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

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 on March 18, 2022, and Chinese patent application CN202211104893.5, filed on September 9, 2022. The entire texts of these applications are incorporated herein by reference.

[0002] [Technical field] The present invention relates to the field of medicine, specifically to salt forms, crystals and methods for preparing the same of Vanin enzyme inhibitors, and the use of said salt forms, crystals in the manufacture for preventing and / or treating cardiovascular and tumor diseases.

[0003] [Background technology] Vanin-1 (vascular anti-inflammatory molecule-1) is an exonuclease with ubiquitinase activity that mainly 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, and the reversible reaction between 2-mercaptoethylamine and cystamine is an important sensor of oxidative stress. More and more studies have shown that deficiency or reduced levels of mercaptoethylamine can enhance γ-GCS activity, leading to increased endogenous GSH storage in tissues, which can prevent or eliminate tissue inflammation. Studies have found that Vanin-1 mRNA is highly expressed in human colon, duodenum, endometrium, liver, kidney, gallbladder, and small intestine. In UC (ulcerative colitis) patients, Vanin-1 is highly expressed, diffuse, and restricted to the brush border. Moreover, the expression level of Vanin-1 in the colon remained significantly higher than that of the control group during the clinical quiescent phase of UC. In the TNBS model experiment, the survival rate of Vanin-1 knockout mice (Vanin-1- / -) was significantly higher than that of the model control group, and there was no significant weight loss. Furthermore, 90% of cystamine-treated Vanin-1- / - mice died within 5 days, indicating that cystamine completely reversed the protective effect of Vanin-1 deficiency against colitis.Histopathological analysis of mice also demonstrated 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 believed to play a regulatory role in cardiovascular and oncological 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 to normal individuals. Gene expression of VNN1 is also upregulated in whole blood of 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] Since the compound represented by formula I is an effective Vanin enzyme inhibitor and has a wide range of medical applications, there is a need to research and develop efficient, low-toxicity and / or long-acting pharma- ceutically acceptable active ingredients to improve the above technical problems.

[0008] Summary of the Invention To solve the problems existing in the prior art, a first aspect of the present invention provides a pharma- ceutically acceptable salt of a compound of formula I, said compound of formula I being as shown below:

[0009] [ka]

[0010] The pharma- ceutically acceptable salt of the compound represented by formula I is a salt formed by 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, pectic acid, persulfate, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxybenzoylbenzo ... The acidic acid is selected from the group consisting of sethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, L-tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid, and thiocyanic acid. By way of example, the acid may be one selected from 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, oxalic acid, formic acid, acetic acid, trifluoroacetic acid, lauric acid, benzoic acid and benzenesulfonic acid.

[0012] In a preferred embodiment, the pharma- ceutically acceptable salt of the compound of formula I is selected from one of its hydrochloride, sulfate, phosphate, methanesulfonate, p-toluenesulfonate, fumarate, maleate, citrate, L-tartrate, succinate, ethanesulfonate, L-malate, L-glutamate, oxalate, D-malate, and pamoate salts.

[0013] In one preferred embodiment, in the pharma- ceutically 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, with the proviso that the ion of the compound of formula I in the salt achieves charge balance with the ion 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 pharma- ceutically 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, malic acid, the pharma- ceutically acceptable salt is selected from the mono-tartrate, mono-fumarate, mono-malate 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 pharma- ceutically acceptable salt of a compound of formula I, comprising the step of reacting a compound of formula I with an acid to prepare a pharma- ceutically acceptable salt of a compound of formula I.

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

[0017] According to an embodiment of the present invention, the acid has the definition as 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 esters, ketones, and alcohols. The esters may be selected from organic carboxylic acid esters, such as methyl formate, ethyl acetate, isobutyl formate, ethyl acetate propyl, isopropyl acetate, or a combination thereof; the ketones may be selected from ketones having 3 to 10 carbon atoms, such as acetone, butanone, pentanone, methyl ethyl ketone, 4-methyl-2-pentanone, or a combination thereof; and the alcohols may be selected from alcohols 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 combinations thereof. The nitriles may be selected from nitriles having 2 to 6 carbon atoms, such as acetonitrile, propionitrile, isopropionitrile, butyronitrile, or combinations 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 combinations thereof, and 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 combinations thereof.

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

[0021] In some embodiments, when the acid is selected from L-tartaric acid, the organic solvent C is selected from an alcoholic system, which may be selected from alcohols 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 product after completion of the reaction to prepare a pharma- ceutically acceptable salt of the compound represented by formula I.

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

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

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

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

[0032] The solvent E is selected from ester solvents, ether solvents, alkane solvents, or combinations thereof. The ester solvent may be selected from organic carboxylic acid esters, such as ethyl acetate, isopropyl acetate, etc., the ether solvent 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, etc., and the alkane solvent may be selected from alkanes having 1 to 8 carbon atoms, such as n-hexane, n-heptane, etc.

[0033] A third aspect of the present invention provides a crystal of a pharma- ceutically 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 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 of 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 measured at 2θ angles using Cu-Kα radiation.

[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 expressed as 2θ angles using Cu-Kα radiation.

[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 expressed as 2θ angles using Cu-Kα radiation.

[0038] Preferably, the A-type crystal has a powder X-ray diffraction pattern expressed in 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 an X-ray powder diffraction spectrum essentially as shown in FIG.

[0041] According to an embodiment of the present invention, the Form 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 a first endothermic peak appears upon heating to a peak temperature of about 150.14°C.

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

[0046] According to an embodiment of the present invention, the A-type crystal is an irregularly shaped crystal. Preferably, the particle size of the A-type crystal 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 of 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 measured at 2θ angles using Cu-Kα radiation.

[0049] Preferably, the B-type crystal has 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 crystal has 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 expressed as 2θ angles using Cu-Kα radiation.

[0051] Preferably, the B-type crystal has 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 expressed as 2θ angles using Cu-Kα radiation.

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

[0053] [Table 2]

[0054] Preferably, the B-type crystal has an X-ray powder diffraction spectrum essentially as shown in FIG.

[0055] According to an embodiment of the present invention, the B-type crystal is 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 when heated to a peak temperature of about 61.57° C., and a second endothermic peak appears when heated 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 crystal has 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 is reduced by 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 of 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 measured at 2θ angles using Cu-Kα radiation.

[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 expressed as 2θ angles using Cu-Kα radiation.

[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 expressed as 2θ angles using Cu-Kα radiation.

[0064] Preferably, the C-type crystal has a powder X-ray diffraction pattern expressed in 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 crystal is a mono-L-tartrate solvate of the compound represented by formula I, 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 is reduced by about 4.59% in the range of 21.47°C to 150°C.

[0071] Preferably, the C-type crystal has 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 grain 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 has characteristic diffraction peaks at 3.50±0.20°, 7.46±0.20°, and 23.04±0.20° in powder X-ray diffraction measured at 2θ angles using Cu-Kα radiation.

[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 expressed as 2θ angles using Cu-Kα radiation.

[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 expressed as 2θ angles using Cu-Kα radiation.

[0077] Preferably, the D-type crystal has a powder X-ray diffraction pattern expressed in 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 crystal is a mono-L-tartrate solvate of the compound represented by formula I, 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 is reduced by 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 pharma- ceutically acceptable salt of a compound represented by formula I.

[0086] According to a preferred embodiment of the present invention, there is provided a method for producing a crystal 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 combinations 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, comprising adding and dissolving the mono-L-tartrate salt of the compound represented by formula I in an alcoholic solvent, and then adding a poor 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 the formula I to the alcoholic solvent and poor solvent 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 the A-type crystal further includes a post-treatment step such as filtration or 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 condition is 80% to 100% RH, and preferably 90% to 100% RH.

[0104] In some embodiments, there is provided a method for producing type B 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 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 of the compound represented by the formula I to the alcohol 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 salt 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 the formula I to the alcohol 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 ether-based 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 from 30°C to 80°C, and preferably from 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 of the compound represented by the 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 preparing the D-type crystals includes post-treatment steps such as filtration, drying, etc.

[0118] The present invention further provides a pharmaceutical composition comprising the pharma- ceutically acceptable salt of the compound represented by formula I or a crystal thereof, and optionally a pharma- ceutically acceptable pharmaceutical auxiliary. In a preferred embodiment of the present invention, the pharma- ceutical 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 crystal, type B crystal, type C crystal, 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 preparation.

[0119] The present invention further provides a formulation comprising the pharma- ceutically acceptable salt of the compound represented by formula I or a crystal thereof, and optionally a pharma- ceutically acceptable pharmaceutical auxiliary. In a preferred embodiment of the present invention, the pharma- ceutically 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 pharma- ceutically acceptable salt of a 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 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, renal diseases, skin diseases, liver diseases, gastrointestinal diseases, oral diseases and hematopoietic diseases, and is, 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 pharma- ceutically acceptable salt of a compound represented by formula I or a crystal thereof, or the pharmaceutical composition.

[0123] According to an embodiment of the present invention, 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, renal diseases, skin diseases, liver diseases, gastrointestinal diseases, oral diseases and hematopoietic diseases, and is, 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 of the pharmaceutically acceptable salts of the compound represented by formula I of the present invention or crystals thereof alone, and administering one, two or more of the 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 should 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 of the alternatives 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. 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 represented by 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, and low hygroscopicity, and have good drug discovery potential.

[0129] (4) The preparation methods of the four crystals of 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 the A-type crystal of the L-tartrate salt of the compound represented by formula I. FIG. 2 is a DSC pattern of the A-type crystals of the L-tartrate salt of the compound represented by formula I. FIG. 3 is a TGA pattern of crystal form A of the L-tartrate salt of the compound represented by formula I. FIG. 4 is a PLM pattern of the A-type crystal of the L-tartrate salt of the compound represented by formula I. FIG. 5 is an XRPD pattern of the B-type crystals of the L-tartrate salt of the compound represented by formula I. FIG. 6 is a DSC pattern of B-type crystals of the L-tartrate salt of the compound represented by formula I. FIG. 7 is a TGA pattern of B-type crystals of the L-tartrate salt of the compound represented by formula I. FIG. 8 is an XRPD pattern of the C-type crystals of the L-tartrate salt of the compound represented by formula I. FIG. 9 is a DSC pattern of C-type crystals of the L-tartrate salt of the compound represented by formula I. FIG. 10 is a TGA pattern of C-type crystals of the L-tartrate salt of the compound represented by formula I. FIG. 11 is a PLM pattern of the C-type crystal of the L-tartrate salt of the compound represented by formula I. FIG. 12 is an XRPD pattern of the D-form crystal of the L-tartrate salt of the compound represented by formula I. FIG. 13 is a DSC pattern of D-form crystals of the L-tartrate salt of the compound represented by formula I. FIG. 14 is a TGA pattern of D-type crystals of the L-tartrate salt of the compound represented by formula I. FIG. 15 is an XRPD pattern of crystal form A of the L-tartrate salt of the compound represented by formula I in Example 7. FIG. 16 is an XRPD pattern of the B-type crystals of the L-tartrate salt of the compound represented by 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 a state in which the product is left open under conditions of 40℃ and 75% humidity.

[0134] "60℃-open" refers to the state in which the product is left open at 60℃.

[0135] 80%RHopen refers to a state in which the product is left open under 80% humidity conditions.

[0136] 92.5% RH-open refers to a state in which the product is left open under 80% humidity conditions.

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

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

[0139] 60℃-closed-2wks refers to the condition of being 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 one day and 3d refers to three days.

[0145] Experimental equipment parameters X-ray Powder Diffraction (XRPD) The instrument is a Shimadzu XRD-6000 and the samples are 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°~50°. The scanning speed is 5 deg / min.

[0148] Thermogravimetric analysis (TGA) Approximately 5 mg of a 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, and a hole was drilled in the crucible lid. Under nitrogen gas protection, the differential calorimetric scan was performed by heating from 30°C to 300°C and maintaining at 300°C for 1 min. The heating rate was 20°C / min.

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

[0151] Dynamic Water Sorption (DVS) Approximately 10 mg of sample was weighed out under a relative humidity (RH) cycle of 0%-95%-0%, and a moisture absorption / desorption test was carried out under the condition of 25° C., 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: 50kV, 1.2mA Exposure time: 50s 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. 3 P (625 g, 1.78 mol) was slowly added dropwise, and the reaction was continued at the same temperature for 2 hours after the addition was complete. After the reaction was completed by LCMS, water was added, stirred, and the solid was precipitated, filtered, and dried to obtain compound 1f (350 g, purity 98%).

[0156] 1 H NMR (400 MHz, CDCl 3):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, 4.64Hz, 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 and heated to 110° C. under reflux, and a solution of compound 1a (352 g, 2.65 mol) in toluene (500 mL) was added dropwise to the reaction solution. After the addition was complete, the mixture was heated and refluxed for 1 hour. After the reaction was complete, the reaction was stopped, cooled to room temperature, and concentrated to remove 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, yield: 80%).

[0160] Step 2 Compound 1c (500 g, 2.1 mol) was dissolved in THF (3000 mL) and cooled to -60°C, then L-tri-sec-butyllithium borohydride (2510 mL, 2.51 mol) was added dropwise slowly. After the addition was completed, it was stirred at -60°C. After the reaction was completed, 1000 mL of water was added slowly to quench the reaction. It was concentrated to remove most of the THF. It was extracted with ethyl acetate (500 mL x 3), the organic phases were combined, 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 added slowly. The reaction solution was reacted at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated to give an oil, which was 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 K 2 CO 3 (862.5 g, 6.25 mol) was dissolved in isopropanol (400 mL) and heated to reflux overnight. After completion of the reaction, it was cooled, filtered, and the filtrate was concentrated. The residue was dissolved in water (300 mL), adjusted to pH 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 the compound of formula I (374 g).

[0163] 1 H NMR (400 MHz, CD 3OD) 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, 4.4Hz, 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 represented by 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 thereto, followed by stirring overnight. Then, isopropyl acetate (18 ml) was added thereto to obtain a solid, which was filtered and vacuum-dried under reduced pressure to obtain the L-tartrate salt of the compound represented by formula I (the molar ratio of the compound represented by formula I and 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 a vial (8 mL), methanol (1 mL) was added, and the solution was dissolved by ultrasonication. The resulting solution was filtered, the filtrate was placed in a new vial (8 mL), and the vial (8 mL) was placed in a vial (40 mL) to which methyl tert-butyl ether (4 mL) had been added with an opening, and the cap of the vial (40 mL) was tightened to culture the single crystal. The single crystal data of the mono L-tartrate salt of the compound represented by formula I is as 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, which was filtered and dried under vacuum 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 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 represented by 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 by adding 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 represented by formula I, especially the L-tartrate salt of the compound represented by formula I, remains 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 at 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 the condition of 37 ° C., 0.5 mL was sampled at 1 h and 24 h, respectively, and centrifuged at 12000 rpm for 5 min, and the supernatant was diluted to an appropriate multiple with 50% acetonitrile, and its concentration was measured. The chromatography conditions for the solubility test are as shown in Table 7.

[0181] Control and linearity: Compound I was not suitable as a control because it was highly hygroscopic and had too many impurities. Therefore, the fumarate salt of compound I (13 mg) was weighed into a 25 mL measuring flask (approximately 10 mg to 25 mL measuring flask based on the free base), dissolved by adding 50% acetonitrile aqueous solution, diluted to the mark, and prepared in duplicate. STD-1 was taken and diluted to 200 μg / mL, 50 μg / mL, and 10 μg / mL with 50% acetonitrile aqueous solution, and 5 μL was injected to draw a standard curve.

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

[0183] [Table 9]

[0184] [Table 10] JPEG2025507207000017.jpg124169

[0185] From Table 8, it can be seen that the compound represented by formula I and its mono-L-tartrate, fumarate, and 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 mono-L-tartrate salt of compound of formula I (prepared according to Example 1) was taken, and 10 mL of acetone was added, stirred, centrifuged, and vacuum-dried at 40° C. under reduced pressure to obtain Form 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 FIG.

[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 FIG.

[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 terms of 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 taken and dissolved in 10 ml of methanol, followed by adding 60 ml of methyl tert-butyl ether, stirring for 1.5 h, centrifuging, filtering and drying to obtain the above-mentioned Form 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 the 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 XRPD characteristic peaks are shown in Table B, and the XRPD spectrum is shown in FIG.

[0199] DSC showed that a first endothermic peak appeared upon heating to a peak temperature of about 61.57° C. and a 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 terms of 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 represented by formula I (prepared according to Example 1) was taken, and 10 mL of methanol was added thereto. After complete dissolution, the solvent was allowed to evaporate naturally to obtain a white solid, which was then dried under reduced pressure to obtain type B crystals.

[0204] The XRPD spectrum of the B-type crystal 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, followed by stirring at 50° C. for 1 day. Then, after cooling to room temperature, a white solid precipitated out, which was filtered and vacuum-dried under reduced pressure to obtain C-type crystals.

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

[0207] The C-type crystal was a solvate 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 from 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 terms of 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 thereto. The mixture was stirred at 50° C. for 1 day, and then cooled to room temperature. After that, a white solid precipitated out, which was filtered and vacuum-dried under reduced pressure to obtain type D crystals.

[0215] XRPD, DSC, and TGA characterizations were carried out for the D-type crystals.

[0216] The D-type crystal was a solvate 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 A-type 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 confirm the changes in the crystals.

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

[0224] Stability sample related substances 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 substances test.

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

[0226] [Table 15]

[0227] [Table 16]

[0228] As shown in Table 9, 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 A-type 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] From Table 10, it was found that type A crystals exhibited good solubility in various media.

[0233] The 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 the above embodiments and description are merely for illustrating 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 included in the scope of the present invention as claimed. [Brief description 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. [Diagram 2] 1 is a DSC pattern of crystalline form A of the L-tartrate salt of the compound of formula I. [Diagram 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. [Diagram 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 crystalline form B of the L-tartrate salt of the compound of formula I. [Figure 7] 1 is a TGA pattern of crystalline form B 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-type 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 crystalline form D 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 the B-type 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 exposure to 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 pharma- ceutically acceptable salt of a compound of formula I, as shown below. 【Chemistry 1】 (The pharma- ceutically acceptable salt of the compound represented by formula I is a salt formed by the compound represented by formula I and an acid.)

2. 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, pectic acid, persulfate, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfuric acid, benzo ...

2. A pharmaceutically acceptable salt of a compound of formula I according to claim 1, characterized in that the salt is an isopropyl acid, butyl ether ...

3. 2. The pharma- ceutically acceptable salt of the compound of formula I according to claim 1, characterized in that the acid may be one selected from 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, oxalic acid, formic acid, acetic acid, trifluoroacetic acid, lauric acid, benzoic acid and benzenesulfonic acid.

4. The pharma- ceutically acceptable salt of the compound of formula I according to claim 1, characterized in that the molar ratio of the compound of formula I to the acid is 1:1, and preferably, the pharma- ceutically acceptable salt is selected from the mono-tartrate, mono-fumarate, mono-malate salts of the compound of formula I, more preferably, the pharma- ceutically acceptable salt is the mono-L-tartrate salt of the compound of formula I.

5. 2. A method for preparing a pharma- ceutically acceptable salt of a compound of formula I according to claim 1, comprising the step of reacting a compound of formula I with an acid to prepare a pharma- ceutically acceptable salt of a compound of formula I, Preferably, the preparation method includes the steps of dissolving the compound represented by formula I in an organic solvent A, adding an acid to react with the compound, and then adding an organic solvent B to prepare a pharma- ceutically acceptable salt of the compound represented by formula I, wherein the organic solvent A is selected from at least one of an ester, a ketone, and an alcohol, and the organic solvent B is selected from a nitrile, an ester, an ether, or a combination thereof; Preferably, the acid is first dissolved in an organic solvent C to prepare an acid solution, and then the solution is added to the reaction. More preferably, when the acid is selected from L-tartaric acid, the organic solvent C is selected from alcohols.

6. A crystal of a pharma- ceutically acceptable salt of the compound represented by formula I according to claim 1, which is a crystal of mono-L-tartrate of the compound represented by formula I.

7. 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; 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 expressed as 2θ angles using Cu-Kα radiation; 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 expressed as 2θ angles using Cu-Kα radiation, Preferably, the A-type crystal has a powder X-ray diffraction pattern expressed by 2θ angles using Cu-Kα radiation as shown in Table 1, with an error range of ±0.20°; Preferably, the A-type crystal has a powder X-ray diffraction spectrum essentially as shown in FIG. Preferably, the A-type crystal is an anhydrous L-tartrate salt of the compound of formula I, Preferably, differential scanning calorimetry (DSC) analysis of said Form A crystals shows that upon heating to a peak temperature of about 150.14° C., a first endothermic peak appears; Preferably, the A-type crystal has a DSC spectrum essentially as shown in FIG. Preferably, thermogravimetric analysis (TGA) of the A-type crystals shows a weight loss of about 0.069% in the range of 22.03° C. to 120° C.; Preferably, the A-type crystal has a TGA spectrum essentially as shown in FIG.

3.

8. The crystal is a B-type crystal of the mono-L-tartrate salt of the compound represented by formula I, and the B-type 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 represented by 2θ angles using Cu-Kα radiation; Preferably, the B-type crystal has 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; Preferably, the B-type crystal has 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 expressed as 2θ angles using Cu-Kα radiation; Preferably, the B-type crystal has 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 expressed as 2θ angles using Cu-Kα radiation; Preferably, the B-type crystal has a powder X-ray diffraction pattern expressed by 2θ angles using Cu-Kα radiation as shown in Table 2, with an error range of ±0.20°; Preferably, the B-type crystal has a powder X-ray diffraction spectrum essentially as shown in FIG. The B-type crystals are a hydrate of the L-tartrate salt of the compound of formula I, Differential scanning calorimetry (DSC) analysis of the B-type crystals showed that a first endothermic peak appeared upon heating to a peak temperature of about 61.57° C. and a second endothermic peak appeared upon heating to a peak temperature of about 152.18° C.; Preferably, the B-type crystal has a DSC spectrum essentially as shown in FIG. Preferably, the thermogravimetric analysis (TGA) of the B-type crystals shows a weight loss of about 2.76% in the range from 21.34°C to 120°C; Preferably, the B-type crystal has a TGA spectrum essentially as shown in FIG.

9. The crystal is a C-type crystal of the mono-L-tartrate salt of the compound represented by formula I, and 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; 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 expressed as 2θ angles using Cu-Kα radiation; 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 expressed as 2θ angles using Cu-Kα radiation; Preferably, the C-type crystal has a powder X-ray diffraction pattern expressed by 2θ angles using Cu-Kα radiation as shown in Table 3, with an error range of ±0.20°; Preferably, the C-type crystal has a powder X-ray diffraction spectrum essentially as shown in FIG. Preferably, the C-type crystal is a solvate of the L-tartrate salt of the compound represented by formula I, preferably an ethanol solvate of the L-tartrate salt of the compound represented by formula I; Preferably, 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.; Preferably, the C-type crystal has a DSC spectrum essentially as shown in FIG. Preferably, thermogravimetric analysis (TGA) of the C-type crystals shows a weight loss of about 4.59% in the range of 21.47° C. to 150° C.; Preferably, the C-type crystal has a TGA spectrum essentially as shown in FIG.

10.

10. The crystal is a D-type crystal of the mono-L-tartrate salt of the compound represented by formula I, and 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; 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 expressed at 2θ angles using Cu-Kα radiation; 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 expressed as 2θ angles using Cu-Kα radiation; Preferably, the D-type crystal has a powder X-ray diffraction pattern expressed by 2θ angles using Cu-Kα radiation as shown in Table 4, with an error range of ±0.20°; Preferably, the D-type crystal has a powder X-ray diffraction spectrum essentially as shown in FIG. Preferably, the D-type crystal is a solvate of the L-tartrate salt of the compound represented by formula I, preferably a tetrahydrofuran solvate of the L-tartrate salt of the compound represented by formula I; Preferably, 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.; Preferably, the D-type crystal has a DSC spectrum essentially as shown in FIG. Preferably, the thermogravimetric analysis (TGA) of the D-type crystals shows a weight loss of about 5.25% in the range from 23.19°C to 120°C; Preferably, the D-type crystal has a TGA spectrum essentially as shown in FIG.

14.

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, 300,000,000 VND ３ 、 Z=2; The crystal according to claim 6 .

12. A method for producing the A-type crystals of the mono-L-tartrate salt of the compound represented by formula I includes the steps of stirring the mono-L-tartrate salt of the compound represented by formula I in a solvent to obtain the A-type crystals, Preferably, the stirring temperature is 20 to 80° C., and the solvent is selected from alcohol solvents, ester solvents, ketone solvents, ether solvents, alkane solvents, haloalkane solvents, and nitrile solvents, or combinations thereof; Preferably, the mass / volume ratio of the mono-L-tartrate salt of the compound represented by formula I to the solvent is 1 g:(20-40) ml; The second method for producing the A-type crystals of the L-tartrate salt of the compound represented by formula I includes the steps of adding and dissolving the mono-L-tartrate salt of the compound represented by formula I in an alcoholic solvent, further adding a poor solvent and stirring the mixture to obtain the A-type crystals, Preferably, the alcohol solvent is one selected from methanol, ethanol, propanol and isopropanol, and the anti-solvent is one or more of an ether solvent or an ester solvent; Preferably, 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; More preferably, the method for producing a crystal according to claim 7 , wherein the first or second method for producing an A-type crystal further comprises a post-treatment step such as filtration or drying.

13. The method for producing the B-type crystals of the mono-L-tartrate salt of the compound represented by formula I includes a step of subjecting the A-type crystals to a high humidity condition to obtain the B-type crystals, and the high humidity condition is preferably 80% to 100% RH, more preferably 90% to 100% RH; The second method for producing type B crystals of the mono-L-tartrate salt of the compound represented by formula I includes the steps of dissolving the mono-L-tartrate salt of the compound represented by formula I in an alcohol solvent and evaporating the solvent to obtain type B crystals, Preferably, the alcohol solvent is one selected from methanol, ethanol and isopropanol, and the dissolution temperature is 15 to 45° C.; The method for producing the crystal according to claim 8, wherein the mass / volume ratio of the mono-L-tartrate salt of the compound represented by formula I to the alcoholic solvent is preferably 1 g:(10-30) ml.

14. 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 alcohol solvent and crystallizing the solution to obtain the type C crystals, Preferably, the alcoholic solvent is selected from methanol, ethanol and / or isopropanol; Preferably, the mass / volume ratio of the mono-L-tartrate salt of the compound represented by formula I to the alcoholic solvent is 1 g:(20-40) ml; More preferably, the method for producing the C-type crystal according to claim 9 further comprises a post-treatment step such as filtration, drying, etc.

15. A method for producing a D-type crystal 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 ether-based solvent, heating and stirring the mixture, cooling the mixture, and then precipitating a solid to obtain the D-type crystal, Preferably, the ether solvent is one selected from ethyl ether, tetrahydrofuran, and methyl tert-butyl ether; the heating temperature is 30° C. to 80° C., the cooling temperature is 20° C. to 30° C., and 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; More preferably, the method for producing the D-type crystal according to claim 10 further comprises post-treatment steps such as filtration and drying.

16. The method includes dissolving the mono-L-tartrate salt of the compound of formula I in a solvent D and then dispersing the solution in an atmosphere of a solvent E; The solvent D is selected from alcohol solvents, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, neopentyl alcohol, or a combination thereof; The method for producing a crystal according to claim 11, characterized in that 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, isopropyl acetate, etc., 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, methyl tert-butyl ether, etc., and the alkane solvent may be selected from an alkane having 1 to 8 carbon atoms, such as n-hexane, n-heptane, etc.

17. A pharmaceutical composition comprising a pharma- ceutically acceptable salt of a compound of formula I according to any one of claims 1 to 4 or a crystal according to any one of claims 6 to 11, and optionally pharma- ceutically acceptable pharmaceutical auxiliaries, preferably in the form of a formulation.

18. Use of a pharma- ceutically acceptable salt of a compound of formula I according to any one of claims 1 to 4, or a crystal according to any one of claims 6 to 11, or a pharmaceutical composition according to claim 17 in the manufacture of a medicament for preventing and / or treating a disease or condition associated with a Vanin enzyme inhibitor, comprising: Preferably, 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, and is, for example, Crohn's disease, inflammatory bowel disease and ulcerative colitis.

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