WO2023174409A1 - Vanin酶抑制剂的盐型、晶型及其制备方法和应用 - Google Patents

Vanin酶抑制剂的盐型、晶型及其制备方法和应用 Download PDF

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WO2023174409A1
WO2023174409A1 PCT/CN2023/082191 CN2023082191W WO2023174409A1 WO 2023174409 A1 WO2023174409 A1 WO 2023174409A1 CN 2023082191 W CN2023082191 W CN 2023082191W WO 2023174409 A1 WO2023174409 A1 WO 2023174409A1
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acid
crystal form
formula
compound
tartrate
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姚元山
田勇
栾林波
陈永凯
王朝东
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上海美悦生物科技发展有限公司
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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    • C07C59/235—Saturated compounds containing more than one carboxyl group
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
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    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention belongs to the field of medicine, and specifically relates to salt forms and crystal forms of Vanin enzyme inhibitors and their preparation methods, and the application of the salt forms and crystal forms in the preparation, prevention and/or treatment of cardiovascular diseases and tumor diseases.
  • Vanin-1 vascular non-inflammatory molecule-1
  • VB5 pantothenic acid
  • Coenzyme A (CoA) synthesized from VB5 regulates biotransformations such as fatty acid synthesis and oxidation as well as energy metabolism, and the reversible reaction between mercaptoethylamine and cystamine is an important sensor of oxidative stress.
  • More and more studies have found that the lack or reduced level of mercaptoethylamine leads to enhanced ⁇ -GCS activity, causing an increase in endogenous GSH reserves in tissues, thereby preventing or eliminating tissue inflammation.
  • Vanin-1 mRNA is highly expressed in the human colon, duodenum, endometrium, liver, kidney, gallbladder and small intestine.
  • Vanin-1 is highly expressed diffusely and restricted to the brush border.
  • the expression level of Vanin-1 in the colon was still significantly higher than that of the control.
  • the survival rate of mice with Vanin-1 knockout was significantly higher than that of the model control group, and they did not show significant weight loss.
  • Vanin-1-/- mice treated with cystamine died within 5 days, indicating that cystamine completely reversed the protective effect of Vanin-1 deficiency on colitis.
  • Vanin-1 is also considered to play a regulatory role in cardiovascular diseases and tumor diseases. Vanin-1 has been shown to regulate 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 deletion prevented the mice from developing adrenocortical neoplasia, suggesting a role for Vanin-1 in certain cancers. Studies in inflammatory diseases have found that Vanin-1 is highly upregulated in skin lesions of psoriasis compared with normal individuals.
  • VNN1 Gene expression of VNN1 is also upregulated in the whole blood of patients with childhood immune thrombocytopenia (ITP), where overexpression of VNN1 is associated with the progression of chronic ITP. Additionally, elevated Vanin-1 has been detected in the urine of patients with a variety of renal disorders, including systemic lupus erythematosus, nephrotoxicant-induced kidney injury, and type 2 diabetes (Rommelaere S , et al. PPARalpha regulates the production of serum Vanin-1 by liver. FEBS Lett. 2013Nov 15;587(22):3742-8).
  • the compound of formula I is an effective Vanin enzyme inhibitor and has broad medicinal prospects. Therefore, it is necessary to research and develop an efficient, low-toxic and/or long-acting pharmaceutically acceptable active ingredient to improve the above technical problems. .
  • the first aspect of the present invention provides a pharmaceutically acceptable salt of the compound of formula I, and the compound of formula I is as follows:
  • the pharmaceutically acceptable salt of the compound of formula I is a salt formed of the compound of formula I and acid.
  • the acid is selected from inorganic acids 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 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,
  • the acid may be 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, ethyl sulfonate 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.
  • the pharmaceutically acceptable salt of the compound of formula I is selected from the group consisting of its hydrochloride, sulfate, phosphate, methanesulfonate, p-toluenesulfonate, fumarate, and maleate.
  • the molar ratio of the compound of formula I to the acid can be selected from 1:1, 2:1 or 3:1, provided that the The ions of the compound of formula I in the salt are charge balanced with the ions of the acid.
  • the compound of formula I when the number of ionizable hydrogen atoms in the acid (such as hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, ethanesulfonic acid) is 1, the compound of formula I and the The molar ratio of the acid is 1:1; when the acid (such as 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 of formula I to the acid may be 1:1 or 2:1; when the number of ionizable hydrogen atoms in the acid (such as phosphoric acid) is 3 , the molar ratio of the compound of formula I to the acid is 1:1, 2:1 or 3:1.
  • the acid such as sulfuric acid, fumaric acid, maleic acid, citric acid, L-tartaric acid, oxalic acid, succinic acid
  • the molar ratio of the compound of formula I to the acid is 1:1; that is, when the acid is L-tartaric acid, fumaric acid , when malic acid is used, the pharmaceutically acceptable salt is selected from the group consisting of monotartrate, monofumarate, and monomalate of the compound of formula I, and is more preferably mono-L-tartrate of the compound of formula I.
  • a second aspect of the present invention provides a method for preparing a pharmaceutically acceptable salt of a compound of formula I, which includes reacting a compound of formula I with the acid to prepare a pharmaceutically acceptable salt of a compound of formula I.
  • the preparation method includes dissolving the compound of formula I in organic solvent A, adding acid to react; and then adding organic solvent B to prepare a pharmaceutically acceptable salt of the compound of formula I.
  • said acid has the definition stated above.
  • the acid is first dissolved in organic solvent C to prepare an acid solution form and then added to the reaction.
  • the organic solvent A is selected from at least one of esters, ketones, and alcohols.
  • the esters can be selected from organic carboxylic acid esters, such as methyl formate, ethyl acetate, isobutyl formate, ethyl propyl acetate, isopropyl acetate or combinations thereof;
  • the ketones can be selected from the group consisting of 3-10 Ketones with 1 to 8 carbon atoms, such as acetone, butanone, pentanone, methyl ethyl ketone, 4-methyl-2-pentanone or combinations thereof;
  • the alcohols can be selected from alcohols with 1 to 8 carbon atoms. , such as methanol, ethanol, n-propanol, isopropanol, n-butanol, neopentyl alcohol or combinations thereof.
  • the organic solvent B is selected from nitriles, esters, ethers or combinations thereof.
  • the nitriles can be selected from nitriles with 2-6 carbon atoms, such as acetonitrile, propionitrile, isopropionitrile, butyronitrile or combinations thereof;
  • the esters can be selected from organic carboxylic acid esters, such as methyl formate, acetic acid Ethyl ester, isobutyl formate, ethyl propyl acetate, isopropyl acetate or combinations thereof;
  • the ethers can be selected from ethers with 2-6 carbon atoms, such as diethyl ether, propyl ether, isopropyl ether, tert-butyl ether, methyl tert-butyl ether or combinations thereof.
  • the organic solvent C is selected from any organic solvent that dissolves the acid.
  • the organic solvent C is selected from alcohols
  • the alcohols can be selected from alcohols with 1-8 carbon atoms, such as methanol, ethanol, n-propanol , isopropyl alcohol, n-butanol, neopentyl alcohol or combinations thereof.
  • the volume ratio of the organic solvent A to the organic solvent B is 1:1 to 5, preferably 1:1.
  • the molar ratio of the compound of formula I to the acid is 1:0.8-1:1.5, preferably 1:0.9-1:1.3, and more preferably 1:1.0-1:1.1.
  • the reaction temperature is 20°C to 80°C, preferably 20°C to 60°C.
  • the preparation method also includes the steps of filtering and/or drying after the reaction is completed to prepare a pharmaceutically acceptable salt of the compound of formula I.
  • the drying temperature may be 30°C to 60°C, more preferably 40°C to 50°C.
  • the drying pressure is 0 to 20KPa, preferably 0 to 10KPa, and more preferably 5 to 10KPa.
  • the present invention also provides crystals of the mono-L-tartrate salt of the compound of formula I, preferably single crystals.
  • the unit cell parameters of the single crystal are as follows:
  • Monoclinic crystal system, space group is P2 1 ,
  • the present invention also provides crystals of the mono-L-tartrate salt of the compound of formula I, especially a method for preparing single crystals, which includes dissolving the mono-L-tartrate salt of the compound of formula I in solvent D and then placing it in the atmosphere of solvent E for diffusion.
  • the solvent D is selected from alcoholic solvents, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, neopentyl alcohol or combinations thereof.
  • the solvent E is selected from ester solvents, ether solvents, alkane solvents or combinations thereof.
  • the ester solvent can be selected from organic carboxylic acid esters, such as ethyl acetate, isopropyl acetate, etc.
  • the ethers can be selected from ethers with 2-6 carbon atoms, such as diethyl ether, propyl ether, isopropyl ether, Tert-butyl ether, methyl tert-butyl ether, etc.
  • the alkanes can be selected from hydrocarbons with 1-8 carbon atoms, such as n-hexane, n-heptane, etc.
  • a third aspect of the present invention provides crystalline forms of pharmaceutically acceptable salts of the compound of formula I.
  • the crystal form of the mono-L-tartrate salt of the compound of formula I is provided, which is selected from the group consisting of crystal form A, crystal form B, crystal form C and crystal form D described below.
  • Form A of the mono-L-tartrate salt of the compound of Formula I is provided.
  • the crystal form A uses Cu-K ⁇ radiation, and X-ray powder diffraction expressed in 2 ⁇ angle has characteristic peaks at 17.06 ⁇ 0.20°, 20.06 ⁇ 0.20°, and 22.58 ⁇ 0.20°.
  • the crystal form A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angle is 17.06 ⁇ 0.20°, 18.00 ⁇ 0.20°, 18.80 ⁇ 0.20°, 19.22 ⁇ 0.20°, 20.06 ⁇ 0.20°, There are characteristic peaks at 22.58 ⁇ 0.20°, 23.72 ⁇ 0.20°, and 24.38 ⁇ 0.20°.
  • the crystal form A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angle is at 8.30 ⁇ 0.20°, 14.24 ⁇ 0.20°, 17.06 ⁇ 0.20°, 18.00 ⁇ 0.20°, 18.80 ⁇ 0.20°, There are characteristic peaks at 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°.
  • the crystal form A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angle is as shown in Table 1, with an error range of ⁇ 0.20°:
  • the Form A has a powder X-ray diffraction pattern substantially as shown in Figure 1.
  • the crystalline form A is the anhydride of the mono-L-tartrate salt of the compound of formula I.
  • differential scanning calorimetry (DSC) analysis of the crystalline form A shows that the first endothermic peak appears when heated to a peak temperature of 150.14°C.
  • the Form A has a DSC pattern substantially as shown in Figure 2.
  • thermogravimetric analysis (TGA) of the Form A shows a weight loss of about 0.069% in the range of 22.03°C to 120°C.
  • the crystal form A has a TGA diagram substantially as shown in Figure 3.
  • the crystal form A is an irregular morphology crystal.
  • the particle size of the crystalline form A does not exceed 10 ⁇ m.
  • the crystal form A has a PLM pattern substantially as shown in Figure 4.
  • Form B of the mono-L-tartrate salt of the compound of Formula I is provided.
  • the crystal form B uses Cu-K ⁇ radiation, and X-ray powder diffraction expressed in 2 ⁇ angle has characteristic peaks at 19.28 ⁇ 0.20°, 19.94 ⁇ 0.20°, 21.30 ⁇ 0.20°, and 23.72 ⁇ 0.20°.
  • the crystal form B uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angle is 7.56 ⁇ 0.20°, 17.36 ⁇ 0.20°, 19.28 ⁇ 0.20°, 19.94 ⁇ 0.20°, 21.30 ⁇ 0.20°, There are characteristic peaks at 23.72 ⁇ 0.20° and 26.02 ⁇ 0.20°.
  • the crystal form B uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angle is 7.56 ⁇ 0.20°, 17.36 ⁇ 0.20°, 18.14 ⁇ 0.20°, 19.28 ⁇ 0.20°, 19.94 ⁇ 0.20°, There are characteristic peaks at 21.30 ⁇ 0.20°, 23.72 ⁇ 0.20°, 24.52 ⁇ 0.20°, 26.02 ⁇ 0.20°, and 29.52 ⁇ 0.20°.
  • the crystal form B uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angle is 3.78 ⁇ 0.20°, 7.56 ⁇ 0.20°, 17.36 ⁇ 0.20°, 18.14 ⁇ 0.20°, 19.28 ⁇ 0.20°, There are characteristic peaks at 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°.
  • the crystal form B uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angle is shown in Table 2, with an error range of ⁇ 0.20°:
  • the Form B has a powder X-ray diffraction pattern substantially as shown in Figure 5.
  • the crystalline form B is the hydrate of the mono-L-tartrate salt of the compound of formula I.
  • the hydrate contains 0.5 to 1 mol of water.
  • differential scanning calorimetry (DSC) analysis of the crystal form B shows that the first endothermic peak appears when heated to a peak temperature of 61.57°C, and the second endothermic peak appears near a peak temperature of 152.18°C. an endothermic peak.
  • the first endothermic peak is the dehydration peak
  • the second endothermic peak is the melting peak.
  • the Form B has a DSC pattern substantially as shown in Figure 6.
  • thermogravimetric analysis (TGA) of the Form B shows a weight loss of about 2.76% in the range of 21.34°C to 120°C.
  • the crystal form B has a TGA diagram substantially as shown in Figure 7.
  • Form C, mono-L-tartrate salt of the compound of Formula I is provided.
  • the crystal form C uses Cu-K ⁇ radiation, and X-ray powder diffraction expressed in 2 ⁇ angle has characteristic peaks at 17.88 ⁇ 0.20°, 19.40 ⁇ 0.20°, and 21.38 ⁇ 0.20°.
  • the crystal form C uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angle is 7.14 ⁇ 0.20°, 17.88 ⁇ 0.20°, 19.40 ⁇ 0.20°, 20.06 ⁇ 0.20°, 21.38 ⁇ 0.20°, There are characteristic peaks at 23.76 ⁇ 0.20° and 25.92 ⁇ 0.20°.
  • the crystal form C uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angle is 3.58 ⁇ 0.20°, 7.14 ⁇ 0.20°, 13.96 ⁇ 0.20°, 17.10 ⁇ 0.20°, 17.88 ⁇ 0.20°, There are characteristic peaks at 19.40 ⁇ 0.20°, 20.06 ⁇ 0.20°, 21.38 ⁇ 0.20°, 25.92 ⁇ 0.20°, and 29.38 ⁇ 0.20°.
  • the crystal form C uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angle is shown in Table 3, with an error range of ⁇ 0.20°:
  • the Form C has a powder X-ray diffraction pattern substantially as shown in Figure 8.
  • the crystalline form C is the mono-L-tartrate solvate of the compound of formula I, preferably the ethanol solvate of the mono-L-tartrate of the compound of formula I.
  • differential scanning calorimetry (DSC) analysis of the crystal form C shows that the first endothermic peak appears near the peak temperature of 129.45°C when heated to, and the third endothermic peak appears near the peak temperature of 151.90°C.
  • Two endothermic peaks The first endothermic peak is the desolvation peak, and the second endothermic peak is the melting peak.
  • the crystalline Form C has a DSC pattern substantially as shown in Figure 9.
  • thermogravimetric analysis (TGA) of the Form C shows a weight loss of about 4.59% in the range of 21.47°C to 150°C.
  • the crystalline Form C has a TGA diagram substantially as shown in Figure 10.
  • the crystal form C is an irregular morphology crystal.
  • the particle size of Form C does not exceed 10 ⁇ m.
  • the crystalline Form C has a PLM pattern substantially as shown in Figure 11.
  • the compound of Formula I is provided as mono-L-tartrate crystalline form D, the crystalline form D having X-ray powder diffraction in 2 ⁇ at 3.50 ⁇ 0.20°, 7.46 ⁇ 0.20° using Cu-K ⁇ radiation. , there is a characteristic peak at 23.04 ⁇ 0.20°.
  • the crystal form D uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angle is 3.50 ⁇ 0.20°, 6.92 ⁇ 0.20°, 7.46 ⁇ 0.20°, 17.22 ⁇ 0.20°, 18.20 ⁇ 0.20°, There are characteristic peaks at 19.88 ⁇ 0.20° and 23.04 ⁇ 0.20°.
  • the crystal form D uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angle is 3.50 ⁇ 0.20°, 6.92 ⁇ 0.20°, 7.46 ⁇ 0.20°, 17.22 ⁇ 0.20°, 18.20 ⁇ 0.20°, There are characteristic peaks at 19.88 ⁇ 0.20°, 20.76 ⁇ 0.20°, 23.04 ⁇ 0.20°, and 25.62 ⁇ 0.20°.
  • the crystal form D uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angle is shown in Table 4, with an error range of ⁇ 0.20°:
  • said Form D has a powder X-ray diffraction pattern substantially as shown in Figure 12.
  • the crystalline form D is the mono-L-tartrate solvate of the compound of formula I, preferably the tetrahydrofuran solvate of the mono-L-tartrate of the compound of formula I.
  • differential scanning calorimetry (DSC) analysis of the crystalline form D shows that the first endothermic peak appears near the peak temperature of 94.15°C when heated to, and the third endothermic peak appears near the peak temperature of 118.79°C. There are two endothermic peaks, and a third endothermic peak appears near the peak temperature of 146.04°C.
  • the first and second endothermic peaks are desolvent peaks, and the third endothermic peak is melting peak.
  • the crystalline Form D has a DSC pattern substantially as shown in Figure 13.
  • thermogravimetric analysis (TGA) of the Form D shows a weight loss of about 5.25% in the range of 23.19°C to 120°C.
  • the crystal form D has a TGA diagram substantially as shown in Figure 14.
  • the fourth aspect of the present invention provides a method for preparing the crystalline form of a pharmaceutically acceptable salt of the compound of formula I.
  • a method for preparing the mono-L-tartrate crystal form of the compound of formula I is provided.
  • a method for preparing the mono-L-tartrate salt of the compound of formula I, crystal form A which includes: stirring the mono-L-tartrate salt of the compound of formula I in a solvent to obtain the crystal form A.
  • the stirring temperature is 20-80°C, preferably 25-55°C.
  • the solvent is selected from alcohol solvents, ester solvents, ketone solvents, ether solvents, alkane solvents, halogenated hydrocarbon solvents and nitrile solvents or combinations thereof.
  • the alcohol solvent is selected from one of methanol, ethanol and isopropyl alcohol.
  • the ester solvent is selected from one of ethyl acetate, propyl acetate and isopropyl acetate.
  • the ketone solvent is selected from one of acetone, 2-butanone, methyl isobutyl ketone and 4-methyl-2-pentanone.
  • the ether solvent is selected from one of diethyl ether, propyl ether, isopropyl ether, methyl tert-butyl ether and tetrahydrofuran.
  • the alkane solvent is selected from one of toluene, n-heptane and cyclohexane.
  • the nitrile solvent is selected from one of acetonitrile, phenylacetonitrile and benzonitrile.
  • the mass-volume ratio of the mono-L-tartrate of the compound of formula I to the solvent is 1g:(20-40)ml, preferably 1g:(20-30)ml.
  • a second method for preparing the mono-L-tartrate crystal form A of the compound of formula I includes: adding the mono-L-tartrate of the compound of formula I into an alcoholic solvent to dissolve, and then adding an anti-solvent for stirring, The crystal form A was obtained.
  • the alcohol solvent is selected from one of methanol, ethanol, propanol and isopropyl alcohol.
  • the antisolvent is one or more of ether solvents or ester solvents.
  • the ether solvent is selected from one of diethyl ether, propyl ether, isopropyl ether and methyl tert-butyl ether.
  • the ester solvent is selected from one of ethyl acetate, propyl acetate and isopropyl acetate. kind.
  • the mass and volume ratio of the mono-L-tartrate of the compound of formula I to alcohol solvent and anti-solvent is 1g:(10-30)ml:(80-120)ml, preferably 1g:(15-25)ml:( 90-110)ml.
  • the preparation method one or two of crystal form A also includes post-processing steps such as filtration and drying.
  • a method for preparing the mono-L-tartrate crystal form B of the compound of formula I includes placing the crystal form A under high humidity conditions to obtain the crystal form B. Preferably, it is left for more than 2 days, and more preferably, it is left for more than 3 days.
  • the high humidity condition is 80% to 100% RH, preferably 90% to 100% RH.
  • a second method for preparing the mono-L-tartrate salt of the compound of formula I, crystal form B which includes dissolving the mono-L-tartrate salt of the compound of formula I in an alcohol solvent, and obtaining crystal form B after the solvent evaporates.
  • the alcohol solvent is selected from one of methanol, ethanol and isopropyl alcohol.
  • the dissolution temperature is 15-45°C, preferably 25-35°C.
  • the mass volume ratio of the mono-L-tartrate of the compound of formula I to the alcoholic solvent is 1g:(10-30)ml, preferably 1g:(15-25)ml.
  • a method for preparing the mono-L-tartrate salt of the compound of formula I, crystalline form C which includes dissolving the mono-L-tartrate salt of the compound of formula I in an alcoholic solvent and crystallizing it to obtain the crystalline form C.
  • the alcohol solvent is selected from methanol, ethanol and/or isopropyl alcohol, preferably methanol.
  • the mass volume ratio of the mono-L-tartrate of the compound of formula I to the alcoholic solvent is 1g:(20-40)ml, preferably 1g:(20-30)ml.
  • the preparation method of the crystalline form C also includes post-processing steps such as filtration and drying.
  • a method for preparing the mono-L-tartrate crystal form D of the compound of formula I includes dissolving the mono-L-tartrate of the compound of formula I in an ether solvent, heating and stirring, and cooling to precipitate a solid, The crystal form D was obtained.
  • the ether solvent is selected from one of diethyl ether, tetrahydrofuran, and methyl tert-butyl ether, and is preferably tetrahydrofuran.
  • the heating temperature is 30°C to 80°C, preferably 45°C to 75°C.
  • the cooling temperature is 20°C to 30°C.
  • the mass volume ratio of the mono-L-tartrate of the compound of formula I and the ether solvent is 1g:(20-40)ml, preferably 1g:(20-30)ml.
  • the preparation method of the crystalline form D includes post-processing steps such as filtration and drying.
  • the present invention also provides a pharmaceutical composition, including a pharmaceutically acceptable salt of the compound of formula I or a crystal form thereof, and optionally pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable salt is the mono-L-tartrate salt of the compound of formula I; the crystal form is selected from the group consisting of mono-L-tartrate salt of the compound of formula I, crystal form A, crystal form B, and crystal form C, Form D.
  • the pharmaceutical composition is in the form of a preparation.
  • the present invention also provides a preparation, including a pharmaceutically acceptable salt or crystal form of the compound of formula I, and optionally pharmaceutically acceptable pharmaceutical excipients.
  • the pharmaceutically acceptable salt is the mono-L-tartrate salt of the compound of formula I; the crystal form is selected from the group consisting of mono-L-tartrate salt of the compound of formula I, crystal form A, crystal form B, and crystal form C, Form D.
  • the present invention also provides a pharmaceutically acceptable salt of the compound of formula I as described above or a crystal form thereof, or the use of the pharmaceutical composition in the preparation of a medicament for preventing and/or treating diseases or conditions associated with Vanin enzyme inhibitors.
  • diseases or conditions associated with the Vanin enzyme inhibitor include autoimmune diseases, inflammatory diseases, allergic diseases, metabolic diseases, infection-based diseases, fibrotic diseases, cardiovascular diseases, respiratory diseases, etc.
  • autoimmune diseases inflammatory diseases, allergic diseases, metabolic diseases, infection-based diseases, fibrotic diseases, cardiovascular diseases, respiratory diseases, etc.
  • systemic diseases renal diseases, dermatological diseases, liver diseases, gastrointestinal diseases, oral diseases and hematopoietic diseases; for example, Crohn's disease, inflammatory bowel disease and ulcerative colitis.
  • the present invention also provides a method for preventing and/or treating diseases or conditions related to Vanin enzyme inhibitors, which includes administering a therapeutically effective amount of a pharmaceutically acceptable salt of the compound of formula I or a crystal form thereof to an individual in need, or the pharmaceutical composition.
  • the diseases or conditions associated with Vanin enzyme inhibitors include autoimmune diseases, inflammatory diseases, allergic diseases, metabolic diseases, infection-based diseases, fibrotic diseases, cardiovascular diseases, respiratory diseases, etc.
  • autoimmune diseases inflammatory diseases, allergic diseases, metabolic diseases, infection-based diseases, fibrotic diseases, cardiovascular diseases, respiratory diseases, etc.
  • systemic diseases renal diseases, dermatological diseases, liver diseases, gastrointestinal diseases, oral diseases and hematopoietic diseases; for example, Crohn's disease, inflammatory bowel disease and ulcerative colitis.
  • the treatment method of the present invention may include separately administering one, two or more pharmaceutically acceptable salts of the compound of formula I of the present invention or its crystal forms, and combining the pharmaceutically acceptable salts of the compound of formula I of the present invention or its crystal forms.
  • One, two or more of the crystalline forms are administered in combination with other chemotherapeutic agents.
  • Combination administration can involve administering different drugs simultaneously or sequentially.
  • the salts of the compound of formula I of the present invention have high stability, especially the mono-L-tartrate salt, which has high solubility in water, which is beneficial to enhancing oral absorption and improving biological availability;
  • Figure 1 is the XRPD pattern of mono-L-tartrate crystal form A of the compound of formula I.
  • Figure 2 is a DSC spectrum of the mono-L-tartrate crystal form A of the compound of formula I.
  • Figure 3 is a TGA spectrum of the mono-L-tartrate crystal form A of the compound of formula I.
  • Figure 4 is a PLM spectrum of the mono-L-tartrate crystal form A of the compound of formula I.
  • Figure 5 is the XRPD pattern of mono-L-tartrate crystal form B of the compound of formula I.
  • Figure 6 is a DSC spectrum of the mono-L-tartrate crystal form B of the compound of formula I.
  • Figure 7 is a TGA spectrum of the mono-L-tartrate crystal form B of the compound of formula I.
  • Figure 8 is the XRPD pattern of the mono-L-tartrate crystal form C of the compound of formula I.
  • Figure 9 is a DSC spectrum of mono-L-tartrate crystal form C of the compound of formula I.
  • Figure 10 is a TGA spectrum of the mono-L-tartrate crystal form C of the compound of formula I.
  • Figure 11 is a PLM spectrum of the mono-L-tartrate crystal form C of the compound of formula I.
  • Figure 12 is the XRPD pattern of mono-L-tartrate crystal form D of the compound of formula I.
  • Figure 13 is a DSC spectrum of the mono-L-tartrate crystal form D of the compound of formula I.
  • Figure 14 is a TGA spectrum of the mono-L-tartrate crystal form D of the compound of formula I.
  • Figure 15 is the XRPD pattern of the mono-L-tartrate crystal form A of the compound of formula I in Example 7.
  • Figure 16 is the XRPD pattern of the mono-L-tartrate crystal form B of the compound of formula I in Example 9.
  • Figure 17 is an XRPD pattern of the mono-L-tartrate crystal form A of the compound of formula I after being placed under high temperature and high humidity conditions for 3 days.
  • Figure 18 is an XRPD pattern of the mono-L-tartrate crystal form A of the compound of formula I after being placed under high temperature and high humidity conditions for 2 weeks.
  • Figure 19 is a single crystal view of the mono-L-tartrate salt of the compound of formula I.
  • 40°C/75%RH-open refers to placing it open at 40°C and 75% humidity.
  • 60°C-open refers to placing it in the open under the condition of 60°C.
  • 80%RHopen refers to placing it open under 80% humidity conditions.
  • 92.5%RH-open refers to placing it open under 80% humidity conditions.
  • 40°C/75%RH-closed-2wks refers to keeping it sealed for 2 weeks at 40°C and 75% humidity.
  • 40°C/75%RH-open-2wks refers to leaving it open for 2 weeks at 40°C and 75% humidity.
  • 60°C-closed-2wks refers to being placed in a sealed container at 60°C for 2 weeks.
  • STD-1 refers to the control sample.
  • Initial refers to the initial state.
  • SGF refers to simulated gastric juice.
  • FaSSIF refers to fasting state simulated intestinal fluid
  • FeSSIF refers to simulated intestinal fluid in the fed state.
  • the equipment is Shimadzu XRD-6000, and the sample is scanned according to the following parameters:
  • the ray source is Cu ⁇ K ⁇ target
  • the minimum operating voltage and current of the light tube are 40kV and 30mA respectively.
  • the sample scan range has 2-Theta values from 2° to 50°.
  • the scanning speed is 5deg/min.
  • the sample is dispersed in the medium (silicone oil), the sample is observed using a 10X eyepiece and a 10X objective lens, and the image is recorded with a camera computer system.
  • the medium silicone oil
  • Dissolve compound 1b (385g, 3.18mol) and tetraethyl titanate (905g, 3.97mol) in toluene (3L), stir and heat to 110°C, and reflux; add compound 1a (352g, 2.65mol) dropwise to the above reaction solution ) in toluene solution (500 mL). After the dropwise addition is completed, continue heating and refluxing for 1 hour. After the reaction was completed, the reaction was stopped, cooled to room temperature, concentrated to remove toluene, the residue was quenched with water (400 mL), diluted with 1000 mL of ethyl acetate, and filtered through diatomaceous earth.
  • the crude product 1d was dissolved in methanol (500 mL), and HCl/MeOH (200 mL 4M) was slowly added. The reaction solution was allowed to react at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain an oily substance, which was added with ethyl acetate (100 mL) and stirred. After filtration, compound 1e was obtained as a red solid powder (300 g, ee value 98%, purity 99%).
  • Stability inspection conditions 40°C/75%RH-closed, 40°C/75%RH-open, 60°C-closed; stability inspection content: changes in related substances and crystal forms.
  • the compound of formula I and its mono-L-tartrate, fumarate, and D-malate salts all have good solubility. In each medium, it can be completely dissolved to the target concentration of 5 mg/mL or 10 mg/mL, calculated as free base.
  • Crystal Form A was characterized by XRPD, DSC, TGA and PLM.
  • the crystal form A is anhydrous.
  • the XRPD characteristic peak positions and intensities are shown in Table 1, and the XRPD spectrum is shown in Figure 1.
  • DSC shows that the first endothermic peak appears near the peak temperature of 150.14°C, as shown in Figure 2.
  • TGA showed a weight loss of about 0.069% in the range from 22.03°C to 120°C, as shown in Figure 3.
  • the PLM image shows that the sample is an irregular morphological crystal below 10 ⁇ m, as shown in Figure 4.
  • Crystal form B was obtained after exposing 500 mg of the mono-L-tartrate crystal form A of the compound of formula I to 92.5% RH for 3 days.
  • Crystal Form B was characterized by XRPD, DSC, TGA and PLM.
  • the crystal form B is a hydrate, which contains 0.5 to 1 mol of water.
  • the position and intensity of the XRPD characteristic peaks are shown in Table B, and the XRPD pattern is shown in Figure 5.
  • DSC shows that the first endothermic peak appears near the peak temperature of 61.57°C, and the second endothermic peak appears near the peak temperature of 152.18°C, as shown in Figure 6.
  • TGA showed a weight loss of approximately 2.76% in the range from 22.03°C to 120°C, as shown in Figure 7 .
  • Crystal Form C was characterized by XRPD, DSC, TGA and PLM.
  • the crystal form C is an ethanol solvate.
  • DSC shows that the first endothermic peak appears near the peak temperature of 129.45°C, as shown in Figure 9.
  • TGA showed a weight loss of approximately 4.59% in the range from 21.47°C to 150°C, as shown in Figure 10 .
  • the PLM image shows that the sample is an irregular morphological crystal below 10 ⁇ m, as shown in Figure 11.
  • Crystal Form D was characterized by XRPD, DSC, and TGA.
  • the crystal form D is a tetrahydrofuran solvate.
  • DSC shows that the first endothermic peak appears near the peak temperature of 94.15°C, as shown in Figure 13.
  • TGA showed a weight loss of approximately 5.25% in the range from 23.19°C to 120°C, as shown in Figure 14.
  • samples placed at 40°C/75%RH-closed, 40°C/75%RH-open, and 60°C-open were taken out at 2wks for stability inspection, including related substances and crystal forms.
  • Stability sample related substance detection method Weigh about 5 mg of sample, add 5 mL of 20% methanol, ultrasonic for a few seconds, the compound can be completely dissolved, and inject 5 ⁇ L for related substance testing.

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Abstract

本发明涉及一种式I所示的Vanin酶抑制剂的盐型、晶型及其制备方法和应用，所述盐型为式Ⅰ化合物与酸形成的盐，所述晶型选自式I化合物L-酒石酸盐晶型A，晶型B，晶型C，晶型D。本发明式I化合物的盐的稳定性高，水溶性好，有利于增强口服吸收能力，提高生物的利用度且制备方法操作简单，容易控制，重现性好，适合工业化生产。本发明的晶型稳定性高，溶解度好，吸湿性少，具有良好的成药前景。

Description

Vanin酶抑制剂的盐型、晶型及其制备方法和应用
本申请要求申请日为2022年3月18日的中国专利申请CN 202210272562.6和申请日为2022年9月9日的中国专利申请CN 202211104893.5的优先权。这些申请的全文通过引用的方式结合于本申请中。
技术领域
本发明属于医药领域，具体涉及Vanin酶抑制剂的盐型、晶型及其制备方法，和所述盐型、晶型在制备预防和/或治疗心血管疾病和肿瘤疾病中的应用。
背景技术
Vanin-1(血管非炎性分子-1)是一种具有泛肽酶活性的外切酶，主要催化泛酰巯基乙胺的水解而产生泛酸(pantothenic acid，VB5)和巯基乙胺。由VB5合成而来的辅酶A(CoA)调节脂肪酸合成和氧化以及能力代谢等生物转化，而巯基乙胺和胱胺之间的可逆反应是氧化应激的重要传感器。越来越多的研究发现，巯基乙胺的缺乏或水平降低导致γ-GCS活性增强，引起组织中内源性GSH储备升高，从而可以预防或消除组织炎症。研究发现，Vanin-1的mRNA在人结肠、十二指肠、子宫内膜、肝、肾、胆囊和小肠中高表达。在UC(溃疡性结肠炎)患者中，Vanin-1弥漫性高表达，而且仅限于刷状缘边界。另外，在UC的临床静止期，结肠中Vanin-1的表达水平仍显著高于对照品。在TNBS模型实验中，小鼠Vanin-1敲除(Vanin-1-/-)后生存率明显高于模型对照组，并且未表现明显体重降低。而且，90％经胱胺处理的Vanin-1-/-小鼠在5天内死亡，说明胱胺完全逆转Vanin-1的缺乏对结肠炎的保护作用。此外，对小鼠组织病理学分析发现，对Vanin-1的抑制或敲除能显著改善小鼠结肠的病变(Berruyer C,等人，Vanin-1-/-mice exhibit a glutathione mediated tissue resistance to oxidative stress.Mol.Cell Biol.2004；24:7214-7224；Berruyer C,等人，Vanin-1licenses inflammatory mediator production by gut epithelial cells and controls colitis by antagonizing peroxisome proliferator-activated receptorγactivity.J.Exp.Med.2006；203:2817-2827)。
另外，Vanin-1也被认为在心血管疾病和肿瘤疾病中起调节作用。有研究证明，Vanin-1在体外调节平滑肌细胞的活化，并在体内调节响应于颈动脉结扎的新内膜增生的发生。VNN1基因的多态性与血压和HDL水平相关。在SF-1转基因小鼠中，Vanin-1缺失防止小鼠发展为肾上腺皮质的瘤形成，表明了Vanin-1在某些癌症中的作用。在炎症性疾病方面的研究发现，与正常个体相比，在牛皮癣的皮肤损伤中，Vanin-1高度上调。在患有儿童免疫血小板减少症(ITP)的患者的全血中，VNN1的基因表达也上调，其中VNN1的过表达与慢性ITP的进展相关。另外，在患有多种肾脏病症的患者尿液中已检测到Vanin-1升高，所述肾脏病症包括***性红斑狼疮、肾脏毒物(nephrotoxicant)-诱导的肾损伤和2型糖尿病(Rommelaere S,等人 PPARalpha regulates the production of serum Vanin-1by liver.FEBS Lett.2013Nov 15；587(22):3742-8)。
中国专利申请CN2021110954656(WO2022063197A1)公开了如下式I结构
该式I化合物为有效的Vanin酶抑制剂，具有广泛的药用前景，因此，有必要研究开发一种高效、低毒和/或长效的药学上可接受的活性成分，以改善上述技术问题。
发明内容
为解决现有技术中存在的问题，本发明第一方面提供一种式Ⅰ化合物药学上可接受的盐，所述式I化合物如下所示：
所述式Ⅰ化合物药学上可接受的盐为式Ⅰ化合物与酸形成的盐。
所述酸选自无机酸或有机酸，例如盐酸、氢氟酸、氢溴酸、氢碘酸、硫酸、焦硫酸、磷酸、硝酸，甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、二葡糖酸、3-羟基-2-萘甲酸、烟酸、扑酸、果胶酯酸、过硫酸、3-苯基丙酸、苦味酸、特戊酸、2-羟基乙磺酸、衣康酸、氨基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、L-酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、藻酸、马来酸、富马酸、D-葡糖酸、扁桃酸、抗坏血酸、葡庚酸、甘油磷酸、天冬氨酸、磺基水杨酸、半硫酸或硫氰酸。作为实例，所述酸可以选自盐酸、氢溴酸、硫酸、磷酸、硝酸、甲磺酸、对甲苯磺酸、富马酸、马来酸、柠檬酸、L-酒石酸、琥珀酸、乙磺酸、L-苹果酸、L-谷氨酸、草酸、D-苹果酸、帕莫酸、草酸、甲酸、乙酸、三氟乙酸、月桂酸、苯甲酸和苯磺酸中的一种。
一种优选地实施方案中，所述式Ⅰ化合物药学上可接受的盐选自其盐酸盐、硫酸盐、磷酸盐、甲磺酸盐、对甲苯磺酸盐、富马酸盐、马来酸盐、柠檬酸盐、L-酒石酸盐、琥珀酸盐、乙磺酸盐、L-苹果酸盐、L-谷氨酸盐、草酸盐、D-苹果酸盐、帕莫酸中的一种。
一种优选地实施方案中，所述式I化合物药学上可接受的盐中，式I化合物与所述酸的摩尔比可以选自1:1、2:1或3:1，条件是所述盐中式I化合物的离子与酸的离子电荷平衡。例如，当所述酸(如盐酸、甲磺酸、对甲苯磺酸、乙磺酸)中可电离的氢原子数为1时，式I化合物与所 述酸的摩尔比为1:1；当所述酸(如硫酸、富马酸、马来酸、柠檬酸、L-酒石酸、草酸、琥珀酸、苹果酸、L-谷氨酸、帕莫酸)中可电离的氢原子数为2时，式I化合物与所述酸的摩尔比可以为1:1或2:1；当所述酸(如磷酸)中可电离的氢原子数为3时，式I化合物与所述酸的摩尔比为1:1、2:1或3:1。
一种更优选地实施方案中，所述式I化合物药学上可接受的盐中，式I化合物与所述酸的摩尔比为1:1；即当所述酸为L-酒石酸、富马酸、苹果酸时，所述药学上可接受的盐选自式I化合物的单酒石酸盐，单富马酸盐，单苹果酸盐，更优选为式I化合物的单L-酒石酸盐。
本发明第二方面提供一种式Ⅰ化合物药学上可接受的盐的制备方法，包括将式Ⅰ化合物与所述酸反应，制备得到式Ⅰ化合物药学上可接受的盐。
根据本发明的实施方案，所述制备方法包括将式Ⅰ化合物溶于有机溶剂A，加入酸进行反应；然后再加入有机溶剂B，制备得到式Ⅰ化合物药学上可接受的盐。
根据本发明的实施方案，所述酸具有上文所述的定义。在一些实施方案中，所述酸先溶解于有机溶剂C制备为酸的溶液形式后再加入反应。
根据本发明的实施方案，所述有机溶剂A选自酯类、酮类、醇类中的至少一种。所述酯类可以选自有机羧酸酯，例如甲酸甲酯、乙酸乙酯、甲酸异丁酯、乙酸乙丙酯、乙酸异丙酯或其组合；所述酮类可以选自具有3-10个碳原子的酮，例如丙酮、丁酮、戊酮、甲基乙基酮、4-甲基-2-戊酮或其组合；所述醇类可以选自具有1-8个碳原子的醇，例如甲醇、乙醇、正丙醇、异丙醇、正丁醇、新戊醇或其组合。
根据本发明的实施方案，所述有机溶剂B选自腈类、酯类、醚类或其组合。所述腈类可以选自2-6个碳原子的腈，例如乙腈、丙腈、异丙腈、丁腈或其组合；所述酯类可以选自有机羧酸酯，例如甲酸甲酯、乙酸乙酯、甲酸异丁酯、乙酸乙丙酯、乙酸异丙酯或其组合；所述醚类可以选自2-6个碳原子的醚，例如***、丙醚、异丙醚、叔丁基醚、甲基叔丁基醚或其组合。
根据本发明的实施方案，本领域技术人员可以理解，所述有机溶剂C选自使所述酸溶解的任意有机溶剂。
在一些实施方案中，当所述酸选自L-酒石酸时，有机溶剂C选自醇类，所述醇类可以选自具有1-8个碳原子的醇，例如甲醇、乙醇、正丙醇、异丙醇、正丁醇、新戊醇或其组合。
所述制备方法中，所述有机溶剂A与有机溶剂B的体积比为1:1～5，优选为1:1。
所述制备方法中，所述式I化合物与所述酸的摩尔比为1:0.8～1:1.5，优选为1:0.9～1:1.3，更优选为1:1.0～1:1.1。
根据本发明的实施方案，所述反应的温度为20℃～80℃，优选为20℃～60℃。
根据本发明的实施方案，所述制备方法还包括反应结束后，进行过滤和/或干燥的步骤，以制备得到式Ⅰ化合物药学上可接受的盐。
所述制备方法中，干燥的温度可以为30℃～60℃，更优选为40℃～50℃。
所述制备方法中，干燥的压力为0～20KPa，优选为0～10KPa，更优选为5～10KPa。
本发明还提供式I化合物单L-酒石酸盐的晶体，优选为单晶。其中，所述单晶的晶胞参数如下：
单斜晶系，空间群为P21，
β＝96.577，
Z＝2。
本发明还提供式I化合物单L-酒石酸盐的晶体，尤其是单晶的制备方法，包括将式I化合物单L-酒石酸盐溶解于溶剂D然后置于溶剂E的气氛中扩散。
所述溶剂D选自醇类溶剂，例如甲醇、乙醇、正丙醇、异丙醇、正丁醇、新戊醇或其组合。
所述溶剂E选自酯类溶剂、醚类溶剂或烷烃类溶剂或其组合。所述酯类溶剂可以选自有机羧酸酯，例如乙酸乙酯，乙酸异丙酯等；所述醚类可以选自2-6个碳原子的醚，例如***、丙醚、异丙醚、叔丁基醚、甲基叔丁基醚等；所述烷烃类可以选自1-8个碳原子烃，例如正己烷，正庚烷等。
本发明第三方面提供所述式Ⅰ化合物药学上可接受的盐的晶型。
根据本发明优选地实施方案，提供所述式I化合物单L-酒石酸盐的晶型，选自下文所述的晶型A、晶型B，晶型C和晶型D。
在一些实施方案中，提供式Ⅰ化合物单L-酒石酸盐的晶型A。所述晶型A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在17.06±0.20°、20.06±0.20°、22.58±0.20°处具有特征峰。
优选地，所述晶型A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、24.38±0.20°处具有特征峰。
优选地，所述晶型A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、25.70±0.20°处具有特征峰。
优选地，所述晶型A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射如表1所示，误差范围±0.20°：
表1晶型A的XRPD解析数据

优选地，所述晶型A具有基本如图1所示的粉末X射线衍射图。
根据本发明的实施方案，所述晶型A为式Ⅰ化合物单L-酒石酸盐的无水物。
根据本发明的实施方案，所述晶型A的差示扫描量热法(DSC)分析显示在加热至峰值温度150.14℃附近出现第一个吸热峰。
优选地，所述晶型A具有基本如图2所示的DSC图。
根据本发明的实施方案，所述晶型A的热重分析(TGA)显示在22.03℃至120℃区间内具有约0.069％的失重。
优选地，所述晶型A具有基本如图3所示的TGA图。
根据本发明的实施方案，所述晶型A为不规则形貌晶体。优选地，所述晶型A的粒径不超过10μm。
优选地，所述晶型A具有基本如图4所示的PLM图谱。
在一些实施方案中，提供式Ⅰ化合物单L-酒石酸盐的晶型B。所述晶型B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在19.28±0.20°、19.94±0.20°、21.30±0.20°、23.72±0.20°处具有特征峰。
优选地，所述晶型B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在7.56±0.20°、17.36±0.20°、19.28±0.20°、19.94±0.20°、21.30±0.20°、23.72±0.20°、26.02±0.20°处具有特征峰。
优选地，所述晶型B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、29.52±0.20°处具有特征峰。
优选地，所述晶型B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、29.52±0.20°处具有特征峰。
优选地，所述晶型B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射如表2所示，误差范围±0.20°：
表2晶型B的XRPD解析数据

优选地，所述晶型B具有基本如图5所示的粉末X射线衍射图。
根据本发明的实施方案，所述晶型B为式Ⅰ化合物单L-酒石酸盐的水合物。
根据本发明的实施方案，所述水合物含有0.5～1mol水。
根据本发明的实施方案，所述晶型B的差示扫描量热法(DSC)分析显示在加热至峰值温度61.57℃附近出现第一个吸热峰，加热至峰值温度152.18℃附近出现第二个吸热峰。第一个吸热峰为脱水峰，第二个吸热峰为熔融峰。
优选地，所述晶型B具有基本如图6所示的DSC图。
根据本发明的实施方案，所述晶型B的热重分析(TGA)显示在21.34℃至120℃区间内具有约2.76％的失重。
优选地，所述晶型B具有基本如图7所示的TGA图。
在一些实施方案中，提供式I化合物单L-酒石酸盐晶型C。所述晶型C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在17.88±0.20°、19.40±0.20°、21.38±0.20°处具有特征峰。
优选地，所述晶型C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在7.14±0.20°、17.88±0.20°、19.40±0.20°、20.06±0.20°、21.38±0.20°、23.76±0.20°、25.92±0.20°处具有特征峰。
优选地，所述晶型C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、29.38±0.20°处具有特征峰。
优选地，所述晶型C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射如表3所示，误差范围±0.20°：
表3晶型C的XRPD解析数据

优选地，所述晶型C具有基本如图8所示的粉末X射线衍射图。
根据本发明的实施方案，所述晶型C为式Ⅰ化合物单L-酒石酸盐溶剂化物，优选为式Ⅰ化合物单L-酒石酸盐的乙醇溶剂化物。
根据本发明的实施方案，所述晶型C的差示扫描量热法(DSC)分析显示在加热至峰值温度129.45℃附近出现第一个吸热峰，在加热至峰值温度151.90℃附近出现第二个吸热峰。第一个吸热峰为脱溶剂峰，第二个吸热峰为熔融峰。
优选地，所述晶型C具有基本如图9所示的DSC图。
根据本发明的实施方案，所述晶型C的热重分析(TGA)显示在21.47℃至150℃区间内具有约4.59％的失重。
优选地，所述晶型C具有基本如图10所示的TGA图。
根据本发明的实施方案，所述晶型C为不规则形貌晶体。优选地，所述晶型C的粒径不超过10μm。
优选地，所述晶型C具有基本如图11所示的PLM图谱。
在一些实施方案中，提供式I化合物单L-酒石酸盐晶型D，所述晶型D使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在3.50±0.20°、7.46±0.20°、23.04±0.20°处具有特征峰。
优选地，所述晶型D使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在3.50±0.20°、6.92±0.20°、7.46±0.20°、17.22±0.20°、18.20±0.20°、19.88±0.20°、23.04±0.20°处具有特征峰。
优选地，所述晶型D使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、25.62±0.20°处具有特征峰。
优选地，所述晶型D使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射如表4所示，误差范围±0.20°：
表4晶型D的XRPD解析数据

优选地，所述晶型D具有基本如图12所示的粉末X射线衍射图。
根据本发明的实施方案，所述晶型D为式Ⅰ化合物单L-酒石酸盐溶剂化物，优选为式Ⅰ化合物单L-酒石酸盐的四氢呋喃溶剂化物。
根据本发明的实施方案，所述晶型D的差示扫描量热法(DSC)分析显示在加热至峰值温度94.15℃附近出现第一个吸热峰，在加热至峰值温度118.79℃附近出现第二个吸热峰，在加热至峰值温度146.04℃附近出现第三个吸热峰。第一个吸热峰和第二个吸热峰为脱溶剂峰，第三个吸热峰为熔融峰。
优选地，所述晶型D具有基本如图13所示的DSC图。
根据本发明的实施方案，所述晶型D的热重分析(TGA)显示在23.19℃至120℃区间内具有约5.25％的失重。
优选地，所述晶型D具有基本如图14所示的TGA图。
本发明第四方面提供所述式Ⅰ化合物药学上可接受的盐的晶型的制备方法。
根据本发明优选地实施方案，提供所述式I化合物单L-酒石酸盐晶型的制备方法。
在一些实施方案中，提供所述式Ⅰ化合物单L-酒石酸盐晶型A的制备方法一，包括：将式Ⅰ化合物单L-酒石酸盐在溶剂中搅拌，得到所述晶型A。
所述搅拌的温度为20～80℃，优选为25～55℃。
所述溶剂选自醇类溶剂、酯类溶剂、酮类溶剂、醚类溶剂、烷烃类溶剂、卤代烃类溶剂和腈类溶剂或其组合。
所述醇类溶剂选自甲醇、乙醇和异丙醇中的一种。
所述酯类溶剂选自乙酸乙酯、乙酸丙酯和乙酸异丙酯中的一种。
所述酮类溶剂选自丙酮、2-丁酮、甲基异丁酮和4-甲基-2-戊酮中的一种。
所述醚类溶剂选自***、丙醚、异丙醚、甲基叔丁基醚和四氢呋喃中的一种。
所述烷烃类溶剂选自甲苯、正庚烷和环己烷中的一种。
所述腈类溶剂选自乙腈、苯乙腈和苯腈中的一种。
所述式Ⅰ化合物单L-酒石酸盐与所述溶剂的质量体积比为1g:(20-40)ml，优选为1g:(20-30)ml。
在一些实施方案中，提供所述式Ⅰ化合物单L-酒石酸盐晶型A的制备方法二，包括：将式Ⅰ化合物单L-酒石酸盐加入醇类溶剂中溶解，然后再加入反溶剂搅拌，得到所述晶型A。
所述醇类溶剂选自甲醇、乙醇、丙醇和异丙醇中的一种。
所述反溶剂为醚类溶剂或酯类溶剂中的一种或多种。所述醚类溶剂选自***、丙醚、异丙醚、甲基叔丁基醚中的一种。所述酯类溶剂选自乙酸乙酯、乙酸丙酯和乙酸异丙酯中的一 种。
所述式Ⅰ化合物单L-酒石酸盐与醇类溶剂和反溶剂的质量体积比为1g:(10-30)ml:(80-120)ml，优选为1g:(15-25)ml:(90-110)ml。
根据本发明的实施方案，晶型A的制备方法一或二中还包括过滤、干燥等后处理步骤。
在一些实施方案中，提供所述式Ⅰ化合物单L-酒石酸盐晶型B的制备方法一，包括将所述晶型A在高湿条件下放置得到晶型B。优选地，放置2天以上，更优选地，放置3天以上。
所述高湿条件为80％～100％RH，优选地，为90％～100％RH。
在一些实施方案中，提供所述式Ⅰ化合物单L-酒石酸盐晶型B的制备方法二，包括将式Ⅰ化合物单L-酒石酸盐在醇类溶剂中溶解，溶剂挥发后得到晶型B。
所述醇类溶剂选自甲醇、乙醇和异丙醇中的一种。
所述溶解的温度为15～45℃，优选为25-35℃。
所述式Ⅰ化合物单L-酒石酸盐与醇类溶剂的质量体积比为1g:(10-30)ml，优选为1g:(15-25)ml。
在一些实施方案中，提供所述式Ⅰ化合物单L-酒石酸盐晶型C的制备方法，包括将式Ⅰ化合物单L-酒石酸盐溶于醇类溶剂结晶得到所述晶型C。
所述醇类溶剂选自甲醇、乙醇和/或异丙醇，优选为甲醇。
所述式Ⅰ化合物单L-酒石酸盐与醇类溶剂的质量体积比为1g:(20-40)ml，优选为1g:(20-30)ml。
根据本发明的实施方案，所述晶型C的制备方法还包括过滤、干燥等后处理步骤。
在一些实施方案中，提供所述式Ⅰ化合物单L-酒石酸盐晶型D的制备方法，包括将式Ⅰ化合物单L-酒石酸盐溶于醚类溶剂中，加热搅拌，降温后，析出固体，得到所述晶型D。
所述醚类溶剂选自***、四氢呋喃、甲基叔丁基醚中的一种，优选为四氢呋喃。
所述加热的温度为30℃～80℃，优选为45℃～75℃。
所述降温的温度为20℃～30℃。
所述式Ⅰ化合物单L-酒石酸盐与醚类溶剂的质量体积比为1g:(20-40)ml，优选为1g:(20-30)ml。
根据本发明的实施方案，所述晶型D的制备方法包括过滤、干燥等后处理步骤。
本发明还提供一种药物组合物，包括所述式Ⅰ化合物药学上可接受的盐或其晶型，以及任选存在的药学上可接受的药用辅料。根据本发明优选地实施方案，所述药学上可接受的盐为式I化合物单L-酒石酸盐；所述晶型选自式I化合物单L-酒石酸盐晶型A，晶型B，晶型C，晶型D。优选地，所述药物组合物为制剂形式。
本发明还提供一种制剂，包括所述式Ⅰ化合物药学上可接受的盐或其晶型，以及任选存在的药学上可接受的药用辅料。根据本发明优选地实施方案，所述药学上可接受的盐为式I化合物单L-酒石酸盐；所述晶型选自式I化合物单L-酒石酸盐晶型A，晶型B，晶型C，晶型D。
本发明还提供如上所述式Ⅰ化合物药学上接受的盐或其晶型，或所述药物组合物在制备预防和/或治疗与Vanin酶抑制剂相关的疾病或病症的药物中的用途。
根据本发明的实施方案，与所述Vanin酶抑制剂相关的疾病或病症包括自身免疫疾病、炎性疾病、***反应性疾病、代谢疾病、基于感染的疾病、纤维变性疾病、心血管疾病、呼吸***疾病、肾疾病、皮肤病学疾病、肝脏疾病、胃肠疾病、口腔疾病和造血疾病中的一种或多种；又例如克罗恩氏病、炎性肠病及溃疡性结肠炎。
本发明还提供一种与Vanin酶抑制剂相关疾病或病症的预防和/或治疗方法，包括向有此需要的个体施用治疗有效量的所述式Ⅰ化合物药学上接受的盐或其晶型，或所述药物组合物。
根据本发明的实施方案，所述与Vanin酶抑制剂相关的疾病或病症包括自身免疫疾病、炎性疾病、***反应性疾病、代谢疾病、基于感染的疾病、纤维变性疾病、心血管疾病、呼吸***疾病、肾疾病、皮肤病学疾病、肝脏疾病、胃肠疾病、口腔疾病和造血疾病中的一种或多种；又例如克罗恩氏病、炎性肠病及溃疡性结肠炎。
本发明的治疗方法可包括单独给予本发明式Ⅰ化合物药学上可接受的盐或其晶型的一种、两种或更多种、以及将本发明式Ⅰ化合物药学上可接受的盐或其晶型中的一种、两种或更多种与其它化学治疗剂组合给药。组合给药可以将不同药物同时或相继进行。
本领域技术人员可以理解，本文中出现的术语“……或其组合”、“……中的一种或多种”等同于“……中的一种、两种或多种”，均表示可以采用选项中的每一种以及每两种或更多种的组合(即不排除采用选项中的两种进行组合)。
有益效果
(1)本发明式Ⅰ化合物的盐的稳定性高，尤其是单L-酒石酸盐，在水中的溶解度高，有利于增强口服吸收能力，提高生物的利用度；
(2)本发明式Ⅰ化合物的盐的制备方法操作简单，容易控制，重现性好，适合工业化生产；
(3)本发明式Ⅰ化合物单L-酒石酸盐的4种晶型稳定性高，溶解度好，吸湿性少，具有良好的成药前景；
(4)本发明式Ⅰ化合物单L-酒石酸盐的4种晶型的制备方法简单，反应条件温和，产品收率高，有利于工业化生产。
附图说明
图1为式I化合物单L-酒石酸盐晶型A的XRPD图谱。
图2为式I化合物单L-酒石酸盐晶型A的DSC图谱。
图3为式I化合物单L-酒石酸盐晶型A的TGA图谱。
图4为式I化合物单L-酒石酸盐晶型A的PLM图谱。
图5为式I化合物单L-酒石酸盐晶型B的XRPD图谱。
图6为式I化合物单L-酒石酸盐晶型B的DSC图谱。
图7为式I化合物单L-酒石酸盐晶型B的TGA图谱。
图8为式I化合物单L-酒石酸盐晶型C的XRPD图谱。
图9为式I化合物单L-酒石酸盐晶型C的DSC图谱。
图10为式I化合物单L-酒石酸盐晶型C的TGA图谱。
图11为式I化合物单L-酒石酸盐晶型C的PLM图谱。
图12为式I化合物单L-酒石酸盐晶型D的XRPD图谱。
图13为式I化合物单L-酒石酸盐晶型D的DSC图谱。
图14为式I化合物单L-酒石酸盐晶型D的TGA图谱。
图15为实施例7中式I化合物单L-酒石酸盐晶型A的XRPD图谱。
图16为实施例9中式I化合物单L-酒石酸盐晶型B的XRPD图谱。
图17为式I化合物单L-酒石酸盐晶型A在高温、高湿条件下放置3天后的XRPD图。
图18为式I化合物单L-酒石酸盐晶型A在高温、高湿条件下放置2周后的XRPD图。
图19为式I化合物单L-酒石酸盐的单晶图。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
40℃/75％RH-open是指在40℃下，75％湿度的条件下敞开放置。
60℃-open是指在60℃的条件下敞口放置。
80％RHopen是指80％湿度的条件下敞开放置。
92.5％RH-open是指80％湿度的条件下敞开放置。
40℃/75％RH-closed-2wks是指在40℃下，75％湿度的条件下密闭放置2周。
40℃/75％RH-open-2wks是指在40℃下，75％湿度的条件下敞开放置2周。
60℃-closed-2wks是指在60℃下密闭放置2周。
STD-1是指对照样品。
Initial是指初始状态。
SGF是指模拟胃液。
FaSSIF是指禁食状态模拟肠液
FeSSIF是指进食状态模拟肠液。
1d是指1天；3d是指3天。
实验仪器参数
X-射线粉末衍射(XRPD)
设备为Shimadzu XRD-6000，按以下参数扫描样品：
射线源为Cu～Kα靶
光管的最小操作电压与电流分别为40kV和30mA，
样品扫描范围的2-Theta值从2°到50°。扫描速度为5deg/min。
热重分析(TGA)
称取大约5mg样品于坩埚中，氮气保护，从30℃升温至300℃，升温速率为20℃/min，300℃保持1min。
差示扫描量热仪(DSC)
称取大约1～5mg粉末样品放置在一个封闭的铝坩埚中，坩埚盖上扎一针孔。氮气保护，从30℃升温到300℃进行差示热量扫描，300°℃保持1分钟。升温速率为20℃/min。
偏光显微镜(PLM)
样品分散在介质中(硅油)，使用10X目镜、10X物镜观察样品，用照相机计算机***记录图像。
动态水分吸附(DVS)
在0％～95％～0％相对湿度(RH)循环下，称取10mg左右的样品在25℃条件下进行吸湿/解吸特性测试，参数如下:
吸湿性分类:
“*”：在25±1℃和80±2％RH条件下(欧洲药典10.0)
“W”:在80％RH时的吸湿增重.
单晶测试仪器和测试条件：
仪器型号：D8 Venture
仪器参数：
光源：Cu靶X射线：
探测器：CMOS面探测器             分辨率：
电流电压：50kV，1.2mA            曝光时间：50s
面探测器至样品距离：40mm         测试温度：170(2)K
中间体1f和式Ⅰ化合物的制备
(1)中间体1f的制备
将2-氯嘧啶-5-羧酸(284g，1.78mol)和8-氧杂-2-氮杂螺[4.5]癸烷盐酸盐(310g，1.78mol)溶于二氯甲烷中，冷却到-10℃，慢慢滴加T3P(625g,1.78mol)，加入完后，在该温度下继续反应2小时。LCMS检测反应完成后，加入水，搅拌，有固体析出，过滤，干燥，得到化合物1f(350g,纯度98％)。
1H NMR(400MHz,CDCl3)：δ8.80(s,2H),3.81-3.57(m,7H),3.36(s,1H),1.93(td,J＝14.58,7.25Hz,2H),1.66(t,J＝5.35Hz,2H),1.58(dd,J＝11.10,4.64Hz,2H)。
(2)式Ⅰ化合物的制备
第一步
将化合物1b(385g，3.18mol)和钛酸四乙酯(905g，3.97mol)溶于甲苯(3L)，搅拌加热至110℃，回流；向上述反应液中滴加化合物1a(352g，2.65mol)的甲苯溶液(500mL)。滴加结束后，继续加热回流1小时。反应完成后，停止反应，冷却至室温，浓缩除去甲苯，剩余物加水(400mL)淬灭，用乙酸乙酯1000mL稀释，硅藻土过滤。将滤液分液，收集有机相，无水硫酸钠干燥，浓缩除去溶剂。剩余物用MTBE(100mL)和石油醚(300mL)搅拌，过滤，滤液浓缩得到化合物1c(500g，收率：80％)。
第二步
将化合物1c(500g，2.1mol)溶于THF(3000mL)，冷却到-60℃，然后慢慢滴加L-三仲丁基硼氢化锂(2510mL，2.51mol)。滴加完成后，在-60℃下搅拌。反应完成后，慢慢加 入1000mL水淬灭反应。浓缩除去大部分THF。用乙酸乙酯萃取(500mL×3)，合并有机相，饱和氯化钠溶液洗涤(200mL)，干燥。减压蒸馏除去溶剂，粗产物1d直接用于下一步。
第三步
将粗产物1d溶于甲醇(500mL)，慢慢加入HCl/MeOH(200mL 4M)。反应液在室温下反应2h。反应完成后，浓缩反应液得到油状物，加入乙酸乙酯(100mL)搅拌，过滤后得到化合物1e，为红色固体粉末(300g，ee值98％，纯度99％)。
第四步
将化合物1e(284g，1.375mol)、化合物1f(350g，1.25mol)和K2CO3(862.5g，6.25mol)溶解在异丙醇(400mL)中，加热回流过夜。反应完成后，冷却，过滤，滤液浓缩。残留物溶于水(300mL)，并用稀盐酸(2N)调节到pH为8～9，二氯甲烷(200mLx3)萃取，饱和氯化钠溶液洗涤(200mLx1)，干燥，浓缩，得到式Ⅰ化合物(374g)。
1H NMR(400MHz,CD3OD)δ8.58(s,2H),8.37(d,J＝5.1Hz,1H),7.77(s,1H),7.26(d,J＝2.5Hz,1H),5.72(t,J＝7.7Hz,1H),4.53(s,2H),3.80–3.58(m,7H),3.54(d,J＝18.8Hz,2H),3.15(ddd,J＝16.9,9.2,3.7Hz,1H),3.02(dt,J＝16.8,8.5Hz,1H),2.68(dq,J＝12.8,4.4Hz,1H),2.14–2.02(m,1H),1.93(q,J＝8.1Hz,2H),1.67(d,J＝5.8Hz,2H),1.59(d,J＝5.7Hz,2H)。
实施例1式Ⅰ化合物单L-酒石酸盐的制备
将式Ⅰ化合物1g溶于丙酮18ml中，加入1.24ml的L-酒石酸的2mol/L的乙醇溶液，搅拌过夜，然后再加入乙酸异丙酯18ml，得到固体，过滤，减压真空干燥得到式Ⅰ化合物L-酒石酸盐(式I化合物与L-酒石酸摩尔比为1:1，即得到单L-酒石酸盐)。
取式Ⅰ化合物L-酒石酸盐50mg于8mL玻璃小瓶中，加入1mL甲醇超声溶解，得到的溶液过滤，滤液放至新的8mL玻璃瓶，将8mL玻璃瓶敞口放置在装有4mL甲基叔丁基醚的40mL玻璃瓶中，拧紧40mL玻璃瓶瓶盖并放置，培养单晶。式Ⅰ化合物单L-酒石酸盐的单晶数据如下：

式Ⅰ化合物单L-酒石酸盐的单晶如图19所示。
实施例2式Ⅰ化合物富马酸盐的制备
将式Ⅰ化合物536mg溶于丙酮10ml中，加入富马酸161.4mg，搅拌过夜，然后再加入乙酸异丙酯10ml中，搅拌，得到固体，过滤，减压真空干燥得到式Ⅰ化合物富马酸盐。
实施例3式Ⅰ化合物D-苹果酸盐的制备
将式Ⅰ化合物517mg溶于乙酸异丙酯10ml中，加入D-苹果酸187.4mg，搅拌溶液变黏稠，再加乙酸异丙酯10ml，得到白色的黏稠状固体，过滤，减压真空干燥得到式Ⅰ化合物D-苹果酸盐。
实施例4式Ⅰ化合物单L-酒石酸盐、富马酸盐、D-苹果酸盐的稳定性测试
对实施例1-3所得式Ⅰ化合物的单L-酒石酸盐、富马酸盐、D-苹果酸盐进行稳定性考察。
稳定性考察条件：40℃/75％RH-closed,40℃/75％RH-open,60℃-closed；稳定性考察内容：有关物质和晶型变化情况。
有关物质检测：分别称取大约5mg的样品于40mL的样品瓶中，加入10mL的50％乙腈水溶液溶解并稀释至刻度，进样5μL。色谱条件见表5。
式I化合物单L-酒石酸盐、富马酸盐、D-苹果酸盐稳定性考察实验结果如表6所示。
表5有关物质测试色谱条件

表6式Ⅰ化合物单L-酒石酸盐、富马酸盐、D-苹果酸盐稳定性考察实验结果
从表6可以看出，式Ⅰ化合物的L-酒石酸盐、富马酸盐、D-苹果酸盐经过加速高湿和高温条件，各种盐型的化学稳定性仍然良好，尤其是式Ⅰ化合物的L-酒石酸盐。
实施例5式Ⅰ化合物及其L-酒石酸盐、富马酸盐、D-苹果酸盐的溶解度测试
考察式Ⅰ化合物及其L-酒石酸盐、富马酸盐、D-苹果酸盐在水、SGF、FaSSIF、FeSSIF、pH7.4中，37℃条件下的溶解度。
实验方法：称取30mg(在水中)或者15mg的样品于4mL的小瓶中，加入3mL的待测介质，于37℃条件下持续搅拌，于1h，24h分别取样0.5mL，12000rpm，离心5min,上清液用50％乙腈稀释适当倍数后测定其浓度。溶解度测试色谱条件见表7。
对照品与线性：因式Ⅰ化合物引湿性较大，杂质太多，不宜作为对照。因此称取13mg的式Ⅰ化合物的富马酸盐于25mL的容量瓶中(以游离碱计为大约10mg至25mL容量瓶)，加入50％乙腈水溶液溶解，并稀释至刻度，平行配制两份。取STD-1，用50％乙腈水溶液稀释至200μg/mL,50μg/mL,10μg/mL，进样5μL，绘制标准曲线。
式Ⅰ化合物及其L-酒石酸盐、富马酸盐、D-苹果酸盐的溶解度测试结果如表8所示。
表7溶解度测试色谱条件
表8式Ⅰ化合物及其L-酒石酸盐、富马酸盐、D-苹果酸盐的溶解度测试结果

从表8可以看出，式Ⅰ化合物及其单L-酒石酸盐、富马酸盐、D-苹果酸盐均具有良好的溶解度。在各介质中，均能够完全溶解至目标浓度5mg/mL或10mg/mL，以游离碱计。
实施例6晶型A的制备方法
取400mg式I化合物的单L-酒石酸盐(按照实施例1制备)，加入10mL丙酮，搅拌，离心，40℃减压真空干燥得到晶型A。
对晶型A进行XRPD、DSC、TGA和PLM表征。
所述晶型A为无水物。XRPD特征峰位置和强度如表1，XRPD图谱如图1。
DSC显示在加热至峰值温度150.14℃附近出现第一个吸热峰，如图2所示。
TGA显示在22.03℃至120℃区间内具有约0.069％的失重，如图3所示。
PLM图显示样品为10μm以下的不规则形貌晶体，如图4所示。
晶型A的XRPD图谱其以2θ角表示的X-射线粉末衍射图中，2θ值如表A所示：
表A晶型A的XRPD解析数据
实施例7晶型A的制备方法
取式Ⅰ化合物单L-酒石酸盐(按照实施例1制备)500mg，加入甲醇10ml溶解，然后再加入甲基叔丁基醚60ml，搅拌1.5h，经离心、过滤、干燥，得到所述晶型A。
所述晶型A的XRPD图谱如图15所示。
实施例8晶型B的制备方法
将500mg式Ⅰ化合物单L-酒石酸盐晶型A在92.5％RH暴露3天后得到晶型B。
对晶型B进行XRPD、DSC、TGA和PLM表征。
所述晶型B为水合物，其含有0.5～1mol水。XRPD特征峰位置和强度如表B，XRPD图谱如图5。
DSC显示在加热至峰值温度61.57℃附近出现第一个吸热峰，加热至峰值温度152.18℃附近出现第二个吸热峰，如图6所示。
TGA显示在22.03℃至120℃区间内具有约2.76％的失重，如图7所示。
晶型B的XRPD图谱其以2θ角表示的X-射线粉末衍射图中，2θ值如表B所示：
表B晶型B的XRPD解析数据
实施例9晶型B的制备方法
取414mg式Ⅰ化合物单L-酒石酸盐(按照实施例1制备)加入10mL甲醇，使其完全溶解，然后将溶剂自然挥发得到白色固体，减压干燥后得到晶型B。
所述晶型B的XRPD如图16所示。
实施例10晶型C的制备方法
取410mg式Ⅰ化合物单L-酒石酸盐(按照实施例1制备)加入16mL乙醇，在50℃下搅拌1天后，降至室温后，有白色固体析出，过滤，减压真空干燥得到晶型C。
对晶型C进行XRPD、DSC、TGA和PLM表征。
所述晶型C为乙醇溶剂化物。
XRPD特征峰位置和强度如表C，XRPD图谱如图8。
DSC显示在加热至峰值温度129.45℃附近出现第一个吸热峰，如图9所示。
TGA显示在21.47℃至150℃区间内具有约4.59％的失重，如图10所示。
晶型C的XRPD图谱其以2θ角表示的X-射线粉末衍射图中，2θ值如表C所示：
表C晶型C的XRPD解析数据
PLM图显示样品为10μm以下的不规则形貌晶体，如图11所示。
实施例11晶型D的制备方法
取410mg式Ⅰ化合物单L-酒石酸盐(按照实施例1制备)加入12mL四氢呋喃，在50℃下搅拌1天后，降至室温后，有白色固体析出，过滤，减压真空干燥得到晶型D。
对晶型D进行XRPD、DSC、TGA表征。
所述晶型D为四氢呋喃溶剂化物。
XRPD特征峰位置和强度如表D，XRPD图谱如图12。
DSC显示在加热至峰值温度94.15℃附近出现第一个吸热峰，如图13所示。
TGA显示在23.19℃至120℃区间内具有约5.25％的失重，如图14所示。
晶型D的XRPD图谱其以2θ角表示的X-射线粉末衍射图中，2θ值如表D所示：
表D晶型D的XRPD解析数据

实施例12晶型A的稳定性考察
将晶型A放置在40℃/75％RH-open，60℃-open，80％RHopen，92.5％RH-open条件下,于3天时取出考察其晶型是否发生改变。
另将40℃/75％RH-closed、40℃/75％RH-open、60℃-open放置的样品于2wks时取出、进行稳定性考察，包括有关物质和晶型。
稳定性样品有关物质检测方法：称取大约5mg的样品，加入5mL的20％甲醇，超声几秒，化合物可以完全溶解，进样5μL进行有关物质测试。
晶型A在高温、高湿条件下放置3天后和放置2周后的XRPD图分别为图17和图18所示。
色谱条件：
表9晶型A的稳定性测试结果

从表9、图17和图18所示，晶型A在60℃、高湿条件80％RH下晶型未发生改变。这说明晶型A的稳定性好。
实施例13晶型A的溶解度考察
评估晶型A在SGF、FaSSIF、FeSSIF、pH7.4中的溶解度。
称取20mg的原料于小瓶中、加入3mL的介质、于37℃条件下，观察其溶解情况。
表10式I化合物单L-酒石酸盐晶型A的溶解度测试结果(37℃)
从表10可以看出，晶型A在各个介质中的溶解度均为良好。
以上是对本发明具体实施例进行了描述。需要理解的是，本发明并不局限于上述实施例的限制，上述实施例和说明书中描述的只是为了说明本发明的原理。本领域技术人员在不脱离本发明构思的前提下，本发明还会有各种非实质性的变化和改进，这些都落入本发明要求保护的范围内。

Claims (18)

  1. 一种式I化合物药学上可接受的盐，所述式I化合物如下所示：
    所述式Ⅰ化合物药学上可接受的盐为式Ⅰ化合物与酸形成的盐。
  2. 根据权利要求1所述一种式I化合物药学上可接受的盐，其特征在于，所述酸选自无机酸或有机酸，例如盐酸、氢氟酸、氢溴酸、氢碘酸、硫酸、焦硫酸、磷酸、硝酸，甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、二葡糖酸、3-羟基-2-萘甲酸、烟酸、扑酸、果胶酯酸、过硫酸、3-苯基丙酸、苦味酸、特戊酸、2-羟基乙磺酸、衣康酸、氨基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、L-酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、藻酸、马来酸、富马酸、D-葡糖酸、扁桃酸、抗坏血酸、葡庚酸、甘油磷酸、天冬氨酸、磺基水杨酸、半硫酸或硫氰酸。
  3. 根据权利要求1所述一种式I化合物药学上可接受的盐，其特征在于，所述酸可以选自盐酸、氢溴酸、硫酸、磷酸、硝酸、甲磺酸、对甲苯磺酸、富马酸、马来酸、柠檬酸、L-酒石酸、琥珀酸、乙磺酸、L-苹果酸、L-谷氨酸、草酸、D-苹果酸、帕莫酸、草酸、甲酸、乙酸、三氟乙酸、月桂酸、苯甲酸和苯磺酸中的一种。
  4. 根据权利要求1所述式Ⅰ化合物药学上可接受的盐，其特征在于，I化合物与所述酸的摩尔比为1:1；优选的，所述药学上可接受的盐选自式I化合物的单酒石酸盐，单富马酸盐，单苹果酸盐；更优选的，所述药学上可接受的盐为式I化合物的单L-酒石酸盐。
  5. 根据权利要求1所述一种式Ⅰ化合物药学上可接受的盐的制备方法，包括将式Ⅰ化合物与所述酸反应，制备得到式Ⅰ化合物药学上可接受的盐；
    优选地，所述制备方法包括将式Ⅰ化合物溶于有机溶剂A，加入酸进行反应；然后再加入有机溶剂B，制备得到式Ⅰ化合物药学上可接受的盐；所述有机溶剂A选自酯类、酮类、醇类中的至少一种；所述有机溶剂B选自腈类、酯类、醚类或其组合；
    优选地，所述酸先溶解于有机溶剂C制备为酸的溶液形式后再加入反应；更优选地，所述酸选自L-酒石酸时，有机溶剂C选自醇类。
  6. 根据权利要求1所述一种式Ⅰ化合物药学上可接受的盐的晶型，其特征在于，所述晶型为式I化合物单L-酒石酸盐的晶型。
  7. 根据权利要求6所述的晶型，其特征在于，所述晶型为式Ⅰ化合物单L-酒石酸盐的晶型A，所述晶型A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在17.06±0.20°、20.06±0.20°、22.58±0.20°处具有特征峰；
    优选地，所述晶型A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、24.38±0.20°处具有特征峰；
    优选地，所述晶型A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、25.70±0.20°处具有特征峰；
    优选地，所述晶型A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射如表1所示，误差范围±0.20°；
    优选地，所述晶型A具有基本如图1所示的粉末X射线衍射图；
    优选地，所述晶型A为式Ⅰ化合物L-酒石酸盐的无水物；
    优选地，所述晶型A的差示扫描量热法(DSC)分析显示在加热至峰值温度150.14℃附近出现第一个吸热峰；
    优选地，所述晶型A具有基本如图2所示的DSC图；
    优选地，所述晶型A的热重分析(TGA)显示在22.03℃至120℃区间内具有约0.069％的失重；
    优选地，所述晶型A具有基本如图3所示的TGA图。
  8. 根据权利要求6所述的晶型，其特征在于，所述晶型为式Ⅰ化合物单L-酒石酸盐的晶型B，所述晶型B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在19.28±0.20°、19.94±0.20°、21.30±0.20°、23.72±0.20°处具有特征峰；
    优选地，所述晶型B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在7.56±0.20°、17.36±0.20°、19.28±0.20°、19.94±0.20°、21.30±0.20°、23.72±0.20°、26.02±0.20°处具有特征峰；
    优选地，所述晶型B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、29.52±0.20°处具有特征峰；
    优选地，所述晶型B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、29.52±0.20°处具有特征峰；
    优选地，所述晶型B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射如表2所示，误差范围±0.20°；
    优选地，所述晶型B具有基本如图5所示的粉末X射线衍射图；
    所述晶型B为式Ⅰ化合物L-酒石酸盐的水合物；
    所述晶型B的差示扫描量热法(DSC)分析显示在加热至峰值温度61.57℃附近出现第一个吸热峰，加热至峰值温度152.18℃附近出现第二个吸热峰；
    优选地，所述晶型B具有基本如图6所示的DSC图；
    优选地，所述晶型B的热重分析(TGA)显示在21.34℃至120℃区间内具有约2.76％的失重；
    优选地，所述晶型B具有基本如图7所示的TGA图。
  9. 根据权利要求6所述的晶型，其特征在于，所述晶型为式Ⅰ化合物单L-酒石酸盐的晶型C，所述晶型C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在17.88±0.20°、 19.40±0.20°、21.38±0.20°处具有特征峰；
    优选地，所述晶型C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在7.14±0.20°、17.88±0.20°、19.40±0.20°、20.06±0.20°、21.38±0.20°、23.76±0.20°、25.92±0.20°处具有特征峰；
    优选地，所述晶型C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、29.38±0.20°处具有特征峰；
    优选地，所述晶型C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射如表3所示，误差范围±0.20°；
    优选地，所述晶型C具有基本如图8所示的粉末X射线衍射图；
    优选地，所述晶型C为式Ⅰ化合物L-酒石酸盐溶剂化物，优选为式Ⅰ化合物L-酒石酸盐的乙醇溶剂化物；
    优选地，所述晶型C的差示扫描量热法(DSC)分析显示在加热至峰值温度129.45℃附近出现第一个吸热峰，在加热至峰值温度151.90℃附近出现第二个吸热峰；
    优选地，所述晶型C具有基本如图9所示的DSC图；
    优选地，所述晶型C的热重分析(TGA)显示在21.47℃至150℃区间内具有约4.59％的失重；
    优选地，所述晶型C具有基本如图10所示的TGA图。
  10. 根据权利要求6所述的晶型，其特征在于，所述晶型为式Ⅰ化合物单L-酒石酸盐的晶型D，所述晶型D使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在3.50±0.20°、7.46±0.20°、23.04±0.20°处具有特征峰；
    优选地，所述晶型D使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在3.50±0.20°、6.92±0.20°、7.46±0.20°、17.22±0.20°、18.20±0.20°、19.88±0.20°、23.04±0.20°处具有特征峰；
    优选地，所述晶型D使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、25.62±0.20°处具有特征峰；
    优选地，所述晶型D使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射如表4所示，误差范围±0.20°；
    优选地，所述晶型D具有基本如图12所示的粉末X射线衍射图；
    优选地，所述晶型D为式Ⅰ化合物L-酒石酸盐溶剂化物，优选为式Ⅰ化合物L-酒石酸盐的四氢呋喃溶剂化物；
    优选地，所述晶型D的差示扫描量热法(DSC)分析显示在加热至峰值温度94.15℃附近出现第一个吸热峰，在加热至峰值温度118.79℃附近出现第二个吸热峰，在加热至峰值温度146.04℃附近出现第三个吸热峰；
    优选地，所述晶型D具有基本如图13所示的DSC图；
    优选地，所述晶型D的热重分析(TGA)显示在23.19℃至120℃区间内具有约5.25％的失重；
    优选地，所述晶型D具有基本如图14所示的TGA图。
  11. 根据权利要求6所述的晶型，其特征在于，其晶胞参数如下：
    单斜晶型，空间群为P21，

    β＝96.577，


    Z＝2。
  12. 根据权利要求7所述的晶型的制备方法，其特征在于，所述式Ⅰ化合物单L-酒石酸盐晶型A的制备方法一包括：将式Ⅰ化合物单L-酒石酸盐在溶剂中搅拌，得到所述晶型A；
    优选地，所述搅拌的温度为20～80℃；所述溶剂选自醇类溶剂、酯类溶剂、酮类溶剂、醚类溶剂、烷烃类溶剂、卤代烃类溶剂和腈类溶剂或其组合；
    优选地，所述式Ⅰ化合物单L-酒石酸盐与所述溶剂的质量体积比为1g:(20-40)ml；
    所述式Ⅰ化合物L-酒石酸盐晶型A的制备选自制备方法二包括：将式Ⅰ化合物单L-酒石酸盐加入醇类溶剂中溶解，然后再加入反溶剂搅拌，得到所述晶型A；
    优选地，所述醇类溶剂选自甲醇、乙醇、丙醇和异丙醇中的一种；所述反溶剂为醚类溶剂或酯类溶剂中的一种或多种；
    优选地，所述式Ⅰ化合物单L-酒石酸盐与醇类溶剂和反溶剂的质量体积比为1g:(10-30)ml:(80-120)ml；
    更优选地，所述晶型A的制备方法一或二中还包括过滤、干燥等后处理步骤。
  13. 根据权利要求8所述的晶型的制备方法，其特征在于，所述式Ⅰ化合物单L-酒石酸盐晶型B的制备方法一包括将所述晶型A在高湿条件下放置得到晶型B；优选地，所述高湿条件为80％～100％RH，更优选地，为90％～100％RH；
    所述式Ⅰ化合物单L-酒石酸盐晶型B的制备方法二包括将式Ⅰ化合物单L-酒石酸盐在醇类溶剂中溶解，溶剂挥发后得到晶型B；
    优选地，所述醇类溶剂选自甲醇、乙醇和异丙醇中的一种；所述溶解的温度为15～45℃；
    优选地，所述式Ⅰ化合物单L-酒石酸盐与醇类溶剂的质量体积比为1g:(10-30)ml。
  14. 根据权利要求9所述的晶型的制备方法，其特征在于，所述式Ⅰ化合物单L-酒石酸盐晶型C的制备方法，包括将式Ⅰ化合物单L-酒石酸盐溶于醇类溶剂结晶得到所述晶型C；
    优选地，所述醇类溶剂选自甲醇、乙醇和/或异丙醇；
    优选地，所述式Ⅰ化合物单L-酒石酸盐与醇类溶剂的质量体积比为1g:(20-40)ml；
    更优选地，所述晶型C的制备方法还包括过滤、干燥等后处理步骤。
  15. 根据权利要求10所述的晶型的制备方法，其特征在于，所述式Ⅰ化合物单L-酒石酸盐晶型D的制备方法，包括将式Ⅰ化合物单L-酒石酸盐溶于醚类溶剂中，加热搅拌，降温后，析出固体，得到所述晶型D；
    优选地，所述醚类溶剂选自***、四氢呋喃、甲基叔丁基醚中的一种；
    所述加热的温度为30℃～80℃；所述降温的温度为20℃～30℃；所述式Ⅰ化合物单L-酒石酸盐与醚类溶剂的质量体积比为1g:(20-40)ml；
    更优选地，所述晶型D的制备方法包括过滤、干燥等后处理步骤。
  16. 根据权利要求11所述的晶型的制备方法，其特征在于，包括将式I化合物单L-酒石酸盐溶解于溶剂D然后置于溶剂E的气氛中扩散；
    所述溶剂D选自醇类溶剂，例如甲醇、乙醇、正丙醇、异丙醇、正丁醇、新戊醇或其组合；
    所述溶剂E选自酯类溶剂、醚类溶剂或烷烃类溶剂或其组合。所述酯类溶剂可以选自有机羧酸酯，例如乙酸乙酯，乙酸异丙酯等；所述醚类可以选自2-6个碳原子的醚，例如***、丙醚、异丙醚、叔丁基醚、甲基叔丁基醚等；所述烷烃类可以选自1-8个碳原子烃，例如正己烷，正庚烷等。
  17. 一种药物组合物，包括权利要求1-4任一项所述式Ⅰ化合物药学上可接受的盐或权利要求6-11任一项所述的晶型，以及任选存在的药学上可接受的药用辅料；优选地，所述药物组合物为制剂形式。
  18. 根据权利要求1-4任一项所述式Ⅰ化合物药学上可接受的盐或权利要求6-11任一项所述的晶型或权利要求17所述的药物组合物在制备预防和/或治疗与Vanin酶抑制剂相关的疾病或病症的药物中的用途；优选地，与所述Vanin酶抑制剂相关的疾病或病症包括自身免疫疾病、炎性疾病、***反应性疾病、代谢疾病、基于感染的疾病、纤维变性疾病、心血管疾病、呼吸***疾病、肾疾病、皮肤病学疾病、肝脏疾病、胃肠疾病、口腔疾病和造血疾病中的一种或多种；又例如克罗恩氏病、炎性肠病及溃疡性结肠炎。
PCT/CN2023/082191 2022-03-18 2023-03-17 Vanin酶抑制剂的盐型、晶型及其制备方法和应用 WO2023174409A1 (zh)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112601748A (zh) * 2018-08-28 2021-04-02 勃林格殷格翰国际有限公司 作为vanin抑制剂的杂芳族化合物
CN113166104A (zh) * 2018-12-03 2021-07-23 勃林格殷格翰国际有限公司 作为vanin抑制剂的杂芳族化合物
CN113226462A (zh) * 2018-12-03 2021-08-06 勃林格殷格翰国际公司 作为vanin抑制剂的杂芳族化合物
WO2022063197A1 (zh) * 2020-09-25 2022-03-31 上海美悦生物科技发展有限公司 一种嘧啶甲酰胺类化合物及其应用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112601748A (zh) * 2018-08-28 2021-04-02 勃林格殷格翰国际有限公司 作为vanin抑制剂的杂芳族化合物
CN113166104A (zh) * 2018-12-03 2021-07-23 勃林格殷格翰国际有限公司 作为vanin抑制剂的杂芳族化合物
CN113226462A (zh) * 2018-12-03 2021-08-06 勃林格殷格翰国际公司 作为vanin抑制剂的杂芳族化合物
WO2022063197A1 (zh) * 2020-09-25 2022-03-31 上海美悦生物科技发展有限公司 一种嘧啶甲酰胺类化合物及其应用

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