mL of ethanol was added thereto. The mixture was stirred at 50°C for 1 day, and then cooled to room temperature. A white solid precipitated out, which was filtered and vacuum-dried under reduced pressure to obtain type C crystals.

[0206] XRPD, DSC, TGA and PLM characterizations were carried out on the C-form crystals.

[0207] The C-type crystals were found to be solvates of ethanol.

[0208] The positions and intensities of the characteristic XRPD peaks are shown in Table C, and the XRPD spectrum is shown in FIG.

[0209] DSC showed that the first endothermic peak appeared upon heating to a peak temperature of 129.45° C., as shown in FIG.

[0210] TGA showed a weight loss of 4.59% in the range of 21.47°C to 150°C, as shown in Figure 10.

[0211] The XRPD spectrum of the C-type crystal is a powder X-ray diffraction spectrum expressed in 2θ angles, and the 2θ values ​​are as shown in Table C below.

[0212] [Table 13]

[0213] The PLM spectrum shows that the sample is composed of irregularly shaped crystals of less than 10 μm, as shown in FIG.

[0214] Example 11: Method for producing D-type crystals 410 mg of the mono-L-tartrate salt of the compound of formula I (prepared according to Example 1) was taken, and 12 mL of tetrahydrofuran was added. The mixture was stirred at 50°C for 1 day, and then cooled to room temperature. A white solid precipitated out, which was filtered and dried under vacuum under reduced pressure to obtain type D crystals.

[0215] XRPD, DSC, and TGA characterization were performed on the D-type crystals.

[0216] The D-type crystals were found to be solvates of tetrahydrofuran.

[0217] The positions and intensities of the characteristic XRPD peaks are shown in Table D, and the XRPD spectrum is shown in FIG.

[0218] DSC showed that the first endothermic peak appeared upon heating to a peak temperature of 94.15° C., as shown in FIG.

[0219] TGA showed a weight loss of 5.25% in the range from 23.19°C to 120°C, as shown in Figure 14.

[0220] The XRPD spectrum of the D-type crystal is a powder X-ray diffraction spectrum expressed as 2θ angles, and the 2θ values ​​are as shown in Table D below.

[0221] [Table 14]

[0222] Example 12 Stability test of type A crystals The A-type crystals were placed under the conditions of 40°C / 75% RH-open, 60°C-open, 80% RH-open, and 92.5% RH-open, and were taken out on the third day to check the changes in the crystals.

[0223] In addition, samples placed at 40°C / 75% RH-closed, 40°C / 75% RH-open, and 60°C-open were removed after 2 weeks and the stability of related substances and crystals was tested.

[0224] Stability sample related substance detection method: Approximately 5 mg of sample was weighed, 20% methanol (5 mL) was added, and the compound was completely dissolved by sonication for a few seconds, and 5 μL was injected to perform the related substance test.

[0225] The XRPD patterns of the A-type crystals after being left under high temperature and high humidity conditions for 3 days and 2 weeks are shown in Figures 17 and 18, respectively.

[0226] [Table 15]

[0227] [Table 16]

[0228] As shown in Table 9 and Figures 17 and 18, the A-type crystals did not change under high humidity conditions of 60°C and 80% RH, indicating that the A-type crystals have good stability.

[0229] Example 13 Solubility test of type A crystals The solubility of type A crystals was evaluated in SGF, FaSSIF, and FeSSIF at pH 7.4.

[0230] 20 mg of the raw material was weighed into a vial, 3 mL of medium was added, and the dissolution state was observed at 37°C.

[0231] [Table 17]

[0232] Table 10 shows that type A crystals exhibit good solubility in a variety of media.

[0233] Specific embodiments of the present invention have been described above. It should be understood that the present invention is not limited to the above embodiments, and that the above embodiments and specification are merely illustrative of the principles of the present invention. Those skilled in the art can make various insubstantial changes and modifications to the present invention without departing from the concept of the present invention, all of which are within the scope of the invention as claimed. [Brief explanation of the drawings]

[0234] [Figure 1] 1 is an XRPD pattern of crystalline Form A of the L-tartrate salt of the compound of Formula I. [Figure 2] 1 is a DSC pattern of crystalline Form A of the L-tartrate salt of the compound of Formula I. [Figure 3] 1 is a TGA pattern of crystalline form A of the L-tartrate salt of the compound of formula I. [Figure 4] 1 is a PLM pattern of crystalline form A of the L-tartrate salt of the compound of formula I. [Figure 5] 1 is an XRPD pattern of crystalline Form B of the L-tartrate salt of the compound of Formula I. [Figure 6] 1 is a DSC pattern of type B crystals of the L-tartrate salt of the compound of formula I. [Figure 7] 1 is a TGA pattern of type B crystals of the L-tartrate salt of the compound of formula I. [Figure 8] 1 is an XRPD pattern of crystalline Form C of the L-tartrate salt of the compound of Formula I. [Figure 9] 1 is a DSC pattern of crystalline form C of the L-tartrate salt of the compound of formula I. [Figure 10] 1 is a TGA pattern of crystalline form C of the L-tartrate salt of the compound of formula I. [Figure 11] 1 is a PLM pattern of the C-form crystal of the L-tartrate salt of the compound of formula I. [Figure 12] 1 is an XRPD pattern of crystalline Form D of the L-tartrate salt of the compound of Formula I. [Figure 13] 1 is a DSC pattern of D-form crystals of the L-tartrate salt of the compound of formula I. [Figure 14] 1 is a TGA pattern of crystalline form D of the L-tartrate salt of the compound of formula I. [Figure 15] 1 is an XRPD pattern of crystalline form A of the L-tartrate salt of the compound represented by formula I in Example 7. [Figure 16]1 is an XRPD pattern of type B crystals of the L-tartrate salt of the compound represented by formula I in Example 9. [Figure 17] 1 is an XRPD pattern of crystalline Form A of the L-tartrate salt of compound of Formula I after storage under high temperature and humidity conditions for 3 days. [Figure 18] 1 is an XRPD pattern of crystalline Form A of the L-tartrate salt of compound of Formula I after storage under high temperature and humidity conditions for 2 days. [Figure 19] 1 is a single crystal pattern of the mono-L-tartrate salt of the compound of formula I.

Claims

1. A pharmaceutically acceptable salt of a compound of formula I shown below; 【Chemistry 1】 (The pharmaceutically acceptable salts of the compound of formula I are selected from the group consisting of monotartrate, monofumarate, and monomalate salts of the compound of formula I).

2. A pharmaceutically acceptable salt of the compound of formula I according to claim 1, wherein the pharmaceutically acceptable salt is a mono-L-tartrate salt of the compound of formula I.

3. 2. A crystalline form of a pharmaceutically acceptable salt of the compound of formula I according to claim 1, which is a crystalline form of mono-L-tartrate of the compound of formula I.

4. The crystal according to claim 3, wherein the crystal is a type A crystal of the mono-L-tartrate salt of the compound represented by formula I, and the type A crystal has characteristic diffraction peaks at 17.06±0.20°, 20.06±0.20°, and 22.58±0.20° in powder X-ray diffraction represented by 2θ angles using Cu-Kα radiation.

5. The type A crystal is the crystal described in claim 4, wherein powder X-ray diffraction expressed in 2θ angles using Cu-Kα radiation has characteristic diffraction peaks at 17.06±0.20°, 18.00±0.20°, 18.80±0.20°, 19.22±0.20°, 20.06±0.20°, 22.58±0.20°, 23.72±0.20°, and 24.38±0.20°.

6. The type A crystal is the crystal described in claim 4, wherein powder X-ray diffraction expressed in 2θ angles using Cu-Kα radiation has characteristic diffraction peaks at 8.30±0.20°, 14.24±0.20°, 17.06±0.20°, 18.00±0.20°, 18.80±0.20°, 19.22±0.20°, 20.06±0.20°, 20.52±0.20°, 22.58±0.20°, 23.72±0.20°, 24.38±0.20°, and 25.70±0.20°.

7. The crystal described in claim 4, wherein the powder X-ray diffraction of the A-type crystal, expressed as 2θ angles using Cu-Kα radiation, is as shown in Table 1 below, with an error range of ±0.20°. Table 1

8. The Type A crystal is an anhydrous mono-L-tartrate salt of the compound represented by formula I, Differential scanning calorimetry (DSC) analysis of the Form A crystals showed that an initial endothermic peak appeared upon heating to a peak temperature of about 150.14°C; 5. The crystal of claim 4, wherein thermogravimetric analysis (TGA) of the Form A crystal shows a weight loss of about 0.069% in the range of 22.03°C to 120°C.

9. the crystal is a type B crystal, a type C crystal, or a type D crystal of the mono-L-tartrate salt of the compound of formula I, The B-type crystals have characteristic diffraction peaks at 19.28±0.20°, 19.94±0.20°, 21.30±0.20°, and 23.72±0.20° in powder X-ray diffraction represented by 2θ angles using Cu-Kα radiation; The C-type crystal has characteristic diffraction peaks at 17.88±0.20°, 19.40±0.20°, and 21.38±0.20° in powder X-ray diffraction represented by 2θ angles using Cu-Kα radiation, The D-type crystal has characteristic diffraction peaks at 3.50±0.20°, 7.46±0.20°, and 23.04±0.20° in powder X-ray diffraction represented by 2θ angles using Cu-Kα radiation. The crystal described in claim 3.

10. The powder X-ray diffraction of the B-type crystals, expressed as 2θ angles using Cu-Kα radiation, is as shown in Table 2 below, with an error range of ±0.20°; Table 2 The powder X-ray diffraction of the C-type crystals, expressed as 2θ angles using Cu-Kα radiation, is as shown in Table 3 below, with an error range of ±0.20°. Table 3 The powder X-ray diffraction of the D-type crystals, expressed as 2θ angles using Cu-Kα radiation, is as shown in Table 4 below, with an error range of ±0.20°. Table 4 The crystal according to claim 9.

11. The unit cell parameters are It is a monoclinic crystal and its space group is P2 １ and a=6.3430(5)Å, b=8.8372(7)Å, β=96.577, c=24.809(2) Å, V=1381.5(2)Å ３ 、 Z=2; The crystal described in claim 3.

12. A pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound of formula I according to any one of claims 1 to 2, and optionally pharmaceutically acceptable pharmaceutical auxiliaries.

13. A pharmaceutical composition comprising a crystal according to any one of claims 3 to 11, and optionally pharmaceutically acceptable pharmaceutical auxiliaries.

14. Use of a pharmaceutically acceptable salt of a compound of formula I according to any one of claims 1 to 2 in the manufacture of a medicament for the prevention and / or treatment of a disease or condition associated with a Vanin enzyme inhibitor.

15. The use of claim 14, wherein the disease or condition associated with the Vanin enzyme inhibitor includes one or more of autoimmune diseases, inflammatory diseases, allergic diseases, metabolic diseases, infectious diseases, fibrotic diseases, cardiovascular diseases, respiratory diseases, kidney diseases, skin diseases, liver diseases, gastrointestinal diseases, oral diseases and hematopoietic diseases.

16. The use according to claim 15, wherein the disease or condition associated with the Vanin enzyme inhibitor is Crohn's disease, inflammatory bowel disease, and ulcerative colitis.

17. Use of the crystal according to any one of claims 3 to 11 in the manufacture of a medicament for preventing and / or treating a disease or condition associated with a Vanin enzyme inhibitor.

18. The use of claim 17, wherein the disease or condition associated with the Vanin enzyme inhibitor includes one or more of autoimmune diseases, inflammatory diseases, allergic diseases, metabolic diseases, infectious diseases, fibrotic diseases, cardiovascular diseases, respiratory diseases, kidney diseases, skin diseases, liver diseases, gastrointestinal diseases, oral diseases and hematopoietic diseases.

19. The use described in claim 18, wherein the disease or condition associated with the Vanin enzyme inhibitor is Crohn's disease, inflammatory bowel disease, and ulcerative colitis.

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