Salt forms of benzoheterocyclic-substituted tetrahydroisoquinoline compounds and methods for producing the same

Abstract

The present invention discloses a salt form of a benzheterocyclic-substituted tetrahydroisoquinoline compound and a method for producing the same. Specifically, the present invention discloses an amorphous and a salt form of the compound represented by formula (I), and use for inhibiting NHE-mediated reverse transport of sodium ions or hydrogen ions. 【Chemical 1】 JPEG2025522524000027.jpg40169 。

Description

[Technical Field]

[0001] This application claims the following priority:

[0002] 1)CN202210701699.9,2022.06.20.

[0003] This invention belongs to the field of drug chemistry, and more specifically, it relates to salt forms of benzoheterocyclic-substituted tetrahydroisoquinoline compounds and methods for producing the same. [Background technology]

[0004] Phosphates are essential minerals that regulate various metabolic processes, including signal transduction, energy production, and mineral metabolism. They are primarily absorbed in the small intestine, filtered by the kidneys, and then reabsorbed or excreted in the renal tubules. Consequently, serum phosphate concentrations remain within the physiological range despite differences in daily phosphate intake. Patients with end-stage chronic kidney disease (CKD) essentially lose renal metabolic phosphate function, leading to hyperphosphatemia. Studies have suggested that hyperphosphatemia is associated with multiple adverse clinical outcomes in CKD patients, including induction of vascular calcification, increased incidence and mortality risk of cardiovascular disease, secondary hyperparathyroidism, metabolic bone disease due to renal osteodystrophy, ectopic calcification, renal failure, and accelerated progression of cardiovascular disease.

[0005] Currently, the main treatment measures for hyperphosphatemia are low-phosphate diet, hemodialysis, and administration of phosphate binders with meals. Clinical experience shows that controlling phosphate intake through diet is relatively difficult and the efficiency of hemodialysis is limited, so the use of phosphate binders is currently an important treatment method for lowering blood phosphorus. Currently, there are mainly two types of phosphate binders commonly used in clinical practice: phosphate binders containing metal ions (calcium / magnesium / iron / lanthanum) and ion-exchange resin binders (sevelamer or sevelamer carbonate). The former are phosphate binders containing metal ions, requiring patients to carefully manage the metal ions in the drug, and the drug's phosphorus-binding effect is relatively weak due to the influence of pH, making it prone to causing diarrhea, which patients cannot tolerate. The latter binds to phosphorus through ion exchange, is not absorbed into the gastrointestinal tract, reduces accumulation, and has fewer side effects than the former. However, both require large doses, are expensive, and have poor patient compliance.

[0006] Currently, two main methods of phosphate absorption in the intestinal tract are known: passive cell bypass transport and active transport by transporters. Passive cell bypass phosphate transport is considered the primary cause of phosphate absorption in the human body. Cell bypass phosphate transport is mainly driven by phosphate concentration gradients and absorbed by close complexes formed between cells. Literature has shown that such close complexes are regulated by signal transduction and have osmotic specificity for specific ions. Sodium-hydrogen antiporter 3 (NHE3 / SLC9A3) is a gastrointestinal transporter expressed at the tips of intestinal epithelial cells. It primarily plays a role in maintaining sodium ion balance and affects sodium absorption in the intestinal tract by inhibiting NHE3 activity. This alters the hydrogen ion concentration in intestinal epithelial cells and can further influence local pH changes, reducing the permeability of the close complexes formed between cells to phosphate and decreasing phosphate absorption via cell bypass. In clinical practice, the need for controlling blood phosphorus levels in patients with end-stage CKD remains unmet, and further development of blood phosphorus-lowering drugs with different mechanisms of action is necessary.

[0007] In the application with application number PCT / CN2021 / 139314 (filing date December 17, 2021), a compound having the following structure that inhibits the reverse transport of NHE-mediated sodium ions or hydrogen ions is provided.

[0008] [ka]

[0009] . [Overview of the project]

[0010] In one embodiment of the present invention, the present invention discloses an amorphous form of the compound represented by formula (I).

[0011] [ka]

[0012] 。

[0013] In some embodiments of the present invention, the amorphous material basically has the XPRD pattern shown in FIG. 1.

[0014] In another aspect of the present invention, the present invention further provides a 1,5-naphthalenedisulfonate of a compound represented by formula (I), which has the following structure.

[0015]

Chemical formula

[0016] , where n = 0.9 - 2.0.

[0017] In another aspect of the present invention, the present invention further provides an amorphous 1,5-naphthalenedisulfonate of a compound represented by formula (I), wherein the molar ratio of the compound represented by formula (I) to 1,5-naphthalenedisulfonic acid is 1.0:(0.9 - 2.0).

[0018] In some embodiments of the present invention, the molar ratio of the compound represented by formula (I) to 1,5-naphthalenedisulfonic acid is 1.0:0.9, 1.0:1.0, 1.0:1.2, 1.0:1.5, 1.0:1.8 or 1.0:2.0.

[0019] In some embodiments of the present invention, the amorphous 1,5-naphthalenedisulfonate basically has the XPRD pattern shown in FIG. 2 or FIG. 4 or FIG. 7.

[0020] In some embodiments of the present invention, the amorphous 1,5-naphthalenedisulfonate basically has the TGA / mDSC shown in FIG. 5 or FIG. 8.

[0021] In some embodiments of the present invention, the amorphous form of the above 1,5-naphthalenedisulfonate basically has the 1 1H NMR spectrum shown in FIG. 6 or FIG. 9 or FIG. 10.

[0022] In another aspect of the present invention, the present invention further provides a method for producing a 1,5-naphthalenedisulfonate of a compound represented by formula (I). The above method includes the reaction shown below.

[0023] [Chemical formula]

[0024] Among them, n = 0.9 to 2.0, and the reaction solvent is selected from isopropanol, ethyl acetate or a mixture of isopropanol and ethyl acetate.

[0025] In some embodiments of the present invention, the above method may include at least one of the following additional technical features.

[0026] In some embodiments of the present invention, n is selected from 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 and 2.0.

[0027] In some embodiments of the present invention, the input molar ratio of the compound represented by the above formula (I) to the above 1,5-naphthalenedisulfonic acid is 1:(1 to 4).

[0028] In some embodiments of the present invention, the input molar ratio of the compound represented by the above formula (I) to the above 1,5-naphthalenedisulfonic acid is 1:1.0 or 1:1.2 or 1:1.5 or 1:1.8 or 1:2.0 or 1:2.2 or 1:2.5 or 1:2.8 or 1:3.0 or 1:3.2 or 1:3.5 or 1:3.8 or 1:4.0.

[0029] In some embodiments of the present invention, the dose ratio of the compound represented by formula (I) to isopropanol is (5-15) mmol:(50-150) mL.

[0030] In some embodiments of the present invention, the dose ratio of the compound represented by formula (I) to isopropanol is 5 mmoL:50 mL, or 6 mmoL:100 mL, or 7 mmoL:100 mL, or 8 mmoL:100 mL, or 9 mmoL:100 mL, or 9.3 mmoL:100 mL, or 10 mmoL:100 mL, or 11 mmoL:100 mL, or 12 mmoL:100 mL, or 13 mmoL:100 mL, or 14 mmoL:150 mL, or 15 mmoL:150 mL.

[0031] In some embodiments of the present invention, the dose ratio of the compound represented by formula (I) to ethyl acetate is (5-15) mmol:(50-150) mL.

[0032] In some embodiments of the present invention, the dose ratio of the compound represented by formula (I) to ethyl acetate is 5 mmoL:50 mL, 6 mmoL:100 mL, 7 mmoL:100 mL, 8 mmoL:100 mL, 9 mmoL:100 mL, 9.3 mmoL:100 mL, 10 mmoL:100 mL, 11 mmoL:100 mL, 12 mmoL:100 mL, 13 mmoL:100 mL, 14 mmoL:150 mL, or 15 mmoL:150 mL.

[0033] In some embodiments of the present invention, the method further includes stirring, suction filtration, and drying after the above reaction.

[0034] In some embodiments of the present invention, the stirring process is carried out at room temperature.

[0035] In some embodiments of the present invention, the stirring treatment is carried out at room temperature for two days.

[0036] In some embodiments of the present invention, the suction filtration process is performed with nitrogen gas protection.

[0037] In some embodiments of the present invention, the drying process is carried out for 2 hours under vacuum conditions at room temperature.

[0038] In another embodiment of the present invention, the present invention further proposes a method for producing amorphous 1,5-naphthalenedisulfonate of a compound represented by formula (I), comprising stirring, suction filtration and drying of the compound represented by formula (I) and 1,5-naphthalenedisulfonic acid in isopropanol or ethyl acetate to obtain amorphous 1,5-naphthalenedisulfonate of the compound represented by formula (I).

[0039] In some embodiments of the present invention, the above method may include at least one of the following additional technical features.

[0040] In some embodiments of the present invention, the molar ratio of the compound represented by formula (I) to the 1,5-naphthalenedisulfonic acid is 1:(1~4).

[0041] In some embodiments of the present invention, the molar ratio of the compound represented by formula (I) to the 1,5-naphthalenedisulfonic acid is 1:1.0, 1:1.2, 1:1.5, 1:1.8, 1:2.0, 1:2.2, 1:2.5, 1:2.8, 1:3.0, 1:3.2, 1:3.5, 1:3.8, or 1:4.0.

[0042] In some embodiments of the present invention, the dose ratio of the compound represented by formula (I) to isopropanol is (5-15) mmol:(50-150) mL.

[0043] In some embodiments of the present invention, the dose ratio of the compound represented by formula (I) to isopropanol is 5 mmoL:50 mL, or 6 mmoL:100 mL, or 7 mmoL:100 mL, or 8 mmoL:100 mL, or 9 mmoL:100 mL, or 9.3 mmoL:100 mL, or 10 mmoL:100 mL, or 11 mmoL:100 mL, or 12 mmoL:100 mL, or 13 mmoL:100 mL, or 14 mmoL:150 mL, or 15 mmoL:150 mL.

[0044] In some embodiments of the present invention, the dose ratio of the compound represented by formula (I) to ethyl acetate is (5-15) mmol:(50-150) mL.

[0045] In some embodiments of the present invention, the dose ratio of the compound represented by formula (I) to ethyl acetate is mmoL:50 mL, or 6 mmoL:100 mL, or 7 mmoL:100 mL, or 8 mmoL:100 mL, or 9 mmoL:100 mL, or 9.3 mmoL:100 mL, or 10 mmoL:100 mL, or 11 mmoL:100 mL, or 12 mmoL:100 mL, or 13 mmoL:100 mL, or 14 mmoL:150 mL, or 15 mmoL:150 mL.

[0046] In some embodiments of the present invention, the stirring process is carried out at room temperature.

[0047] In some embodiments of the present invention, the stirring treatment is carried out at room temperature for two days.

[0048] In some embodiments of the present invention, the suction filtration process is performed with nitrogen gas protection.

[0049] In some embodiments of the present invention, the drying process is carried out for 2 hours under vacuum conditions at room temperature.

[0050] In another embodiment of the present invention, the present invention further proposes a hydrochloride salt of the compound represented by formula (I) having the following structure.

[0051] [ka]

[0052] , Of these, m is between 1.6 and 4.2.

[0053] In some embodiments of the present invention, the above m is selected from 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, and 4.2.

[0054] In some embodiments of the present invention, the hydrochloride salt is selected from monohydrochloride, dihydrochloride, trihydrochloride, and tetrahydrochloride salts. The inventors have found that tetrahydrochloride salts have higher stability and are less susceptible to oxidation compared to the other salt forms.

[0055] In another embodiment of the present invention, the present invention further proposes a method for producing the compound represented by formula (III-1). The above method comprises the reaction shown below.

[0056] [ka]

[0057] , Of these, m1 is between 1.6 and 2.5, and the reaction solvent is selected from methyl tert-butyl ether.

[0058] In some embodiments of the present invention, the above method may include at least one of the following additional technical features.

[0059] In some embodiments of the present invention, the molar ratio of the compound represented by formula (I) to the ethyl acetate-hydrogen chloride is (2-10):(1-5).

[0060] In some embodiments of the present invention, the molar ratio of the compound represented by formula (I) to the ethyl acetate-hydrogen chloride is 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 3:2, 4:3, 5:3, 5:2, 5:4, 6:5, 7:2, 7:3, 7:4, 7:5, 7:6, 8:3, 8:5, 8:7, 9:2, 9:4, 9:5, 9:7, 9:8, 10:3, 10:7, or 10:9.

[0061] In some embodiments of the present invention, the dose ratio of the compound represented by formula (I) to methyl tert-butyl ether is (5-15) mmol:(50-150) mL.

[0062] In some embodiments of the present invention, the dose ratio of the compound represented by formula (I) to methyl tert-butyl ether is 5 mmol:50 mL, 6 mmol:100 mL, 7 mmol:100 mL, 8 mmol:100 mL, 9 mmol:100 mL, 9.3 mmol:100 mL, 10 mmol:100 mL, 11 mmol:100 mL, 12 mmol:100 mL, 13 mmol:100 mL, 14 mmol:150 mL, or 15 mmol:150 mL.

[0063] In some embodiments of the present invention, after the reaction described above, the method further includes stirring, suction filtration, and drying.

[0064] In some embodiments of the present invention, the stirring process is carried out at room temperature.

[0065] In some embodiments of the present invention, the stirring treatment is carried out at room temperature for two days.

[0066] In some embodiments of the present invention, the suction filtration process is performed with nitrogen gas protection.

[0067] In some embodiments of the present invention, the drying process is carried out for 2 hours under vacuum conditions at room temperature.

[0068] In some embodiments of the present invention, the molar ratio of the compound represented by formula (I) to hydrochloric acid is 1.0:(1.6~2.1).

[0069] In another embodiment of the present invention, the present invention further proposes a method for producing the compound represented by formula (III-2), among which,

[0070] [ka]

[0071] , Of these, m2 = 3.8 to 4.2, and methanol is selected as the reaction solvent.

[0072] In some embodiments of the present invention, the above method may include at least one of the following additional technical features.

[0073] In some embodiments of the present invention, the above reaction is carried out under nitrogen gas conditions.

[0074] In some embodiments of the present invention, the molar ratio of the compound represented by formula (I) to the ethyl acetate-hydrogen chloride is (2-10):(1-5).

[0075] In some embodiments of the present invention, the molar ratio of the compound represented by formula (I) to the ethyl acetate-hydrogen chloride is 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 3:2, 4:3, 5:3, 5:2, 5:4, 6:5, 7:2, 7:3, 7:4, 7:5, 7:6, 8:3, 8:5, 8:7, 9:2, 9:4, 9:5, 9:7, 9:8, 10:3, 10:7, or 10:9.

[0076] In some embodiments of the present invention, the dose ratio of the compound represented by formula (I) to methyl tert-butyl ether is (5-15) mmol:(50-150) mL.

[0077] In some embodiments of the present invention, the dose ratio of the compound represented by formula (I) to methyl tert-butyl ether is 5 mmol:50 mL, 6 mmol:100 mL, 7 mmol:100 mL, 8 mmol:100 mL, 9 mmol:100 mL, 9.3 mmol:100 mL, 10 mmol:100 mL, 11 mmol:100 mL, 12 mmol:100 mL, 13 mmol:100 mL, 14 mmol:150 mL, or 15 mmol:150 mL.

[0078] In some embodiments of the present invention, after the reaction described above, the method further includes stirring, suction filtration, and drying.

[0079] In some embodiments of the present invention, the stirring process is carried out at room temperature.

[0080] In some embodiments of the present invention, the stirring treatment is carried out at room temperature for two days.

[0081] In some embodiments of the present invention, the suction filtration process is performed with nitrogen gas protection.

[0082] In some embodiments of the present invention, the drying process is carried out for 2 hours under vacuum conditions at room temperature.

[0083] In some embodiments of the present invention, the molar ratio of the compound represented by formula (I) to hydrochloric acid is 1.0:(1.6~2.1).

[0084] In another embodiment of the present invention, the present invention further proposes an amorphous form of the hydrochloride salt of the compound represented by formula (I), wherein the molar ratio of the compound represented by formula (I) to hydrochloric acid is 1.0:(1.6~4.2).

[0085] In some embodiments of the present invention, the amorphous form of the hydrochloride salt is selected from amorphous forms of monohydrochloride, dihydrochloride, trihydrochloride, and tetrahydrochloride. The inventors have found that amorphous forms of tetrahydrochloride have higher stability and are less susceptible to oxidation compared to the other amorphous forms.

[0086] In some embodiments of the present invention, the molar ratios of the compound shown in (I) to hydrochloric acid are 1.0:1.6, 1.0:1.8, 1.0:2.1, 1.0:2.5, 1.0:2.8, 1.0:3.1, 1.0:3.5, 1.0:3.8, and 1.0:4.2.

[0087] In some embodiments of the present invention, when the amorphous material is a dihydrochloride salt (i.e., the molar ratio of the compound shown in (I) to hydrochloric acid is 1.0:(1.6~2.1)), the amorphous material of the hydrochloride salt basically has the XPRD pattern shown in Figure 3 or Figure 11.

[0088] In some embodiments of the present invention, when the amorphous material is a tetrahydrochloride salt (i.e., the molar ratio of the compound shown in (I) to hydrochloric acid is 1.0:(2.2~4.2)), the amorphous material of the hydrochloride salt basically has the XPRD pattern shown in Figure 15.

[0089] In some embodiments of the present invention, when the amorphous material is a dihydrochloride salt (i.e., the molar ratio of the compound shown in (I) to hydrochloric acid is 1.0:(1.6~2.1)), the amorphous material of the hydrochloride salt basically has the TGA / mDSC shown in Figure 12.

[0090] In some embodiments of the present invention, when the amorphous material is a dihydrochloride salt (i.e., the molar ratio of the compound shown in (I) to hydrochloric acid is 1.0:(1.6~2.1)), the amorphous material of the hydrochloride salt is basically as shown in Figure 13 or Figure 14. 1 The 1H NMR spectrum is evaluated.

[0091] In some embodiments of the present invention, when the amorphous material is a tetrahydrochloride salt (i.e., the molar ratio of the compound shown in (I) to hydrochloric acid is 1.0:(2.2~4.2)), the amorphous form of the hydrochloride salt is basically as shown in Figure 16. 1 The 1H NMR spectrum is evaluated.

[0092] In another embodiment of the present invention, the present invention further proposes a method for producing an amorphous form of the dihydrochloride salt of a compound represented by formula (I), comprising stirring, suction filtration and drying the compound represented by formula (I) and ethyl acetate-hydrogen chloride in methyl tert-butyl ether to obtain an amorphous form of the dihydrochloride salt of the compound represented by formula (I).

[0093] In another embodiment of the present invention, the present invention further proposes a method for producing an amorphous dihydrochloride salt of a compound represented by formula (I), comprising stirring the compound represented by formula (I) and ethyl acetate-hydrogen chloride in methyl tert-butyl ether, then suction filtration under nitrogen gas protection, and then vacuum drying at room temperature to obtain an amorphous dihydrochloride salt of the compound represented by formula (I).

[0094] In some embodiments of the present invention, the molar ratio of the compound represented by formula (I) to the ethyl acetate-hydrogen chloride is (2-10):(1-5).

[0095] In some embodiments of the present invention, the molar ratio of the compound represented by formula (I) to the ethyl acetate-hydrogen chloride is 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 3:2, 4:3, 5:3, 5:2, 5:4, 6:5, 7:2, 7:3, 7:4, 7:5, 7:6, 8:3, 8:5, 8:7, 9:2, 9:4, 9:5, 9:7, 9:8, 10:3, 10:7, or 10:9.

[0096] In some embodiments of the present invention, the dose ratio of the compound represented by formula (I) to methyl tert-butyl ether is (5-15) mmol:(50-150) mL.

[0097] In some embodiments of the present invention, the dose ratio of the compound represented by formula (I) to methyl tert-butyl ether is 5 mmol:50 mL, 6 mmol:100 mL, 7 mmol:100 mL, 8 mmol:100 mL, 9 mmol:100 mL, 9.3 mmol:100 mL, 10 mmol:100 mL, 11 mmol:100 mL, 12 mmol:100 mL, 13 mmol:100 mL, 14 mmol:150 mL, or 15 mmol:150 mL.

[0098] In some embodiments of the present invention, the stirring process is carried out at room temperature.

[0099] In some embodiments of the present invention, the stirring treatment is carried out at room temperature for two days.

[0100] In some embodiments of the present invention, the suction filtration process is performed with nitrogen gas protection.

[0101] In some embodiments of the present invention, the drying process is carried out for 2 hours under vacuum conditions at room temperature.

[0102] In some embodiments of the present invention, the molar ratio of the compound represented by formula (I) to hydrochloric acid is 1.0:(1.6~2.1).

[0103] In another embodiment of the present invention, the present invention further proposes a method for producing an amorphous tetrahydrochloride salt of a compound represented by formula (I), comprising adding an HCl / MeOH solution dropwise to the compound represented by formula (I) in a methanol solvent under nitrogen gas protection, followed by stirring, concentration, slurring, filtration, and drying to obtain an amorphous tetrahydrochloride salt of the compound represented by formula (I).

[0104] In another embodiment of the present invention, the present invention further proposes a method for producing an amorphous tetrahydrochloride salt of a compound represented by formula (I), comprising dissolving the compound represented by formula (I) in anhydrous methanol, adding an HCl / MeOH solution dropwise under nitrogen gas protection, stirring after the addition is complete, then concentrating the reaction mixture to obtain a crude product, slurring the crude product, and filtering it to obtain an amorphous tetrahydrochloride salt of the compound represented by formula (I).

[0105] In some embodiments of the present invention, the methanol is anhydrous methanol.

[0106] In some embodiments of the present invention, the molar ratio of the compound represented by formula (I) to the HCl / MeOH is (1-5):(2-10).

[0107] In some embodiments of the present invention, the molar ratio of the compound represented by formula (I) to the HCl / MeOH is 1:2, 1:2.5, 1:3, 1:4, 1:4.25, 1:4.5, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 2:3, 2:5, 2:7, 2:9, 3:4, 3:5, 3:7, 3:8, 3:9, 4:5, 4:7, 4:9, 5:6, 5:7, 5:8, or 5:9, etc.

[0108] In some embodiments of the present invention, the dose ratio of the compound represented by formula (I) to methanol is (1-5) kg:(10-50) L.

[0109] In some embodiments of the present invention, the dose ratio of the compound represented by formula (I) to methanol is 4.05 kg:40 L.

[0110] In some embodiments of the present invention, the stirring treatment is performed for 30 minutes.

[0111] In some embodiments of the present invention, the slurrying treatment is carried out in ethyl acetate for 2 hours.

[0112] In some embodiments of the present invention, the molar ratio of the compound represented by formula (I) to hydrochloric acid is 1.0:(2.9~4.2).

[0113] In another aspect of the present invention, the present invention further proposes the use of amorphous forms of the compound represented by formula (I) described above, or 1,5-naphthalenedisulfonate of the compound represented by formula (I) described above, or 1,5-naphthalenedisulfonate of the compound represented by formula (I) described above, or 1,5-naphthalenedisulfonate of the compound represented by formula (I) described above produced by the method described above, or hydrochloride of the compound represented by formula (I) described above, or compound represented by formula (III-1) produced by the method described above, or compound represented by formula (III-2) produced by the method described above, or amorphous forms of 1,5-naphthalenedisulfonate of the compound represented by formula (I) described above, or amorphous forms of 1,5-naphthalenedisulfonate of the compound represented by formula (I) described above, or amorphous forms of hydrochloride of the compound represented by formula (I) described above, or amorphous forms of dihydrochloride of the compound represented by formula (I) produced by the method described above, or amorphous forms of tetrahydrochloride of the compound represented by formula (I) produced by the method described above, in drugs for inhibiting the reverse transport of NHE-mediated sodium ions or hydrogen ions.

[0114] In another embodiment of the present invention, the present invention relates to an amorphous form of the compound represented by formula (I) described above, or a 1,5-naphthalenedisulfonate of the compound represented by formula (I) described above, or a 1,5-naphthalenedisulfonate of the compound represented by formula (I) described above produced by the method described above, or a hydrochloride of the compound represented by formula (III-1) described above, or a compound represented by formula (III-2) produced by the method described above, or a 1, Further suggestions are made for the use of amorphous 5-naphthalenedisulfonate, amorphous 1,5-naphthalenedisulfonate of the compound represented by formula (I) produced by the method described above, amorphous hydrochloride of the compound represented by formula (I) described above, amorphous dihydrochloride of the compound represented by formula (I) produced by the method described above, or amorphous tetrahydrochloride of the compound represented by formula (I) produced by the method described above in the manufacture of drugs for the treatment of diseases selected from irritable bowel syndrome, heart failure, chronic kidney disease, end-stage renal disease, or hepatic disease.

[0115] Definition and Description Unless otherwise specified, all technical and scientific terms used in this invention have the same meaning as those commonly understood by those skilled in the art to which this invention pertains. All patents and published works relating to this invention are incorporated collectively by reference. Any methods and materials similar to or identical to those described in this invention may be used in the practice or testing of this invention, but preferred methods, equipment and materials are described in this invention.

[0116] "Crystal form" or "crystalline morphology" refers to a solid having a highly regular chemical structure, and includes, but is not limited to, single-component or multi-component crystals and / or crystalline polymorphs of compounds, solvates, hydrates, inclusion compounds, cocrystals, salts, solvates of salts, and hydrates of salts. The crystalline morphology of a substance can be obtained by many methods known in the art. Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in confined spaces such as nanopores and capillaries, crystallization on surfaces or templates such as polymers, crystallization in the presence of additives such as cocrystal antimolecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reaction crystallization, poor solvent addition, grinding, and solvent dropwise grinding.

[0117] "Amorphous" or "amorphous form" refers to a material formed when the particles (molecules, atoms, ions) of a substance are arranged without periodicity in three-dimensional space, and is characterized by having an X-ray powder diffraction pattern without scattered peaks. Amorphous is a special physical form of solid material, and its locally regular structural features suggest a close relationship with crystalline materials. The amorphous form of a substance can be obtained by many methods known in the art. These methods include, but are not limited to, rapid quenching, poor solvent flocculation, ball milling, spray drying, freeze-drying, wet granulation, and solid dispersion techniques.

[0118] "Solvent" refers to a substance (typically a liquid) that can completely or partially dissolve another substance (typically a solid). Solvents used in the implementation of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, t-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, 1-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-acetone, pyridine, tetrahydrofuran, toluene, xylene, and mixtures thereof.

[0119] A "poor solvent" refers to a fluid that promotes the precipitation of products (or precursors to products) from a solvent. Poor solvents may include cold gases, fluids that promote precipitation through chemical reactions, or fluids that reduce the solubility of products in the solvent, and may be the same liquid as the solvent but at a different temperature, or they may be a different liquid from the solvent.

[0120] "Solvate" means that the crystal is present on its surface or in its crystal lattice, or has a solvent on its surface and in its crystal lattice, and the solvent may be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, t-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methylpyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-acetone, pyridine, tetrahydrofuran, toluene, xylene, and mixtures thereof. A specific example of a solvate is a hydrate in which the solvent is water on the surface or in the crystal lattice, or on the surface and in the crystal lattice. The hydrate may or may not have other solvents besides water on the surface or in the crystal lattice, or on the surface and in the crystal lattice.

[0121] The crystalline or amorphous form can be identified by various technical means, including X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance spectroscopy, Raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility, and dissolution rate.

[0122] X-ray powder diffraction (XRPD) can detect information such as changes in crystal form, degree of crystallinity, and crystal structure state, and is a common means of identifying crystal forms. The peak positions of the XRPD pattern mainly depend on the structure of the crystal form and are relatively insensitive to experimental details, while the relative peak heights depend on many factors related to the preparation of the sample and the geometric shape of the instrument. Therefore, in some embodiments, the crystal form of the present invention is characterized by having an XRPD pattern with certain peak positions, as basically shown by the XRPD patterns provided in the drawings of the present invention. At the same time, the measured value of 2θ of the XRPD pattern may have experimental errors, and the measured value of 2θ of the XRPD pattern may differ slightly between different instruments and different samples, so the above value of 2θ cannot be considered absolute. Based on the conditions of the instrument used in the test of the present invention, the diffraction peak has a tolerance of ±0.2°.

[0123] Differential scanning calorimetry (DSC) is a technique that measures the change in the energy difference between a sample and an inert reference material (usually α-Al2O3) with respect to temperature by continuously heating or cooling under programmatic control. The height of the melting peak in the DSC curve depends on many factors related to the preparation of the sample and the geometric shape of the instrument, while the position of the peak is relatively insensitive to the details of the experiment. Therefore, in some embodiments, the crystal forms described in the present invention are characterized by having a DSC pattern with a characteristic peak position, as basically shown by the DSC pattern provided in the drawings of the present invention. At the same time, the DSC pattern may have experimental errors, and the peak position and peak value of the DSC pattern may differ slightly between different instruments and different samples, so the peak position or peak value of the DSC endothermic peak cannot be considered absolute. Based on the conditions of the instrument used in the test of the present invention, the melting peak has a tolerance of ±3°C.

[0124] Glass transition refers to the transition of an amorphous material between a highly elastic state and a glassy state, and is an intrinsic property of the material. The corresponding transition temperature is the glass transition temperature (Tg), which is an important physical property of amorphous materials. Since glass transition is a phenomenon related to molecular motion, the glass transition temperature (Tg) mainly depends on the structure of the material, while being relatively insensitive to experimental details. In some examples, the glass transition temperature (Tg) of the amorphous material described in the present invention is measured by differential scanning calorimetry (DSC) and is characterized by having a glass transition temperature of 107.44°C. Based on the conditions of the equipment used in the tests of the present invention, the glass transition temperature has a tolerance of ±3°C.

[0125] Differential scanning calorimetry (DSC) can also be used to detect and analyze whether a crystal form is transcrystalline or mixed crystal.

[0126] Solids with the same chemical composition often form isomers with different crystalline structures, also known as mutants, under different thermodynamic conditions. This phenomenon is called polycrystalline or polyphase. When temperature and pressure conditions change, interconversion occurs between mutants, a phenomenon called crystalline transformation. Crystalline transformation significantly alters the mechanical, electrical, and magnetic properties of the crystal. If the temperature of crystalline transformation is within a measurable range, this transformation process can be observed in a differential scanning calorimetry (DSC) pattern. The DSC pattern has a heat dissipation peak that reflects this transformation process, and simultaneously has two or more endothermic peaks, each characteristic of the different crystalline forms before and after the transformation. The crystalline or amorphous forms of the compounds of the present invention can undergo crystalline transformation under appropriate conditions.

[0127] Thermogravimetric analysis (TGA) is a technique that measures the change in mass of a substance with temperature under programmatic control. It is suitable for detecting the loss of solvent in crystals or the sublimation and decomposition processes of a sample, and can infer the presence of crystal water or crystalline solvent in the crystals. The mass change shown by the TGA curve depends on many factors, such as the sample's manufacturing process and the equipment used, and the mass change detected by TGA will differ slightly between different equipment and different samples. In some examples, calcium salt crystal form A described in the present invention shows a weight loss of approximately 5.1% at a temperature of approximately 150°C. Based on the conditions of the equipment used in the tests of the present invention, the mass change has a tolerance of ±0.3%.

[0128] In the context of this invention, all 2θ values ​​in the X-ray powder diffraction pattern are expressed in degrees (°).

[0129] What needs to be explained is that "wt%" refers to the mass ratio (g / g). For example, in a hydrate, a water content of crystalline form A of 3.0 wt% means that the ratio (g / g) of the mass of water in crystalline form A to the mass of crystalline form A is 3.0. Similarly, in a solvate, a 1,4-dioxane content of crystalline form C of 3.1 wt% means that the ratio (g / g) of the mass of 1,4-dioxane in crystalline form C to the mass of crystalline form C is 3.1.

[0130] The phrase "basically shown in the figure" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in the X-ray powder diffraction pattern, DSC pattern, or TGA result are shown in the figure.

[0131] When referring to data appearing in spectra and / or figures, “peaks” refer to features that are not background noise and can be recognized by those skilled in the art.

[0132] "Basically pure" means that one crystal form basically contains no other one or more crystal forms, i.e., the purity of the crystal form is at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, or that the crystal form contains other crystal forms that make up less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01% of the total volume or total weight of the crystal form.

[0133] "Basically not included" means that the percentage of one or more other crystalline forms in the total volume or total weight of the crystalline forms is less than 20%, or less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.

[0134] "Relative intensity" refers to the ratio of the intensity of the other peaks to the intensity of the first strong peak among all diffraction peaks in an X-ray powder diffraction pattern (XRPD), with the intensity of the first strong peak being set to 100%.

[0135] In the context of this invention, wherever terms such as “approximately” or “about” are used, or where they are not used, they mean within 10%, preferably within 5%, and especially within 1% of a given value or range. Alternatively, to those skilled in the art, the terms “approximately” or “about” mean within the range of the acceptable standard error of the mean. Whenever a number having a value of N is disclosed, any number within the range of N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, or N+ / -10% is explicitly disclosed, where “+ / -” refers to plus or minus.

[0136] The term "includes" is an open expression, meaning it includes the content specified in this invention but does not exclude the content of other embodiments.

[0137] "Free base" refers to the form in which the compound shown in formula (I) does not form a salt.

[0138] X-ray powder diffraction (XRPD) data was collected using a PANalytacal X-ray powder diffraction analyzer, and the scan parameters are shown in Table 1.

[0139] [Table 1]

[0140] TGA and mDSC patterns were collected using a TA5500 thermogravimetric analyzer and a TA2500 differential scanning calorimetry analyzer, respectively, and the measurement parameters are listed in Table 2.

[0141] [Table 2]

[0142] Dynamic moisture adsorption (DVS) curves were collected using a Surface Measurement Systems (SMS) DVS IntrInsic. Relative humidity at 25°C was corrected for the deliquescence points of LiCl, Mg(NO3)2, and KCl. DVS measurement parameters are listed in Table 3.

[0143] [Table 3]

[0144] Liquid-state nuclear magnetic resonance spectra were collected using a Bruker 400M nuclear magnetic resonance spectrometer with DMSO-d6 as the solvent.

[0145] In high-performance liquid chromatography and ion chromatography (HPLC / IC), In the tests, molar ratio and stability tests were performed using an Agilent 1260 high-performance liquid chromatograph, and the ion salt formation molar ratio test was performed using ion chromatography. The analytical conditions are shown in Tables 4 and 5.

[0146] [Table 4]

[0147] [Table 5]

[0148] The HPLC test conditions for the manufacturing process of tetrahydrochloride are shown in Table 6 below.

[0149] [Table 6]

[0150] The apparatus and test method for measuring hydrochloric acid by titration are shown in Table 7 below.

[0151] [Table 7]

[0152] The method is as follows: Preparation of the solution (1) Blank solution: 80 mL of distilled water was measured into a 200 mL beaker, 10 mL of nitric acid solution was added, and then 20 mL of acetonitrile solution was added.

[0153] (2) Sample solution: Approximately 100 mg of the sample was weighed into a 200 mL beaker, approximately 80 mL of diluent was added, followed by 10 mL of nitric acid solution, and then 20 mL of acetonitrile solution (acetonitrile was added to aid dissolution because the sample is poorly soluble in a mixture of pure water and nitric acid). The mixture was shaken uniformly and dissolved by ultrasound. Two sets were prepared in parallel by repeating the weighing process. [Brief explanation of the drawing]

[0154] [Figure 1] This is the amorphous XPRD pattern of the free base of the compound shown in formula (I). [Figure 2] This is the XPRD pattern of 1,5-naphthalenedisulfonate of the compound shown in formula (I). [Figure 3] This is the XPRD pattern of sample 1 of the dihydrochloride salt of the compound shown in formula (I). [Figure 4] This is the XPRD pattern of sample 1 of the 1,5-naphthalenedisulfonate of the compound shown in formula (I). [Figure 5] This is the TGA / mDSC of sample 1 of the 1,5-naphthalenedisulfonate of the compound shown in formula (I). [Figure 6] This is the 1H NMR spectrum of sample 1 of the 1,5-naphthalenedisulfonate of the compound shown in formula (I). [Figure 7] This is the XPRD pattern of sample 2 of 1,5-naphthalenedisulfonate of the compound shown in formula (I). [Figure 8] This is the TGA / mDSC of sample 2 of 1,5-naphthalenedisulfonate of the compound shown in formula (I). [Figure 9] This is the 1H NMR spectrum of sample 2 of the 1,5-naphthalenedisulfonate of the compound shown in formula (I). [Figure 10] This is the 1H NMR spectrum of the repeated preparation of 1,5-naphthalenedisulfonate of the compound shown in formula (I). [Figure 11] This is the XPRD pattern of sample 1 of the dihydrochloride salt of the compound shown in formula (I). [Figure 12] This is the TGA / mDSC pattern of sample 1 of the dihydrochloride salt of the compound shown in formula (I). [Figure 13] This is the 1H NMR spectrum of sample 1 of the dihydrochloride salt of the compound shown in formula (I). [Figure 14]This is the 1H NMR spectrum of the repeated preparation of the dihydrochloride salt of the compound shown in formula (I). [Figure 15] This is the XPRD pattern of a tetrahydrochloride salt sample of the compound shown in formula (I). [Figure 16] This is the 1H NMR spectrum of a tetrahydrochloride salt sample of the compound shown in formula (I). [Figure 17] nP is the standardized and corrected value of urinary phosphorus excretion relative to phosphorus intake from food. [Figure 18] This is the standardized and corrected value (nNa) of urinary sodium excretion relative to sodium intake from food. [Figure 19] This is a fecal morphology score. [Figure 20] This is a flowchart of the experiment. [Figure 21] This is the blood phosphorus concentration in rats. [Figure 22] nP is the standardized and corrected value of 24-hour urinary phosphorus excretion relative to phosphorus intake from food. [Figure 23] This is the standardized and corrected value (nNa) of 24-hour urinary sodium excretion relative to sodium intake from food. [Figure 24] This is a fecal morphology score. [Modes for carrying out the invention]

[0155] The present application will be described in detail below with reference to examples, but this does not mean that there are any unfavorable limitations to the present application. This specification has already described the present application in detail, including the forms of specific embodiments, but it will be clear to those skilled in the art that various changes and improvements can be made to specific embodiments of the present application without departing from the spirit and scope of the present application.

[0156] Unless otherwise specified, all raw materials used in this invention are commercially available.

[0157] The abbreviations or English terms used in this invention, along with their Japanese meanings, are shown in Table 8 below.

[0158] [Table 8]

[0159] Example 1: Preparation of the compound shown in formula (I)

[0160] [ka]

[0161] Step 1 Under room temperature conditions, tributyl(1-ethoxyvinyl)tin (515 g, 1.3 moL) and Pd(dppf)Cl2 (3.15 g, 857.47 mmol) were added to dioxane (2 L) of A2 (363 g, 1.30 moL). The reaction mixture was replaced by suction with nitrogen gas and stirred at 100°C for 16 hours under nitrogen gas protection. After monitoring the completion of the reaction by LC-MS, the reaction was quenched with 10% KF solution (1.5 L), stirred for 1 hour, diluted with 3 L of ethyl acetate, filtered, and the filtered cake was washed with ethyl acetate. The solution was separated, the aqueous phase was extracted with ethyl acetate (2.5 L x 2), the organic phases were combined, dried, filtered, and concentrated to obtain 344 g of crude A3 product, which was used directly in the next step.

[0162] Step 2 Under 0°C conditions, NBS (230.8 g, 1.3 moL) was added to a mixed solvent (THF:H2O=3:1, 2 L) containing A3 (344 g, 1.30 moL). Water (1.5 L), 200 mL of saturated Na2SO3 solution, and 200 mL of sodium bicarbonate solution were sequentially added to the reaction mixture, and the mixture was stirred for half an hour. The aqueous phase was extracted with ethyl acetate (0.5 L x 3), the organic phase was combined, washed with saturated brine (1 L), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 380 g of crude A4 product, which was used directly in the next step.

[0163] Step 3 Under 0°C conditions, A5 (244.7 g, 1.3 moL) and DIPEA (503 g, 3.89 moL) were added to A4 (380 g, 1.30 moL) dioxane (2 L). After the addition was complete, the mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LC-MS. The reaction mixture was then filtered, and water (1.5 L) and 2 L of ethyl acetate were added sequentially to the filtrate. The liquid-liquid was separated, the aqueous phase was extracted with ethyl acetate (0.5 L x 2), the organic phases were combined, washed with saturated brine (1 L), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 900 g of crude A6 product, which was used directly in the next step.

[0164] Step 4 Under 0°C conditions, NaBH4 (49 g, 1.3 moL) was added to methanol (4 L) with A6 (900 g, 1.30 moL of crude product), and after the addition was complete, the mixture was stirred at 0°C for 1 hour. After monitoring the completion of the reaction by LC-MS, saturated NH4Cl solution (500 mL) was added sequentially to the reaction mixture, followed by 3 N HCl solution until neutral. The reaction mixture was concentrated, dissolved with DCM, separated, the aqueous phase was extracted with DCM (0.5 L x 2), the organic phase was combined, washed with saturated brine (1 L), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to obtain 300 g of product A7, which was used directly in the next step.

[0165] Step 5 80 g, 187.23 mmol of A7 was added to 400 mL of THF, and 400 mL of 4 N HCl solution was added. After the addition was complete, the mixture was stirred at 40°C for 16 hours. The reaction mixture was monitored by LC-MS to ensure that the reactants had basically converted. The reaction mixture was neutralized with saturated sodium bicarbonate solution, diluted with 1 L of ethyl acetate, and separated. The aqueous phase was extracted with ethyl acetate (0.8 L x 2), the organic phase was combined, washed with saturated brine (800 mL), dried over anhydrous sodium sulfate, and concentrated to obtain 75 g of A8 product, which was used directly in the next step.

[0166] Step 6 60 g, 156.6 mmol of A8 was added to 600 mL of DCE with 120 mL of CF3SO3H. After the addition was complete, the mixture was stirred at 65°C for 24 hours, and the conversion of most of the reaction materials was monitored by LC-MS. The reaction mixture was gradually poured into an ice bath and neutralized with saturated sodium bicarbonate solution. The aqueous phase was extracted with DCM (0.5 L x 3), and the combined organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography to obtain 33 g of the A9 product.

[0167] Step 7 100 g of A9 can be separated by chiral column chromatography to obtain 41 g of A9A, a single-configuration product, which can also be separated by chemical resolution using di-p-benzoyl-L-tartaric acid as the resolution reagent.

[0168] Salt formation by chemical resolution was performed as follows: Approximately 8.4 g of racemic A9 (A9-CHP4075) was weighed and dissolved in 210 mL of acetone. Approximately 800 mg of seed crystal (A9A:(D)(+)-p-methyldibenzoyl tartaric acid = 1:1) was added. 1.1 equivalents of (D)(+)-p-methyldibenzoyl tartaric acid were weighed and dissolved in 70 mL of acetone. The acetone solution containing the ligand was gradually added dropwise to the racemic solution (addition time 4 hours), and the suspension was stirred at room temperature for 3 days. The solid was separated by vacuum suction filtration, and the obtained solid was washed in 35 mL of acetone for approximately 30 minutes. The ee value of the obtained solid was 97.2%, the configuration concentration of impurities in the supernatant was 3.2 mg / mL, and the target configuration concentration was 3.7 mg / mL.

[0169] The solid was further separated by vacuum suction filtration, and the obtained solid was washed in 50 mL of acetone for 30 minutes. The ee value of the obtained solid was 97.9%, the configuration concentration of impurities in the supernatant was 0.3 mg / mL, and the target configuration concentration was 3.5 mg / mL. The solid (823325-43-C) obtained by the final salt formation was 6.9 g, with an ee value of 97.9% and a yield of approximately 35%.

[0170] Purification / liberation was performed as follows: Disodium hydrogen phosphate (50 g) was taken and added to water (1000 mL), and stirred until clear to dissolve, then prepared for use. The solid obtained by salt formation (100 g, 0.13 mol) was taken and added to dichloromethane (1000 mL), and a disodium hydrogen phosphate solution prepared at room temperature was gradually added dropwise. After the addition was complete, the mixture was stirred for 2-3 hours, and the liquid-liquid was separated. The aqueous phase was extracted twice with 250 mL of dichloromethane. The organic phases were combined and washed twice with 500 mL of water. The dichloromethane phase was concentrated under reduced pressure with water, and after adding water, the volume was increased to 1500 mL. 50 g of 200-300 mesh silica gel was added, and the mixture was stirred for 0.5-1 hour. The mixture was filtered using a sand core funnel, the silica gel was rinsed with 500-1000 mL of dichloromethane, and the filtrate was concentrated under reduced pressure until it became oily. 200-500 mL of methyl tert-butyl ether was added, and the concentration under reduced pressure was continued until it was dry, yielding a yellow solid. Ethyl acetate / n-heptane (500 mL, v / v=1:10) was added and the mixture was slurryed overnight. The mixture was filtered, and a pale yellow solid A9A was obtained.

[0171] Step 8 Under room temperature conditions, A9A (100.0 g, 0.27 moL), EtOH (500 mL), and A10 (74.8 g, 0.30 moL) were added to a 2 L three-necked flask. Stirring was started, the flask was protected with N2, and the temperature was raised to 70°C for 4 hours. The process control reaction was as follows: HPLC starting material A9A ≤ 5.00% (254 nm). After the process control was achieved, the temperature was lowered to 20-30°C, and tri-n-butylphosphine (163.9 g, 0.81 moL) was added to the reaction flask. The temperature was raised to 70°C, and stirring was continued for approximately 12-18 hours. The process control reaction was as follows: imine intermediate ≤ 2.00% (254 nm). After the reaction was complete and cooled, the A11 reaction solution was used directly in the next step.

[0172] Step 9 A 300 mL ethanol dilution of a 216 mL hydrogen chloride ethanol solution was gradually added dropwise, the temperature was raised to 40°C, and the mixture was stirred for 12-18 hours. The mixture was then stirred overnight at room temperature, and the reaction endpoint, i.e., HPLC starting material A11 ≤ 2% (254 nm), was monitored by HPLC. The reaction mixture was concentrated under reduced pressure until dry, and dichloromethane (1 L) was added in two batches, with the mixture concentrated under reduced pressure until dry. Water (1 L) was added and dissolved until clear, then ethyl acetate (500 mL) was added for extraction, and this extraction process was repeated four times. The aqueous phase was cooled to 0-5°C, and 20% sodium hydroxide aqueous solution was gradually added dropwise until the pH was greater than 12. Dichloromethane (1 L) was added for extraction, and the aqueous phase was extracted with dichloromethane (500 mL). The organic phases were combined and concentrated until dry.

[0173] The purification procedure was as follows: The crude product was dissolved in ethyl acetate (500 mL) and wet column chromatography (100-200 mesh silica gel, 1 kg silica gel) using ethyl acetate:methanol = 4:1. After washing away impurity spots above the product spot, the column was washed with dichloromethane:methanol = 5:1 (1% aqueous ammonium compound) until no product spots remained. After concentration under reduced pressure, dichloromethane (1.5 L) was added in three separate additions, and concentration under reduced pressure was continued until dry, yielding a total of 108 g of intermediate A12. The overall yield for the two steps was 86.3%.

[0174] Step 10 A12 (94.0 g, 0.20 moL) (based on content) was dissolved in dichloromethane (940 mL). The reaction mixture was cooled to 0-10°C, protected with nitrogen gas, and a solution of A13 (14.0 g, 0.10 moL) in DCM (1.5 L) was added dropwise. After addition was complete, the temperature was raised to 20-30°C and the mixture was stirred for 2 hours. The reaction endpoint, i.e., A12 ≤ 1.0%, was monitored by HPLC. If this was not met, the temperature was cooled to 0-10°C, and A13 was added (added with 0.5 equivalents of the residual A12 content in the actual process control). After addition was complete, the temperature was raised to 20-30°C and the mixture was stirred for 6 hours, and the reaction endpoint was monitored by HPLC. The reaction mixture was concentrated under reduced pressure to obtain the crude product.

[0175] Purification by column chromatography was performed as follows: The crude product was dissolved in a small amount of ethyl acetate:methanol = 2:1, wet sampling was performed (100-200 mesh silica gel, 1 kg silica gel), eluted with the eluent ethyl acetate:methanol = 4:1 to remove the cross-points, then eluted again with ethyl acetate:methanol = 2:1 until the product spot was clearly fainter (approximately 8 L), and then washed away the cross-points with ethyl acetate:methanol = 1:1. After concentrating the cross-points until dry, secondary column chromatography was performed (the same method as above), the pure products were combined and concentrated until dry, ethyl formate (300 mL) was added and dispersed by vigorous stirring, isopropyl ether (1.8 L) was rapidly added dropwise, stirred for 10-30 min, filtered, washed with isopropyl ether (200 mL), and the filtration cake was dried under vacuum at 40°C to obtain the liberated amine purified product, totaling 57.0 g, with a yield of 53.4%. The free product, represented by formula (I), has its XPRD pattern shown in Figure 1.

[0176] Example 2 Screening of salt forms of the compound shown in formula (I) Hydrochloric acid (with a molar ratio of 4:1 to the compound shown in formula (I)), sulfuric acid (with a molar ratio of 2:1 to the compound shown in formula (I)), 1,5-naphthalenedisulfonic acid (with a molar ratio of 1:1 to the compound shown in formula (I)), and ethyl acetate-hydrogen chloride (with a molar ratio of 2:1 to the compound shown in formula (I)) were screened, and the results are shown in Table 9 below.

[0177] [Table 9]

[0178] The inventors found that the compound shown in formula (I) can form only 1,5-naphthalenedisulfonate and hydrochloride.

[0179] Example 3: 1,5-Naphthalenedisulfonate Sample Salt mold manufacturing Sample (1) of 1,5-naphthalenedisulfonate was obtained by stirring 20.0 mg of the free base form of the compound shown in formula (I) and 5.6 mg of 1,5-naphthalenedisulfonic acid (molar ratio 1:1, acid / base) in 0.5 mL of IPA at room temperature for 2 days, followed by suction filtration under nitrogen gas protection, and vacuum drying at room temperature for 2 hours. The sample was a white powder. The XRPD of the sample was an amorphous product, as shown in Figure 4. The TGA / mDSC results are shown in detail in Figure 5. The TGA results showed an 11.8% weight loss when the sample was heated to 150°C, and no clear glass transition temperature was observed from the mDSC results. 1 ¹H NMR was measured using DMSO-d6, and the results are shown in Figure 6. The results showed a molar ratio of 1,5-naphthalenedisulfonic acid to free base of 1.0:1, and a 3.4 wt% IPA solvent residue was observed.

[0180] Sample (2) of 1,5-naphthalenedisulfonate was prepared using the free base form of the compound shown in formula (I) (20.2 mg) and 5.6 mg of 1,5-naphthalenedisulfonic acid (molar ratio 1:1, acid / base) as starting materials. The mixture was stirred in 0.5 mL of ethyl acetate at room temperature for 2 days, then filtered by suction under nitrogen gas protection, and vacuum dried at room temperature for 2 hours. The sample was a white powder. The XRPD of the sample was amorphous, as shown in Figure 7. The TGA / mDSC results are shown in detail in Figure 8. The TGA results showed a 6.1% weight loss when the sample was heated to 150°C, and no clear glass transition temperature was observed from the mDSC results. 1 ¹H NMR was measured using DMSO-d6, and the results are shown in Figure 9. The results showed a molar ratio of 1,5-naphthalenedisulfonic acid to free base of 0.9:1, and no HCl solvent residue was observed.

[0181] The repeated preparation of the 1,5-naphthalenedisulfonate type on a 200 mg scale was as follows: 199.2 mg of the free base form of the compound shown in formula (I) and 51.4 mg of 1,5-naphthalenedisulfonic acid were weighed, and 5.0 mL of IPA was added. The suspension was stirred at room temperature for 2 days, the suspension was filtered by suction, and the mixture was vacuum-dried at room temperature for 5 hours to collect 204.5 mg of the sample. As shown in Figure 1, the XRPD was an amorphous product, and no oil formation or colloid formation was observed during the salt formation process. 1 ¹H NMR was measured using DMSO-d6, and the results are shown in Figure 10. In this sample, the molar ratio of 1,5-naphthalenedisulfonic acid to free base was 1.0:1, and 12.0 wt% of IPA solvent residue was observed.

[0182] Example 4 Hydrochloride Sample The dihydrochloride salt sample was obtained by stirring 0.5 mL of MTBE in room temperature for 2 days with the free base form of the compound shown in formula (I) (20.0 mg) and an ethyl acetate-hydrogen chloride solution (molar ratio 4:1, acid / base) as starting materials, followed by suction filtration under nitrogen gas protection and vacuum drying at room temperature for 2 hours. The sample was a white powder. The XRPD pattern of the sample was amorphous, as shown in Figure 11. The TGA / mDSC results are shown in Figure 12. The TGA results showed a weight loss of 6.82% when the sample was heated to 150°C, and no clear glass transition temperature was observed from the mDSC results. 1 ¹H NMR was measured using DMSO-d6, and the results, as shown in Figure 13, revealed a 0.2% MTBE solvent residue in the sample. HPLC / IC results showed that the molar ratio of the hydrochloride in the amorphous sample was 2.1:1 (hydrochloric acid:free base).

[0183] The repeated production on a 200 mg scale of the dihydrochloride form is as follows. 375.2 μL of a 2 moL / L ethyl acetate - hydrogen chloride solution was weighed out and diluted by adding 5.0 mL of MTBE. 200.1 mg of the free base was weighed and added to the clear solution in Step 1, and the mixture was suspended and stirred at room temperature for 2 days. The suspension was suction - filtered and vacuum - dried at room temperature for 5 hours, and 174.3 mg of the sample was collected. The XRPD of the repeatedly - produced hydrochloride sample is shown in Figure 2. 1 1H NMR was measured in DMSO - d6, and the results are shown in Figure 14. No residual MTBE solvent was observed. The HPLC / IC results showed that the molar ratio of the hydrochloride sample was 1.6:1 (hydrochloric acid: free base).

[0184] The production of the tetrahydrochloride sample is as follows. Ethyl acetate (480 mL) and the free base (24.0 g, 22.49 mmoL) were added to a 1 L three - necked flask, protected with nitrogen gas, cooled to 0 - 10 °C, and a solution of hydrogen chloride in ethyl acetate was gradually added dropwise. After the addition was complete, the temperature was raised to 20 - 30 °C, and the mixture was vigorously stirred for 24 - 30 hours, then filtered and washed with ethyl acetate (240 mL) (the filter cake was kept consistent in the ethyl acetate solution). The filter cake was returned to the flask, ethyl acetate (480 mL) was added, and the mixture was stirred for 0.5 - 1 hour, then filtered, washed with ethyl acetate (240 mL), quickly taken out and placed in a vacuum drying oven, and vacuum - dried at 50 °C for 12 - 24 hours to obtain the purified product. The total amount was 26.2 g, and the yield was 96.3%. The XRPD of the produced hydrochloride sample is shown in Figure 15. 1 1H NMR was measured in DMSO - d6, and the results are shown in Figure 16. Residual ethyl acetate as a solvent was observed. The results of hydrochloric acid measurement by HPLC and titration showed that the molar ratio of the hydrochloride sample was 4.15:1 (hydrochloric acid: free base) (the measured total purity was 97.32%, the free base content measured by quantitative nuclear magnetic resonance was 83%, and the hydrochloric acid content was 11.8%. The calculation method was the calculation method of the hydrochloric acid molar ratio. Number of moles of hydrochloric acid: hydrochloric acid content / mw(HCl)=11.8% / 36.5 = 3.23×10 -3 , number of moles of free base: free base content / mw(free base)=83% / 1066.95 = 7.78×10-4 Therefore, the molar ratio of hydrochloric acid to free base = moles of hydrochloric acid / moles of free base = 3.23 × 10⁻⁶ -3 / 7.8×10 -4 (=4.15).

[0185] Comparative Example 1: Screening test of hydrochloride solvent The inventors set up 10 suspension stirring tests at room temperature and 10 at 50°C using different solvents. Approximately 20 mg of the free base of the compound shown in formula (I) was weighed and placed in an HPLC glass vial, and 0.5 mL of the solvents shown in Tables 10 and 11 were added to each sample. The results showed that only colloid formation and clarified solutions were observed.

[0186] [Table 10]

[0187] [Table 11]

[0188] Experimental Example 1: Inhibition of phosphate and sodium absorption in the rat intestinal tract by single administration. The compounds represented by formula (I) were evaluated by measuring urinary phosphorus and sodium concentrations and fecal morphology.

[0189] Six-week-old Sprague-Dawley rats were purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. Two rats were placed in each cage in an SPF-grade animal room and allowed to acclimate for one week. Throughout the study period, the animals had free access to feed and water, and light exposure was cyclical, with 12 hours on and 12 hours off. The animals were divided into groups as follows: a solvent group (n=5), a tenapanor 0.3 mg / kg group (n=5), a compound represented by formula (I) 0.03 mg / kg group (n=5), a compound represented by formula (I) 0.1 mg / kg group (n=5), a compound represented by formula (I) 0.3 mg / kg group (n=5), and a compound represented by formula (I) 1.0 mg / kg group (n=5).

[0190] On the day of the experiment, the animals were fasted for 8 hours, after which the test compound or solvent (0.5% Tween 80 + 99.5% distilled water) was administered intragastricly. The animals were then moved to metabolic cages and housed in single cages, and their diet was restored. Sixteen hours after administration, urine samples were collected and food intake was recorded, and the fecal morphology in the collection funnel was evaluated based on two independent observations. The scoring criteria for fecal morphology were as follows: 1. Normal pellet, 2. Slightly soft stool (pellets adhering to the side wall of the collector due to moisture), 3. Soft stool (lost normal pellet shape), 4. Loose and irregular (completely lost shape with an imprint pattern), 5. Diarrhea (watery stool). The rat fecal morphology score (FFS) was measured by averaging two independent observation scores from all rats in the same group (n=5), with the mean value for the solvent group being 1.

[0191] Urine samples were centrifuged at 4°C and 3220 g for 5 minutes, and urinary phosphorus concentration (phosphomolybdate ultraviolet endpoint colorimetric method) and urinary sodium concentration (ion-selective electrode method) were measured.

[0192] The results were expressed as mean ± standard error (Means ± SEM). For standardization correction of urinary phosphorus excretion (or urinary sodium excretion) in rats and phosphorus (or sodium) intake from each food, the formulas were: Standardized correction value of urinary phosphorus excretion (expressed as nP) = urinary phosphorus excretion ÷ phosphorus intake from food, and Standardized correction value of urinary sodium excretion (expressed as nNa) = urinary sodium excretion ÷ sodium intake from food. One-way ANOVA was used, and fecal morphology scores were assessed using non-parametric tests. *, p<0.05, **, p<0.01, ***, p<0.001, ****, p<0.0001.

[0193] Figures 17-19 show the effects of a single dose of the compound represented by formula (I) on urinary phosphorus and sodium excretion and fecal morphology in normal rats. These results indicate that the compound represented by formula (I) exhibits a dose-response relationship in reducing urinary phosphorus excretion, and that doses of 0.3 mg / kg and 1.0 mg / kg significantly reduce urinary phosphorus excretion. At the same dose (0.3 mg / kg), the compound represented by formula (I) was more effective than Tenapanor in reducing urinary phosphorus excretion. The compound represented by formula (I) can significantly reduce urinary sodium excretion. The water content of rat feces tended to increase with increasing doses of the compound represented by formula (I).

[0194] Experimental Example 3: Effects of Multiple Administrations on Blood Phosphorus Concentration in Rats The compounds represented by formula (I) were evaluated by measuring serum phosphorus concentration, urinary phosphorus concentration, urinary sodium concentration, and fecal morphology in rats.

[0195] Six-week-old Sprague-Dawley rats were purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. Two rats were placed in each cage in an SPF-grade animal room and allowed to acclimate for one week. Throughout the study period, the animals had free access to feed and water, and light exposure was cyclical, with 12 hours on and 12 hours off. The animals were divided into the following groups: a solvent group (n=5), a Tenapanor 0.05 mg / kg group (n=5), a compound represented by formula (I) 0.01 mg / kg group (n=5), a compound represented by formula (I) 0.05 mg / kg group (n=5), a compound represented by formula (I) 0.5 mg / kg group (n=5), and a compound represented by formula (I) 1.0 mg / kg group (n=5).

[0196] After the start of the experiment, the rats were fasted for 16 hours overnight, and their feeding rhythm was adjusted to daytime feeding by allowing them to replenish their diet for 8 hours during the day. After the start of administration, the test compound or solvent (0.5% Tween 80 + 99.5% distilled water) was administered intragastricly twice a day at 4-hour intervals for 14 consecutive days between diet intakes. The animals' body weight and food intake were measured daily, serum phosphorus concentration (including baseline value before administration), 24-hour urinary phosphorus excretion, and 24-hour urinary sodium excretion were measured 1-2 times per week, and fecal morphology in the collection funnel was scored (fecal morphology was evaluated from two independent observations). The scoring criteria for fecal morphology were as follows: 1. Normal pellet, 2. Slightly soft stool (pellets adhering to the side wall of the collector due to moisture), 3. Soft stool (lost normal pellet shape), 4. Loose and irregular (completely lost shape with imprint pattern), 5. Diarrhea (watery stool). The rat fecal morphology score (FFS) was measured by averaging two independent observational scores from all rats in the same group (n=5), with the mean value for the solvent group being 1.

[0197] The experimental process is shown in Figure 20 below.

[0198] After allowing the blood to stand at room temperature for 2 hours, it was centrifuged at 4°C and 4500 g for 10 minutes, and the urine was centrifuged at 4°C and 3220 g for 5 minutes. Blood phosphorus concentration and urinary phosphorus concentration (phosphomolybdate ultraviolet endpoint colorimetric method) and urinary sodium concentration (indirect ion electrode method) were measured.

[0199] The results are expressed as mean ± standard error (Means ± SEM), with n=5 rats / group. For the standardized correction of urinary phosphorus excretion (or urinary sodium excretion) in rats to phosphorus (or sodium) intake from each food, the formulas are: Standardized correction value of urinary phosphorus excretion (expressed as nP) = urinary phosphorus excretion ÷ phosphorus intake from food, and Standardized correction value of urinary sodium excretion (expressed as nNa) = urinary sodium excretion ÷ sodium intake from food. Two-way ANOVA was used, and fecal morphology scores were assessed using non-parametric tests. *, p<0.05, **, p<0.01, ***, p<0.001, ****, p<0.0001.

[0200] Experimental results Blood phosphorus concentration Compared to the blood phosphorus concentration of rats in the solvent control group, the compound shown in formula (I) significantly reduced the blood phosphorus concentration of rats after 4 days of treatment at doses of 0.5 mg / kg or 1.0 mg / kg. Similarly, after 10 days of treatment at doses of 0.01 mg / kg, 0.05 mg / kg, 0.5 mg / kg, and 1.0 mg / kg, the blood phosphorus concentration of rats also significantly decreased. Except for the highest dose group of 1.0 mg / kg, the blood phosphorus levels in the other groups tended to remain stable. The compound shown in formula (I) has a blood phosphorus-lowering effect at a dose of 0.01 mg / kg, similar to the effect of Tenapanor at a dose of 0.05 mg / kg. Further details are shown in Figure 21 below.

[0201] Phosphorus excretion in urine When comparing the 24-hour nP levels of rats in each group with those of rats treated with a solvent, the compound shown in formula (I) showed a tendency to decrease in nP levels after 1 day of treatment at doses of 0.01 mg / kg, 0.05 mg / kg, 0.5 mg / kg, and 1.0 mg / kg. The decrease in nP levels increased with higher doses, and a significant decrease was observed at a dose of 1.0 mg / kg. After 10 days of treatment, nP levels decreased significantly at doses of 0.01 mg / kg, 0.05 mg / kg, 0.5 mg / kg, and 1.0 mg / kg. From there to 15 days, nP levels tended to stabilize, although the nP levels in the low-dose group (0.01 mg / kg) showed an increasing tendency. The compound shown in formula (I) has an effect of lowering rat nP levels at a dose of 0.01 mg / kg, similar to the effect of Tenapanor at a dose of 0.05 mg / kg. Further details are shown in Figure 22 below.

[0202] Urinary sodium excretion When comparing the 24-hour nNa levels of rats in each group with those of the solvent control group, the compound shown in formula (I) significantly reduced the nNa levels of rats after 1 day of treatment at doses of 0.01 mg / kg, 0.05 mg / kg, 0.5 mg / kg, and 1.0 mg / kg. However, after 10 days of treatment, the nNa levels of rats showed an increasing trend at doses of 0.01 mg / kg and 0.05 mg / kg. Further details are shown in Figure 23 below.

[0203] Fecal morphology score Compared to a solvent control group of rats, the compound shown in formula (I) significantly increased the fecal morphology score of rats after treatment for 1 day at doses of 0.05 mg / kg, 0.5 mg / kg, and 1.0 mg / kg. While rats receiving the higher doses of 0.5 mg / kg and 1.0 mg / kg experienced relatively severe loose stools, the number of observed loose stools decreased with continued administration. No loose stools occurred in rats treated with the low dose of 0.01 mg / kg. Further details are shown in Figure 24.

[0204] In this description, the terms "one embodiment," "several embodiments," "example," "specific example," or "several examples" mean that the specific features, structures, materials, or properties described in accordance with the embodiment or example are included in at least one embodiment or example of the present invention. In this description, the descriptive expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or properties described can be combined in an appropriate manner in any one or more embodiments or examples. Moreover, those skilled in the art can combine different embodiments or examples and the features of different embodiments or examples described in this description without contradiction.

[0205] Although the above examples have been described, these examples are illustrative and should not be understood as limiting the present invention. Those skilled in the art will understand that the above examples can be modified, altered, substituted, or transformed within the scope of the present invention.

Claims

1. A 1,5-naphthalenedisulfonate of the compound represented by formula (I) having the following structure, 【Chemistry 1】 、 Eventually, n = 0.9 to 2.

0. 1,5-naphthalenedisulfonate of the compound shown in formula (I).

2. A method for producing 1,5-naphthalenedisulfonate of the compound shown in formula (I), comprising the reaction shown below, 【Chemistry 2】 Eventually, n = 0.9 to 2.0, The reaction solvent is selected from isopropanol, ethyl acetate, or a mixture of isopropanol and ethyl acetate. method.

3. The molar ratio of the compound shown in formula (I) to the 1,5-naphthalenedisulfonic acid is 1:(1-4), Selectively, the dose ratio of the compound shown in formula (I) to isopropanol is (5-15) mmol:(50-150) mL. Optionally, the dose ratio of the compound represented by formula (I) to ethyl acetate is (5-15) mmol:(50-150) mL. Optionally, after the reaction, the method further includes stirring, suction filtration, and drying. Optionally, the stirring treatment may be carried out at room temperature for 2 days. Optionally, the suction filtration process is performed with nitrogen gas protection. Optionally, the drying process is carried out under vacuum conditions at room temperature for 2 hours. The method according to claim 2.

4. A hydrochloride salt of the compound shown in formula (I), having the following structure, 【Transformation 3】 、 Eventually, m = 1.6 to 4.

2. The hydrochloride salt of the compound shown in formula (I).

5. A method for producing the compound shown in formula (III-1), comprising the reaction shown below, 【Chemistry 4】 、 Eventually, m1 = 1.6 to 2.5, The reaction solvent is selected from methyl tert-butyl ether. method.

6. The molar ratio of the compound shown in formula (I) to the ethyl acetate-hydrogen chloride is (2-10):(1-5), Selectively, the dose ratio of the compound represented by formula (I) to methyl tert-butyl ether is (5-15) mmol:(50-150) mL. Optionally, after the reaction, the method further includes stirring, suction filtration, and drying. Optionally, the stirring treatment may be carried out at room temperature for 2 days. Optionally, the suction filtration process is performed with nitrogen gas protection. Optionally, the drying process is carried out under vacuum conditions at room temperature for 2 hours. The method according to claim 5.

7. A method for producing the compound shown in formula (III-2), 【Transformation 5】 、 Eventually, m2=3.8-4.2、 The reaction solvent is selected from methanol. method.

8. The above reaction was carried out under nitrogen gas conditions. Selectively, the molar ratio of the compound represented by formula (I) to the HCl / MeOH is (1-5):(2-10), Optionally, the dose ratio of the compound represented by formula (I) to methanol is (1-5) kg: (10-50) L. Optionally, the stirring process may be performed for 30 minutes. Optionally, the slurrying process is carried out in ethyl acetate for 2 hours. The method according to claim 7.

9. In the manufacture of a drug for inhibiting the reverse transport of NHE-mediated sodium ions or hydrogen ions, the 1,5-naphthalenedisulfonate of the compound represented by formula (I) according to claim 1, or the hydrochloride of the compound represented by formula (I) according to claim 4, use.

10. Use of 1,5-naphthalenedisulfonate of the compound represented by formula (I) according to claim 1, or hydrochloride of the compound represented by formula (I) according to claim 4, in the manufacture of a drug for treating a disease selected from irritable bowel syndrome, heart failure, chronic kidney disease, end-stage renal disease, or hepatic disease.

Images