WO2024008174A1 - Glp-1r激动剂的盐及其制备方法和应用 - Google Patents

Glp-1r激动剂的盐及其制备方法和应用 Download PDF

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WO2024008174A1
WO2024008174A1 PCT/CN2023/106237 CN2023106237W WO2024008174A1 WO 2024008174 A1 WO2024008174 A1 WO 2024008174A1 CN 2023106237 W CN2023106237 W CN 2023106237W WO 2024008174 A1 WO2024008174 A1 WO 2024008174A1
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salt
compound
crystal form
ray powder
powder diffraction
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French (fr)
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张龙
牛张明
胡杨
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MindRank AI Ltd
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MindRank AI Ltd
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Priority to EP23834940.1A priority Critical patent/EP4553073A4/en
Priority to CN202380052247.5A priority patent/CN119487023A/zh
Priority to KR1020257002458A priority patent/KR20250027761A/ko
Priority to AU2023303622A priority patent/AU2023303622A1/en
Priority to IL318207A priority patent/IL318207A/en
Priority to CA3261368A priority patent/CA3261368A1/en
Priority to JP2025500324A priority patent/JP7818322B2/ja
Publication of WO2024008174A1 publication Critical patent/WO2024008174A1/zh
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Definitions

  • the invention belongs to the field of drug development, and specifically relates to a salt of a GLP-1R agonist and its preparation method and application.
  • Diabetes is a chronic disease characterized by hyperglycemia due to insufficient (relative or absolute) insulin secretion or insulin action impairment.
  • IDF International Diabetes Federation
  • Insulin secretagogues including sulfonylureas, dipeptidyl peptidase IV (PP-IV) inhibitors, and glucagon-like peptide-1 receptor (GLP-1R) agonists, pass on pancreatic beta cells Act to increase insulin secretion.
  • Sulfonylureas have limited efficacy and tolerability, cause weight gain, and often induce hypoglycemia.
  • DP-IV inhibitors have limited efficacy.
  • GLP-1R agonists are peptides administered by subcutaneous injection. Liraglutide is additionally approved to treat obesity.
  • Biguanides (such as metformin) are thought to act primarily by reducing hepatic glucose production. Biguanides often cause gastrointestinal discomfort and lactic acidosis, further limiting their use.
  • Alpha-glucosidase inhibitors such as acarbose reduce intestinal glucose absorption. These agents often cause gastrointestinal discomfort.
  • Thiazolidinediones act on specific receptors in liver, muscle, and adipose tissue. They regulate lipid metabolism and subsequently enhance the response of these tissues to the action of insulin. Regular use of these drugs may cause weight gain and may induce edema and anemia.
  • Insulin is used alone or in combination with the above agents in more severe cases, and regular use may also cause weight gain and carry the risk of hypoglycemia.
  • SGLT2 Sodium-glucose-linked transporter co-transporter 2
  • SGLT2 inhibitors e.g., dapagliflozin, empagliflozin, canagliflozin, ertugliflozin
  • This emerging drug class which reabsorbs glucose in the kidney and thereby reduces glucose levels in the blood, may be associated with ketoacidosis and urinary tract infections.
  • GLP-1 is a 30-amino acid incretin hormone secreted by intestinal L cells in response to food intake. GLP-1 has been shown to stimulate insulin secretion, reduce glucagon secretion, inhibit gastric emptying, reduce appetite, and stimulate ⁇ -cell proliferation in a physiological and glucose-dependent manner. In nonclinical trials, GLP-1 promotes sustained ⁇ -cell competence by stimulating the transcription of genes important for glucose-dependent insulin secretion and by promoting ⁇ -cell neogenesis (Meier et al., Biodrugs. 17) 2):93-102,2013)
  • GLP-1 plays an important role in regulating postprandial blood glucose levels by stimulating glucose-dependent insulin secretion from the pancreas, thereby increasing peripheral glucose absorption. GLP-1 also inhibits glucagon secretion, reducing hepatic glucose output. In addition, GLP-1 delays gastric emptying and slows small intestinal motility, thereby delaying food absorption. In people with T2DM, GLP-1 does not rise normally or rises in reduced amounts after meals (Vilsbol et al., Diabetes. 50609-613, 2001).
  • This type of compound can significantly improve the agonistic effect of the GLP-1R target, increase the therapeutic window, reduce clinical toxic and side effects, and meet the current domestic and foreign needs for diabetes treatment.
  • compound I-1 is (S)-2-(4-(6-(4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid.
  • compound I-2 is (S)-2-(4-(6-(4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidine-1- (yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid.
  • the first aspect of the present invention provides a pharmaceutically acceptable salt of the compound represented by formula (I);
  • R is selected from halogen or CN.
  • the compound represented by formula (I) is selected from the following compound I-1 or compound I-2;
  • the pharmaceutically acceptable salt refers to a pharmaceutically nontoxic acid addition salt or a base addition salt
  • the acid addition salt is a salt formed by a compound represented by formula (I) and an inorganic acid or an organic acid, including hydrobromide, hydrochloride, sulfate, hydrogen sulfate, and sulfurous acid.
  • Salt Salt, phosphate, borate, acetate, oxalate, valerate, benzoate, lactate, toluate, citrate, malate, maleate, fumarate acid salt, succinate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate; more preferred acid addition salts are hydrochloride, acetate, citrate, malate, Succinate, tartrate, fumarate, maleate, methanesulfonate; especially citrate and maleate;
  • the base addition salt is a salt formed by a compound represented by formula (I) and an inorganic base or an organic base, including, for example, a salt formed with an alkali metal, such as sodium salt, lithium salt, potassium salt, Calcium salts, magnesium salts, etc.; amine salts, including salts formed with ammonia (NH 3 ), primary amines, secondary amines or tertiary amines, such as: tetramethylamine salt, tetraethylamine salt, methylamine salt, dimethylamine salt Amine salt, trimethylamine salt, triethylamine salt, ethylamine salt, meglumine salt, choline salt, tromethamine salt; more preferred alkali addition salts are sodium salt, potassium salt, calcium salt, magnesium salt , meglumine salt, choline salt, tromethamine salt; especially sodium salt, potassium salt, magnesium salt, meglumine salt and tromethamine salt.
  • an alkali metal such as sodium salt, lithium salt,
  • the acid addition salt of compound I-1 is hydrochloride, tartrate, maleate, methanesulfonate, or citrate;
  • the acid addition salt of compound I-2 is The salt form is citrate, tartrate, malate (such as L-malate), fumarate, methanesulfonate or maleate;
  • the base addition salt of compound I-1 is a sodium salt, potassium salt, meglumine salt or tromethamine salt;
  • the base addition salt of compound I-2 is a sodium salt , potassium salt, calcium salt, magnesium salt, meglumine salt or tromethamine salt.
  • the present invention provides the citrate crystal form A of Compound I-1, whose X-ray powder diffraction pattern (XRPD) includes positions at 19.77 ⁇ 0.2°, 16.59 ⁇ 0.2°, 22.47 ⁇ 0.2° and Peak at 20.20 ⁇ 0.2° diffraction angle (2 ⁇ ).
  • XRPD X-ray powder diffraction pattern
  • the X-ray powder diffraction pattern (XRPD) of the citrate crystal form A of the compound I-1 includes positions at 16.59 ⁇ 0.2°, 19.77 ⁇ 0.2°, 22.47 ⁇ 0.2°, and 20.20 ⁇ Peaks at diffraction angles (2 ⁇ ) of 0.2°, 24.84 ⁇ 0.2° and 17.51 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the citrate crystal form A has a diffraction angle (2 ⁇ ) as shown in Table 1, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the citrate crystal form A has an X-ray powder diffraction intensity as shown in Table 1.
  • the citrate crystalline Form A has an X-ray powder diffraction pattern substantially as shown in Figure 3.
  • the citrate Form A has a DSC thermogram with endothermic peaks at temperatures of about 107.80°C and 130.63°C.
  • the citrate crystalline Form A has a DSC pattern substantially as shown in Figure 4.
  • the citrate crystalline Form A has a TGA diagram substantially as shown in Figure 5.
  • the present invention provides the sodium salt crystal form A of Compound I-1, whose X-ray powder diffraction pattern (XRPD) includes positions at 19.24 ⁇ 0.2°, 20.68 ⁇ 0.2°, 6.81 ⁇ 0.2°, 14.43 Peak at diffraction angle (2 ⁇ ) of ⁇ 0.2°.
  • XRPD X-ray powder diffraction pattern
  • the present invention provides the sodium salt crystal form A of Compound I-1, whose X-ray powder diffraction pattern (XRPD) includes positions at 19.24 ⁇ 0.2°, 20.68 ⁇ 0.2°, 6.81 ⁇ 0.2°, 14.43 Peaks at diffraction angles (2 ⁇ ) of ⁇ 0.2°, 14.98 ⁇ 0.2° and 6.40 ⁇ 0.2°.
  • XRPD X-ray powder diffraction pattern
  • the X-ray powder diffraction pattern of the sodium salt crystal form A has a diffraction angle (2 ⁇ ) as shown in Table 2, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the sodium salt crystal form A has X-ray powder diffraction intensity as shown in Table 2.
  • the sodium salt crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 8.
  • the sodium salt crystal form A has a DSC thermogram with endothermic peaks at temperatures of about 149.11°C and 174.11°C.
  • the sodium salt crystal form A has a DSC pattern substantially as shown in Figure 9.
  • the sodium salt crystal form A has a TGA diagram substantially as shown in Figure 10.
  • the present invention provides the potassium salt crystal form A of compound I-1, whose X-ray powder diffraction pattern (XRPD) includes position Peaks at diffraction angles (2 ⁇ ) of 13.90 ⁇ 0.2°, 14.43 ⁇ 0.2°, 16.20 ⁇ 0.2°, and 11.67 ⁇ 0.2°.
  • XRPD X-ray powder diffraction pattern
  • the present invention provides the potassium salt crystal form A of compound I-1, whose X-ray powder diffraction pattern (XRPD) includes positions at 13.90 ⁇ 0.2°, 14.43 ⁇ 0.2°, 16.20 ⁇ 0.2°, 11.67 Peaks at diffraction angles (2 ⁇ ) of ⁇ 0.2°, 20.99 ⁇ 0.2° and 16.79 ⁇ 0.2°.
  • XRPD X-ray powder diffraction pattern
  • the X-ray powder diffraction pattern of the potassium salt crystal form A has a diffraction angle (2 ⁇ ) as shown in Table 3, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the potassium salt crystal form A has X-ray powder diffraction intensity as shown in Table 3.
  • the potassium salt crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 11.
  • the present invention provides the potassium salt crystal form B of compound I-1, whose X-ray powder diffraction pattern (XRPD) includes positions at 5.92 ⁇ 0.2°, 14.10 ⁇ 0.2°, 17.62 ⁇ 0.2°, and Peak at diffraction angle (2 ⁇ ) of 17.94 ⁇ 0.2°.
  • XRPD X-ray powder diffraction pattern
  • the present invention provides the potassium salt crystal form B of compound I-1, whose X-ray powder diffraction pattern (XRPD) includes positions at 5.92 ⁇ 0.2°, 14.10 ⁇ 0.2°, 17.62 ⁇ 0.2°, and 17.94 Peaks at diffraction angles (2 ⁇ ) of ⁇ 0.2°, 11.92 ⁇ 0.2° and 7.01 ⁇ 0.2°.
  • XRPD X-ray powder diffraction pattern
  • the X-ray powder diffraction pattern of the potassium salt crystal form B has a diffraction angle (2 ⁇ ) as shown in Table 4, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the potassium salt crystal form B has X-ray powder diffraction intensity as shown in Table 4.
  • the potassium salt crystal Form B has an X-ray powder diffraction pattern substantially as shown in Figure 12.
  • the present invention provides meglumine salt crystal form A of compound I-1, whose X-ray powder diffraction pattern (XRPD) includes positions at 18.15 ⁇ 0.2°, 12.87 ⁇ 0.2°, and 22.87 ⁇ 0.2°. and a peak at a diffraction angle (2 ⁇ ) of 24.66 ⁇ 0.2°.
  • XRPD X-ray powder diffraction pattern
  • the present invention provides meglumine salt crystal form A of compound I-1, whose X-ray powder diffraction pattern (XRPD) includes positions at 18.15 ⁇ 0.2°, 12.87 ⁇ 0.2°, and 22.87 ⁇ 0.2°. , 24.66 ⁇ 0.2°, 23.21 ⁇ 0.2° and 19.57 ⁇ 0.2° peaks at diffraction angles (2 ⁇ ).
  • XRPD X-ray powder diffraction pattern
  • the X-ray powder diffraction pattern of the meglumine salt crystal form A has a diffraction angle (2 ⁇ ) as shown in Table 5, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the meglumine salt crystal form A has X-ray powder diffraction intensity as shown in Table 5.
  • the meglumine salt crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 13.
  • meglumine salt crystal form A has a DSC thermogram with an endothermic peak at a temperature of about 120.06°C.
  • the meglumine salt crystal form A has a DSC pattern substantially as shown in Figure 14.
  • the meglumine salt crystal form A has a TGA diagram substantially as shown in Figure 15.
  • the present invention provides the tromethamine salt crystal form A of compound I-1, whose X-ray powder diffraction pattern (XRPD) includes locations at 3.50 ⁇ 0.2°, 6.97 ⁇ 0.2°, and 13.91 ⁇ 0.2 ° and peaks at diffraction angles (2 ⁇ ) of 22.19 ⁇ 0.2°.
  • XRPD X-ray powder diffraction pattern
  • the present invention provides the tromethamine salt crystal form A of compound I-1, whose X-ray powder diffraction pattern (XRPD) includes locations at 3.50 ⁇ 0.2°, 6.97 ⁇ 0.2°, and 13.91 ⁇ 0.2 °, 22.19 ⁇ 0.2°, 31.61 ⁇ 0.2°, 18.11 ⁇ 0.2° and 20.55 ⁇ 0.2° peaks at diffraction angles (2 ⁇ ).
  • XRPD X-ray powder diffraction pattern
  • the tromethamine salt crystal form A has an X-ray powder diffraction intensity as shown in Table 6.
  • the trometamol salt crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 16.
  • the tromethamine salt Form A has a DSC thermogram with endothermic peaks at temperatures of about 109.95°C and 166.02°C.
  • the tromethamine salt crystal form A has a DSC pattern substantially as shown in Figure 17.
  • the tromethamine salt crystal form A has a TGA diagram substantially as shown in Figure 18.
  • the tromethamine salt crystal form A is in the form of N-methylpyrrolidone solvate.
  • the present invention provides the maleate crystal form A of Compound I-2, whose X-ray powder diffraction pattern (XRPD) includes positions at 5.43 ⁇ 0.2°, 9.89 ⁇ 0.2°, and 12.76 ⁇ 0.2°. and a peak at a diffraction angle (2 ⁇ ) of 8.30 ⁇ 0.2°.
  • XRPD X-ray powder diffraction pattern
  • the present invention provides the maleate crystal form A of Compound I-2, whose X-ray powder diffraction pattern (XRPD) includes positions at 5.43 ⁇ 0.2°, 9.89 ⁇ 0.2°, and 12.76 ⁇ 0.2°. , 8.30 ⁇ 0.2°, 21.31 ⁇ 0.2° and 14.24 ⁇ 0.2° peaks at diffraction angles (2 ⁇ ).
  • XRPD X-ray powder diffraction pattern
  • the X-ray powder diffraction pattern of the maleate crystal form A has a diffraction angle (2 ⁇ ) as shown in Table 7, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the maleate crystal form A has an X-ray powder diffraction intensity as shown in Table 7.
  • the maleate salt Form A has an X-ray powder diffraction pattern substantially as shown in Figure 24.
  • the maleate crystal form A has a DSC thermogram having an endothermic peak at a temperature of about 119.30°C.
  • the maleate salt Form A has a DSC pattern substantially as shown in Figure 25.
  • the maleate crystal form A has a TGA pattern substantially as shown in Figure 26.
  • the present invention provides the potassium salt crystal form A of compound I-2, whose X-ray powder diffraction pattern (XRPD) includes positions at 11.51 ⁇ 0.2°, 15.42 ⁇ 0.2°, 20.20 ⁇ 0.2°, and Peak at diffraction angle (2 ⁇ ) of 9.52 ⁇ 0.2°.
  • XRPD X-ray powder diffraction pattern
  • the present invention provides the potassium salt crystal form A of compound I-2, whose X-ray powder diffraction pattern (XRPD) includes positions at 11.51 ⁇ 0.2°, 15.42 ⁇ 0.2°, 20.20 ⁇ 0.2°, and 9.52 Peaks at diffraction angles (2 ⁇ ) of ⁇ 0.2°, 5.06 ⁇ 0.2° and 25.38 ⁇ 0.2°.
  • XRPD X-ray powder diffraction pattern
  • the X-ray powder diffraction pattern of the potassium salt crystal form A has a diffraction angle (2 ⁇ ) as shown in Table 8, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the maleate crystal form A has an X-ray powder diffraction intensity as shown in Table 8.
  • the potassium salt crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 28.
  • the potassium salt crystal form A has a DSC thermogram with an endothermic peak at a temperature of about 118.44°C.
  • the potassium salt crystal form A has a DSC pattern substantially as shown in Figure 29.
  • the potassium salt crystal form A has a TGA diagram substantially as shown in Figure 30.
  • the present invention provides crystal form A of the magnesium salt of compound I-2, whose X-ray powder diffraction pattern (XRPD) includes positions at 13.92 ⁇ 0.2°, 13.46 ⁇ 0.2°, 14.74 ⁇ 0.2° and 20.43 Peak at diffraction angle (2 ⁇ ) of ⁇ 0.2°.
  • XRPD X-ray powder diffraction pattern
  • the present invention provides crystal form A of the magnesium salt of compound I-2, whose X-ray powder diffraction pattern (XRPD) includes locations at 13.92 ⁇ 0.2°, 13.46 ⁇ 0.2°, 14.74 ⁇ 0.2°, and 20.43 Peaks at diffraction angles (2 ⁇ ) of ⁇ 0.2°, 20.16 ⁇ 0.2° and 17.21 ⁇ 0.2°.
  • XRPD X-ray powder diffraction pattern
  • the X-ray powder diffraction pattern of the magnesium salt crystal form A has a diffraction angle (2 ⁇ ) as shown in Table 9, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the magnesium salt crystal form A has X-ray powder diffraction intensity as shown in Table 9.
  • the magnesium salt crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 32.
  • the present invention provides meglumine salt crystal form A of compound I-2, whose X-ray powder diffraction pattern (XRPD) includes locations at 3.05 ⁇ 0.2°, 9.38 ⁇ 0.2°, and 17.62 ⁇ 0.2°. and a peak at a diffraction angle (2 ⁇ ) of 12.01 ⁇ 0.2°.
  • XRPD X-ray powder diffraction pattern
  • the present invention provides meglumine salt crystal form A of compound I-2, whose X-ray powder diffraction pattern (XRPD) includes locations at 3.05 ⁇ 0.2°, 9.38 ⁇ 0.2°, and 17.62 ⁇ 0.2°. , 12.01 ⁇ 0.2°, 20.39 and 14.88 ⁇ 0.2° peaks at diffraction angles (2 ⁇ ).
  • XRPD X-ray powder diffraction pattern
  • the X-ray powder diffraction pattern of the meglumine salt crystal form A has a diffraction angle (2 ⁇ ) as shown in Table 10, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the meglumine salt crystal form A has X-ray powder diffraction intensity as shown in Table 10.
  • the meglumine salt crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 33.
  • the meglumine salt crystal form A has a DSC thermogram with an endothermic peak at a temperature of about 123.07°C.
  • the meglumine salt crystal form A has a DSC pattern substantially as shown in Figure 34.
  • the meglumine salt crystal form A has a TGA diagram substantially as shown in Figure 35.
  • the present invention provides the tromethamine salt crystal form A of compound I-2, whose X-ray powder diffraction pattern (XRPD) includes locations at 3.68 ⁇ 0.2°, 7.48 ⁇ 0.2°, and 17.21 ⁇ 0.2 ° and peaks at diffraction angles (2 ⁇ ) of 19.15 ⁇ 0.2°.
  • XRPD X-ray powder diffraction pattern
  • the present invention provides the tromethamine salt crystal form A of compound I-2, whose X-ray powder diffraction pattern (XRPD) includes locations at 3.68 ⁇ 0.2°, 7.48 ⁇ 0.2°, and 17.21 ⁇ 0.2 °, 19.15 ⁇ 0.2°, 16.73 ⁇ 0.2° and 15.74 ⁇ 0.2° peaks at diffraction angles (2 ⁇ ).
  • XRPD X-ray powder diffraction pattern
  • the X-ray powder diffraction pattern of the tromethamine salt crystal form A has a diffraction angle (2 ⁇ ) as shown in Table 11, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the tromethamine salt crystal form A has an X-ray powder diffraction intensity as shown in Table 11.
  • the tromethamine salt crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 36.
  • the tromethamine salt Form A has a DSC thermogram with an endothermic peak at a temperature of about 167.96°C.
  • the tromethamine salt crystal form A has a DSC pattern substantially as shown in Figure 37.
  • the tromethamine salt crystal form A has a TGA diagram substantially as shown in Figure 38.
  • a second aspect of the present invention provides a method for preparing a pharmaceutically acceptable salt of Compound I-1 or Compound I-2.
  • the preparation method includes mixing Compound I-1 or Compound I-2 with an acid or a base in a solvent. reaction to prepare a pharmaceutically acceptable salt of compound I-1 or compound I-2.
  • the acid is selected from inorganic acid or organic acid
  • the inorganic acid can be selected from hydrobromic acid, hydrochloric acid, sulfuric acid, sulfurous acid, phosphoric acid, and boric acid
  • the organic acid can be selected from acetic acid, oxalic acid , valeric acid, benzoic acid, lactic acid, toluic acid, citric acid, malic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid;
  • the base is selected from an inorganic base or an organic base
  • the inorganic base may be selected from an alkali metal hydroxide or an alkaline earth metal hydroxide, such as sodium hydroxide, lithium hydroxide, potassium hydroxide , calcium hydroxide, magnesium hydroxide
  • the organic base can be selected from ammonia (NH 3 ), primary amine, secondary amine or tertiary amine, such as tetramethylamine salt, tetraethylamine salt, methylamine, dimethylamine , trimethylamine, triethylamine, ethylamine, meglumine, choline, tromethamine;
  • the preparation method further includes the step of creating a degree of supersaturation to precipitate the product after the reaction is completed.
  • the method of creating a degree of supersaturation includes one or more of the following: adding seed crystals, evaporating solvents , add an antisolvent or obtain the acid salt or basic salt of compound I by cooling.
  • the solvent may be selected from alcohols, chlorinated alkanes, ketones, ethers, cyclic ethers, esters, alkanes, cycloalkanes, benzene, amides, sulfoxides, Nitrile organic solvents, a combination of two or more of the solvents, or a mixture of the above solvents or combinations with water.
  • the ketones may be selected from ketones having 3 to 10 carbon atoms, such as acetone, butanone, pentanone, methyl ethyl ketone, methyl isobutyl ketone, 4-methyl- 2-pentanone or a combination thereof;
  • the nitriles can be selected from acetonitrile;
  • the alcohols can be selected from alcohols or haloalcohols with 1-8 carbon atoms, such as methanol, ethanol, n-propanol, isopropanol , n-butanol, neopentyl alcohol, trifluoroethanol or combinations thereof;
  • the esters can be selected from organic formates, such as methyl formate, ethyl acetate, isobutyl formate, ethyl propyl acetate or combinations thereof ;
  • the ethers can be linear or branched alkyl ethers or cyclic ether compounds, such as methyl tert-
  • the solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, acetonitrile, acetone, methyl isobutyl ketone, 1,4-dioxane, tetrahydrofuran, N, N - dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, 2-methoxyethyl ether, acetonitrile, water or mixtures thereof.
  • the molar ratio of the compound I-1 or I-2 to the acid or base may be 1:0.8 ⁇ 1:2, preferably 1:0.9 ⁇ 1:1.8, more preferably 1 :1.0 ⁇ 1:1.5.
  • the reaction temperature in the preparation method, can be selected within a wide range, for example, 20°C to 80°C, preferably 25°C to 60°C.
  • the preparation method further includes the steps of filtering and/or drying after the reaction is completed to prepare a pharmaceutically acceptable salt of Compound I-1 or Compound I-2.
  • the drying temperature in the preparation method, can be selected within a wide range, for example, it can be 20°C to 80°C, preferably 30°C to 60°C.
  • the present invention also provides a method for preparing a pharmaceutically acceptable salt of compound I-1:
  • Method 1a includes: dissolving compound I-1 in acetonitrile, adding concentrated hydrochloric acid, L-tartaric acid, maleic acid or methanesulfonic acid, stirring at room temperature, filtering, and drying to obtain the hydrochloride and compound of compound I-1.
  • Method 1b includes: dissolving compound I-1 and citric acid in acetone, stirring at room temperature, filtering, and drying to obtain the citrate salt of compound I-1;
  • Method 1c includes: dissolving compound I-1 and sodium hydroxide or potassium hydroxide in acetonitrile or methyl isobutyl ketone, stirring at room temperature, filtering, and drying to obtain the sodium salt of compound I-1 or compound I-1 of potash;
  • Method 1d includes: dissolving compound I-1 and meglumine in acetonitrile, stirring at room temperature, filtering, and drying to obtain the meglumine salt of compound I-1;
  • Method 1e includes: dissolving compound I-1 and tromethamine in N-methylpyrrolidone, adding them to toluene, stirring at room temperature, filtering, and drying to obtain the tromethamine salt of compound I-1;
  • the volume ratio of N-methylpyrrolidone/toluene is 2:15.
  • the present invention also provides a method for preparing a pharmaceutically acceptable salt of compound I-2:
  • Method 2a includes: dissolving compound I-2 and citric acid or L-tartaric acid in acetone, stirring at room temperature, filtering, and drying to obtain the citrate salt of compound I-2 or the tartrate salt of compound I-2;
  • Method 2b includes: dissolving Compound I-2 and L-malic acid or fumaric acid in acetonitrile/water, stirring at room temperature, filtering, and drying to obtain the malate of Compound I-2 or the rich salt of Compound I-2. Malate; preferably, the volume ratio of acetonitrile/water is 1:1;
  • Method 2c includes: dissolving compound I-2 and methanesulfonic acid or maleic acid in ethyl acetate, stirring at room temperature, filtering, and drying to obtain the methanesulfonate salt of compound I-2 or the maleic acid salt of compound I-2. acid salt;
  • Method 2d includes: dissolving compound I-2 and sodium hydroxide, potassium hydroxide, calcium hydroxide or magnesium hydroxide in a mixed solvent of acetonitrile/water or ethyl acetate, stirring at room temperature, filtering, and drying to obtain The sodium salt of Compound I-2, the potassium salt of Compound I-2, the calcium salt of Compound I-2, and the magnesium salt of Compound I-2; preferably, the volume ratio of acetonitrile/water is 1:1;
  • Method 2e includes: dissolving compound I-2 and meglumine in acetone, stirring at room temperature, filtering, and drying to obtain the meglumine salt of compound I-2;
  • Method 2f includes: dissolving compound I-2 and tromethamine in isopropyl alcohol, stirring at room temperature, filtering, and drying to obtain the tromethamine salt of compound I-2.
  • the third aspect of the present invention provides a pharmaceutical composition, including at least one pharmaceutically acceptable salt of the compound represented by formula (I) and a pharmaceutically acceptable carrier.
  • the fourth aspect of the present invention provides the use of at least one pharmaceutically acceptable salt of the compound represented by formula (I) in the preparation of a drug for treating metabolic diseases, tumors, autoimmune diseases or metastatic diseases.
  • the fifth aspect of the present invention provides a pharmaceutically acceptable salt of the compound represented by the aforementioned formula (I), which is used as a drug for treating metabolic diseases, tumors, autoimmune diseases or metastatic diseases.
  • the sixth aspect of the present invention provides a pharmaceutically acceptable salt of the compound represented by the aforementioned formula (I), which is used to treat T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition Associated Diabetes, Gestational Diabetes, Hyperglycemia, Insulin Resistance, Hepatic Insulin Resistance, Glucose Intolerance, Diabetic Neuropathy, Diabetic Nephropathy, Kidney Disease, Diabetic Retinopathy, Adipocyte Dysfunction, Visceral Adipocyte Hoarding, Sleep apnea, obesity, eating disorders, weight gain due to use of other drugs, excessive sugar craving, dyslipidemia, hyperinsulinemia, NAFLD, NAS, fibrosis, sclerosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis sclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial
  • the pharmaceutically acceptable salt of the compound represented by the aforementioned formula (I) is used to treat T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, and malnutrition-related diabetes.
  • gestational diabetes hyperglycemia, insulin resistance, hepatic insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, obesity, eating disorders, weight gain caused by use of other agents, excessive sugar craving, and dyslipidemia disease and hyperinsulinemia.
  • the present invention also provides a method for treating diseases, comprising administering to an individual in need a therapeutically effective amount of a pharmaceutically acceptable salt of the compound represented by formula (I) as described above or at least one of the pharmaceutical compositions. kind.
  • the disease is selected from metabolic diseases, tumors, autoimmune diseases or metastatic diseases.
  • the disease is selected from the group consisting of T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-associated diabetes, gestational diabetes, hyperglycemia, insulin resistance, liver Insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral adipocyte accumulation, sleep apnea, obesity, eating disorders, weight loss due to use of other agents Increased, hyperglycemia, dyslipidemia, hyperinsulinemia, NAFLD, NAS, fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial function Disorders, impaired vascular compliance, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic
  • the inventor of the present invention has studied various acidic or basic salts of Compound I.
  • This salt-formed form greatly improves the physical and chemical properties of Compound I such as solubility, hygroscopicity and chemical stability.
  • the raw materials of the salt-type compound are in line with industrial requirements.
  • the production requirements can meet the needs of clinical drug preparation development, have very important clinical application value, and are expected to accelerate the development of a new generation of GLP-1R small molecule agonists.
  • Figure 1 shows the X-ray powder diffraction pattern of the hydrochloride salt of compound I-1 of the present invention.
  • the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity.
  • Figure 2 shows the X-ray powder diffraction pattern of the tartrate salt of Compound 1-1 of the present invention.
  • the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity.
  • Figure 3 shows the X-ray powder diffraction pattern of the citrate salt of compound I-1 of the present invention.
  • the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity.
  • FIG. 4 shows a DSC pattern of the citrate salt of compound I-1 of the present invention.
  • the abscissa represents temperature (°C), and the ordinate represents heat flow (mW).
  • FIG. 5 shows a TGA chart of the citrate salt of compound I-1 of the present invention.
  • the abscissa represents temperature (° C.), and the ordinate represents weight (%).
  • Figure 6 shows the X-ray powder diffraction pattern of the maleate salt of compound I-1 of the present invention.
  • the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity.
  • Figure 7 shows the X-ray powder diffraction pattern of the mesylate salt of compound I-1 of the present invention.
  • the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity.
  • Figure 8 shows the X-ray powder diffraction pattern of the sodium salt of compound I-1 of the present invention.
  • the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity.
  • Figure 9 shows the DSC chart of the sodium salt of compound I-1 of the present invention.
  • the abscissa represents temperature (°C), and the ordinate represents heat flow (mW).
  • Figure 10 shows the TGA chart of sodium of compound I-1 of the present invention.
  • the abscissa represents temperature (° C.), and the ordinate represents weight (%).
  • Figure 11 shows the X-ray powder diffraction pattern of Form A of the potassium salt of Compound I-1 of the present invention.
  • the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity.
  • Figure 12 shows the X-ray powder diffraction pattern of Form B of the potassium salt of Compound I-1 of the present invention.
  • the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity.
  • Figure 13 shows the X-ray powder diffraction pattern of the meglumine salt of Compound 1-1 of the present invention.
  • the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity.
  • Figure 14 shows a DSC chart of the meglumine salt of compound I-1 of the present invention.
  • the abscissa represents temperature (°C), and the ordinate represents heat flow (mW).
  • Figure 15 shows a TGA chart of the meglumine salt of compound I-1 of the present invention.
  • the abscissa represents temperature (° C.), and the ordinate represents weight (%).
  • Figure 16 shows the X-ray powder diffraction pattern of the trometamol salt of compound I-1 of the present invention.
  • the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity.
  • Figure 17 shows a DSC chart of the tromethamine salt of compound I-1 of the present invention.
  • the abscissa represents temperature (°C), and the ordinate represents heat flow (mW).
  • Figure 18 shows a TGA chart of the tromethamine salt of compound I-1 of the present invention.
  • the abscissa represents temperature (° C.), and the ordinate represents weight (%).
  • Figure 19 shows the X-ray powder diffraction pattern of the citrate salt of Compound 1-2 of the present invention.
  • the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity.
  • Figure 20 shows the X-ray powder diffraction pattern of the malate salt of Compound 1-2 of the present invention.
  • the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity.
  • Figure 21 shows the X-ray powder diffraction pattern of the tartrate salt of Compound 1-2 of the present invention.
  • the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity.
  • Figure 22 shows the X-ray powder diffraction pattern of the fumarate salt of Compound 1-2 of the present invention.
  • the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity.
  • Figure 23 shows the X-ray powder diffraction pattern of the mesylate salt of Compound 1-2 of the present invention.
  • the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity.
  • Figure 24 shows the X-ray powder diffraction pattern of the maleate salt of Compound 1-2 of the present invention.
  • the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity.
  • Figure 25 shows a DSC chart of the maleate salt of Compound 1-2 of the present invention.
  • the abscissa represents temperature (°C), and the ordinate represents heat flow (mW).
  • Figure 26 shows a TGA chart of the maleate salt of Compound 1-2 of the present invention.
  • the abscissa represents temperature (° C.), and the ordinate represents weight (%).
  • Figure 27 shows the X-ray powder diffraction pattern of the sodium salt of Compound 1-2 of the present invention.
  • the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity.
  • Figure 28 shows the X-ray powder diffraction pattern of the potassium salt of Compound 1-2 of the present invention.
  • the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity.
  • Figure 29 shows a DSC chart of the potassium salt of compound I-2 of the present invention.
  • the abscissa represents temperature (°C), and the ordinate represents heat flow (mW).
  • Figure 30 shows a TGA chart of the potassium salt of compound I-2 of the present invention.
  • the abscissa represents temperature (° C.), and the ordinate represents weight (%).
  • Figure 31 shows the X-ray powder diffraction pattern of the calcium salt of Compound 1-2 of the present invention.
  • the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity.
  • Figure 32 shows the X-ray powder diffraction pattern of the magnesium salt of Compound 1-2 of the present invention.
  • the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity.
  • Figure 33 shows the X-ray powder diffraction pattern of the meglumine salt of Compound 1-2 of the present invention.
  • the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity.
  • Figure 34 shows the DSC pattern of the meglumine salt of Compound 1-2 of the present invention.
  • the abscissa represents temperature (°C), and the ordinate represents heat flow (mW).
  • Figure 35 shows a TGA chart of the meglumine salt of Compound 1-2 of the present invention.
  • the abscissa represents temperature (° C.), and the ordinate represents weight (%).
  • Figure 36 shows the X-ray powder diffraction pattern of the tromethamine salt of Compound 1-2 of the present invention.
  • the abscissa represents the 2 ⁇ value (degrees), and the ordinate represents the peak intensity.
  • Figure 37 shows a DSC chart of the tromethamine salt of compound I-2 of the present invention.
  • the abscissa represents temperature (°C), and the ordinate represents heat flow (mW).
  • Figure 38 shows a TGA chart of the tromethamine salt of compound I-2 of the present invention.
  • the abscissa represents temperature (° C.), and the ordinate represents weight (%).
  • Figure 39 shows the DVS pattern of compound I-1 of the present invention.
  • the abscissa represents relative humidity (%), and the ordinate represents weight change (%).
  • Figure 40 shows the DVS chart of compound I-2 of the present invention.
  • the abscissa represents relative humidity (%), and the ordinate represents weight change (%).
  • Figure 41 shows the DVS diagram of the tromethamine salt of compound I-1 of the present invention.
  • the abscissa represents relative humidity (%), and the ordinate represents weight change (%).
  • Figure 42 shows the DVS diagram of the tromethamine salt of compound I-2 of the present invention.
  • the abscissa represents relative humidity (%), and the ordinate represents weight change (%).
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or physiologically/pharmaceutically acceptable salts or prodrugs thereof, together with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients.
  • the purpose of pharmaceutical compositions is to facilitate administration to living organisms and facilitate the absorption of active ingredients to exert biological activity.
  • salt refers to a compound prepared by reacting an organic acid or base drug with a pharmaceutically acceptable inorganic or organic acid or base.
  • the intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and those skilled in the art.
  • Well-known equivalents and preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • the structure of the compound was determined by nuclear magnetic resonance (NMR). NMR shifts ( ⁇ ) are given in parts per million (ppm) units. NMR was measured using a Bruker assemble-400MHz nuclear magnetic instrument. The measurement solvent was deuterated dimethyl sulfoxide (DMSO-d6) or deuterated methanol (MeOD-d4). The internal standard was tetramethylsilane (TMS). The chemical shift The unit is 10 -6 ppm).
  • HPLC determination uses Agilent 1260 high performance liquid chromatography or a high performance liquid chromatograph with equivalent performance (Sunfire C18 150 ⁇ 4.6m chromatographic column or a chromatographic column with equivalent performance).
  • the crystalline form of the acid salt or base salt of Compound I is characterized by X-ray powder diffraction patterns.
  • X-ray powder diffraction patterns of the salt were collected on a Bruker D8 Advance powder diffractometer operated in reflection mode using Cu K ⁇ radiation.
  • the instrument uses Cu K ⁇ irradiation (40kV, 40mA) and uses the SSD160-2 detector at room temperature.
  • the scanning range is from 3° to 40° in 2 ⁇ , and the scanning speed is 0.1s/step.
  • Use DIFFRAC.MEA.CENTER software to analyze the diffraction pattern.
  • XRPD samples are prepared by placing the sample on a single crystal silicon wafer and pressing the sample powder with a glass plate or equivalent to ensure that the surface of the sample is flat and has an appropriate height. The sample holder was then placed into the Bruker D8 Advance instrument and X-ray powder diffraction patterns were collected using the instrument parameters described above. Measurement differences associated with the results of such X-ray powder diffraction analysis arise from a variety of factors including: (a) errors in sample preparation (e.g., sample height), (b) instrument errors, (c) calibration differences, ( d) operator errors (including those occurring in determining peak positions), and (e) properties of the material (eg preferred orientation errors). Calibration errors and sample height errors often cause all peaks to be shifted in the same direction. Generally speaking, this calibration factor will bring the measured peak position consistent with the expected peak position and within ⁇ 0.2° of the expected 2 ⁇ value.
  • the experimental method of using differential scanning calorimetry (DSC) to characterize the crystalline form of the acidic salt or basic salt of Compound I is to take a small amount of the powder of the acidic salt or basic salt of the crystalline Compound I and place it with the instrument. In the matching aluminum crucible that can be pressed, the sample is loaded and covered with an aluminum plate, and then sent to the instrument for testing.
  • the instrument model used in the differential scanning calorimetry in this patent is METTLER TOLEDO DSC 3. The scanning parameters are set to use a nitrogen atmosphere and the temperature rise rate is 10.0k/min.
  • thermogravimetric analysis TGA
  • the experimental method of using thermogravimetric analysis (TGA) to characterize the crystal form of the acid salt or basic salt of Compound I is to take a small amount of the powder of the acid salt or basic salt of the crystalline Compound I and place it in a After loading the sample into the alumina crucible, it is sent to the instrument for testing.
  • the instrument model used in the differential scanning calorimetry of the present invention is METTLER TOLEDO TGA 2, the scanning parameters are set to use a nitrogen atmosphere, and the heating rate is 10.0 k/min.
  • the experimental method of using the dynamic moisture adsorption method (DVS) to characterize the acid salt or basic salt of compound I is to take a small amount of the acid salt or basic salt powder of compound I, place it in a precision sample tray matched with the instrument, and load After the sample is collected, it is sent to the instrument for testing. All instruments used in the dynamic moisture adsorption method in this invention are Intrinsic PLUS.
  • the experimental parameters are set to set a constant temperature of 25°C.
  • the mass percentage change rate per unit time (dm/dt) 0.02%/min is used as a judgment to reach equilibrium.
  • the standard, programmed humidity change cycle is set with an initial relative humidity of 0% and an endpoint relative humidity of 90%.
  • Step 1 (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl Synthesis of methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate
  • Step 2 (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl Synthesis of 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • Step 1 (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl) Synthesis of methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate
  • Step 2 (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl) Synthesis of methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • Free Compounds I-1 and Compounds I-2 and corresponding representative tromethamine salts were tested for their equilibrium solubility in water (H 2 O).
  • the solid was prepared into a suspension ( ⁇ 10 mg/mL) in the corresponding buffer solution and stirred at 37 ⁇ 2°C. After 24 hours, the suspension was sampled, and the supernatant was filtered to determine the concentration.
  • the test results are shown in the table below:
  • the hygroscopic behavior of compounds affects the production, storage, stability and quality of pharmaceuticals.
  • the inventor followed the dynamic moisture adsorption method to evaluate the stability risk of the sample with changes in humidity at 25°C, and conducted a DVS test on the representative salt forms of trometamol salts of compounds I-1 and I-2 to evaluate the hygroscopicity of the salt forms of the compounds.
  • the DVS spectrum of free compound I-1 is shown in Figure 39
  • the DVS spectrum of free compound I-2 is shown in Figure 40
  • the DVS spectrum of the tromethamine salt of compound I-1 is shown in Figure 41
  • the results are as follows:

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Abstract

本发明涉及GLP-1R激动剂化合物I的盐型及其制备方法和应用。本发明的盐具有优异GLP-1R激动活性，且在动物体内的生物利用度良好，适于制备治疗代谢性疾病、肿瘤、自身免疫性疾病或转移性疾病的制剂。

Description

GLP-1R激动剂的盐及其制备方法和应用 技术领域
本发明属于药物开发领域，具体涉及一种GLP-1R激动剂的盐及其制备方法和应用。
背景技术
糖尿病是由于人体胰岛素分泌(相对或绝对)不足或者胰岛素作用障碍导致的以高血糖为特征的慢性疾病。根据国际糖尿病-联盟(International diabetes federation,IDF)最新颁布的第九版世界糖尿病地图显示，2019年全球约有4.63亿成人(20-79岁)患糖尿病，预计到2030年糖尿病患病人数将达到5.78亿。若按照此趋势持续下去，2045年全球将有7亿糖尿病患者。因此，糖尿病已成为21世纪全球范围内面临的最为严峻的社会健康问题之一。
目前已有各种药理学方法用来治疗高血糖症及伴随发生的T2DM(Hampp等人，《美国抗糖尿病药物的使用(Use of Antidiabetic Drugs in the U.S.)》,2003-2012,Diabetes Care 37:1367-1374,2014)。这些方法可分成六个主要类别，每个类别是通过不同的主要机制起作用。
胰岛素促分泌素，包含磺酰脲类、二肽基肽酶IV(PP-IV)抑制剂以及类升糖素肽-1受体(GLP-1R)激动剂，其通过在胰脏β细胞上作用而提高胰岛素分泌。磺酰脲的功效及耐受性有限，引起增重且常诱发低血糖症。DP-IV抑制剂的功效有限。市场上销售的GLP-1R激动剂是经皮下注射给药的肽。利拉鲁肽另外被批准用于治疗肥胖症。
双胍(例如甲福明(metformin))被认为主要通过降低肝脏葡萄糖生产而起作用双胍常引起胃肠不适及乳酸中毒，进一步限制了其用途。
α-葡萄糖苷酶抑制剂(例如阿卡波糖(acarbose))会降低肠道葡萄糖吸收。这些药剂常引起胃肠不适。
噻唑烷二酮(thiazolidinedione)(例如匹格列酮(pioglitazone)、罗格列酮(rosiglitazone))是在肝、肌肉及脂肪组织的特定受体上起作用。它们调节脂质代谢且随后増强这些组织对胰岛素作用的反应。常使用这些药物可能导致增重且可能诱发水肿及贫血。
胰岛素单独或与上述药剂组合而用于更严重的病例，且常使用也可能导致增重且带有低血糖症风险。
钠-葡萄糖连结的转运蛋白共转运蛋白2(SGLT2)抑制剂(例如达格列净(dapagliflozin)、恩格列净(empagliflozin)、卡格列净(canagliflozin)、依格列净(ertugliflozin)抑制葡萄糖在肾脏中的再吸收且从而降低血液中的葡萄糖含量这种新兴药物类别可能与酮酸中毒及尿道感染相关联。
然而，除了GLP-1R激动剂及SGLT2抑制剂之外，所述药物的功效有限且未解决最重要的问题:β细胞功能衰退及相关的肥胖症。因此需要具有较少副作用且方便投药的更有效的药物介入。
GLP-1是肠内L细胞在反应食物摄取时所分泌的30个氨基酸长度的肠促胰岛素激素。已显示GLP-1以生理及葡萄糖依赖性方式刺激胰岛素分泌、降低升糖素分泌、抑制胃排空、降低食欲及刺激β细胞増生。在非临床试验中，GLP-1通过刺溵对葡萄糖依赖性胰岛素分泌重要的基因转录及通过促进β细胞新生而促进持续的β细胞能力(Meier等人，《生物药物(Biodrugs.)》17(2):93-102,2013)
在健康的个体中，GLP-1通过刺激胰脏的葡萄糖依赖性胰岛素分泌，从而使末稍的葡萄糖吸收增加而起到调节餐后血糖含量的重要作用。GLP-1还抑制升糖素分泌，使得肝脏葡萄糖排岀量降低。另外，GLP-1延迟胃排空及减慢小肠运动而延迟食物吸收。在患有T2DM的人中，餐后GLP-1不会正常上升或上升量减少(Vilsbol1等人，《糖尿病(iabetes.)》50609-613，2001)。
科学研究已经对GLP-1的结构进行相应的改造和修饰，以增加其半衰期进而延长体内生物学效应。然而，目前临床上投入使用的长效GLP-1类似物如利拉鲁肽、艾塞那肽等均为多肽，频繁多次注射给药导致患者的依从性较差，因此小分子GLP-1R激动剂的开发将从提高患者的依从性、用药方便性以及降低药物副作用的目的出发，具有广阔的临床市场前景。
杭州德睿智药科技有限公司(Mindrank AI Ltd.)研发了一种结构新颖的具有GLP-1R抑制效果的小分子化合物，其代表性化合物I-1和化合物I-2的结构如下：
该类化合物能显着提高GLP-1R靶点的激动作用，提高治疗窗口，降低临床毒副作用，满足现阶段国内外对糖尿病治疗的需求。
化合物I-1的化学名称为(S)-2-(4-(6-(4-氯-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸。
化合物I-2的化学名称为(S)-2-(4-(6-(4-氰基-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸。
化合物I-1或化合物I-2的药学固体形态的成功开发通常要具有合成后能方便地分离与纯化的固体型态，可适用于大规模制造，能以较长的期限保存并最低限度的吸收水分、分解或转化为其他固体型态，并适用于给药后个体能速地吸收的剂型(如能溶解于水以及胃液中)等性质。
为满足临床研究以及上市药物制剂需要，迫切需要开发一种能够方便分离纯化，适合工业化生产，具有稳定的物理化学性质的药物固体形态。
发明内容
为了解决现有技术存在的问题，本发明的第一方面，提供了一种式(I)所示化合物的药学上可接受的盐；
其中，R选自卤素或CN。
根据本发明的实施方案，式(I)所示化合物选自如下化合物I-1或化合物I-2；
根据本发明的实施方案，所述药学上可接受的盐是指在药学上无毒的酸加成盐或碱加成盐；
根据本发明的实施方案，所述酸加成盐为式(I)所示化合物与无机酸或有机酸形成的盐，包括氢溴酸盐、盐酸盐、硫酸盐、硫酸氢盐、亚硫酸盐、磷酸盐、硼酸盐、乙酸盐、草酸盐、戊酸盐、苯甲酸盐、乳酸盐、甲苯甲酸盐、柠檬酸盐、苹果酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐；更加优选的酸加成盐为盐酸盐、乙酸盐、柠檬酸盐、苹果酸盐、琥珀酸盐、酒石酸盐、富马酸盐、马来酸盐、甲磺酸盐；特别是柠檬酸盐和马来酸盐；
根据本发明的实施方案，所述碱加成盐为式(I)所示化合物与无机碱或有机碱形成的盐，包括例如与碱金属形成的盐，如钠盐、锂盐、钾盐、钙盐、镁盐等；胺盐，包括与氨(NH3)、伯胺、仲胺或叔胺形成的盐，如：四甲基胺盐、四乙基胺盐、甲胺盐、二甲胺盐、三甲胺盐、三乙胺盐、乙胺盐、葡甲胺盐、胆碱盐、氨丁三醇盐；更加优选的碱加成盐为钠盐、钾盐、钙盐、镁盐、葡甲胺盐、胆碱盐、氨丁三醇盐；特别是钠盐、钾盐、镁盐、葡甲胺盐和氨丁三醇盐。
根据本发明的实施方案，所述化合物I-1的酸加成盐为盐酸盐、酒石酸盐、马来酸盐、甲磺酸盐、或柠檬酸盐；所述化合物I-2的酸加成盐为柠檬酸盐、酒石酸盐、苹果酸盐(如L-苹果酸盐)、富马酸盐、甲磺酸盐或马来酸盐；
根据本发明的实施方案，所述化合物I-1的碱加成盐为钠盐、钾盐、葡甲胺盐或氨丁三醇盐；所述化合物I-2的碱加成盐为钠盐、钾盐、钙盐、镁盐、葡甲胺盐或氨丁三醇盐。
根据本发明的优选技术方案，本发明提供化合物I-1的柠檬酸盐晶型A，其X-射线粉末衍射图(XRPD)包括位于19.77±0.2°、16.59±0.2°、22.47±0.2°和20.20±0.2°的衍射角(2θ)处的峰。
根据本发明的优选技术方案，所述化合物I-1的柠檬酸盐晶型A的X-射线粉末衍射图(XRPD)包括位于16.59±0.2°、19.77±0.2°、22.47±0.2°、20.20±0.2°、24.84±0.2°和17.51±0.2°的衍射角(2θ)处的峰。
优选地，所述的柠檬酸盐晶型A，其X-射线粉末衍射图具有如表1所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：
表1
优选地，所述的柠檬酸盐晶型A具有如表1所示的X-射线粉末衍射强度。
优选地，所述柠檬酸盐晶型A具有基本如图3所示的X射线粉末衍射图。
优选地，所述柠檬酸盐晶型A在约107.80℃和130.63℃的温度处具有吸热峰的DSC热谱图。
优选地，所述柠檬酸盐晶型A具有基本如图4所示的DSC图。
优选地，所述柠檬酸盐晶型A具有基本如图5所示的TGA图。
作为更进一步优选的方案，本发明提供了化合物I-1的钠盐晶型A，其X-射线粉末衍射图(XRPD)包括位于19.24±0.2°、20.68±0.2°、6.81±0.2°、14.43±0.2°的衍射角(2θ)处的峰。
作为更进一步优选的方案，本发明提供了化合物I-1的钠盐晶型A，其X-射线粉末衍射图(XRPD)包括位于19.24±0.2°、20.68±0.2°、6.81±0.2°、14.43±0.2°、14.98±0.2°和6.40±0.2°的衍射角(2θ)处的峰。
优选地所述的钠盐晶型A，其X-射线粉末衍射图具有如表2所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：
表2
优选地，所述的钠盐晶型A具有如表2所示的X-射线粉末衍射强度。
优选地，所述钠盐晶型A具有基本如图8所示的X射线粉末衍射图。
优选地，所述钠盐晶型A在约149.11℃和174.11℃的温度处具有吸热峰的DSC热谱图。
优选地，所述钠盐晶型A具有基本如图9所示的DSC图。
优选地，所述钠盐晶型A具有基本如图10所示的TGA图。
作为更进一步优选的方案，本发明提供了化合物I-1的钾盐晶型A，其X-射线粉末衍射图(XRPD)包括位 于13.90±0.2°、14.43±0.2°、16.20±0.2°、和11.67±0.2°的衍射角(2θ)处的峰。
作为更进一步优选的方案，本发明提供了化合物I-1的钾盐晶型A，其X-射线粉末衍射图(XRPD)包括位于13.90±0.2°、14.43±0.2°、16.20±0.2°、11.67±0.2°、20.99±0.2°和16.79±0.2°的衍射角(2θ)处的峰。
优选地，所述的钾盐晶型A，其X-射线粉末衍射图具有如表3所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：
表3
优选地，所述的钾盐晶型A具有如表3所示的X-射线粉末衍射强度。
优选地，所述钾盐晶型A具有基本如图11所示的X射线粉末衍射图。
作为更进一步优选的方案，本发明提供了化合物I-1的钾盐晶型B，其X-射线粉末衍射图(XRPD)包括位于5.92±0.2°、14.10±0.2°、17.62±0.2°、和17.94±0.2°的衍射角(2θ)处的峰。
作为更进一步优选的方案，本发明提供了化合物I-1的钾盐晶型B，其X-射线粉末衍射图(XRPD)包括位于5.92±0.2°、14.10±0.2°、17.62±0.2°、17.94±0.2°、11.92±0.2°和7.01±0.2°的衍射角(2θ)处的峰。
优选地，所述的钾盐晶型B，其X-射线粉末衍射图具有如表4所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：
表4
优选地，所述的钾盐晶型B具有如表4所示的X-射线粉末衍射强度。
优选地，所述钾盐晶型B具有基本如图12所示的X射线粉末衍射图。
作为更进一步优选的方案，本发明提供了化合物I-1的葡甲胺盐晶型A，其X-射线粉末衍射图(XRPD)包括位于18.15±0.2°、12.87±0.2°、22.87±0.2°和24.66±0.2°的衍射角(2θ)处的峰。
作为更进一步优选的方案，本发明提供了化合物I-1的葡甲胺盐晶型A，其X-射线粉末衍射图(XRPD)包括位于18.15±0.2°、12.87±0.2°、22.87±0.2°、24.66±0.2°、23.21±0.2°和19.57±0.2°的衍射角(2θ)处的峰。
优选地，所述的葡甲胺盐晶型A，其X-射线粉末衍射图具有如表5所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：
表5
优选地，所述的葡甲胺盐晶型A具有如表5所示的X-射线粉末衍射强度。
优选地，所述葡甲胺盐晶型A具有基本如图13所示的X射线粉末衍射图。
优选地，葡甲胺盐晶型A在约120.06℃的温度处具有吸热峰的DSC热谱图。
优选地，所述葡甲胺盐晶型A具有基本如图14所示的DSC图。
优选地，所述葡甲胺盐晶型A具有基本如图15所示的TGA图。
作为更进一步优选的方案，本发明提供了化合物I-1的氨丁三醇盐晶型A，其X-射线粉末衍射图(XRPD)包括位于3.50±0.2°、6.97±0.2°、13.91±0.2°和22.19±0.2°的衍射角(2θ)处的峰。
作为更进一步优选的方案，本发明提供了化合物I-1的氨丁三醇盐晶型A，其X-射线粉末衍射图(XRPD)包括位于3.50±0.2°、6.97±0.2°、13.91±0.2°、22.19±0.2°、31.61±0.2°、18.11±0.2°和20.55±0.2°的衍射角(2θ)处的峰。
作为最优选方案，所述的氨丁三醇盐晶型A，其X射线粉末衍射数据如下表6所示：
表6
优选地，所述的氨丁三醇盐晶型A具有如表6所示的X-射线粉末衍射强度。优选地，所述氨丁三醇盐晶型A具有基本如图16所示的X射线粉末衍射图。
优选地，所述氨丁三醇盐晶型A在约109.95℃和166.02℃的温度处具有吸热峰的DSC热谱图。
优选地，所述氨丁三醇盐晶型A具有基本如图17所示的DSC图。
优选地，所述氨丁三醇盐晶型A具有基本如图18所示的TGA图。
优选地，所述氨丁三醇盐晶型A为N-甲基吡咯烷酮溶剂合物形式。
作为更进一步优选的方案，本发明提供了化合物I-2的马来酸盐晶型A，其X-射线粉末衍射图(XRPD)包括位于5.43±0.2°、9.89±0.2°、12.76±0.2°和8.30±0.2°的衍射角(2θ)处的峰。
作为更进一步优选的方案，本发明提供了化合物I-2的马来酸盐晶型A，其X-射线粉末衍射图(XRPD)包括位于5.43±0.2°、9.89±0.2°、12.76±0.2°、8.30±0.2°、21.31±0.2°和14.24±0.2°的衍射角(2θ)处的峰。
优选地，所述的马来酸盐晶型A，其X-射线粉末衍射图具有如表7所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：
表7
优选地，所述的马来酸盐晶型A具有如表7所示的X-射线粉末衍射强度。
优选地，所述马来酸盐晶型A具有基本如图24所示的X射线粉末衍射图。
优选地，所述马来酸盐晶型A该晶型在约119.30℃的温度处具有吸热峰的DSC热谱图。
优选地，所述马来酸盐晶型A具有基本如图25所示的DSC图。
优选地，所述马来酸盐晶型A具有基本如图26所示的TGA图。
作为更进一步优选的方案，本发明提供了化合物I-2的钾盐晶型A，其X-射线粉末衍射图(XRPD)包括位于11.51±0.2°、15.42±0.2°、20.20±0.2°、和9.52±0.2°的衍射角(2θ)处的峰。
作为更进一步优选的方案，本发明提供了化合物I-2的钾盐晶型A，其X-射线粉末衍射图(XRPD)包括位于11.51±0.2°、15.42±0.2°、20.20±0.2°、9.52±0.2°、5.06±0.2°和25.38±0.2°的衍射角(2θ)处的峰。
优选地，所述的钾盐晶型A，其X-射线粉末衍射图具有如表8所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：
表8
优选地，所述的马来酸盐晶型A具有如表8所示的X-射线粉末衍射强度。
优选地，所述钾盐晶型A具有基本如图28所示的X射线粉末衍射图。
优选地，所述钾盐晶型A在约118.44℃的温度处具有吸热峰的DSC热谱图。
优选地，所述钾盐晶型A具有基本如图29所示的DSC图。
优选地，所述钾盐晶型A具有基本如图30所示的TGA图。
作为更进一步优选的方案，本发明提供了化合物I-2的镁盐晶型A，其X-射线粉末衍射图(XRPD)包括位于13.92±0.2°、13.46±0.2°、14.74±0.2°和20.43±0.2°的衍射角(2θ)处的峰。
作为更进一步优选的方案，本发明提供了化合物I-2的镁盐晶型A，其X-射线粉末衍射图(XRPD)包括位于13.92±0.2°、13.46±0.2°、14.74±0.2°、20.43±0.2°、20.16±0.2°和17.21±0.2°的衍射角(2θ)处的峰。
优选地，所述的镁盐晶型A，其X-射线粉末衍射图具有如表9所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：
表9

优选地，所述的镁盐晶型A具有如表9所示的X-射线粉末衍射强度。
优选地，所述镁盐晶型A具有基本如图32所示的X射线粉末衍射图。
作为更进一步优选的方案，本发明提供了化合物I-2的葡甲胺盐晶型A，其X-射线粉末衍射图(XRPD)包括位于3.05±0.2°、9.38±0.2°、17.62±0.2°和12.01±0.2°的衍射角(2θ)处的峰。
作为更进一步优选的方案，本发明提供了化合物I-2的葡甲胺盐晶型A，其X-射线粉末衍射图(XRPD)包括位于3.05±0.2°、9.38±0.2°、17.62±0.2°、12.01±0.2°、20.39和14.88±0.2°的衍射角(2θ)处的峰。
优选地，所述的葡甲胺盐晶型A，其X-射线粉末衍射图具有如表10所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：
表10
优选地，所述的葡甲胺盐晶型A具有如表10所示的X-射线粉末衍射强度。
优选地，所述葡甲胺盐晶型A具有基本如图33所示的X射线粉末衍射图。
优选地，所述葡甲胺盐晶型A在约123.07℃的温度处具有吸热峰的DSC热谱图。
优选地，所述葡甲胺盐晶型A具有基本如图34所示的DSC图。
优选地，所述葡甲胺盐晶型A具有基本如图35所示的TGA图。
作为更进一步优选的方案，本发明提供了化合物I-2的氨丁三醇盐晶型A，其X-射线粉末衍射图(XRPD)包括位于3.68±0.2°、7.48±0.2°、17.21±0.2°和19.15±0.2°的衍射角(2θ)处的峰。
作为更进一步优选的方案，本发明提供了化合物I-2的氨丁三醇盐晶型A，其X-射线粉末衍射图(XRPD)包括位于3.68±0.2°、7.48±0.2°、17.21±0.2°、19.15±0.2°、16.73±0.2°和15.74±0.2°的衍射角(2θ)处的峰。
优选地，所述的氨丁三醇盐晶型A，其X-射线粉末衍射图具有如表11所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：
表11
优选地，所述的氨丁三醇盐晶型A具有如表11所示的X-射线粉末衍射强度。
优选地，所述氨丁三醇盐晶型A具有基本如图36所示的X射线粉末衍射图。
优选地，所述氨丁三醇盐晶型A在约167.96℃的温度处具有吸热峰的DSC热谱图。
优选地，所述氨丁三醇盐晶型A具有基本如图37所示的DSC图。
优选地，所述氨丁三醇盐晶型A具有基本如图38所示的TGA图。
本发明第二方面提供一种化合物Ⅰ-1或化合物I-2的药学上可接受的盐的制备方法，所述制备方法包括将化合物Ⅰ-1或化合物I-2与酸或碱在溶剂中反应，制备得到化合物Ⅰ-1或化合物I-2的药学上可接受的盐。
根据本发明的实施方案，所述酸选自无机酸或有机酸，所述无机酸可以选自氢溴酸、盐酸、硫酸、亚硫酸、磷酸、硼酸；所述有机酸可以选自乙酸、草酸、戊酸、苯甲酸、乳酸、甲苯甲酸、柠檬酸、苹果酸、马来酸、富马酸、琥珀酸、酒石酸、甲磺酸、苯磺酸、对甲苯磺酸；
根据本发明的实施方案，所述碱选自无机碱或有机碱，所述无机碱可以选自碱金属氢氧化物或碱土金属的氢氧化物，如氢氧化钠、氢氧化锂、氢氧化钾、氢氧化钙、氢氧化镁；所述有机碱可以选自氨(NH3)、伯胺、仲胺或叔胺，例如四甲基胺盐、四乙基胺盐、甲胺、二甲胺、三甲胺、三乙胺、乙胺、葡甲胺、胆碱、氨丁三醇；
根据本发明的实施方案，所述制备方法中在反应完成后还包括创造过饱合度使产物析出的步骤，所述创造过饱合度的方法包括如下一种或多种：加入晶种、挥发溶剂、加入反溶剂或者通过降温的方法得到化合物I的酸式盐或碱式盐。
根据本发明的实施方案，所述溶剂可以选自醇类、氯代烷烃、酮类、醚类、环醚类、酯类、烷烃类、环烷烃类、苯类、酰胺类、亚砜类、腈类有机溶剂，所述溶剂中两种以上的组合，或上述溶剂或组合分别与水的混合物。
根据本发明的实施方案，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、甲基异丁酮、4-甲基-2-戊酮或其组合；所述腈类可以选自乙腈；所述醇类可以选自具有1-8个碳原子的醇或卤代醇，例如甲醇、乙醇、正丙醇、异丙醇、正丁醇、新戊醇、三氟乙醇或其组合；所述酯类可以选自有机甲酸酯，例如甲酸甲酯、乙酸乙酯、甲酸异丁酯、乙酸乙丙酯或其组合；所述醚类可以为直链或支链烷基醚或环醚类化合物，例如甲基叔丁基醚、四氢呋喃、2-甲基-四氢呋喃或其组合；所述氯类可以选自二氯甲烷、三氯甲烷、1,2-二氯乙烷。
根据本发明的实施方案，所述溶剂选自选自甲醇、乙醇、正丙醇、异丙醇、乙腈、丙酮、甲基异丁酮、1,4-二氧六环、四氢呋喃、N，N-二甲基甲酰胺、乙酸乙酯、乙酸异丙酯、甲基叔丁基醚、2-甲氧基乙醚、乙腈、水或其混合物。
根据本发明的实施方案，所述化合物I-1或I-2与所述酸或碱的摩尔比可以为1:0.8～1:2，优选为1:0.9～1:1.8，更优选为1:1.0～1:1.5。
根据本发明的实施方案，所述制备方法中，反应的温度可以在较宽的范围内选择，例如为20℃～80℃，优选为25℃～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，以制备得到化合物Ⅰ-1或化合物I-2的药学上可接受的盐。
根据本发明的实施方案，所述制备方法中，干燥的温度可以在较宽的范围内选择，例如可以为20℃～80℃，优选为30℃～60℃。
本发明还提供化合物I-1的药学上可接受盐的制备方法：
方法1a，包括：将化合物I-1溶于乙腈，加入浓盐酸、L-酒石酸、马来酸或甲磺酸，室温下搅拌后过滤，烘干，得到化合物I-1的盐酸盐、化合物I-1的酒石酸盐、化合物I-1的马来酸盐或化合物I-1的甲磺酸盐；
方法1b，包括：将化合物I-1和柠檬酸溶于丙酮，室温下搅拌后过滤，烘干，得到化合物I-1的柠檬酸盐；
方法1c，包括：将化合物I-1和氢氧化钠或氢氧化钾溶于乙腈或甲基异丁酮，室温下搅拌后过滤，烘干，得到化合物I-1的钠盐或化合物I-1的钾盐；
方法1d，包括：将化合物I-1和葡甲胺溶于乙腈，室温下搅拌后过滤，烘干，得到化合物I-1的葡甲胺盐；
方法1e，包括：将化合物I-1和氨丁三醇溶于N-甲基吡咯烷酮后，加入到甲苯中，室温下搅拌后过滤，烘干，得到化合物I-1的氨丁三醇盐；优选地，N-甲基吡咯烷酮/甲苯的体积比为2:15。
本发明还提供化合物I-2的药学上可接受盐的制备方法：
方法2a，包括：将化合物I-2和柠檬酸或L-酒石酸溶于丙酮，室温下搅拌后过滤，烘干，得到化合物I-2的柠檬酸盐或化合物I-2的酒石酸盐；
方法2b，包括：将化合物I-2和L-苹果酸或富马酸溶于乙腈/水，室温下搅拌后过滤，烘干，得到化合物I-2的苹果酸盐或化合物I-2的富马酸盐；优选地，乙腈/水的体积比为1:1；
方法2c，包括：将化合物I-2和甲磺酸或马来酸溶于乙酸乙酯，室温下搅拌后过滤，烘干，得到化合物I-2的甲磺酸盐或化合物I-2的马来酸盐；
方法2d，包括：将化合物I-2和氢氧化钠、氢氧化钾、氢氧化钙或氢氧化镁溶于乙腈/水的混合溶剂或乙酸乙酯中，室温下搅拌后过滤，烘干，得到化合物I-2的钠盐、化合物I-2的钾盐、化合物I-2的钙盐、化合物I-2的镁盐；优选地，乙腈/水的体积比为1:1；
方法2e，包括：将化合物I-2和葡甲胺溶于丙酮，室温下搅拌后过滤，烘干，得到化合物I-2的葡甲胺盐；
方法2f，包括：将化合物I-2和氨丁三醇溶于异丙醇，室温下搅拌后过滤，烘干，得到化合物I-2的氨丁三醇盐。
本发明第三方面提供一种药物组合物，包括前述式(I)所示化合物的药学上可接受的盐中的至少一种及可药用的载体。
本发明第四方面提供一种前述式(I)所示化合物的药学上可接受的盐中的至少一种在制备治疗代谢性疾病、肿瘤、自身免疫性疾病或转移性疾病药物中的应用。
本发明第五方面提供一种前述式(I)所示化合物的药学上可接受的盐，其用作治疗代谢性疾病、肿瘤、自身免疫性疾病或转移性疾病的药物。
本发明第六方面提供一种前述式(I)所示化合物的药学上可接受的盐，其用作治疗T1D、T2DM、糖尿病前期、特发性T1D、LADA、EOD、YOAD、MODY、营养不良相关性糖尿病、妊娠糖尿病、高血糖症、胰岛素抗性、肝脏胰岛素抗性、葡萄糖耐受不良、糖尿病神经病变、糖尿病肾病变、肾疾病、糖尿病视网膜病变、脂肪细胞功能障碍、内脏脂肪细胞囤积、睡眠窒息症、肥胖症、进食障碍、使用其它药剂导致的体重增加、过度嗜糖、血脂异常症、高胰岛素血症、NAFLD、NAS、纤维变性、硬化、肝细胞癌、心血管疾病、动脉粥样硬化、冠状动脉疾病、外周血管疾病、高血压、内皮功能障碍、受损的血管顺应性、充血心力衰竭、心肌梗塞、中风、出血性中风、缺血性中风、创伤性脑损伤、肺性高血压、血管成形术后再狭窄、间歇性跛行、餐后脂血症、代谢性酸中毒、酮体症、关节炎、骨质疏松症、帕金森病、左心室肥大、外周动脉疾病、黄斑变性、白内障、肾小球硬化、慢性肾衰竭、代谢综合征、综合征Ⅺ、经前综合征、心绞痛、血栓症、动脉粥样硬化、短暂性脑缺血发作、血管再狭窄、葡萄糖代谢不良、受损的空腹血糖病况、高尿酸血症、痛风、勃起功能障碍、皮肤和结缔组织异常、牛皮癣、足部溃疡、溃疡性结肠炎、高apoB脂蛋白血症、阿尔茨海默病、精神分裂症、认知功能受损、炎性肠病、短肠征、克隆病、结肠炎、肠易激综合征、多囊性卵巢综合征的预防或治疗及成瘾的治疗的药物。
作为优选的方案，前述式(I)所示化合物的药学上可接受的盐，其用作治疗T1D、T2DM、糖尿病前期、特发性T1D、LADA、EOD、YOAD、MODY、营养不良相关性糖尿病、妊娠糖尿病、高血糖症、胰岛素抗性、肝脏胰岛素抗性、葡萄糖耐受不良、糖尿病神经病变、糖尿病肾病变、肥胖症、进食障碍、使用其它药剂导致的体重增加、过度嗜糖、血脂异常症、高胰岛素血症的药物。
本发明还提供一种治疗疾病的方法，包括向有此需要的个体施用治疗有效量的如上所述式(I)所示化合物的药学上可接受的盐或所述药物组合物中的至少一种。
根据本发明的实施方案，所述疾病选自代谢性疾病、肿瘤、自身免疫性疾病或转移性疾病。
根据本发明的实施方案，所述疾病选自T1D、T2DM、糖尿病前期、特发性T1D、LADA、EOD、YOAD、MODY、营养不良相关性糖尿病、妊娠糖尿病、高血糖症、胰岛素抗性、肝脏胰岛素抗性、葡萄糖耐受不良、糖尿病神经病变、糖尿病肾病变、肾疾病、糖尿病视网膜病变、脂肪细胞功能障碍、内脏脂肪细胞囤积、睡眠窒息症、肥胖症、进食障碍、使用其它药剂导致的体重增加、过度嗜糖、血脂异常症、高胰岛素血症、NAFLD、NAS、纤维变性、硬化、肝细胞癌、心血管疾病、动脉粥样硬化、冠状动脉疾病、外周血管疾病、高血压、内皮功能障碍、受损的血管顺应性、充血心力衰竭、心肌梗塞、中风、出血性中风、缺血性中风、创伤性脑损伤、肺性高血压、血管成形术后再狭窄、间歇性跛行、餐后脂血症、代谢性酸中毒、酮体症、关节炎、骨质疏松症、帕金森病、左心室肥大、外周动脉疾病、黄斑变性、白内障、肾小球硬化、慢性肾衰竭、代谢综合征、综合征Ⅺ、经前综合征、心绞痛、血栓症、动脉粥样硬化、短暂性脑缺血发作、血管再狭窄、葡萄糖代谢不良、受损的空腹血糖病况、高尿酸血症、痛风、勃起功能障碍、皮肤和结缔组织异常、牛皮癣、足部溃疡、溃疡性结肠炎、高apoB脂蛋白血症、阿尔茨海默病、精神分裂症、认知功能受损、炎性肠病、短肠征、克隆病、结肠炎、肠易激综合征、多囊性卵巢综合征。
有益效果
本发明的发明人研究了化合物I的多种酸式或碱式盐，该成盐形式大大改善了化合物I的溶解性、吸湿性和化学稳定性等物化性能，所述盐型化合物原料符合工业生产要求，能够满足临床药物制剂开发需要，具有非常重要的临床应用价值，有望加速开发成新一代GLP-1R小分子激动剂。
附图说明
图1显示了本发明的化合物I-1的盐酸盐的X-射线粉末衍射图。横坐标表示2θ值(度)，纵坐标表示峰强度。
图2显示了本发明的化合物I-1的酒石酸盐的X-射线粉末衍射图。横坐标表示2θ值(度)，纵坐标表示峰强 度。
图3显示了本发明的化合物I-1的柠檬酸盐的X-射线粉末衍射图。横坐标表示2θ值(度)，纵坐标表示峰强度。
图4显示了本发明的化合物I-1的柠檬酸盐的DSC图。横坐标表示温度(℃)，纵坐标表示热流(mW)。
图5显示了本发明的化合物I-1的柠檬酸盐的TGA图。横坐标表示温度(℃)，纵坐标表示重量(％)。
图6显示了本发明的化合物I-1的马来酸盐的X-射线粉末衍射图。横坐标表示2θ值(度)，纵坐标表示峰强度。
图7显示了本发明的化合物I-1的甲磺酸盐的X-射线粉末衍射图。横坐标表示2θ值(度)，纵坐标表示峰强度。
图8显示了本发明的化合物I-1的钠盐的X-射线粉末衍射图。横坐标表示2θ值(度)，纵坐标表示峰强度。
图9显示了本发明的化合物I-1的钠盐的DSC图。横坐标表示温度(℃)，纵坐标表示热流(mW)。
图10显示了本发明的化合物I-1的钠的TGA图。横坐标表示温度(℃)，纵坐标表示重量(％)。
图11显示了本发明的化合物I-1的钾盐晶型A的X-射线粉末衍射图。横坐标表示2θ值(度)，纵坐标表示峰强度。
图12显示了本发明的化合物I-1的钾盐晶型B的X-射线粉末衍射图。横坐标表示2θ值(度)，纵坐标表示峰强度。
图13显示了本发明的化合物I-1的葡甲胺盐的X-射线粉末衍射图。横坐标表示2θ值(度)，纵坐标表示峰强度。
图14显示了本发明的化合物I-1的葡甲胺盐的DSC图。横坐标表示温度(℃)，纵坐标表示热流(mW)。
图15显示了本发明的化合物I-1的葡甲胺盐的TGA图。横坐标表示温度(℃)，纵坐标表示重量(％)。
图16显示了本发明的化合物I-1的氨丁三醇盐的X-射线粉末衍射图。横坐标表示2θ值(度)，纵坐标表示峰强度。
图17显示了本发明的化合物I-1的氨丁三醇盐的DSC图。横坐标表示温度(℃)，纵坐标表示热流(mW)。
图18显示了本发明的化合物I-1的氨丁三醇盐的TGA图。横坐标表示温度(℃)，纵坐标表示重量(％)。
图19显示了本发明的化合物I-2的柠檬酸盐的X-射线粉末衍射图。横坐标表示2θ值(度)，纵坐标表示峰强度。
图20显示了本发明的化合物I-2的苹果酸盐的X-射线粉末衍射图。横坐标表示2θ值(度)，纵坐标表示峰强度。
图21显示了本发明的化合物I-2的酒石酸盐的X-射线粉末衍射图。横坐标表示2θ值(度)，纵坐标表示峰强度。
图22显示了本发明的化合物I-2的富马酸盐的X-射线粉末衍射图。横坐标表示2θ值(度)，纵坐标表示峰强度。
图23显示了本发明的化合物I-2的甲磺酸盐的X-射线粉末衍射图。横坐标表示2θ值(度)，纵坐标表示峰强度。
图24显示了本发明的化合物I-2的马来酸盐的X-射线粉末衍射图。横坐标表示2θ值(度)，纵坐标表示峰强度。
图25显示了本发明的化合物I-2的马来酸盐的DSC图。横坐标表示温度(℃)，纵坐标表示热流(mW)。
图26显示了本发明的化合物I-2的马来酸盐的TGA图。横坐标表示温度(℃)，纵坐标表示重量(％)。
图27显示了本发明的化合物I-2的钠盐的X-射线粉末衍射图。横坐标表示2θ值(度)，纵坐标表示峰强度。
图28显示了本发明的化合物I-2的钾盐的X-射线粉末衍射图。横坐标表示2θ值(度)，纵坐标表示峰强度。
图29显示了本发明的化合物I-2的钾盐的DSC图。横坐标表示温度(℃)，纵坐标表示热流(mW)。
图30显示了本发明的化合物I-2的钾盐的TGA图。横坐标表示温度(℃)，纵坐标表示重量(％)。
图31显示了本发明的化合物I-2的钙盐的X-射线粉末衍射图。横坐标表示2θ值(度)，纵坐标表示峰强度。
图32显示了本发明的化合物I-2的镁盐的X-射线粉末衍射图。横坐标表示2θ值(度)，纵坐标表示峰强度。
图33显示了本发明的化合物I-2的葡甲胺盐的X-射线粉末衍射图。横坐标表示2θ值(度)，纵坐标表示峰强度。
图34显示了本发明的化合物I-2的葡甲胺盐的DSC图。横坐标表示温度(℃)，纵坐标表示热流(mW)。
图35显示了本发明的化合物I-2的葡甲胺盐的TGA图。横坐标表示温度(℃)，纵坐标表示重量(％)。
图36显示了本发明的化合物I-2的氨丁三醇盐的X-射线粉末衍射图。横坐标表示2θ值(度)，纵坐标表示峰强度。
图37显示了本发明的化合物I-2的氨丁三醇盐的DSC图。横坐标表示温度(℃)，纵坐标表示热流(mW)。
图38显示了本发明的化合物I-2的氨丁三醇盐的TGA图。横坐标表示温度(℃)，纵坐标表示重量(％)。
图39显示了本发明的的化合物I-1的DVS图。横坐标表示相对湿度(％)，纵坐标表示重量变化(％)。
图40显示了本发明的的化合物I-2的DVS图。横坐标表示相对湿度(％)，纵坐标表示重量变化(％)。
图41显示了本发明的的化合物I-1的氨丁三醇盐的DVS图。横坐标表示相对湿度(％)，纵坐标表示重量变化(％)。
图42显示了本发明的的化合物I-2的氨丁三醇盐的DVS图。横坐标表示相对湿度(％)，纵坐标表示重量变化(％)。
术语定义与说明
除非有相反陈述，下列用在说明书和权利要求书中的术语具有下述含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照普通的含义去理解。当本文出现商品名时,旨在指代其对应的商品或其活性成分。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
本文应用的“盐”是指通过有机酸或碱类药物与可药用无机或有机酸或碱反应制备的化合物。
本发明的中间体化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式,优选的实施方式包括但不限于本发明的实施例。
本发明具体实施方式的化学反应是在合适的溶剂中完成的,所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物,有时需要本领域技术人员在已有实施方式的基础对合成步骤或者反应流程进行修改或选择。
下面会通过实施例具体描述本发明,这些实施例并不意味着对本发明的任何限制。
本发明所使用的所有溶剂是市售的,无需进一步纯化即可使用。
在无特殊说明的情况下，本发明的所有反应均在连续的磁力搅拌下，溶剂为干燥溶剂，温度单位为摄氏度(℃)。
方法和材料
化合物的结构是通过核磁共振(NMR)来确定的。NMR位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用Bruker avance-400MHz核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)或氘代甲醇(MeOD-d4)，内标为四甲基硅烷(TMS)，化学位移是以10-6ppm)作为单位。
HPLC的测定使用Agilent 1260高效液相色谱仪或效能相当的高效液相色谱仪(Sunfire C18 150×4.6m色谱柱或效能相当的色谱柱)。
化合物I的酸式盐或碱式盐的晶型通过X射线粉末衍射图来表征。在具有使用Cu Kα辐射以反射方式操作Bruker D8 Advance粉末衍射仪上采集所述盐的X射线粉末衍射图。该仪器采用Cu Kα照射(40kV，40mA)，于室温下使用SSD160-2探测器进行。扫描范围在2θ区间自3°至40°，扫描速度为0.1s/step。使用DIFFRAC.MEA.CENTER软件，分析衍射图。
XRPD样品的制备，通过是将样品至于单晶硅片上，用玻璃片或等效物压样品粉末以确保样品的表面平坦并有适当的高度。然后将样品支架放入Bruker D8 Advance仪器，并使用上文描述的仪器参数采集X射线粉末衍射图。由包括以下的多种因素产生与这类X射线粉末衍射分析结果相关的测量差异：(a)样品制备物(例如样品高度)中的误差，(b)仪器误差，(c)校准差异，(d)操作人员误差(包括在测定峰位置时出现的那些误差)，和(e)物质的性质(例如优选的定向误差)。校准误差和样品高度误差经常导致所有峰在相同方向中的位移。一般地说，这个校准因子将使测量的峰位置与预期的峰位置一致并且可以在预期的2θ值±0.2°的范围中。
用差示扫描量热法(DSC)表征化合物I的酸式盐或碱式盐的晶型的实验方法为，取少量结晶型化合物I的酸式盐或碱式盐的粉末，置于与仪器配套并可压盖的铝坩埚中，装载样品后用铝盘压盖，压盖后送入仪器检测。本专利中差示扫描量热法所有使用的仪器型号为METTLER TOLEDO DSC 3，扫描参数设置为采用氮气气氛，升温速度为10.0k/min。
用热重分析法(TGA)表征化合物I的酸式盐或碱式盐的晶型的实验方法为，取少量结晶型化合物I的酸式盐或碱式盐的粉末，置于与仪器配套的氧化铝坩埚中，装载样品后，送入仪器检测。本发明中差示扫描量热法所有使用的仪器型号为METTLER TOLEDO TGA 2，扫描参数设置为采用氮气气氛，升温速度为10.0 k/min。
用动态水分吸附法(DVS)表征化合物I的酸式盐或碱式盐的实验方法为，取少量化合物I的酸式盐或碱式盐粉末，置于与仪器配套的精密样品盘中，装载样品后，送入仪器检测。本发明中动态水分吸附法所有使用的仪器型号为Intrinsic PLUS，实验参数设置为设定恒定温度为25℃，单位时间的质量百分比变化率(dm/dt)＝0.02％/min作为达到平衡的判定标准，程序湿度变化循环设置为，初始相对湿度为0％，终点时相对湿度为90％。
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。
实施例1(S)-2-((4-((6-((4-氯-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲甲酸(化合物I-1)的制备
步骤一：(S)-2-((4-((6-((4-氯-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯的合成
将溶有(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(1.5g，5.1mmol)、2-(4-氯-2-氟苯氧基)甲基)-6-(哌啶-4-氧基)吡啶(1.8g，5.5mmol)和碳酸钾(1.8g，13.0mmol)的N,N-二甲基甲酰胺(80mL)混合溶液在60℃下搅拌3小时，然后用水(100mL)淬灭，用乙酸乙酯(50mL×3)萃取。用盐水(50mL×3)洗涤合并的有机层，用无水硫酸钠干燥，过滤并浓缩。通过硅胶柱层析(二氯甲烷/甲醇＝20/1)纯化残余物，得到(S)-2-((4-((6-((4-氯基-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(1.0g，收率：33.5％)。
步骤二：(S)-2-((4-((6-((4-氯-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸的合成
向溶有(S)-2-((4-((6-((4-氯-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(1.0g，1.7mmol)的四氢呋喃/水(20mL/20mL)的混合溶液中添加氢氧化锂(0.13g，5.4mmol)，并在室温下搅拌混合物16小时。用甲酸将所得混合物调节至pH＝5-6，在真空中除去溶剂。残留物通过反相快速柱层析纯化，得到(S)-2-((4-((6-((4-氯-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸(0.69g，收率：70.5％)。1H NMR(400MHz,DMSO-d6):δ8.27(s,1H),7.80(dd,J＝8.4Hz,1.2Hz,1H),7.72(t,J＝7.6Hz,1H),7.64(d,J＝8.4Hz,1H),7.44(dd,J＝11.2Hz,2.0Hz,1H),7.28(t,J＝8.8Hz,1H),7.18(d,J＝8.4Hz,1H),7.04(d,J＝7.2Hz,1H),6.72(d,J＝8.0Hz,1H),5.18(s,2H),5.12-5.06(m,1H),4.95-4.93(m,1H),4.81-4.76(m,1H),4.66-4.62(m,1H),4.51-4.49(m,1H),4.38-4.36(m,1H),3.94(d,J＝13.6Hz,1H),3.78(d,J＝13.6Hz,1H),2.79-2.67(m,2H),2.46-2.41(m,1H),2.32(s,2H),1.92-1.91(m,2H),1.63-1.59(m,2H).
实施例2(S)-2-((4-((6-((4-氰基-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸(化合物I-2)的制备
步骤一：(S)-2-((4-((6-((4-氰基-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯的合成
将溶有(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(1.5g，5.1mmol)、2-(4-氰基-2-氟苯氧基)甲基)-6-(哌啶-4-氧基)吡啶(1.8g，5.5mmol)和碳酸钾(1.8g，13.0mmol)的N,N-二甲基甲酰胺(80mL)混合溶液在60℃下搅拌3小时，然后用水(100mL)淬灭，用乙酸乙酯(50mL×3)萃取。用盐水(50mL×3)洗涤合并的有机层，用无水硫酸钠干燥，过滤并浓缩。通过硅胶柱层析(二氯甲烷/甲醇＝20/1)纯化残余物，得到(S)-2-((4-((6-((4-氰基-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(1.1g，收率：37.2％)。
步骤二：(S)-2-((4-((6-((4-氰基-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸的合成
向溶有(S)-2-((4-((6-((4-氰基-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(1.1g，1.9mmol)的四氢呋喃/水(20mL/20mL)的混合溶液中添加氢氧化锂(0.13g，5.4mmol)，并在室温下搅拌混合物16小时。用甲酸将所得混合物调节至pH＝5-6，在真空中除去溶剂。残留物通过反相快速柱层析纯化，得到(S)-2-((4-((6-((4-氯-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸(0.70g，收率：65.5％)。1HNMR(400MHz,DMSO-d6):δ8.23(s,1H),7.88(dd,J＝2.0Hz,11.6Hz,1H),7.80(dd,J＝1.6,8.8Hz,1H),7.73(t,J＝8.0Hz,1H),7.67(d,J＝8.4Hz,1H),7.60(d,J＝8.8Hz,1H),7.45(t,J＝8.4Hz,1H),7.06(d,J＝7.6Hz,1H),6.74(d,J＝8.4Hz,1H),5.31(s,2H),5.10-5.08(m,1H),4.92-4.90(m,1H),4.80-4.74(m,1H),4.65-4.61(m,1H),4.50-4.47(m,1H),4.40-4.35(m,1H),3.93(d,J＝13.6Hz,1H),3.78(d,J＝13.6Hz,1H),2.79-2.67(m,3H),2.51-2.41(m,1H),2.32-2.27(m,2H),1.92-1.89(m,2H)1.63-1.60(m,2H).
实施例3化合物I-1的盐酸盐的制备
将20mg化合物I-1加入到1mL乙腈中，加入浓盐酸10mg，室温下搅拌1天，过滤，滤饼50℃烘箱烘干，得化合物I-1的盐酸盐，对产物进行XRPD(图1)分析表征。
实施例4化合物I-1的酒石酸盐的制备
将20mg化合物I-1加入到1mL乙腈中，加入L-酒石酸7.7mg，室温下搅拌1天，过滤，滤饼50℃烘箱烘干，得化合物I-1的酒石酸盐，对产物进行XRPD(图2)分析表征。
实施例5化合物I-1的柠檬酸盐的制备
将199.8mg化合物I-1和66.8mg柠檬酸加入到5mL丙酮中，室温下搅拌1天，过滤，滤饼50℃烘箱烘干，得化合物I-1的柠檬酸盐。对产物收集分析数据，包括通过XRPD(图3)、DSC(图4)以及TGA(图5)进行的表征。柠檬酸盐显示在约107.80℃和130.63℃的温度处具有吸热峰的DSC热谱图。1H NMR(400MHz,CD3OD):δ8.33(s,1H),7.98(dd,J＝8.4Hz,1.2Hz,1H),7.71-7.65(m,2H),7.21-7.05(m,4H),6.69(d,J＝8.0Hz,1H),5.25-5.23(1H),5.13(s,3H),4.72-4.62(m,3H),4.48-4.43(m,1H),4.26-4.13(m,2H),3.06-3.01(m,2H),2.89-2.75(m,7H),2.56-2.49(m,1H),2.08-2.06(m,2H),1.89-1.87(m,2H).
实施例6化合物I-1的马来酸盐的制备
将20mg化合物I-1加入到1mL乙腈中，加入5mg马来酸，室温下搅拌1天，过滤，滤饼50℃烘箱烘干，得化合物I-1的马来酸盐，对产物进行XRPD(图6)分析表征。
实施例7化合物I-1的甲磺酸盐的制备
将20mg化合物I-1加入到1mL乙腈中，加入5.0mg甲磺酸，室温下搅拌1天，过滤，滤饼50℃烘箱烘干，得化合物I-1的甲磺酸盐，对产物进行XRPD(图7)分析表征。
实施例8化合物I-1的钠盐的制备
将199.8mg化合物I-1和16.5mg氢氧化钠加入到10mL乙腈中，室温下搅拌3天，过滤，滤饼50℃烘箱烘干，得化合物I-1的钠盐。对产物收集分析数据，包括通过XRPD(图8)、DSC(图9)以及TGA(图10)进行的表征。钠盐显示在约149.11℃和174.11℃的温度处具有吸热峰的DSC热谱图。
实施例9化合物I-1的钾盐的制备
将20mg化合物I-1加入到0.4mL甲基异丁酮中，加入2.3mg氢氧化钾，室温下搅拌3天，过滤，滤饼40℃烘箱烘干，得化合物I-1的钾盐。对产物收集分析数据，对产物进行XRPD(图11)分析表征。
实施例10化合物I-1的钾盐的制备
将20mg化合物I-1加入到0.4mL乙腈中，加入2.3mg氢氧化钾，室温下搅拌16小时，过滤，滤饼40℃烘箱烘干，得化合物I-1的钾盐。对产物收集分析数据，对产物进行XRPD(图12)分析表征。
实施例11化合物I-1的葡甲胺盐的制备
将199.9mg化合物I-1和67.5mg葡甲胺加入到10mL乙腈，室温下搅拌3天，过滤，滤饼40℃烘箱烘干，得化合物I-1的葡甲胺盐。对产物收集分析数据，包括通过XRPD(图13)、DSC(图14)以及TGA(图15)进行的表征。葡甲胺盐显示在约120.06℃的温度处具有吸热峰的DSC热谱图。1H NMR(400MHz,CD3OD):δ8.19(s,1H),7.94(dd,J＝8.4Hz,1.2Hz,1H),7.67-7.57(m,2H),7.20-7.03(m,4H),6.66(d,J＝8.0Hz,1H),5.28-5.26(1H),5.13(s,2H),5.05-5.04(m,1H),4.90-4.86(m,2H),4.73-4.62(m,2H),4.47-4.45(m,1H),4.04-3.64(m,9H),3.14-3.12(m,2H),2.81-2.77(m,3H),2.68(s,3H),2.52-41(m,3H),2.00-1.98(m,2H),1.78-1.76(m,2H).
实施例12化合物I-1的氨丁三醇盐的制备
将200mg化合物I-1和42mg氨丁三醇加入到2.0mL N-甲基吡咯烷酮中，将该溶液滴加到15mL甲苯中，室温搅拌16小时，过滤，滤饼50℃烘箱烘干，得化合物I-1的氨丁三醇盐。对产物收集分析数据，包括通过XRPD(图16)、DSC(图17)以及TGA(图18)进行的表征。氨丁三醇盐显示在约109.95℃和166.02℃的温度处具有吸热峰的DSC热谱图。1H NMR(400MHz,CD3OD):δ8.20(s,1H),7.94(dd,J＝8.4Hz,1.2Hz,1H),7.66-7.57(m,2H),7.21-7.03(m,4H),6.66(d,J＝8.0Hz,1H),5.28-5.25(1H),5.12(s,2H),5.05-5.03(m,1H),4.73-4.62(m,2H),4.47-4.45(m,1H),4.02-3.88(m,2H),3.65(s,6H),3.44(d,J＝7.2Hz,3.5H),2.82-2.77(m,8H),2.51-2.33(m,6.5H),2.07-1.99(m,5.5H),1.77-1.76(m,2H).
实施例13化合物I-2的柠檬酸盐的制备
将20mg化合物I-2和6.7mg柠檬酸加入到0.4mL丙酮中，室温下搅拌1天，过滤，滤饼50℃烘箱烘干，得化合物I-2的柠檬酸盐，对产物进行XRPD(图19)分析表征。
实施例14化合物I-2的苹果酸盐的制备
将20mg化合物I-2和5.6mg L-苹果酸加入到0.4mL乙腈/水(1:1v:v)中，室温下搅拌3天，过滤，滤饼50℃烘箱烘干，得化合物I-2的苹果酸盐，对产物进行XRPD(图20)分析表征。
实施例15化合物I-2的酒石酸盐的制备
将20mg化合物I-2和6.3mg L-酒石酸加入到0.4mL丙酮中，室温下搅拌3天，过滤，滤饼50℃烘箱烘干，得化合物I-2的酒石酸盐，对产物进行XRPD(图21)分析表征。
实施例16化合物I-2的富马酸盐的制备
将20mg化合物I-2和4.9mg富马酸加入到0.4mL乙腈/水(1:1v:v)中，室温下搅拌3天，过滤，滤饼50℃烘箱烘干，得化合物I-2的富马酸盐，对产物进行XRPD(图22)分析表征。
实施例17化合物I-2的甲磺酸盐的制备
将20mg化合物I-2和4.0mg甲磺酸加入到0.4mL乙酸乙酯中，室温下搅拌3天，过滤，滤饼50℃烘箱烘干，得化合物I-2的甲磺酸盐，对产物进行XRPD(图23)分析表征。
实施例18化合物I-2的马来酸盐的制备
将200.1mg化合物I-2和48.6mg马来酸加入到5mL乙酸乙酯中，室温下搅拌3天，过滤，滤饼50℃ 烘箱烘干，得化合物I-2的马来酸盐。对产物收集分析数据，包括通过XRPD(图24)、DSC(图25)以及TGA(图26)进行的表征。马来酸盐显示在约119.30℃的温度处具有吸热峰的DSC热谱图。1HNMR(400MHz,CD3OD):δ8.34(s,1H),8.02(d,J＝2.2,8.6Hz,1H),7.79-7.71(m,2H),7.58-7.50(m,2H),7.33-7.31(m,1H),7.12(d,J＝7.6Hz,1H),6.78(d,J＝8.5Hz,1H),6.26(s,2H),5.28-5.24(m,4H),4.86-4.67(m,5H),4.45-4.42(m,1H),3.52-3.45(m,4H),2.90-2.88(m,1H),2.51-2.49(m,1H),2.25-2.05(m,4H).
实施例19化合物I-2的钠盐的制备
将20mg化合物I-2和2.8mg氢氧化钠加入到0.4mL乙腈/水(1:1v:v)中，室温下搅拌3天，过滤，滤饼50℃烘箱烘干，得化合物I-2的钠盐，对产物进行XRPD(图27)分析表征。
实施例20化合物I-2的钾盐的制备
将199.8mg化合物I-2和23.6mg氢氧化钾加入到5mL乙酸乙酯中，室温下搅拌3天，过滤，滤饼50℃烘箱烘干，得化合物I-2的钾盐。对产物收集分析数据，包括通过XRPD(图28)、DSC(图29)以及TGA(图30)进行的表征。钾盐显示在约118.44℃的温度处具有吸热峰的DSC热谱图。1HNMR(400MHz,CD3OD):δ8.21(s,1H),7.94(d,J＝8.6Hz,1H),7.65(dd,J＝1.6,8.5Hz,1H),7.64-7.55(m,2H),7.51-7.49(m,1H),7.34-7.30(m,1H),7.04(d,J＝7.6Hz,1H),6.68(d,J＝8.5Hz,1H),5.26-5.24(m,3H),5.10-5.08(m,1H),4.90-4.88(m,1H),4.73-4.62(m,2H),4.46-4.44(m,1H),4.02-3.92(m,2H),2.81-2.77(m,3H),2.50-2.40(m,3H),1.92-1.89(m,2H),1.78-1.75(m,2H).
实施例21化合物I-2的钙盐的制备
将20mg化合物I-2和5.2mg氢氧化钙加入到0.4mL乙腈/水(1:1v:v)中，室温下搅拌3天，过滤，滤饼50℃烘箱烘干，得化合物I-2的钙盐，对产物进行XRPD(图31)分析表征。
实施例22化合物I-2的镁盐的制备
将199.8mg化合物I-2和22.4mg氢氧化镁加入到5mL乙腈/水(1:1v:v)中，室温下搅拌3天，过滤，滤饼50℃烘箱烘干，得化合物I-2的镁盐，对产物进行XRPD(图32)分析表征。
实施例23化合物I-2的葡甲胺盐的制备
将200.0mg化合物I-2和82.0mg葡甲胺加入到5mL丙酮中，室温下搅拌3天，过滤，滤饼50℃烘箱烘干，得化合物I-2的葡甲胺盐。对产物收集分析数据，包括通过XRPD(图33)、DSC(图34)以及TGA(图35)进行的表征。葡甲胺盐显示在约123.07℃的温度处具有吸热峰的DSC热谱图。1HNMR(400MHz,CD3OD):δ8.19(s,1H),7.94(dd,J＝2.0Hz,8.6Hz,1H),7.66(dd,J＝1.6,8.5Hz,1H),7.64-7.55(m,2H),7.51-7.49(m,1H),7.32(t,J＝8.5Hz,1H),7.04(d,J＝7.6Hz,1H),6.68(d,J＝8.5Hz,1H),5.27-5.24(m,3H),5.10-5.08(m,1H),4.90-4.85(m,1H),4.72-4.62(m,2H),4.47-4.45(m,1H),4.03-4.01(m,2H),3.98-3.92(m,1H),3.89-3.81(m,2H),3.79-3.62(m,3H),3.13-3.11(m,2H),2.80-2.77(m,3H),2.68(s,3H),2.51-2.40(m,3H),2.00-1.98(m,2H),1.78-1.76(m,2H).
实施例24化合物I-2的氨丁三醇盐的制备
将20mg化合物I-2和4.2mg氨丁三醇加入到0.5mL异丙醇中，室温下搅拌3天，过滤，滤饼50℃烘箱烘干，得化合物I-2的氨丁三醇盐。对产物收集分析数据，包括通过XRPD(图36)、DSC(图37)以及TGA(图38)进行的表征。氨丁三醇盐显示在约167.96℃的温度处具有吸热峰的DSC热谱图。1HNMR(400MHz,CD3OD):δ8.20(s,1H),7.94(dd,J＝2.0Hz,8.6Hz,1H),7.66(dd,J＝1.6,8.5Hz,1H),7.64-7.54(m,2H),7.51-7.50(m,1H),7.32(t,J＝8.5Hz,1H),7.04(d,J＝7.6Hz,1H),6.68(d,J＝8.5Hz,1H),5.27-5.24(m,3H),5.10-5.08(m,1H),4.90-4.88(m,1H),4.73-4.62(m,2H),4.47-4.45(m,1H),4.00(d,J＝13.5Hz,1H),3.90(d,J＝13.5Hz,1H),3.65(s,6H),2.81-2.77(m,3H),2.51-2.41(m,3H),1.91-1.89(m,2H),1.79-1.76(m,2H).
实施例25化合物盐型在水中的溶解度研究
对游离态化合物I-1和化合物I-2以及相应的代表性氨丁三醇盐测试其在水(H2O)中的平衡溶解度。试验中，将固体在对应缓冲液中配置成悬浮液(～10mg/mL)，并在37±2℃下搅拌。24小时后对悬浮液进行取样，上清液过滤测定浓度，检测结果如下表所示：

从上述实验结果可以看出，相较于游离态，大部分本发明的化合物I-1的代表性盐型如氨丁三醇盐、钠盐、钾盐和葡甲胺盐等在水(H2O)中的溶解度显著提高，提高倍数在几倍到几十倍。
实施例26化合物氨丁三醇盐在其它介质中的溶解度研究
对游离态化合物I-1和化合物I-2以及相应的代表性氨丁三醇盐测试其在模拟空腹胃液(FaSSGF)、模拟空腹肠液(FaSSIF)和模拟饱腹肠液(FeSSIF)中的平衡溶解度。试验中，将固体在对应缓冲液中配置成悬浮液(～10mg/mL)，并在37±2℃下搅拌。24小时后对悬浮液进行取样，上清液过滤测定浓度，检测结果如下表所示：
从上述实验结果可以看出，相较于游离态，化合物I-1和化合物I-2的代表性氨丁三醇盐在模拟空腹胃液(FaSSGF)、模拟空腹肠液(FaSSIF)或模拟饱腹肠液(FeSSIF)中的溶解度明显优于游离态化合物。
实施例27吸湿行为测试
化合物的吸湿行为影响着药物的生产、储存、稳定性和质量。发明人按照动态水分吸附法，评估25℃下样品随湿度变化的稳定性风险，对化合物I-1和I-2代表盐型氨丁三醇盐进行DVS测试，评价化合物盐型的吸湿性，游离态化合物I-1的DVS图谱如图39所示，游离态化合物I-2的DVS图谱如图40所示，化合物I-1的氨丁三醇盐的DVS图谱如图41所示，化合物I-2的氨丁三醇盐的DVS图谱如图42所示，所得结果如下表：
从上述实验结果意外发现：相较于碱基，尽管成盐后溶解度有显著增加，但引湿性并没有显著变化。在0-90％RH的吸附曲线上，在80％RH条件下，游离态化合物I-1、I-2和化合物I-1、I-2的氨丁三醇盐都仅略有引湿性，无明显差异，均未观察到固体形态变化。
本发明化合物的部分盐型的热分析汇总如下表：

以上对本发明技术方案的实施方式进行了示例性的说明。应当理解，本发明的保护范围不拘囿于上述实施方式。凡在本发明的精神和原则之内，本领域技术人员所做的任何修改、等同替换、改进等，均应包含在本申请权利要求书的保护范围之内。

Claims (16)

  1. 一种式(I)所示化合物的药学上可接受的盐；
    其中，R选自卤素或CN；
    所述药学上可接受的盐是指在药学上无毒的酸加成盐或碱加成盐；
    优选地，所述酸加成盐为式(I)所示化合物与无机酸或有机酸形成的盐，包括氢溴酸盐、盐酸盐、硫酸盐、硫酸氢盐、亚硫酸盐、磷酸盐、硼酸盐、乙酸盐、草酸盐、戊酸盐、苯甲酸盐、乳酸盐、甲苯甲酸盐、柠檬酸盐、苹果酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐；更加优选的酸加成盐为盐酸盐、乙酸盐、柠檬酸盐、苹果酸盐、琥珀酸盐、酒石酸盐、富马酸盐、马来酸盐、甲磺酸盐；特别是柠檬酸盐和马来酸盐；
    优选地，所述碱加成盐为式(I)所示化合物与无机碱或有机碱形成的盐，包括例如与碱金属形成的盐，如钠盐、锂盐、钾盐、钙盐、镁盐等；胺盐，包括与氨(NH3)、伯胺、仲胺或叔胺形成的盐，如：四甲基胺盐、四乙基胺盐、甲胺盐、二甲胺盐、三甲胺盐、三乙胺盐、乙胺盐、葡甲胺盐、胆碱盐、氨丁三醇盐；更加优选的碱加成盐为钠盐、钾盐、钙盐、镁盐、葡甲胺盐、胆碱盐、氨丁三醇盐；特别是钠盐、钾盐、镁盐、葡甲胺盐和氨丁三醇盐；
    优选地，式(I)所示化合物选自如下化合物I-1或化合物I-2：
    优选地，所述化合物I-1的酸加成盐为盐酸盐、酒石酸盐、马来酸盐、甲磺酸盐、或柠檬酸盐；所述化合物I-2的酸加成盐为柠檬酸盐、酒石酸盐、苹果酸盐(如L-苹果酸盐)、富马酸盐、甲磺酸盐或马来酸盐；
    优选地，所述化合物I-1的碱加成盐为钠盐、钾盐、葡甲胺盐或氨丁三醇盐；所述化合物I-2的碱加成盐为钠盐、钾盐、钙盐、镁盐、葡甲胺盐或氨丁三醇盐。
  2. 权利要求1所述化合物I-1的柠檬酸盐晶型A，其X-射线粉末衍射图(XRPD)包括位于19.77±0.2°、16.59±0.2°、22.47±0.2°和20.20±0.2°的衍射角(2θ)处的峰；
    优选地，其X-射线粉末衍射图(XRPD)包括位于16.59±0.2°、19.77±0.2°、22.47±0.2°、20.20±0.2°、24.84±0.2°和17.51±0.2°的衍射角(2θ)处的峰；
    优选地，所述的柠檬酸盐晶型A，其X-射线粉末衍射图具有如表1所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：
    表1

    优选地，所述的柠檬酸盐晶型A具有如表1所示的X-射线粉末衍射强度；
    优选地，所述柠檬酸盐晶型A具有基本如图3所示的X射线粉末衍射图；
    优选地，所述柠檬酸盐晶型A在约107.80℃和130.63℃的温度处具有吸热峰的DSC热谱图；
    优选地，所述柠檬酸盐晶型A具有基本如图4所示的DSC图；
    优选地，所述柠檬酸盐晶型A具有基本如图5所示的TGA图。
  3. 权利要求1所述化合物I-1的钠盐晶型A，其X-射线粉末衍射图(XRPD)包括位于19.24±0.2°、20.68±0.2°、6.81±0.2°和14.43±0.2°的衍射角(2θ)处的峰；
    优选地，其X-射线粉末衍射图(XRPD)包括位于19.24±0.2°、20.68±0.2°、6.81±0.2°、14.43±0.2°、14.98±0.2°和6.40±0.2°的衍射角(2θ)处的峰。
    优选地，所述的钠盐晶型A，其X-射线粉末衍射图具有如表2所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：
    表2
    优选地，所述的钠盐晶型A具有如表2所示的X-射线粉末衍射强度；
    优选地，所述钠盐晶型A具有基本如图8所示的X射线粉末衍射图；
    优选地，所述钠盐晶型A在约149.11℃和174.11℃的温度处具有吸热峰的DSC热谱图；
    优选地，所述钠盐晶型A具有基本如图9所示的DSC图；
    优选地，所述钠盐晶型A具有基本如图10所示的TGA图。
  4. 权利要求1所述化合物I-1的钾盐晶型A，其X-射线粉末衍射图(XRPD)包括位于13.90±0.2°、14.43±0.2°、16.20±0.2°、和11.67±0.2°的衍射角(2θ)处的峰；
    优选地，其X-射线粉末衍射图(XRPD)包括位于13.90±0.2°、14.43±0.2°、16.20±0.2°、11.67±0.2°、20.99±0.2°和16.79±0.2°的衍射角(2θ)处的峰；
    优选地，所述的钾盐晶型A，其X-射线粉末衍射图具有如表3所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：
    表3
    优选地，所述的钾盐晶型A具有如表3所示的X-射线粉末衍射强度；
    优选地，所述钾盐晶型A具有基本如图11所示的X射线粉末衍射图。
  5. 权利要求1所述化合物I-1的钾盐晶型B，其X-射线粉末衍射图(XRPD)包括位于5.92±0.2°、14.10±0.2°、 17.62±0.2°、和17.94±0.2°的衍射角(2θ)处的峰；
    优选地，其X-射线粉末衍射图(XRPD)包括位于5.92±0.2°、14.10±0.2°、17.62±0.2°、17.94±0.2°、11.92±0.2°和7.01±0.2°的衍射角(2θ)处的峰；
    优选地，所述的钾盐晶型B，其X-射线粉末衍射图具有如表4所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：
    表4
    优选地，所述的钾盐晶型B具有如表4所示的X-射线粉末衍射强度；
    优选地，所述钾盐晶型B具有基本如图12所示的X射线粉末衍射图。
  6. 权利要求1所述化合物I-1的葡甲胺盐晶型A，其X-射线粉末衍射图(XRPD)包括位于18.15±0.2°、12.87±0.2°、22.87±0.2°和24.66±0.2°的衍射角(2θ)处的峰；
    优选地，其X-射线粉末衍射图(XRPD)包括位于18.15±0.2°、12.87±0.2°、22.87±0.2°、24.66±0.2°、23.21±0.2°和19.57±0.2°的衍射角(2θ)处的峰；
    优选地，所述的葡甲胺盐晶型A，其X-射线粉末衍射图具有如表5所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：
    表5
    优选地，所述的葡甲胺盐晶型A具有如表5所示的X-射线粉末衍射强度；
    优选地，所述葡甲胺盐晶型A具有基本如图13所示的X射线粉末衍射图；
    优选地，葡甲胺盐晶型A在约120.06℃的温度处具有吸热峰的DSC热谱图；
    优选地，所述葡甲胺盐晶型A具有基本如图14所示的DSC图；
    优选地，所述葡甲胺盐晶型A具有基本如图15所示的TGA图。
  7. 权利要求1所述化合物I-1的氨丁三醇盐晶型A，其X-射线粉末衍射图(XRPD)包括位于3.50±0.2°、6.97±0.2°、13.91±0.2°和22.19±0.2°的衍射角(2θ)处的峰；
    优选地，，其X-射线粉末衍射图(XRPD)包括位于3.50±0.2°、6.97±0.2°、13.91±0.2°、22.19±0.2°、31.61±0.2°、18.11±0.2°和20.55±0.2°的衍射角(2θ)处的峰；
    优选地，所述的氨丁三醇盐晶型A，其X射线粉末衍射数据如下表6所示：
    表6

    优选地，所述的氨丁三醇盐晶型A具有如表6所示的X-射线粉末衍射强度；
    优选地，所述氨丁三醇盐晶型A具有基本如图16所示的X射线粉末衍射图；
    优选地，所述氨丁三醇盐晶型A在约109.95℃和166.02℃的温度处具有吸热峰的DSC热谱图；
    优选地，所述氨丁三醇盐晶型A具有基本如图17所示的DSC图；
    优选地，所述氨丁三醇盐晶型A具有基本如图18所示的TGA图；
    优选地，所述氨丁三醇盐晶型A为N-甲基吡咯烷酮溶剂合物。
  8. 权利要求1所述化合物I-2的马来酸盐晶型A，其X-射线粉末衍射图(XRPD)包括位于5.43±0.2°、9.89±0.2°、12.76±0.2°、8.30±0.2°的衍射角(2θ)处的峰；
    优选地，其X-射线粉末衍射图(XRPD)包括位于5.43±0.2°、9.89±0.2°、12.76±0.2°、8.30±0.2°、21.31±0.2°和14.24±0.2°的衍射角(2θ)处的峰；
    优选地，所述的马来酸盐晶型A，其X-射线粉末衍射图具有如表7所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：
    表7
    优选地，所述的马来酸盐晶型A具有如表7所示的X-射线粉末衍射强度；
    优选地，所述马来酸盐晶型A具有基本如图24所示的X射线粉末衍射图；
    优选地，所述马来酸盐晶型A该晶型在约119.30℃的温度处具有吸热峰的DSC热谱图；
    优选地，所述马来酸盐晶型A具有基本如图25所示的DSC图；
    优选地，所述马来酸盐晶型A具有基本如图26所示的TGA图。
  9. 权利要求1所述化合物I-2的钾盐晶型A，其X-射线粉末衍射图(XRPD)包括位于11.51±0.2°、15.42±0.2°、20.20±0.2°和9.52±0.2°的衍射角(2θ)处的峰；
    优选地，其X-射线粉末衍射图(XRPD)包括位于11.51±0.2°、15.42±0.2°、20.20±0.2°、9.52±0.2°、5.06±0.2°和25.38±0.2°的衍射角(2θ)处的峰；
    优选地，所述的钾盐晶型A，其X-射线粉末衍射图具有如表8所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：
    表8
    优选地，所述的马来酸盐晶型A具有如表8所示的X-射线粉末衍射强度；
    优选地，所述钾盐晶型A具有基本如图28所示的X射线粉末衍射图；
    优选地，所述钾盐晶型A在约118.44℃的温度处具有吸热峰的DSC热谱图；
    优选地，所述钾盐晶型A具有基本如图29所示的DSC图；
    优选地，所述钾盐晶型A具有基本如图30所示的TGA图。
  10. 权利要求1所述化合物I-2的镁盐晶型A，其X-射线粉末衍射图(XRPD)包括位于13.92±0.2°、13.46±0.2°、14.74±0.2°和20.43±0.2°；
    优选地，其X-射线粉末衍射图(XRPD)包括位于13.92±0.2°、13.46±0.2°、14.74±0.2°、20.43±0.2°、20.16±0.2°和17.21±0.2°的衍射角(2θ)处的峰；
    优选地，所述的镁盐晶型A，其X-射线粉末衍射图具有如表9所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：
    表9
    优选地，所述的镁盐晶型A具有如表9所示的X-射线粉末衍射强度；
    优选地，所述镁盐晶型A具有基本如图32所示的X射线粉末衍射图。
  11. 权利要求1所述化合物I-2的葡甲胺盐晶型A，其X-射线粉末衍射图(XRPD)包括位于3.05±0.2°、9.38±0.2°、17.62±0.2°和12.01±0.2°的衍射角(2θ)处的峰；
    优选地，其X-射线粉末衍射图(XRPD)包括位于3.05±0.2°、9.38±0.2°、17.62±0.2°、12.01±0.2°、20.39和14.88±0.2°的衍射角(2θ)处的峰；
    优选地，所述的葡甲胺盐晶型A，其X-射线粉末衍射图具有如表10所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：
    表10
    优选地，所述的葡甲胺盐晶型A具有如表10所示的X-射线粉末衍射强度；
    优选地，所述葡甲胺盐晶型A具有基本如图33所示的X射线粉末衍射图；
    优选地，所述葡甲胺盐晶型A在约123.07℃的温度处具有吸热峰的DSC热谱图；
    优选地，所述葡甲胺盐晶型A具有基本如图34所示的DSC图；
    优选地，所述葡甲胺盐晶型A具有基本如图35所示的TGA图。
  12. 权利要求1所述化合物I-2的氨丁三醇盐晶型A，其X-射线粉末衍射图(XRPD)包括四个或四个以上位于3.68±0.2°、7.48±0.2°、17.21±0.2°和19.15±0.2°的衍射角(2θ)处的峰；
    优选地，其X-射线粉末衍射图(XRPD)包括位于3.68±0.2°、7.48±0.2°、17.21±0.2°、19.15±0.2°、16.73±0.2°和15.74±0.2°的衍射角(2θ)处的峰；
    优选地，所述的氨丁三醇盐晶型A，其X-射线粉末衍射图具有如表11所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：
    表11
    优选地，所述的氨丁三醇盐晶型A具有如表11所示的X-射线粉末衍射强度；
    优选地，所述氨丁三醇盐晶型A具有基本如图36所示的X射线粉末衍射图；
    优选地，所述氨丁三醇盐晶型A在约167.96℃的温度处具有吸热峰的DSC热谱图；
    优选地，所述氨丁三醇盐晶型A具有基本如图37所示的DSC图；
    优选地，所述氨丁三醇盐晶型A具有基本如图38所示的TGA图。
  13. 权利要求1-12任一项所述化合物Ⅰ-1或化合物I-2的药学上可接受的盐、晶型A的制备方法，包括将化合物Ⅰ-1或化合物I-2与酸或碱在溶剂中反应，制备得到化合物Ⅰ-1或化合物I-2的药学上可接受的盐；
    优选地，所述酸选自无机酸或有机酸，所述无机酸可以选自氢溴酸、盐酸、硫酸、亚硫酸、磷酸、硼酸；所述有机酸可以选自乙酸、草酸、戊酸、苯甲酸、乳酸、甲苯甲酸、柠檬酸、苹果酸、马来酸、富马酸、琥珀酸、酒石酸、甲磺酸、苯磺酸、对甲苯磺酸；
    优选地，所述碱选自无机碱或有机碱，所述无机碱可以选自碱金属氢氧化物或碱土金属的氢氧化物，如氢氧化钠、氢氧化锂、氢氧化钾、氢氧化钙、氢氧化镁；所述有机碱可以选自氨、伯胺、仲胺或叔胺，例如四甲基胺盐、四乙基胺盐、甲胺、二甲胺、三甲胺、三乙胺、乙胺、葡甲胺、胆碱、氨丁三醇；
    优选地，所述化合物I-1或I-2与所述酸或碱的摩尔比可以为1:0.8～1:2，优选为1:0.9～1:1.8。
  14. 根据权利要求13所述的制备方法，其特征在于，化合物I-1的药学上可接受盐的制备方法包括以下方法1a-1e：
    方法1a，包括：将化合物I-1溶于乙腈，加入浓盐酸、L-酒石酸、马来酸或甲磺酸，室温下搅拌后过滤，烘干，得到化合物I-1的盐酸盐、化合物I-1的酒石酸盐、化合物I-1的马来酸盐或化合物I-1的甲磺酸盐；
    方法1b，包括：将化合物I-1和柠檬酸溶于丙酮，室温下搅拌后过滤，烘干，得到化合物I-1的柠檬酸盐；
    方法1c，包括：将化合物I-1和氢氧化钠或氢氧化钾溶于乙腈或甲基异丁酮，室温下搅拌后过滤，烘干，得到化合物I-1的钠盐或化合物I-1的钾盐；
    方法1d，包括：将化合物I-1和葡甲胺溶于乙腈，室温下搅拌后过滤，烘干，得到化合物I-1的葡甲胺盐；
    方法1e，包括：将化合物I-1和氨丁三醇溶于N-甲基吡咯烷酮后，加入到甲苯中，室温下搅拌后过滤，烘干，得到化合物I-1的氨丁三醇盐；优选地，N-甲基吡咯烷酮/甲苯的体积比为2:15；
    化合物I-2的药学上可接受盐的制备方法包括以下方法2a-2f：
    方法2a，包括：将化合物I-2和柠檬酸或L-酒石酸溶于丙酮，室温下搅拌后过滤，烘干，得到化合物I-2的柠檬酸盐或化合物I-2的酒石酸盐；
    方法2b，包括：将化合物I-2和L-苹果酸或富马酸溶于乙腈/水，室温下搅拌后过滤，烘干，得到化合物I-2的苹果酸盐或化合物I-2的富马酸盐；优选地，乙腈/水的体积比为1:1；
    方法2c，包括：将化合物I-2和甲磺酸或马来酸溶于乙酸乙酯，室温下搅拌后过滤，烘干，得到化合物I-2的甲磺酸盐或化合物I-2的马来酸盐；
    方法2d，包括：将化合物I-2和氢氧化钠、氢氧化钾、氢氧化钙或氢氧化镁溶于乙腈/水的混合溶剂或乙酸乙酯中，室温下搅拌后过滤，烘干，得到化合物I-2的钠盐、化合物I-2的钾盐、化合物I-2的钙盐、化合物I-2的镁盐；优选地，乙腈/水的体积比为1:1；
    方法2e，包括：将化合物I-2和葡甲胺溶于丙酮，室温下搅拌后过滤，烘干，得到化合物I-2的葡甲胺盐；
    方法2f，包括：将化合物I-2和氨丁三醇溶于异丙醇，室温下搅拌后过滤，烘干，得到化合物I-2的氨丁三醇盐。
  15. 一种药物组合物，包括权利要求1-12任一项所述式(I)所示化合物的药学上可接受的盐、晶型A中的至少一种及可药用的载体。
  16. 权利要求1-12任一项所述式(I)所示化合物的药学上可接受的盐、晶型A中的至少一种在制备治疗代谢性疾病、肿瘤、自身免疫性疾病或转移性疾病药物中的应用；
    优选地，所述疾病选自T1D、T2DM、糖尿病前期、特发性T1D、LADA、EOD、YOAD、MODY、营养不良相关性糖尿病、妊娠糖尿病、高血糖症、胰岛素抗性、肝脏胰岛素抗性、葡萄糖耐受不良、糖尿病神经病变、糖尿病肾病变、肾疾病、糖尿病视网膜病变、脂肪细胞功能障碍、内脏脂肪细胞囤积、睡眠窒息症、肥胖症、进食障碍、使用其它药剂导致的体重增加、过度嗜糖、血脂异常症、高胰岛素血症、NAFLD、NAS、纤维变性、硬化、肝细胞癌、心血管疾病、动脉粥样硬化、冠状动脉疾病、外周血管疾病、高血压、内皮功能障碍、受损的血管顺应性、充血心力衰竭、心肌梗塞、中风、出血性中风、缺血性中风、创伤性脑损伤、肺性高血压、血管成形术后再狭窄、间歇性跛行、餐后脂血症、代谢性酸中毒、酮体症、关节炎、骨质疏松症、帕金森病、左心室肥大、外周动脉疾病、黄斑变性、白内障、肾小球硬化、慢性肾衰竭、代谢综合征、综合征Ⅺ、经前综合征、心绞痛、血栓症、动脉粥样硬化、短暂性脑缺血发作、血管再狭窄、葡萄糖代谢不良、受损的空腹血糖病况、高尿酸血症、痛风、勃起功能障碍、皮肤和结缔组织异常、牛皮癣、足部溃疡、溃疡性结肠炎、高apoB脂蛋白血症、阿尔茨海默病、精神分裂症、认知功能受损、炎性肠病、短肠征、克隆病、结肠炎、肠易激综合征、多囊性卵巢综合征的预防或治疗及成瘾的治疗的药物。
PCT/CN2023/106237 2022-07-07 2023-07-07 Glp-1r激动剂的盐及其制备方法和应用 Ceased WO2024008174A1 (zh)

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