Pharmaceutical composition containing heterocyclic compound and preparation method and application thereof

Abstract

# imgabs0 provides a pharmaceutical composition containing a heterocyclic compound as well as a preparation method and application of the pharmaceutical composition. The invention also provides a pharmaceutical composition Q, which comprises a substance X and pharmaceutic adjuvants, and the substance X is a compound as shown in the formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof. The pharmaceutical composition has one or more advantages as follows: the pharmaceutical composition is good in stability, good in dissolution performance, simple in preparation method and suitable for industrial production.

Description

Pharmaceutical composition containing heterocyclic compound and preparation method and application thereof

[0001] This application claims priority to Chinese patent application No. 202210938921.7, filed on August 5, 2022. This application incorporates the entire text of the aforementioned Chinese patent application. Technical Field

[0002] The present invention relates to a pharmaceutical composition comprising a heterocyclic compound, a preparation method and an application thereof. Background Art

[0003] Cation channels (such as transient receptor potential (TRP) cation channel subfamily C, member 5 (TRPC5)) regulate the flow of calcium and sodium ions through the cell membrane. The influx of sodium and calcium leads to the depolarization of the cell. This increases the possibility that voltage-gated ion channels will reach the threshold required for activation. Therefore, the activation of non-selective cation channels can increase electrical excitability and increase the frequency of voltage-dependent events. Voltage-dependent events include but are not limited to neuronal action potentials, cardiac action potentials, smooth muscle contraction, myocardial contraction, and skeletal muscle contraction.

[0004] The calcium influx caused by the activation of non-selective cation channels (such as TRPC5) also changes the intracellular free calcium concentration. Calcium is a ubiquitous second messenger molecule in cells, and the change of intracellular calcium levels has a profound impact on signal transduction and gene expression. Therefore, the activation of non-selective cation channels (such as TRPC5) can cause the change of gene expression and cell phenotype. Gene expression events include but are not limited to the generation of mRNA encoding cell surface receptors, ion channels and kinases. These changes in gene expression can cause the hyperexcitability in this cell.

[0005] Homomeric TRPC5 ion channels are signaling-gated, Ca-gated ion channels primarily expressed in neurons. 2+ Can pass through the channel. TRPC5 forms homomeric multi-subunit structures (such as tetramers (i.e., TRPC5 homo-multimers)) and heteromeric multi-subunit structures (such as tetramers (i.e., TRPC5-TRPC1 hetero-multimers)). Unless explicitly stated otherwise, when the term TRPC5 is used herein (e.g., when identifying a modulator of TRPC5, such as a TRPC5 antagonist), the term TRPC5 is used generally to include one or both of TRPC5 homo-multimers or hetero-multimers (e.g., TRPC5-TPRC1 or TRPC5-TRPC4 hetero-multimers).

[0006] Modulating the function of TRPC5 protein provides methods for regulating calcium homeostasis, sodium homeostasis, membrane polarization and / or intracellular calcium levels, and compounds that can modulate TRPC5 function can be used in many aspects, including but not limited to maintaining calcium homeostasis, regulating intracellular calcium levels, regulating membrane polarization, and treating or preventing diseases, disorders or conditions related to calcium and / or sodium homeostasis or dyshomeostasis.

[0007] Compounds that inhibit TRPC5 containing ion channels are useful, for example, for treating disorders by modulating the activity of transient receptor potential cation channel subfamily C, member 5 (TRPC5), which can exist in homomultimeric forms and in heteromultimeric forms with other ion channels such as TRPC1 or TRPC3 (i.e., TRPC5-TRPC1 and TRPC1-TRPC3-TRPC5).

[0008] TRPC5 is associated with diseases such as FSGS and diabetic nephropathy (J. Clin. Invest., December 2, 2013; 123(12): 5298-5309, Zhou et al., Science 358, 1332-1336 (2017). Focal segmental glomerulosclerosis (FSGS) is a clinicopathological syndrome with clinical manifestations of massive proteinuria or nephrotic syndrome. The pathology is characterized by focal segmental glomerular sclerosis and podocyte degeneration leading to foot process fusion or disappearance. FSGS accounts for approximately 5% to 10% of adult nephrotic syndrome in my country, and patients are more common in young and middle-aged men. In patients with persistent nephrotic syndrome, more than 50% progress to end-stage renal disease within 5 to 10 years.

[0009] In healthy glomeruli, TRPC5 is sequestered in the cytoplasm, maintaining normal filtration barriers. When podocytes are damaged, podocyte damage activates RAC1, causing TRPC5 to transfer from the cytoplasm to the cell membrane, which promotes AT1 receptor-induced calcium ion influx through the TRPC5 channel, further promoting RAC1 activity. RAC1 activation induces actin reorganization and podocyte detachment from the glomerulus; the loss of podocytes destroys the filtration barrier, allowing serum proteins to leak into the urine.

[0010] Currently, the main clinical treatments for FSGS are hormones, immunosuppressants, CNIs, and alkylating agents. These all have significant side effects, many require combination therapy with other medications to be effective, and are prone to relapse. Therefore, the development of new TRPC5 inhibitors holds great promise for the treatment of these diseases. Furthermore, developing pharmaceutical formulations containing these compounds that are suitable for drug development, such as those with stability and safety, to achieve optimal results during both the manufacturing and administration stages, remains a pressing technical challenge.

[0011] Summary of the Invention

[0012] The technical problem to be solved by the present invention is the lack of preparations of the heterocyclic compound represented by Formula I in the prior art. To this end, the present invention provides a pharmaceutical composition comprising the heterocyclic compound, a preparation method thereof, and an application thereof. The pharmaceutical composition has good stability and can be rapidly dissolved in phosphate buffer; and the preparation method of the pharmaceutical composition is simple and suitable for industrial production.

[0013] The present invention provides a pharmaceutical composition Q, which comprises a substance X and a pharmaceutical excipient;

[0014] Wherein, the substance X is a compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate of a compound represented by formula I, or a solvate of a pharmaceutically acceptable salt thereof;

[0015] The pharmaceutical excipients are selected from one or more of diluents, excipients, fillers, adhesives, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants and glidants.

[0016] In a certain embodiment, the pharmaceutical excipient is selected from one or more of a disintegrant, a filler, a lubricant and a glidant.

[0017] In one embodiment, the substance X is the only active ingredient.

[0018] In one embodiment, the amount of substance X is a therapeutically effective amount.

[0019] In one embodiment, the solvate of the compound of formula I is a conventional solvate in the art, including but not limited to a hydrate of the compound of formula I, an acetonitrile compound of the compound of formula I, or an N-methylpyrrolidone compound of the compound of formula I.

[0020] In one embodiment, the compound represented by formula I is in crystalline form.

[0021] In one embodiment, the solvate of the compound represented by formula I is a crystalline form.

[0022] In one embodiment, the substance X is a crystalline form B of the compound represented by formula I, wherein the crystalline form B of the compound represented by formula I has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles of 8.95±0.20°, 12.92±0.20°, 16.39±0.20°, 17.00±0.20°, 17.44±0.20°, 17.7 There are diffraction peaks at 6±0.20°, 18.08±0.20°, 19.02±0.20°, 21.95±0.20°, 22.20±0.20°, 23.49±0.20°, 24.15±0.20°, 24.92±0.20°, 25.94±0.20°, 27.14±0.20° and 29.68±0.20°.

[0023] In one embodiment, the crystalline form B of the compound represented by formula I has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, which further has diffraction peaks at one or more of the following positions: 10.63±0.20°, 11.69±0.20°, 13.52±0.20°, 14.49±0.20°, 14.74±0.20°, 15.83±0.20°, 18.81±0.20°, 19.72±0.20°, 21.27±0.20°, 22.62±0.20°, 22.99±0.20°, 25.41±0.20°, 25.74±0.20°, 26.18±0.20°, 26.58±0.20°, 27.85±0.20°, 28.23±0.20°, 28.70±0.20°, 29.16±0.20°, 30.17±0.20°, 30.51±0.20°, 31.20±0.20°, 32.16±0.20°, 32.52±0.20°, 32.74± 0.20°, 32.89±0.20°, 34.36±0.20°, 35.45±0.20°, 35.98±0.20°, 36.65±0.20°, 37.00±0.20°, 37.45±0.20°, 37.73±0.20°, 38.04±0.20°, 38.36±0.20° and 39.11±0.20°.

[0024] In one embodiment, the crystalline form B of the compound represented by formula I has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles of 8.95±0.20°, 10.63±0.20°, 11.69±0.20°, 12.92±0.20°, 13.52±0.20°, 14.49±0.20°, 14.74±0.20°, 15.83±0.20°, 16.39±0.20°, 17.00±0.20°, 17. .44±0.20°, 17.76±0.20°, 18.08±0.20°, 18.81±0.20°, 19.02±0.20°, 19.72±0.20°, 21.27±0.20°, 21.95±0.20°, 22.20±0.20°, 22.62±0.20°, 22.99±0.20°, 23.49±0.20°, 24.15±0.20°, 24.92±0.20°, 25. 41±0.20°, 25.74±0.20°, 25.94±0.20°, 26.18±0.20°, 26.58±0.20°, 27.14±0.20°, 27.85±0.20°, 28.23±0.20°, 28.70±0.20°, 29.16±0.20°, 29.68±0.20°, 30.17±0.20°, 30.51±0.20°, 31.20±0.20°, 32.1 There are diffraction peaks at 6±0.20°, 32.52±0.20°, 32.74±0.20°, 32.89±0.20°, 34.36±0.20°, 35.45±0.20°, 35.98±0.20°, 36.65±0.20°, 37.00±0.20°, 37.45±0.20°, 37.73±0.20°, 38.04±0.20°, 38.36±0.20° and 39.11±0.20°.

[0025] In one embodiment, the crystalline form B of the compound represented by formula I has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles having diffraction peaks as shown in Table 1.

[0026] In one embodiment, the crystalline form B of the compound represented by Formula I uses Cu-Kα radiation, and its X-ray powder diffraction (XRPD) pattern is shown in FIG8 .

[0027] In one embodiment, the crystalline form B of the compound represented by formula I has an endothermic peak at 247.7°C±3°C in its differential scanning calorimetry (DSC) curve.

[0028] In one embodiment, the differential scanning calorimetry curve of Form B of the compound represented by Formula I is shown in FIG9 .

[0029] In one embodiment, the crystalline form B of the compound represented by formula I has a thermogravimetric analysis (TGA) curve showing a weight loss of 1.0% in the temperature range of 35°C±3°C to 220°C±3°C.

[0030] In one embodiment, the thermogravimetric analysis curve of Form B of the compound represented by Formula I is shown in FIG10 .

[0031] In one embodiment, the crystalline form B of the compound represented by formula I is a solvent-free form.

[0032] In one embodiment, the crystalline form B of the compound represented by formula I is a solvent-free compound, and the solvent includes water, trifluoroacetic acid, and dichloromethane; for example, the solvent includes one or more of water, trifluoroacetic acid, and dichloromethane.

[0033] In a certain embodiment, in the pharmaceutical composition Q, the filler is conventional in the art. Preferably, the filler is one or more of lactose, lactose monohydrate, mannitol and microcrystalline cellulose. The microcrystalline cellulose is, for example, microcrystalline cellulose PH102, the lactose monohydrate is, for example, lactose monohydrate GRANULAC200, the mannitol is, for example, mannitol 200SD, and the lactose is, for example, lactose Flowlac100.

[0034] In a certain embodiment, in the pharmaceutical composition Q, the filler is any one of the following groups:

[0035] (a) The filler is a mixture of microcrystalline cellulose and lactose monohydrate, for example, a mixture of microcrystalline cellulose PH102 and lactose monohydrate GRANULAC200;

[0036] (b) the filler is a mixture of microcrystalline cellulose and lactose, for example, a mixture of microcrystalline cellulose PH102 and lactose Flowlac100;

[0037] (c) the filler is a mixture of microcrystalline cellulose and mannitol, for example, a mixture of microcrystalline cellulose PH102 and mannitol 200SD;

[0038] (d) The filler is mannitol, for example, mannitol 200SD.

[0039] In one embodiment, in the pharmaceutical composition Q, the disintegrant is conventional in the art. Preferably, the disintegrant is cross-linked sodium carboxymethyl cellulose, such as cross-linked sodium carboxymethyl cellulose SD711.

[0040] In a certain embodiment, in the pharmaceutical composition Q, the glidant is a conventional glidant in the art, for example, the glidant is silicon dioxide.

[0041] In one embodiment, in the pharmaceutical composition Q, the lubricant is a conventional lubricant in the art, for example, the lubricant is magnesium stearate.

[0042] In a certain embodiment, the pharmaceutical composition Q consists of the substance X and the pharmaceutical excipients.

[0043] In a certain embodiment, the pharmaceutical composition Q consists of the substance X, the disintegrant, the filler, the lubricant and the glidant.

[0044] In one embodiment, the content of the substance X in the pharmaceutical composition Q can be 5% to 15% by weight of the total weight of the pharmaceutical composition, for example, 10%.

[0045] In one embodiment, in the pharmaceutical composition Q, the content of the filler by weight may be 70% to 90% of the total weight of the pharmaceutical composition, preferably 80% to 90%, for example 85% or 88%.

[0046] In one embodiment, in the pharmaceutical composition Q, the filler is a mixture of microcrystalline cellulose and lactose monohydrate, a mixture of microcrystalline cellulose and lactose, or a mixture of microcrystalline cellulose and mannitol. The content of the filler by weight may be 70% to 90% of the total weight of the pharmaceutical composition, preferably 80% to 90%, for example 85% or 88%.

[0047] In one embodiment, in the pharmaceutical composition Q, the filler is mannitol, and the content of the filler by weight can be 80% to 90% of the total weight of the pharmaceutical composition, for example, 85% or 88%.

[0048] In one embodiment, in the pharmaceutical composition Q, the filler is a mixture of microcrystalline cellulose and lactose monohydrate, and the mass ratio of the lactose monohydrate to the microcrystalline cellulose can be 50:35 to 70:15, preferably 56:29 to 64:21, for example 56:29 or 64:21.

[0049] In one embodiment, in the pharmaceutical composition Q, the filler is a mixture of microcrystalline cellulose and lactose, and the mass ratio of the lactose to the microcrystalline cellulose can be 60:25 to 68:17, for example, 64:21.

[0050] In one embodiment, in the pharmaceutical composition Q, the filler is a mixture of microcrystalline cellulose and mannitol, and the mass ratio of the mannitol to the microcrystalline cellulose can be 60:25 to 68:17, for example, 64:21.

[0051] In the pharmaceutical composition Q, the content of the disintegrant by weight may be 2% to 5%, for example, 3%, of the total weight of the pharmaceutical composition.

[0052] In one embodiment, in the pharmaceutical composition Q, the disintegrant is croscarmellose sodium, and the content of croscarmellose sodium by weight can be 2% to 5%, for example, 3%, of the total weight of the pharmaceutical composition.

[0053] In one embodiment, the content of the glidant in the pharmaceutical composition Q can be 1% to 5% by weight, for example, 1% by weight, of the total weight of the pharmaceutical composition.

[0054] In one embodiment, the lubricant content in the pharmaceutical composition Q can be 1% to 5% by weight, for example, 1% by weight, of the total weight of the pharmaceutical composition.

[0055] In a certain embodiment, in the pharmaceutical composition Q, the mass ratio of the glidant to the lubricant may be 0.5:1.5 to 1.5:0.5, for example, 1:1.

[0056] In a certain embodiment, the pharmaceutical composition Q is composed of 5% to 15% of the substance X, 80% to 90% of the filler, 2% to 5% of the disintegrant, 1% to 5% of the lubricant and 1% to 5% of the glidant. Preferably, the pharmaceutical composition is composed of 10% of the substance X, 85% of the filler, 3% of the disintegrant, 1% of the lubricant and 1% of the glidant. Furthermore, the pharmaceutical composition is composed of 10% of the crystalline form B of the compound represented by Formula I, 85% of the filler, 3% of the cross-linked sodium carboxymethyl cellulose, 1% of the magnesium stearate and 1% of the silicon dioxide. The percentages are the mass ratios of the pharmaceutical composition.

[0057] In a certain embodiment, the pharmaceutical composition Q is selected from any one of the following groups:

[0058] Pharmaceutical composition 1: 10% substance X, 56% lactose monohydrate, 29% microcrystalline cellulose, 3% croscarmellose sodium, 1% silicon dioxide, and 1% magnesium stearate;

[0059] Pharmaceutical composition 2: 10% substance X, 64% lactose monohydrate, 21% microcrystalline cellulose, 3% croscarmellose sodium, 1% silicon dioxide, and 1% magnesium stearate;

[0060] Pharmaceutical composition 3: 10% substance X, 64% mannitol, 21% microcrystalline cellulose, 3% croscarmellose sodium, 1% silicon dioxide, and 1% magnesium stearate;

[0061] Pharmaceutical composition 4: 10% substance X, 64% lactose, 21% microcrystalline cellulose, 3% croscarmellose sodium, 1% silicon dioxide, and 1% magnesium stearate;

[0062] Pharmaceutical composition 5: 10% substance X, 85% mannitol, 3% croscarmellose sodium, 1% silicon dioxide, and 1% magnesium stearate;

[0063] The percentage is the mass ratio of the pharmaceutical composition.

[0064] In a certain embodiment, the pharmaceutical composition Q is selected from any one of the following groups:

[0065] Pharmaceutical composition 6: 10% crystalline form B of the compound of formula I, 56% lactose monohydrate GRANULAC200, 29% microcrystalline cellulose PH102, 3% croscarmellose sodium SD711, 1% silicon dioxide and 1% magnesium stearate;

[0066] Pharmaceutical composition 7: 10% crystalline form B of the compound of formula I, 64% lactose monohydrate GRANULAC200, 21% microcrystalline cellulose PH102, 3% croscarmellose sodium SD711, 1% silicon dioxide, and 1% magnesium stearate;

[0067] Pharmaceutical composition 8: 10% Form B of the compound of Formula I, 64% mannitol 200SD, 21% microcrystalline cellulose PH102, 3% croscarmellose sodium SD711, 1% silicon dioxide, and 1% magnesium stearate;

[0068] Pharmaceutical composition 9: 10% Form B of the compound of Formula I, 64% lactose Flowlac100, 21% microcrystalline cellulose PH102, 3% croscarmellose sodium SD711, 1% silicon dioxide, and 1% magnesium stearate;

[0069] Pharmaceutical composition 10: 10% crystalline form B of the compound represented by Formula I, 85% mannitol 200SD, 3% cross-linked carboxymethyl cellulose sodium SD711, 1% silicon dioxide and 1% magnesium stearate; the percentages are the mass ratios of the pharmaceutical composition.

[0070] In one embodiment, the pharmaceutical composition Q is administered orally.

[0071] In a certain embodiment, the pharmaceutical composition Q has a strength of 10 mg / portion or 40 mg / portion.

[0072] In one embodiment, the pharmaceutical composition Q can be a solid preparation, such as a solid oral preparation.

[0073] In one embodiment, the pharmaceutical composition Q can be a tablet or a capsule, for example, a capsule.

[0074] In one embodiment, the pharmaceutical composition Q is a pharmaceutical composition for treating and / or preventing psychiatric disorders, neurological disorders, neurodegenerative disorders or renal diseases.

[0075] In one embodiment, the psychiatric disorder, neurological disorder or neurodegenerative disorder can be selected from: diseases associated with dysregulated emotional processing (e.g., borderline personality disorder or depression, such as major depressive disorder, major depressive disorder, dysthymia, dysthymia and postpartum depression, and bipolar disorder), disorders associated with anxiety and fear (e.g., post-traumatic stress disorder, panic disorder, agoraphobia, social phobia, generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder and separation anxiety), memory disorders (e.g., Alzheimer's disease, amnesia, aphasia, brain injury, brain tumor, chronic fatigue syndrome, Creutzfeldt-Jakob disease, dissociative amnesia, fugue amnesia, Huntington's disease, learning disorders, sleep disorders, multiple personality disorder, pain, post-traumatic stress disorder, schizophrenia, sports injuries, stroke and Weil-Cohen syndrome), disorders associated with impaired impulse control and addiction, Parkinson's disease, amyotrophic lateral sclerosis, epilepsy, and other brain disorders caused by trauma or other insults including aging.

[0076] The renal disease may be focal segmental glomerulosclerosis, minimal change disease, diabetic nephropathy, Alport syndrome, hypertensive nephropathy, nephrotic syndrome, steroid-resistant nephrotic syndrome, membranous nephropathy, idiopathic membranous nephropathy, membranoproliferative glomerulonephritis, immune complex-mediated MPGN, complement-mediated MPGN, lupus nephritis, post-infectious glomerulonephritis, thin basement membrane disease, mesangial proliferative glomerulonephritis, amyloidosis nephropathy (preferably primary amyloidosis nephropathy), C1q nephropathy, rapidly progressive glomerulonephritis, anti-glomerular basement membrane disease, C3 glomerulonephritis, hypertensive nephrosclerosis, primary glomerular disease (preferably IgA nephropathy).

[0077] The present invention provides a pharmaceutical composition R, which comprises the pharmaceutical composition Q and a capsule shell, wherein the pharmaceutical composition Q is filled in the capsule shell.

[0078] In one embodiment, in the pharmaceutical composition R, the capsule shell is a conventional capsule shell in the art, such as an HPMC capsule shell or a gelatin capsule shell, preferably an HPMC capsule shell.

[0079] In one embodiment, the pharmaceutical composition R is composed of the pharmaceutical composition Q and a capsule shell, and the pharmaceutical composition Q is filled in the capsule shell.

[0080] In a certain embodiment, the pharmaceutical composition R is selected from any one of the following groups:

[0081] Pharmaceutical composition 1: 10% substance X, 56% lactose monohydrate, 29% microcrystalline cellulose, 3% croscarmellose sodium, 1% silicon dioxide, 1% magnesium stearate and the capsule shell;

[0082] Pharmaceutical composition 2: 10% substance X, 64% lactose monohydrate, 21% microcrystalline cellulose, 3% croscarmellose sodium, 1% silicon dioxide, 1% magnesium stearate, and the capsule shell;

[0083] Pharmaceutical composition 3: 10% substance X, 64% mannitol, 21% microcrystalline cellulose, 3% croscarmellose sodium, 1% silicon dioxide, 1% magnesium stearate and the capsule shell;

[0084] Pharmaceutical composition 4: 10% substance X, 64% lactose, 21% microcrystalline cellulose, 3% croscarmellose sodium, 1% silicon dioxide, 1% magnesium stearate, and the capsule shell;

[0085] Pharmaceutical composition 5: 10% substance X, 85% mannitol, 3% croscarmellose sodium, 1% silicon dioxide, 1% magnesium stearate and the capsule shell;

[0086] The percentage is the mass ratio of the pharmaceutical composition.

[0087] In a certain embodiment, the pharmaceutical composition R is selected from any one of the following groups:

[0088] Pharmaceutical composition 6: 10% crystalline form B of the compound represented by formula I, 56% lactose monohydrate GRANULAC200, 29% microcrystalline cellulose PH102, 3% cross-linked sodium carboxymethylcellulose SD711, 1% silicon dioxide, 1% magnesium stearate and the HPMC capsule shell;

[0089] Pharmaceutical composition 7: 10% crystalline form B of the compound represented by formula I, 64% lactose monohydrate GRANULAC200, 21% microcrystalline cellulose PH102, 3% cross-linked carboxymethyl cellulose sodium SD711, 1% silicon dioxide, 1% magnesium stearate and the HPMC capsule shell;

[0090] Pharmaceutical composition 8: 10% crystalline form B of the compound of formula I, 64% mannitol 200SD, 21% microcrystalline cellulose PH102, 3% croscarmellose sodium SD711, 1% silicon dioxide, 1% magnesium stearate, and the HPMC capsule shell;

[0091] Pharmaceutical composition 9: 10% crystalline form B of the compound of formula I, 64% lactose Flowlac100, 21% microcrystalline cellulose PH102, 3% cross-linked sodium carboxymethylcellulose SD711, 1% silicon dioxide, 1% magnesium stearate and the HPMC capsule shell;

[0092] Pharmaceutical composition 10: 10% crystalline form B of the compound represented by formula I, 85% mannitol 200SD, 3% cross-linked carboxymethylcellulose sodium SD711, 1% silicon dioxide, 1% magnesium stearate and the HPMC capsule shell;

[0093] Pharmaceutical composition 11: 10% crystalline form B of the compound represented by formula I, 56% lactose monohydrate GRANULAC200, 29% microcrystalline cellulose PH102, 3% cross-linked sodium carboxymethyl cellulose SD711, 1% silicon dioxide, 1% magnesium stearate, and the gelatin capsule shell;

[0094] Pharmaceutical composition 12: 10% crystalline form B of the compound represented by formula I, 64% lactose monohydrate GRANULAC200, 21% microcrystalline cellulose PH102, 3% cross-linked carboxymethyl cellulose sodium SD711, 1% silicon dioxide, 1% magnesium stearate, and the gelatin capsule shell;

[0095] Pharmaceutical composition 13: 10% crystalline form B of the compound represented by formula I, 64% mannitol 200SD, 21% microcrystalline cellulose PH102, 3% croscarmellose sodium SD711, 1% silicon dioxide, 1% magnesium stearate, and the gelatin capsule shell;

[0096] Pharmaceutical composition 14: 10% crystalline form B of the compound represented by formula I, 64% lactose Flowlac100, 21% microcrystalline cellulose PH102, 3% cross-linked carboxymethyl cellulose sodium SD711, 1% silicon dioxide, 1% magnesium stearate, and the gelatin capsule shell;

[0097] Pharmaceutical composition 15: 10% crystalline form B of the compound represented by Formula I, 85% mannitol 200SD, 3% cross-linked carboxymethyl cellulose sodium SD711, 1% silicon dioxide, 1% magnesium stearate and the gelatin capsule shell; the percentages are the mass ratios of the pharmaceutical composition.

[0098] In one embodiment, the pharmaceutical composition R is administered orally.

[0099] In a certain embodiment, the pharmaceutical composition R has a dosage of 10 mg / pill or 40 mg / pill.

[0100] In one embodiment, the pharmaceutical composition R may be a solid preparation, such as a solid oral preparation.

[0101] In one embodiment, the pharmaceutical composition R may be a capsule.

[0102] In one embodiment, the pharmaceutical composition R is a pharmaceutical composition for treating and / or preventing psychiatric disorders, neurological disorders, neurodegenerative disorders or renal diseases.

[0103] In one embodiment, the psychiatric disorder, neurological disorder or neurodegenerative disorder can be selected from the group consisting of disorders associated with dysregulated emotional processing (e.g., borderline personality disorder or depression, such as major depressive disorder, major depressive disorder, dysthymia, dysthymia and postpartum depression, and bipolar disorder), disorders associated with anxiety and fear (e.g., post-traumatic stress disorder, panic disorder, agoraphobia, social phobia, generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder, and separation anxiety), memory disorders (e.g., Alzheimer's disease, amnesia, aphasia, brain injury, brain tumors, chronic fatigue syndrome, Creutzfeldt-Jakob disease, dissociative amnesia, fugue amnesia, Huntington's disease, learning disorders, sleep disorders, multiple personality disorder, pain, post-traumatic stress disorder, schizophrenia, sports injuries, stroke, and Weil-Cohen syndrome), disorders associated with impaired impulse control and addiction, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, epilepsy, and other brain disorders caused by trauma or other insults including aging.

[0104] The renal disease is focal segmental glomerulosclerosis, minimal change disease, diabetic nephropathy, Alport syndrome, hypertensive nephropathy, nephrotic syndrome, steroid-resistant nephrotic syndrome, membranous nephropathy, idiopathic membranous nephropathy, membranoproliferative glomerulonephritis, immune complex-mediated MPGN, complement-mediated MPGN, lupus nephritis, post-infectious glomerulonephritis, thin basement membrane disease, mesangial proliferative glomerulonephritis, amyloidosis nephropathy (preferably primary amyloidosis nephropathy), C1q nephropathy, rapidly progressive glomerulonephritis, anti-glomerular basement membrane disease, C3 glomerulonephritis, hypertensive nephrosclerosis, primary glomerular disease (preferably IgA nephropathy).

[0105] The present invention provides a method for preparing the pharmaceutical composition Q, which preferably comprises the following steps:

[0106] (a) mixing the substance X and a portion of the filler to obtain a mixture M;

[0107] (b) mixing the remaining filler, the disintegrant, and the silicon dioxide with the obtained mixture M, and adding magnesium stearate to obtain the pharmaceutical composition Q;

[0108] Wherein, the types and contents of the substance X, the disintegrant and the filler are as described in any one of the present invention; the silicon dioxide is a glidant, and the magnesium stearate is a lubricant.

[0109] In the method for preparing the pharmaceutical composition, in step (a), the mass ratio of the filler to the substance X may be 3:1.

[0110] In the preparation method of the pharmaceutical composition, in step (a), the filler can be one or more of the lactose, the lactose monohydrate and the mannitol.

[0111] In the method for preparing the pharmaceutical composition, in step (b), the disintegrant may be croscarmellose sodium.

[0112] In the method for preparing the pharmaceutical composition, in step (a), the substance X or the filler may be the substance X or the filler of 30 mesh.

[0113] In the method for preparing the pharmaceutical composition, in step (b), the filler, the disintegrant or the silicon dioxide can be the filler of 30 mesh, the disintegrant of 30 mesh or the silicon dioxide of 30 mesh.

[0114] In the method for preparing the pharmaceutical composition, in step (b), the mixing condition may be stirring at 20 rpm for 10 to 60 min, for example, stirring at 20 rpm for 20 min.

[0115] In the method for preparing the pharmaceutical composition, in step (b), the magnesium stearate may be 60-mesh magnesium stearate.

[0116] In the method for preparing the pharmaceutical composition, in step (b), the adding condition may be stirring at 20 rpm for 2 to 10 minutes, for example, 3 minutes.

[0117] The preparation method of the pharmaceutical composition preferably comprises the following steps: mixing 3 times the mass of the substance X of 30-mesh lactose (e.g., lactose Flowlac100), 30-mesh lactose monohydrate (e.g., lactose monohydrate GRANULAC200), or 30-mesh mannitol (mannitol 200SD) with the 30-mesh substance X to obtain a mixture M; mixing the 30-mesh filler, the 30-mesh disintegrant, and the 30-mesh silicon dioxide with the mixture M (e.g., stirring at 20 rpm for 20 minutes); and adding 60-mesh magnesium stearate and mixing (e.g., stirring at 20 rpm for 3 minutes) to obtain the pharmaceutical composition Q.

[0118] The present invention provides a method for preparing a pharmaceutical composition R, which comprises filling the pharmaceutical composition Q into capsules.

[0119] In the preparation method of the pharmaceutical composition R, the capsule can be a conventional capsule in the art, such as an HPMC capsule shell or a gelatin capsule shell, preferably an HPMC capsule shell.

[0120] In the preparation method of the pharmaceutical composition R, the capsule filling can be performed using a fully automatic capsule filling machine, for example, the model of the fully automatic capsule filling machine is In-Cap XL.

[0121] The present invention provides a use of a substance Y in preparing a medicine, wherein the substance Y is the above-mentioned pharmaceutical composition Q or pharmaceutical composition R; the medicine is a medicine for treating and / or preventing TRPC5-mediated diseases.

[0122] In the application, the TRPC5-mediated disease can be a psychiatric disorder, a neurological disorder, a neurodegenerative disorder or a renal disease.

[0123] The psychiatric, neurological or neurodegenerative disorder can be selected from the group consisting of disorders associated with dysregulated emotional processing (e.g., borderline personality disorder or depression, such as major depressive disorder, major depressive disorder, dysthymia, dysthymia and postpartum depression, and bipolar disorder), disorders associated with anxiety and fear (e.g., post-traumatic stress disorder, panic disorder, agoraphobia, social phobia, generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder and separation anxiety), memory disorders (e.g., Alzheimer's disease, amnesia, aphasia, brain injury, brain tumors, chronic fatigue syndrome, Creutzfeldt-Jakob disease, dissociative amnesia, fugue amnesia, Huntington's disease, learning disorders, sleep disorders, multiple personality disorder, pain, post-traumatic stress disorder, schizophrenia, sports injuries, stroke and Weil-Cohen syndrome), disorders associated with impaired impulse control and addiction, Parkinson's disease, amyotrophic lateral sclerosis, epilepsy, and other brain disorders caused by trauma or other insults including aging.

[0124] The renal disease is focal segmental glomerulosclerosis, minimal change disease, diabetic nephropathy, Alport syndrome, hypertensive nephropathy, nephrotic syndrome, steroid-resistant nephrotic syndrome, membranous nephropathy, idiopathic membranous nephropathy, membranoproliferative glomerulonephritis, immune complex-mediated MPGN, complement-mediated MPGN, lupus nephritis, post-infectious glomerulonephritis, thin basement membrane disease, mesangial proliferative glomerulonephritis, amyloidosis nephropathy (preferably primary amyloidosis nephropathy), C1q nephropathy, rapidly progressive glomerulonephritis, anti-glomerular basement membrane disease, C3 glomerulonephritis, hypertensive nephrosclerosis, primary glomerular disease (preferably IgA nephropathy).

[0125] The present invention provides a use of a substance Y in preparing a medicine, wherein the substance Y is the above-mentioned pharmaceutical composition Q or pharmaceutical composition R, and the medicine is a medicine for treating and / or preventing mental disorders, neurological disorders, neurodegenerative disorders or kidney diseases.

[0126] In such applications, the psychiatric, neurological or neurodegenerative disorder may be selected from the group consisting of disorders associated with dysregulated emotional processing (e.g., borderline personality disorder or depression, such as major depressive disorder, major depressive disorder, dysthymia, dysthymia and postpartum depression, and bipolar disorder), disorders associated with anxiety and fear (e.g., post-traumatic stress disorder, panic disorder, agoraphobia, social phobia, generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder and separation anxiety), memory disorders (e.g., Alzheimer's disease, amnesia, aphasia, brain injury, brain tumor, chronic fatigue syndrome, Creutzfeldt-Jakob disease, dissociative amnesia, fugue amnesia, Huntington's disease, learning disorders, sleep disorders, multiple personality disorder, pain, post-traumatic stress disorder, schizophrenia, sports injuries, stroke and Weil-Cohen syndrome), disorders associated with impaired impulse control and addiction, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, epilepsy, and other brain disorders caused by trauma or other insults including aging.

[0127] The renal disease is focal segmental glomerulosclerosis, minimal change disease, diabetic nephropathy, Alport syndrome, hypertensive nephropathy, nephrotic syndrome, steroid-resistant nephrotic syndrome, membranous nephropathy, idiopathic membranous nephropathy, membranoproliferative glomerulonephritis, immune complex-mediated MPGN, complement-mediated MPGN, lupus nephritis, post-infectious glomerulonephritis, thin basement membrane disease, mesangial proliferative glomerulonephritis, amyloidosis nephropathy (preferably primary amyloidosis nephropathy), C1q nephropathy, rapidly progressive glomerulonephritis, anti-glomerular basement membrane disease, C3 glomerulonephritis, hypertensive nephrosclerosis or primary glomerular disease (preferably IgA nephropathy).

[0128] Explanation of terms:

[0129] The term "filler," also known as "diluent," refers to a class of excipients used in a scientific context to increase the bulk and weight of a pharmaceutical composition product dosage form. Thus, fillers can include, for example, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, cellulose acetate, ethyl cellulose, fructose, lactose, lactose monohydrate, lactitol, maltose, maltodextrin, maltitol, mannitol, microcrystalline cellulose, polydextrose, polyethylene glycol, sodium bicarbonate, sodium carbonate, sodium chloride, sorbitol, corn starch, dextrin, sucrose, trehalose, and xylitol.

[0130] The term "disintegrant" refers to a class of excipients used in a scientific context to promote the breakdown of pharmaceutical composition product dosage forms into smaller fragments in an aqueous environment. Thus, disintegrants can be, for example, alginic acid, calcium alginate, calcium carboxymethylcellulose, chitosan, colloidal silicon dioxide, croscarmellose sodium, crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, hypromellose, glycine, guar gum, hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose, povidone, sodium alginate, sodium carboxymethyl cellulose, sodium starch glycolate, and starch.

[0131] The term "lubricant" refers to a class of excipients used in a scientific context to improve the processing of pharmaceutical composition product dosage forms. Examples of lubricants include calcium stearate, glyceryl monostearate, glyceryl behenate, magnesium stearate, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium benzoate, sodium lauryl sulfate, sodium stearate, sodium stearyl fumarate, stearic acid, talc, micronized silica gel, and zinc stearate.

[0132] The term "glidant" refers to a type of excipient that reduces interparticle friction and improves powder flowability. Glidants can be, for example, silicon dioxide or micronized silica gel.

[0133] The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention with a relatively nontoxic, pharmaceutically acceptable acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acid includes inorganic acids, including, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. The pharmaceutically acceptable acid includes organic acids, including but not limited to acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid, tannic acid, pantothenic acid, bitartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e., 4,4'-methylene-bis(3-hydroxy-2-naphthoic acid)), amino acids (e.g., glutamic acid, arginine), etc. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0134] The term "solvate" refers to a compound of the present invention combined with a stoichiometric or non-stoichiometric amount of a solvent. The solvent molecules in the solvate may be present in an ordered or non-ordered arrangement. Such solvents include, but are not limited to, water, methanol, and ethanol.

[0135] The term "pharmaceutically acceptable salt" and "solvate" as used herein refer to substances prepared from the compounds of the present invention and relatively non-toxic, pharmaceutically acceptable acids or bases, in combination with stoichiometric or non-stoichiometric amounts of solvents.

[0136] As used herein, the term "pharmaceutical excipients" refers to excipients and additives used in the production of pharmaceuticals and the preparation of prescriptions. These excipients are all substances contained in pharmaceutical preparations, other than the active ingredient. For a complete list, see the Pharmacopoeia of the People's Republic of China (2020 Edition), Part IV, or the Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

[0137] The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that leads to or causes the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.

[0138] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0139] The term "patient" refers to any animal, preferably a mammal, that is about to be or has been administered a compound or composition according to embodiments of the present invention. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., preferably humans.

[0140] The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a patient, is sufficient to effectively treat a disease or condition described herein. The "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, and can be adjusted as needed by those skilled in the art.

[0141] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0142] The reagents and raw materials used in the present invention are commercially available.

[0143] The positive progress of the present invention is that the pharmaceutical composition provided by the present invention has good stability and good dissolution performance; the preparation method of the pharmaceutical composition is simple and suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0144] Figure 1 is the XRPD spectrum of Form A.

[0145] Figure 2 is the DSC spectrum of Form A.

[0146] Figure 3 is the TGA spectrum of Form A.

[0147] Figure 4 shows the crystal form A 1 H-NMR spectrum (DMSO-d6);

[0148] Figure 5 shows the crystal form A 1 H-NMR spectrum (D2O).

[0149] Figure 6 is the PLM spectrum of Form A.

[0150] FIG7 is the FT-IR spectrum of Form A.

[0151] FIG8 is an XRPD spectrum of Form B of the compound represented by Formula I.

[0152] FIG9 is a DSC spectrum of Form B of the compound represented by Formula I.

[0153] Figure 10 is a TGA spectrum of Form B of the compound represented by Formula I.

[0154] Figure 11 is a diagram of the crystal form B of the compound represented by Formula I 1 H-NMR spectrum.

[0155] Figure 12 is a PLM spectrum of Form B of the compound represented by Formula I.

[0156] FIG13 is an FT-IR spectrum of Form B of the compound represented by Formula I.

[0157] FIG14 shows the dissolution curves of 10 mg and 40 mg HPMC capsules of Formulation 1.

[0158] FIG15 shows the dissolution curves of 10 mg and 40 mg HPMC capsules of Formulation 2.

[0159] FIG16 shows the dissolution curves of 10 mg and 40 mg HPMC capsules and 40 mg gelatin capsules of Formulation 3.

[0160] FIG17 shows the dissolution curves of 40 mg HPMC capsules and gelatin capsules of prescription 4.

[0161] FIG18 shows the dissolution curves of 10 mg and 40 mg HPMC capsules of Formulation 5.

[0162] FIG19 shows the dissolution curves of 10 mg and 40 mg gelatin capsules of prescription 5.

[0163] FIG20 is the stability dissolution curve of 10 mg HPMC capsules of Formulation 5 under 25° C. / 60% RH conditions.

[0164] FIG21 is the stability dissolution curve of 40 mg HPMC capsules of Formulation 5 under 25° C. / 60% RH conditions.

[0165] FIG22 is the stability dissolution curve of 10 mg HPMC capsules of Formulation 5 under 40° C. / 75% RH conditions.

[0166] FIG23 is the stability dissolution curve of 40 mg HPMC capsules of Formulation 5 under 40° C. / 75% RH conditions.

[0167] FIG24 is a comparison of XRPD patterns of 10 mg HPMC capsules of Formulation 5 at 40° C. / 75% RH for 0 days and 2 months.

[0168] FIG25 is a comparison of XRPD patterns of 40 mg HPMC capsules of Formulation 5 at 40° C. / 75% RH for 0 days and 2 months.

[0169] FIG26 is the stability dissolution curve of 10 mg gelatin capsules of Formulation 5 under 40° C. / 75% RH conditions.

[0170] FIG27 is the stability dissolution curve of 40 mg gelatin capsules of prescription 5 under 40° C. / 75% RH conditions.

[0171] FIG28 is a comparison of XRPD patterns of 10 mg gelatin capsules of prescription 5 at 40° C. / 75% RH for 0 days and 1 month.

[0172] FIG29 is a comparison of XRPD patterns of 40 mg gelatin capsules of Formulation 5 at 40° C. / 75% RH for 0 days and 1 month.

[0173] Figure 30 is the stability dissolution curve of 40 mg gelatin capsules of prescription 5 under high temperature conditions of 60°C.

[0174] FIG31 is an XRPD overlay of Form B of the compound of Formula I before and after pressure and grinding tests. DETAILED DESCRIPTION

[0175] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0176] Abbreviations:

[0177] ACN: acetonitrile; API: active pharmaceutical ingredient; DMSO: dimethyl sulfoxide; DSC: differential scanning calorimetry; DVS: dynamic water sorption; FT-IR: Fourier transform infrared spectroscopy; HPLC: high performance liquid chromatography; PLM: polarizing microscopy; RH: relative humidity; SD: standard deviation; TGA: thermogravimetric analysis; T onset : initial temperature / onset temperature; XRPD: X-ray powder diffraction.

[0178] Instrumental method:

[0179] 1. X-ray diffraction (XRPD), the method is shown in the following table:

[0180] 2. Differential Scanning Calorimetry (DSC) analysis, the method is shown in the following table:

[0181] 3. Thermogravimetric analysis (TGA), the method is shown in the following table:

[0182] 4. Nuclear Magnetic Resonance ( 1 H-NMR), the method is shown in the following table:

[0183] 5. Fourier transform infrared spectroscopy (FT-IR), the method is shown in the following table:

[0184] 6.Karl Fisher, the method is shown in the following table:

[0185] 7. Polarized light microscopy (PLM), the method is as shown in the following table:

[0186] 8. Information on excipients used in the experiment is shown in the table below:

[0187] 9. Capsule dissolution method, see the table below:

[0188] 10. The relevant parameters of capsule dissolution solution are shown in the table below:

[0189] 11. Capsules canned:

[0190] The sub-packaged materials are canned using a fully automatic capsule filling machine (model: In-Cap XL). The canning parameters are as follows:

[0191] Preparation Example

[0192] Compound 1-1 was prepared according to the method described in WO2022 / 001767A1.

[0193] Example 1 Preparation of Form A

[0194] Synthesis route:

[0195] 1.1 Preparation of Compound 1-2

[0196] Compound 1-1 (100 g, 0.23 mol), sodium iodide (37.3 g, 0.25 mmol) and tetrahydrofuran (1 L) were added to the reaction flask, stirred to dissolve, and cooled to about 0°C in an ice bath. Lithium tert-butoxide (1 M tetrahydrofuran solution, 271.6 mL, 0.28 mol) was added dropwise to the reaction solution. After the addition was complete, di-tert-butyl chloromethyl phosphate (87.8 g, 0.34 mol) was added to the reaction solution. The reaction solution was warmed to room temperature (about 18°C) and reacted for 12 hours. The reaction solution was quenched with water and concentrated to remove tetrahydrofuran at a temperature below 25°C. Ethyl acetate (1 L × 2) was added to the concentrated system for extraction. The organic phase was washed with saturated brine (1 L), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 1-2 (55 g). LC-MS [M+H] + =664.2.

[0197] 1.2 Preparation of Form A

[0198] Compound 1-2 (55 g, 83 mmol) was dissolved in dichloromethane (500 mL). Trifluoroacetic acid (100 mL) was added dropwise to the reaction mixture with stirring, and the mixture was stirred at 25°C for 1 hour. After the reaction was completed (LCMS showed a purity of 80%), the mixture was concentrated under reduced pressure to obtain a crude oily product of the compound represented by Formula I. Acetonitrile (50 mL) was added to the crude product for dispersion, resulting in solid precipitation. Ethanol (400 mL) was slowly added dropwise to the system, resulting in a large amount of solid precipitation. The mixture was stirred at room temperature (approximately 17°C) for 1 hour and filtered. The filter cake was slurried with a mixed solvent of acetonitrile and water (300 mL, 5 / 1 (v / v)) at room temperature (approximately 17°C). This operation was repeated several times until the purity of the compound reached 98% or higher. The resulting solid was lyophilized to obtain Form A as a white solid. Its XRPD spectrum analysis data are shown in the table below.

[0199] LC-MS[M+H] + =552.0; 1H NMR (400MHz, DMSO-d6): δ8.14(s,1H),7.84(dd,J=9.2,2.8Hz,1H),7.79(dd,J=8.4,5.6Hz,1H),7.68(td,J=8 .4, 2.6Hz, 1H), 7.36 (s, 1H), 5.68 (d, J = 7.6Hz, 2H), 4.91 (s, 2H), 4.54 (t, J = 5.6Hz, 2H), 3.98 (t, J = 5.6Hz, 2H).

[0200] The characterization data of Form A are shown in the following table:

[0201] The XRPD pattern analysis data of Form A are shown in the table below:

[0202] Example 2 Preparation of Form B of the Compound of Formula I

[0203] Weigh approximately 30 mg of Form A obtained in Example 1 and add 0.3 mL of water to ensure a suspension of appropriate concentration. Stir the suspension at 50°C to 5°C for 10 cycles at a heating and cooling rate of 0.1°C / min. After the cycles, centrifuge the resulting solid through a 0.45 μm filter at 5°C for 5 minutes. The resulting solid was used as seed crystals for the next step.

[0204] Weigh 400 mg of Form A and place it in an 8 mL glass bottle. Add 4 mL of water and stir at 50 ° C for 30 minutes to obtain a suspension. Add about 5 mg of the seed crystals prepared above to the above suspension. Place the sample on a temperature-controlled cycler and stir the suspension at 50 ° C to 5 ° C for 6 cycles at a temperature-controlled rate of 0.1 ° C / min. Centrifuge and filter to collect the solid. After the solid was vacuum-dried at 50 ° C for 2 hours, 333.0 mg of off-white Form B was obtained with a yield of 83.3%. The XRPD spectrum analysis data are shown in Table 1 below. Form B of the compound shown in Formula I is the API in the following prescription.

[0205] The characterization data of Form B of the compound represented by Formula I are shown in the table below:

[0206] Table 1. XRPD pattern analysis data of Form B

[0207] Example 3 Preparation of Prescription 1

[0208] Lactose monohydrate (filler) at a volume three times that of the API (Form B of the compound of Formula I) was mixed with the API and passed through a 30-mesh sieve. The remaining lactose monohydrate, the prescribed amount of microcrystalline cellulose PH102, croscarmellose sodium SD711, and silicon dioxide were then sequentially sieved through a 30-mesh sieve. The sieved material was transferred to a 3L mixing drum and mixed at 20 rpm for 20 minutes. Magnesium stearate was passed through a 60-mesh sieve and added to the mixing drum, where mixing continued at 20 rpm for 3 minutes. Capsules were then filled using a fully automatic capsule filling machine. The 10 mg dose used a No. 4 HPMC capsule shell and a No. 4 dose tray; the 40 mg dose used a No. 0 HPMC capsule shell and a No. 1 dose tray. The dissolution data is shown in Figure 14.

[0209] The composition information of the obtained prescription 1 is shown in the following table:

[0210] The dissolution data are shown in the following table:

[0211] Example 4 Preparation of Prescription 2

[0212] The preparation method of Prescription 2 is the same as that of Prescription 1, except that a No. 5 dose disc is used for the 10 mg strength. The composition information of the resulting Prescription 2 is shown in the table below, and its dissolution data is shown in Figure 15.

[0213] The composition information of the obtained prescription 2 is shown in the following table:

[0214] The dissolution data are shown in the following table:

[0215] Example 5 Preparation of Prescription 3 and Prescription 4

[0216] The filler (3 times the amount of API) was mixed with the API and passed through a 30-mesh sieve. The remaining filler, croscarmellose sodium SD711, and silicon dioxide were then passed through a 30-mesh sieve. The sieved material was transferred to a 3L mixing barrel and mixed at 20 rpm for 20 minutes. Magnesium stearate was passed through a 60-mesh sieve, added to the mixing barrel, and mixed at 20 rpm for 3 minutes. The capsules were then filled using a fully automatic capsule filling machine. The 10 mg specification capsules were filled using a No. 5 dose disc and a No. 4 HPMC capsule shell; the 40 mg specification capsules were filled using a No. 0 dose disc, and two types of capsules were prepared using No. 0 HPMC capsule shells and No. 0 gelatin capsule shells (except for the capsule shells, the contents and process were exactly the same). The composition information of the 10 mg HPMC capsules, 40 mg HPMC capsules, and gelatin capsules of the resulting formulation 3 is shown in the table below, and their dissolution data are shown in Figure 16. The composition information of the 10 mg HPMC capsules, 40 mg HPMC capsules, and gelatin capsules of the resulting formulation 4 is shown in the table below, and their dissolution data are shown in Figure 17.

[0217] The composition of the HPMC capsules of prescription 3 is shown in the table below:

[0218] The composition of the gelatin capsule of prescription 3 is shown in the table below:

[0219] The dissolution data of the two capsules of prescription 3 are shown in the table below:

[0220] The composition of the HPMC capsules of prescription 4 is shown in the table below:

[0221] The composition of the gelatin capsule of prescription 4 is shown in the table below:

[0222] The dissolution data of the two capsules of prescription 4 are shown in the table below:

[0223] Example 6 Preparation of Prescription 5

[0224] Method 1: Preparation of HPMC capsules of formulation 5

[0225] Mannitol 200SD, 3 times the amount of API, was mixed with the API and passed through a 30-mesh sieve. The remaining filler, croscarmellose sodium SD711, and silicon dioxide were then sequentially passed through a 30-mesh sieve. The sieved material was transferred to a 3L mixing drum and mixed at 20 rpm for 20 minutes. Magnesium stearate was passed through a 60-mesh sieve and added to the mixing drum, where mixing continued at 20 rpm for 3 minutes. The capsules were then filled using a fully automatic capsule filling machine. The 10mg capsules were filled using a No. 5 dosing tray and No. 4 HPMC capsule shells; the 40mg capsules were filled using a No. 0 dosing tray and No. 0 HPMC capsule shells. The composition of the resulting HPMC capsules for Formulation 5 is shown below, and its dissolution data is shown in Figure 18.

[0226] The composition of the HPMC capsules of prescription 5 is shown in the table below:

[0227] The dissolution data of HPMC capsules of prescription 5 are shown in the table below:

[0228] Method 2: Preparation of Gelatin Capsules of Recipe 5

[0229] Mannitol 200SD (3 times the amount of API) was mixed with the API and passed through a 30-mesh sieve. The remaining filler, cross-linked sodium carboxymethyl cellulose SD711, and silicon dioxide were then passed through a 30-mesh sieve in sequence. The sieved material was transferred to a 3L mixing barrel and mixed at 20 rpm for 25 minutes. The material in the mixing barrel was taken out and weighed, and the required amount of magnesium stearate was converted. The converted magnesium stearate that passed through a 60-mesh sieve was weighed and added to the mixing barrel, and continued to mix at 20 rpm for 3 minutes. The total mixed powder was then filled into capsules using a fully automatic capsule filling machine. The 10 mg specification capsules were filled using a No. 5 dose disc and a No. 4 capsule shell; the 40 mg specification capsules were filled using a No. 0 dose disc and a No. 0 capsule shell. The formulation composition of the resulting gelatin capsules of Formula 5 is shown in the following table, and its dissolution data is shown in Figure 19.

[0230] The composition of the gelatin capsule of prescription 5 is shown in the table below:

[0231] The dissolution data of the gelatin capsule of prescription 5 is shown in the table below:

[0232] Example 7 Stability Study of Preparation Formula

[0233] 7.1 Stability Study of HPMC Capsules of Formulation 5

[0234] The HPMC capsule product of Formula 5 obtained in Method 1 of Example 6 was packaged and subjected to a stability study. The 10 mg and 40 mg HPMC capsules were placed at 25°C (±2°C) / 60% (±5%) RH for 0 day and 3 months for stability study. At the same time, the 10 mg and 40 mg HPMC capsules were placed at 40°C (±2°C) / 75% (±5%) RH for 0 day, 1 month, 2 months, and 3 months for stability study.

[0235] Packaging information: The packaging container is a medicinal high-density polyethylene bottle + oral solid medicinal polypropylene child-safe combination bottle cap;

[0236] Packaging specifications: 7 capsules / bottle

[0237] 7.1.1 Stability Results at 25°C / 60% RH

[0238] The stability data of HPMC capsules at 25°C / 60% RH are shown in the following table and Figures 20 and 21.

[0239] The stability dissolution data of 10mg HPMC capsules at 25℃ / 60%RH are shown in the table below:

[0240] The stability dissolution data of 40mg HPMC capsules at 25℃ / 60%RH are shown in the table below:

[0241] The changes in API content, related substances, and moisture content of 10mg and 40mg HPMC capsules stored at 25°C / 60% RH for 0 days and 3 months are summarized in the table below:

[0242] 7.1.2 Stability results at 40°C / 75% RH

[0243] The stability data of HPMC capsules at 40°C / 75% RH are shown in the following table and Figures 22, 23, 24, and 25.

[0244] The stability dissolution data of 10mg HPMC capsules at 40℃ / 75%RH are shown in the table below:

[0245] The stability dissolution data of 40mg HPMC capsules at 40℃ / 75%RH are shown in the table below:

[0246] The following table summarizes the changes in API content, related substances, and moisture content of 10mg HPMC capsules at 40°C / 75% RH:

[0247] The following table summarizes the changes in API content, related substances, and moisture content of 40mg HPMC capsules at 40°C / 75% RH:

[0248] As shown in Figures 22 and 23, the properties of the 10 mg HPMC capsules were stable after 0 day, 1 month, 2 months, and 3 months. Similarly, the properties of the 40 mg HPMC capsules were stable after 0 day, 1 month, 2 months, and 3 months.

[0249] In stability studies of 10mg and 40mg HPMC capsules at 25°C (±2°C) / 60% (±5%) RH and 40°C (±2°C) / 75% (±5%) RH, no significant changes in appearance, identification, content, dissolution, related substances, and moisture were observed within 3 months, indicating good stability.

[0250] 7.2 Stability Study of Gelatin Capsules of Formulation 5

[0251] The packaged gelatin capsules of Formulation 5 obtained in Method 2 of Example 6 were placed under 40°C (±2°C) / 75% (±5%) RH conditions for stability testing at 0 days, 2 weeks, and 1 month. Furthermore, 40 mg gelatin capsules were placed under 60°C (±2°C) to assess their stability at 0 days and 2 weeks.

[0252] Packaging information: The packaging container is a 45mL oral solid pharmaceutical high-density polyethylene bottle + oral solid pharmaceutical polypropylene child-safe combination bottle cap;

[0253] Packaging specifications: 10 tablets / bottle.

[0254] 7.2.1 Stability Results at 40°C / 75% RH

[0255] The stability data of gelatin capsules under 40°C / 75% RH conditions are shown in the following table and in Figures 26, 27, 28 and 29.

[0256] As shown in Figure 26, the stability dissolution data of 10 mg gelatin capsules placed under 40°C / 75% RH conditions for 0 days, 2 weeks, and 4 weeks (i.e., 1 month) are shown in the table below:

[0257] As shown in Figure 27, the stability dissolution data of 40 mg gelatin capsules placed under 40°C / 75% RH conditions for 0 days, 2 weeks, and 4 weeks (i.e., 1 month) are shown in the table below:

[0258] The following table summarizes the changes in API content, related substances, and moisture content of 10mg and 40mg gelatin capsules stored at 40°C / 75% RH for 0 days, 2 weeks, and 1 month:

[0259] Stability data for the gelatin capsule samples at 40°C / 75% RH showed that after two weeks of accelerated storage, dissolution in pH 4.5 acetate buffer was not significantly different from the 0-day sample. Content and moisture content were also similar to the 0-day sample, and impurity results were favorable. After four weeks (i.e., one month), content and moisture content were similar to the 0-day sample, and impurity results were favorable.

[0260] 7.2.2 Stability results at 60℃

[0261] The stability results of the 40 mg capsules at 60°C for 0 days and 2 weeks are shown in the following table and Figure 30.

[0262] As shown in Figure 30, the stability dissolution data of 40mg gelatin capsules at 60℃ for 0 days and 2 weeks are shown in the table below:

[0263] Example 8 Feasibility Assessment of Form B (API Component) Formulation of the Compound of Formula I

[0264] 8.1 Study on Transformation Behavior under Pressure

[0265] Approximately 10 mg of Form B of the compound represented by Formula I was weighed and compressed using a small tablet press at a pressure of 10 MPa for 5 minutes. XRPD characterization was performed to investigate the crystal transformation and changes in crystallinity. The results showed that the crystallinity of Form B of the compound represented by Formula I did not change significantly under this pressure, as shown in Figure 31.

[0266] 8.2 Simulated dry grinding experiment

[0267] About 10 mg of Form B of the compound represented by Formula I was weighed and ground in a mortar for 3 minutes. The crystal transformation and change in crystallinity were studied by XRPD characterization. The results showed that the crystallinity of Form B of the compound represented by Formula I did not change significantly in this experiment, as shown in Figure 31.

[0268] 8.3 Simulated wet grinding experiment

[0269] Approximately 10 mg of Form B of the compound represented by Formula I was weighed, 20 μL of water or ethanol was added, and then ground in a mortar for 3 minutes. The crystal transformation and change in crystallinity were studied by XRPD characterization. The results showed that the crystallinity of Form B of the compound represented by Formula I did not change significantly when ground in water or ethanol, as shown in Figure 31.

[0270] Effect embodiment:

[0271] Biological activity test

[0272] Effect Example 1

[0273] TRPC5 is a non-selective cation channel that is permeable to calcium ions. Therefore, this experiment used the TRPC5 agonist Englerin A (EA) and the TRPC5 inhibitor Pico145 as positive controls, and used Fluo-4AM fluorescent dye to detect the effects of compounds on Ca2+ in TRPC5-HEK 293 cells. 2+ The effect of the compound on TRPC5 channels can be indirectly reflected by the effect of the compound on the TRPC5 channel.

[0274] Pico145: MCE, lot number 31245;

[0275] DMEM high glucose: Gibco, lot number 2230805;

[0276] FBS: Gibco, lot number 1981614;

[0277] P / S: Gibco, lot number 2289326;

[0278] HEPES: Sigma, lot number WXBD0664V;

[0279] Blasticidin: Gibco, lot number 1737347;

[0280] Hygromycine: Yeasen, batch number H18010;

[0281] Doxycycline: Sigma, lot number BCBL6540V;

[0282] Fluo-4AM: Molecular Devices, lot number 1231041;

[0283] Poly-D-Lysine: Sigma, lot number SLBQ9797V.

[0284] 1. Cell Culture

[0285] 1.1 TRPC5-HEK 293 cell recovery

[0286] Recovery medium: 100% DMEM (Dulbecco's Modified Eagle Medium) high glucose

[0287] Selection medium: DMEM high glucose + 10% FBS (Phosphate Buffered Saline) + 1% P / S (Penicillin-Streptomycin Solution) + 1% HEPES (4-hydroxyethylpiperazineethanesulfonic acid) + Blastidicin (5 μg / mL) + Hygromycine (50 μg / mL)

[0288] Induction medium: DMEM high glucose + 10% FBS + 1% P / S + 1% HEPES + doxycycline (Doxycycline, 1 μg / mL)

[0289] Recovery process: Take out the cells from the liquid nitrogen tank, transfer them to a water bath in an ice box, and transfer the cryopreservative solution to the recovery solution when it dissolves in circles until it contains a small piece of ice. Centrifuge at 1000 rpm for 5 minutes, discard the supernatant, transfer to the selective culture medium, and expand the culture in a CO2 incubator (5% CO2, 95% humidity, 37°C).

[0290] 1.2 TRPC5-HEK 293 cell plating

[0291] 14 h before the real-time fluorescence experiment, cells were washed with PBS, digested with trypsin containing EDTA (TRYPSIN-EDTA), diluted with induction medium to 200,000 cells / mL, and plated into 96-well black-bottom transparent plates coated with poly-D-lysine (PDL) (stock solution 10 mg / mL, final concentration 10 μg / mL) at 100 μL / well, i.e. 20,000 cells / well.

[0292] 2. Buffer Preparation

[0293] 500 mL external solution for TRPC5 calcium signal detection: 4.0908 g NaCl, 0.1864 g KCl, 0.111 g CaCl2, 0.0476 g MgCl2, 0.9 g Glucose, 1.1915 g HEPES (4-hydroxyethylpiperazineethanesulfonic acid).

[0294] Calcium fluorescent dye: The external solution for TRPC5 calcium signal detection contains a final concentration of 4μM Fluo-4 (containing 0.5% BSA)

[0295] 3. Preparation of Compounds

[0296] Agonist: Englerin A (EA)

[0297] Agonist concentration: EC of EA for activation of TRPC5 50 About 0.35nM, use 0.3nM EA

[0298] Positive inhibitor: Pico145 (HC608)

[0299] Positive inhibitor concentration: 100 nM

[0300] Test compounds: Compound 1-1 and compound represented by formula I

[0301] Concentration of test compound: conventional preparation, prepared with DMSO, prepared to 8 times the final concentration of the test solution (the final concentrations of the test are: 1nM, 3nM, 10nM, 30nM, 100nM, 300nM and 1000nM), 60μL per bottom plate well.

[0302] 4. Data Processing

[0303] The fluorescence value of the Flipr test was subtracted from the value of the unstained cell well (i.e., the background fluorescence value). Graphpad Prism 6.0 software was used for statistics and data processing. The trajectory graph was normalized by removing the baseline and displayed as a ratio. The AUC (area under the curve formed by the calcium flux signal) was calculated for the dose-effect graph. The data were collected and the log value of the compound concentration was compared. The IC was calculated using the log[Inhibitor] vs. response—Variable slope. 50 value.

[0304] The results are shown in the table below:

[0305] The compound shown in formula I has no inhibitory activity on TRPC5 channels

[0306] PK study of male SD rats after single oral administration of the compound of Example 2 (using 5% Solutol as solvent)

[0307] 1. Experimental purpose:

[0308] The time-blood concentration curves of the compound represented by formula I (125 mg / kg) and compound 1-1 (100 mg / kg) in the plasma of male rats after single oral administration were explored to obtain the PK parameters (C max , T max , AUC last , AUC inf , T1 / 2 , MRT, etc.).

[0309] 2. Experimental Plan

[0310] 2.1 Experimental instruments

[0311] The experimental instruments are shown in the table below:

[0312] 2.2 Experimental Preparation

[0313] 2.2.1 Experimental preparation of the compound represented by Formula I

[0314] Rats: 3 male SD rats, SPF grade, weighing 180–200 g (source: Beijing Weitonglihua Laboratory Animal Technology Co., Ltd., certificate number: 110011201109106028);

[0315] Animals were kept in a standard animal room with free access to food and water, 3 animals per cage, a 12 / 12 hour light / dark cycle (7:00 am / 7:00 pm), and a temperature of 23 ± 1°C.

[0316] Dispensing: After accurately weighing the compound of PO group formula I, first add the required volume of 5% solutol (5% polyethylene glycol (15)-hydroxystearate, Beijing Fengli Jingqiu Pharmaceutical Co., Ltd., batch number 1760094G0), vortex mix for 2 minutes, ultrasonicate for 30 minutes, and stir for 2 hours until no obvious particles are visible to the naked eye. Administer the drug while stirring, and take the middle layer of the drug solution for administration.

[0317] Before administration, the drug solution needs to be sampled for analysis. Accurately sample 2 portions of 100 μL each from the upper, middle and lower parts of the suspension and send them for analysis and testing on the same day. The backup samples should be stored in a -75°C refrigerator for future use.

[0318] 2.2.2 Experimental preparation of compound 1-1

[0319] Rats: 3 male SD rats, SPF grade, weighing 220–300 g (source: Beijing Sibeifu Biotechnology Co., Ltd., certificate number: 110324200103216838);

[0320] Animals were kept in a standard animal room with free access to food and water, 3 animals per cage, a 12 / 12 hour light / dark cycle (7:00 am / 7:00 pm), and a temperature of 23 ± 1°C.

[0321] Preparation: After accurately weighing compound 1-1 for the PO group, add the required volume of 5% solutol, vortex mix for 2 minutes, sonicate for 30 minutes, and stir for 3 hours until no obvious particles are visible to the naked eye before oral administration;

[0322] Prepare for immediate use. Samples of the suspension must be retained for analysis. Take 2 portions of 100 μL each from the upper, middle, and lower portions of the suspension and send them for analysis and testing on the same day.

[0323] 2.3 Dosage regimen

[0324] Rats were randomly divided into 3 groups according to body weight. The specific grouping and dosing are as follows:

[0325] 1. Animals in the PO group were fasted overnight but not watered before administration, and food was returned 4 hours after administration;

[0326] 2. Time of blood sampling: The time of blood sampling in the PO group was 0.167, 0.5, 1, 2, 3, 4, 6, 9, 12 and 24 h.

[0327] The group dosing information is shown in the table below:

[0328] 1. Animals in the PO group were fasted overnight but not watered before administration, and food was returned 4 hours after administration;

[0329] 2. Time of blood sampling: The time of blood sampling in the PO group was 0.167, 0.5, 1, 2, 3, 4, 6, 9, 12 and 24 h.

[0330] 2.4 Sample collection and preparation

[0331] After administration to rats, blood was collected from the orbital venous plexus according to the sampling time point. Approximately 0.2-0.3 mL of blood was collected at each time point in an anticoagulant EP tube (containing 4 μL EDTA-K2, 375 mg / mL), which was slowly inverted up and down 3 times and stored in an ice box (no more than 30 minutes). The tube was centrifuged at 3500 × g for 10 minutes at 4°C, and the supernatant was transferred to a labeled EP tube. The plasma hemolysis was observed and recorded, and then sent for bioanalysis. If the test could not be performed on the same day, the sample should be stored at -80°C until testing (be careful not to perform multiple freezing / thawing processes).

[0332] 2.5 Sample analysis

[0333] 2.5.1 Sample Analysis of the Compound of Formula I of the Present Invention

[0334] 2.5.1.1 Experimental instruments:

[0335] High-performance liquid chromatography pump (Pump): Exion LC AD Pump, Sciex

[0336] Autosampler (Exion LC AD Autosampler, Sciex

[0337] Column Oven: Exion LC AD Column Oven, Sciex

[0338] Mass spectrometer: AB Sciex Qtrap 3500

[0339] High-speed refrigerated centrifuge: Thermo Fisher, ST16R, GG1206085-093

[0340] Analytical balance (Electronic balance): Mettler Toledo, MS-105DU, GG1206363

[0341] Vortex: Shanghai Huxi Analytical Instrument Factory, WH-2, GG1206487

[0342] Experimental materials: Rat plasma (EDTA-K2)

[0343] Analyte: Compound 1-1

[0344] Internal standard: Tolbutamide

[0345] Analytical method: LC-MS / MS

[0346] 2.5.1.2 Mass spectrometry conditions:

[0347] Mass spectrometry parameters

[0348] Ion source: Ion Electrospray (ESI)

[0349] Ionization mode: Positive

[0350] Detection mode: Multiple reaction monitoring (MRM)

[0351] Electrospray voltage: 5500

[0352] Turbo Ion Spray Temp: 550°C

[0353] Curtain Gas: 35

[0354] Collision cell gas (CAD Gas): Medium

[0355] Nebulizing Gas (Gas 1): 55.00

[0356] Auxiliary Gas (Gas 2): 55.00

[0357] Detection ion pairs, see the table below:

[0358] 2.5.1.3 Liquid Phase Method:

[0359] Chromatographic column: Poroshell 120EC-C18 (2.1×50mm, 2.7μm)

[0360] Mobile Phase A: 0.1% formic acid in water

[0361] Mobile Phase B: 0.1% formic acid in methanol

[0362] Rinse Port Wash Solution: Methanol: Water: Acetonitrile: Isopropanol = 1:1:1:1

[0363] Column Temperature: 40°C

[0364] Flow Rate: 0.65 mL / min

[0365] Sample Tray Temp: 15°C

[0366] Injection Volume: 8 μL

[0367] Needle Stroke: 49mm

[0368] Rinse Pump Setting: Rinse the injection port only

[0369] Rinse Mode: Rinse before aspiration

[0370] Rinse Volume of Autosampler: 500 μL

[0371] Rinse Dip Time: 2 seconds

[0372] Elution gradient, see the table below:

[0373] 2.5.1.4 Pretreatment methods

[0374] Sample pretreatment: 3 μL of working solution was added to 57 μL of blank matrix (rat blank plasma) in a 1.5 mL centrifuge tube. Protein was precipitated by adding 240 μL of acetonitrile containing 200 ng / mL tolbutamide and 0.1% FA (formic acid). The sample was vortexed for 1 minute and centrifuged at 13,000 rpm for 15 minutes at 4°C. 100 μL of the supernatant was transferred to another 96-well plate and 100 μL of a methanol:water (1:3, v:v) solution containing 0.1% FA was added. The sample was vortexed for 1 minute and centrifuged at 3,500 rpm in a 96-well plate centrifuge for 5 minutes before direct injection.

[0375] 2.5.2 Sample analysis of compound 1-1

[0376] 2.5.2.1 Experimental instruments:

[0377] High performance liquid chromatography pump (Pump): LC-30AD, Shimadzu

[0378] Auto sampler: SIL-30AC, Prominence, Shimadzu

[0379] Column Oven: CTO-30A, Shimadzu

[0380] Mass spectrometer: AB Sciex Qtrap 3500

[0381] High-speed refrigerated centrifuge (Centrifuge): Thermo Fisher, ST16R, GG1206085-093

[0382] Analytical balance (Electronic balance): Mettler Toledo, MS-105D, GG1206363

[0383] Micro vortex analyzer (Vortex): Shanghai Huxi Analytical Instrument Factory, WH-2, GG1206487

[0384] Experimental materials: Rat plasma (EDTA-K2)

[0385] Analyte: Compound 1-1

[0386] Internal standard: Tolbutamide

[0387] Analytical method: LC-MS / MS

[0388] 2.5.2.2 Mass spectrometry conditions:

[0389] Mass spectrometry parameters

[0390] Ion source: Ion Electrospray (ESI)

[0391] Ionization mode: Positive

[0392] Detection mode: Multiple reaction monitoring (MRM)

[0393] Electrospray voltage: 5500

[0394] Turbo Ion Spray Temp: 550°C

[0395] Curtain Gas: 35

[0396] Collision cell gas (CAD Gas): Medium

[0397] Nebulizing Gas (Gas 1): 55.00

[0398] Auxiliary Gas (Gas 2): 55.00

[0399] Detection ion pairs, see the table below:

[0400] 2.5.2.3 Liquid Phase Method:

[0401] Chromatographic column: Poroshell 120EC-C18 (4.6×50mm, 2.7μm)

[0402] Mobile Phase A: 0.1% formic acid in water

[0403] Mobile Phase B: 0.1% formic acid in methanol

[0404] Rinse Port Wash Solution: Methanol: Acetonitrile: Water: Isopropanol = 1:1:1:1

[0405] Flow Rate: 0.8mL / min

[0406] Sample Tray Temp: 15°C

[0407] Injection Volume: 15 μL

[0408] Needle Stroke: 49mm

[0409] Rinse Pump Setting: Rinse the injection port only

[0410] Rinse Mode: Rinse before aspiration

[0411] Rinse Volume of Autosampler: 500 μL

[0412] Rinse Dip Time: 2 seconds

[0413] Elution gradient, see the table below:

[0414] 2.5.2.4 Pretreatment methods

[0415] Sample pretreatment: 30 μL of sample was added to 120 μL of acetonitrile containing 0.1% FA and 200 ng / mL standard solution to precipitate protein. The sample was vortexed and centrifuged at 13,000 rpm for 10 minutes at 4°C. 100 μL of the supernatant was transferred to another 96-deep-well plate, and 100 μL of a methanol:water (1:3, v:v) solution was added. The sample was shaken for 10 minutes.

[0416] 2.6 Data Analysis

[0417] The data will be analyzed by non-compartmental model using WinNonlin (version 5.2.1 Pharsight, Mountain View, CA) to obtain PK parameters (C max , T max , AUC last , AUC inf , T 1 / 2 , MRT and other parameters). Specific results are shown in the table below. The analyte of the data listed in the table is compound 1-1.

[0418] The analysis results are shown in the table below: Note: 1. 100* here means that 125 mg / kg of the compound represented by Formula I is equivalent to 100 mg / kg of compound 1-1. 2. T 1 / 2 Middle Belt # The data are abnormal data in this experiment and have been eliminated when calculating the mean.

[0419] Experimental conclusion: The compound represented by formula I of the present invention has a better exposure amount compared with compound 1-1.

Claims

1. A pharmaceutical composition Q, characterized in that It contains substance X and pharmaceutical excipients; Wherein, the substance X is a compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate of a compound represented by formula I, or a solvate of a pharmaceutically acceptable salt thereof; The pharmaceutical excipients are selected from one or more of diluents, excipients, fillers, adhesives, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants and glidants.

2. The pharmaceutical composition Q according to claim 1, characterized in that The pharmaceutical composition satisfies one or more of the following conditions: (1) The pharmaceutical excipient is selected from one or more of a disintegrant, a filler, a glidant, and a lubricant; (2) The substance X is the only active ingredient; (3) The amount of substance X is a therapeutically effective amount; (4) The compound of formula I is a crystalline form B of the compound of formula I, wherein the crystalline form B of the compound of formula I has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles of 8.95±0.20°, 12.92±0.20°, 16.39±0.20°, 17.00±0.20°, 17.44±0.20°, 17.7 There are diffraction peaks at 6±0.20°, 18.08±0.20°, 19.02±0.20°, 21.95±0.20°, 22.20±0.20°, 23.49±0.20°, 24.15±0.20°, 24.92±0.20°, 25.94±0.20°, 27.14±0.20°, and 29.68±0.20°; Preferably, the crystalline form B of the compound represented by formula I has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles and has diffraction peaks at one or more of the following positions: 10.63±0.20°, 11.69±0.20°, 13.52±0.20°, 14.49±0.20°, 14.74±0.20°, 15.83±0.20°, 18.81±0.20°, 19.72±0.20°, 21.27±0.20°, 22.62±0.20°, 22.99±0.20°, 25.41±0.20°, 25.74±0.20°, 26.18±0.20°, 26.58±0.20°, 27.85±0.20°, .20°, 28.23±0.20°, 28.70±0.20°, 29.16±0.20°, 30.17±0.20°, 30.51±0.20°, 31.20±0.20°, 32.16±0.20°, 32.52±0.20°, 32.74±0.20°, 32.89±0.2 0°, 34.36 ± 0.20°, 35.45 ± 0.20°, 35.98 ± 0.20°, 36.65 ± 0.20°, 37.00 ± 0.20°, 37.45 ± 0.20°, 37.73 ± 0.20°, 38.04 ± 0.20°, 38.36 ± 0.20°, and 39.11 ± 0.20°; Furthermore, the crystalline form B of the compound represented by formula I has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles of 8.95±0.20°, 10.63±0.20°, 11.69±0.20°, 12.92±0.20°, 13.52±0.20°, 14.49±0.20°, 14.74±0.20°, 15.83±0.20°, 16.39±0.20°, 17.00±0.20°, 17. 44±0.20°, 17.76±0.20°, 18.08±0.20°, 18.81±0.20°, 19.02±0.20°, 19.72±0.20°, 21.27±0.20°, 21.95±0.20°, 22.20±0.20°, 22.62±0.20°, 22.99±0.20°, 23.49±0.20°, 24.15±0.20°, 24.92±0.20°, 25.4 1±0.20°, 25.74±0.20°, 25.94±0.20°, 26.18±0.20°, 26.58±0.20°, 27.14±0.20°, 27.85±0.20°, 28.23±0.20°, 28.70±0.20°, 29.16±0.20°, 29.68±0.20°, 30.17±0.20°, 30.51±0.20°, 31.20±0.20°, 32.1 There are diffraction peaks at 6±0.20°, 32.52±0.20°, 32.74±0.20°, 32.89±0.20°, 34.36±0.20°, 35.45±0.20°, 35.98±0.20°, 36.65±0.20°, 37.00±0.20°, 37.45±0.20°, 37.73±0.20°, 38.04±0.20°, 38.36±0.20° and 39.11±0.20°; (5) The compound represented by Formula I is a crystalline form B of the compound represented by Formula I, and the crystalline form B of the compound represented by Formula I is an unsolvated form; (6) The filler is one or more of lactose, lactose monohydrate, mannitol and microcrystalline cellulose, the microcrystalline cellulose is, for example, microcrystalline cellulose PH102, the lactose monohydrate is, for example, lactose monohydrate GRANULAC200, the mannitol is, for example, mannitol 200SD, and the lactose is, for example, lactose Flowlac100; (7) The disintegrant is cross-linked sodium carboxymethylcellulose, for example, cross-linked sodium carboxymethylcellulose SD711; (8) The glidant is silicon dioxide; (9) The pharmaceutical composition Q is composed of the substance X and the pharmaceutical excipients; (10) The pharmaceutical composition Q is administered orally; (11) The pharmaceutical composition Q is a solid preparation, for example, a solid oral preparation; (12) The pharmaceutical composition Q is in the form of a tablet or capsule, for example, a capsule; (13) The pharmaceutical composition Q is in a strength of 10 mg / portion or 40 mg / portion; (14) The pharmaceutical composition Q is a pharmaceutical composition for treating and / or preventing psychiatric disorders, neurological disorders, neurodegenerative disorders or renal diseases; (15) The lubricant is magnesium stearate.

3. The pharmaceutical composition Q according to claim 2, characterized in that The pharmaceutical composition satisfies one or more of the following conditions: (1) Form B of the compound of Formula I, which has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, having diffraction peaks as shown in Table 1; (2) Form B of the compound of Formula I, using Cu-Kα radiation, has an X-ray powder diffraction pattern as shown in FIG8 ; (3) Form B of the compound of Formula I, having an endothermic peak at 247.7°C ± 3°C in its differential scanning calorimetry curve; (4) Form B of the compound represented by Formula I, whose differential scanning calorimetry curve is shown in FIG9 ; (5) Form B of the compound of Formula I, having a thermogravimetric analysis curve showing a weight loss of 1.0% within the temperature range of 35°C ± 3°C to 220°C ± 3°C; (6) Form B of the compound represented by Formula I, the thermogravimetric analysis curve of which is shown in FIG10 ; (7) In the pharmaceutical composition Q, the filler is any one of the following groups: (a) The filler is a mixture of microcrystalline cellulose and lactose monohydrate, for example, a mixture of microcrystalline cellulose PH102 and lactose monohydrate GRANULAC200; (b) the filler is a mixture of microcrystalline cellulose and lactose, for example, a mixture of microcrystalline cellulose PH102 and lactose Flowlac100; (c) the filler is a mixture of microcrystalline cellulose and mannitol, for example, a mixture of microcrystalline cellulose PH102 and mannitol 200SD; (d) the filler is mannitol, for example, mannitol 200SD; (8) The pharmaceutical composition Q is composed of the substance X, the disintegrant, the filler, the glidant and the lubricant; (9) The psychiatric, neurological or neurodegenerative disorder is selected from the group consisting of disorders associated with dysregulated emotional processing (e.g., borderline personality disorder or depression, such as major depressive disorder, major depressive disorder, dysthymia, dysthymia and postpartum depression, and bipolar disorder), disorders associated with anxiety and fear (e.g., post-traumatic stress disorder, panic disorder, agoraphobia, social phobia, generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder and separation anxiety), memory disorders (e.g., Alzheimer's disease, amnesia, aphasia, brain injury, brain tumor, chronic fatigue syndrome, Creutzfeldt-Jakob disease, dissociative amnesia, fugue amnesia, Huntington's disease, disorders related to impaired impulse control and addiction, Parkinson's disease, amyotrophic lateral sclerosis, epilepsy, and other brain disorders resulting from trauma or other insults, including aging; (10) The renal disease is focal segmental glomerulosclerosis, minimal change disease, diabetic nephropathy, Alport syndrome, hypertensive nephropathy, nephrotic syndrome, steroid-resistant nephrotic syndrome, membranous nephropathy, idiopathic membranous nephropathy, membranoproliferative glomerulonephritis, immune complex-mediated MPGN, complement-mediated MPGN, lupus nephritis, post-infectious glomerulonephritis, thin basement membrane disease, mesangial proliferative glomerulonephritis, amyloidosis nephropathy (preferably primary amyloidosis nephropathy), C1q nephropathy, rapidly progressive glomerulonephritis, anti-glomerular basement membrane disease, C3 glomerulonephritis, hypertensive nephrosclerosis, primary glomerular disease (preferably IgA nephropathy).

4. The pharmaceutical composition Q according to claim 3, characterized in that The pharmaceutical composition satisfies one or more of the following conditions: (1) In the pharmaceutical composition Q, the content of the substance X is 5% to 15% by weight of the total weight of the pharmaceutical composition, for example, 10%; (2) In the pharmaceutical composition Q, the filler content is 70% to 90% by weight of the total weight of the pharmaceutical composition, preferably 80% to 90%, for example, 85% or 88%; (3) In the pharmaceutical composition Q, the filler is a "mixture of microcrystalline cellulose and lactose monohydrate", a "mixture of microcrystalline cellulose and lactose", or a "mixture of microcrystalline cellulose and mannitol", and the content of the filler is 70% to 90% by weight of the total weight of the pharmaceutical composition, preferably 80% to 90%, for example, 85% or 88%; (4) In the pharmaceutical composition Q, the filler is mannitol, and the content of the filler is 80% to 90% by weight of the total weight of the pharmaceutical composition, for example, 85% or 88%; (5) In the pharmaceutical composition Q, the content of the disintegrant is 2% to 5% by weight of the total weight of the pharmaceutical composition, for example, 3%; (6) In the pharmaceutical composition Q, the content of the glidant is 1% to 5% by weight of the total weight of the pharmaceutical composition, for example, 1%; (7) In the pharmaceutical composition Q, the lubricant content is 1% to 5% by weight of the total weight of the pharmaceutical composition, for example, 1%.

5. The pharmaceutical composition Q according to claim 4, characterized in that The pharmaceutical composition satisfies one or more of the following conditions: (1) In the pharmaceutical composition Q, the filler is a mixture of microcrystalline cellulose and lactose monohydrate, and the mass ratio of the lactose monohydrate to the microcrystalline cellulose is 50:35 to 70:15, preferably 56:29 to 64:21, for example 56:29 or 64:21; (2) In the pharmaceutical composition Q, the filler is a mixture of microcrystalline cellulose and lactose, and the mass ratio of the lactose to the microcrystalline cellulose is 60:25 to 68:17, for example, 64:21; (3) In the pharmaceutical composition Q, the filler is a mixture of microcrystalline cellulose and mannitol, and the mass ratio of mannitol to microcrystalline cellulose is 60:25 to 68:17, for example, 64:21; (4) In the pharmaceutical composition Q, the disintegrant is croscarmellose sodium, and the content of croscarmellose sodium is 2% to 5% by weight, for example, 3% by weight, of the total weight of the pharmaceutical composition; (5) In the pharmaceutical composition Q, the mass ratio of the glidant to the lubricant is 0.5:1.5 to 1.5:0.5, for example, 1:1; (6) The pharmaceutical composition Q is composed of 5% to 15% of the substance X, 80% to 90% of the filler, and 2% to 5% of the disintegrant. Preferably, the pharmaceutical composition is composed of 10% of the substance X, 85% of the filler, 3% of the disintegrant, 1% of the lubricant and 1% of the glidant. Further, the pharmaceutical composition is composed of 10% of the crystalline form B of the compound represented by Formula I, 85% of the filler, 3% of the cross-linked carboxymethyl cellulose sodium, 1% of the magnesium stearate and 1% of the silicon dioxide. The percentages are the mass ratios of the pharmaceutical composition.

6. The pharmaceutical composition Q according to any one of claims 1 to 5, characterized in that The pharmaceutical composition Q is selected from any one of the following groups: Pharmaceutical composition 1: 10% substance X, 56% lactose monohydrate, 29% microcrystalline cellulose, 3% croscarmellose sodium, 1% silicon dioxide, and 1% magnesium stearate; Pharmaceutical composition 2: 10% substance X, 64% lactose monohydrate, 21% microcrystalline cellulose, 3% croscarmellose sodium, 1% silicon dioxide, and 1% magnesium stearate; Pharmaceutical composition 3: 10% substance X, 64% mannitol, 21% microcrystalline cellulose, 3% croscarmellose sodium, 1% silicon dioxide, and 1% magnesium stearate; Pharmaceutical composition 4: 10% substance X, 64% lactose, 21% microcrystalline cellulose, 3% croscarmellose sodium, 1% silicon dioxide, and 1% magnesium stearate; Pharmaceutical composition 5: 10% substance X, 85% mannitol, 3% croscarmellose sodium, 1% silicon dioxide, and 1% magnesium stearate; Pharmaceutical composition 6: 10% crystalline form B of the compound of formula I, 56% lactose monohydrate GRANULAC 200, 29% microcrystalline cellulose PH102, 3% croscarmellose sodium SD711, 1% silicon dioxide, and 1% magnesium stearate; Pharmaceutical composition 7: 10% crystalline form B of the compound of formula I, 64% lactose monohydrate GRANULAC 200, 21% microcrystalline cellulose PH102, 3% croscarmellose sodium SD711, 1% silicon dioxide, and 1% magnesium stearate; Pharmaceutical composition 8: 10% Form B of the compound of Formula I, 64% mannitol 200SD, 21% microcrystalline cellulose PH102, 3% croscarmellose sodium SD711, 1% silicon dioxide, and 1% magnesium stearate; Pharmaceutical composition 9: 10% Form B of the compound of Formula I, 64% lactose Flowlac 100, 21% microcrystalline cellulose PH102, 3% croscarmellose sodium SD711, 1% silicon dioxide, and 1% magnesium stearate; Pharmaceutical composition 10: 10% crystalline form B of the compound represented by Formula I, 85% mannitol 200SD, 3% cross-linked carboxymethyl cellulose sodium SD711, 1% silicon dioxide and 1% magnesium stearate; the percentages are the mass ratios of the pharmaceutical composition.

7. A method for preparing the pharmaceutical composition Q according to any one of claims 1 to 6, characterized in that: The preparation method of the pharmaceutical composition comprises the following steps: (a) mixing the substance X and a portion of the filler to obtain a mixture M; (b) mixing the remaining filler, the disintegrant, and the silicon dioxide with the mixture M, and adding magnesium stearate to obtain the pharmaceutical composition Q; Wherein, the silicon dioxide is a glidant and the magnesium stearate is a lubricant; Preferably, the preparation method satisfies one or more of the following conditions: (1) In step (a), the mass ratio of the filler to the substance X is 3:1; (2) In step (a), the filler is one or more of the lactose, lactose monohydrate, and mannitol; (3) In step (b), the disintegrant is croscarmellose sodium; (4) In step (a), the substance X or the filler before mixing is a 30-mesh substance X or a 30-mesh filler; (5) In step (b), the filler, the disintegrant, or the silicon dioxide is a filler of 30 mesh, a disintegrant of 30 mesh, or a silicon dioxide of 30 mesh; (6) In step (b), the mixing condition is stirring at 20 rpm for 10 to 60 min, for example, stirring at 20 rpm for 20 min; (7) In step (b), the magnesium stearate is 60 mesh magnesium stearate; (8) In step (b), the addition condition is stirring at 20 rpm for 2 to 10 minutes, for example, 3 minutes; (9) The preparation method of the pharmaceutical composition preferably comprises the following steps: mixing 3 times the mass of the substance X with the 30-mesh lactose, 30-mesh lactose monohydrate or 30-mesh mannitol and the 30-mesh substance X to obtain a mixture M; mixing the 30-mesh filler, the 30-mesh disintegrant and the 30-mesh silicon dioxide with the mixture M; and adding the 60-mesh magnesium stearate to mix, thereby obtaining the pharmaceutical composition Q.

8. A pharmaceutical composition R, characterized in that It comprises the pharmaceutical composition Q according to any one of claims 1 to 6 and a capsule shell, wherein the pharmaceutical composition Q is filled in the capsule shell; Preferably, the pharmaceutical composition R satisfies one or more of the following conditions: (1) The capsule shell is an HPMC capsule shell or a gelatin capsule shell, preferably an HPMC capsule shell; (2) The pharmaceutical composition R consists of the pharmaceutical composition Q and a capsule shell; (3) The pharmaceutical composition R is taken orally; (4) The pharmaceutical composition R is in a strength of 10 mg / pill or 40 mg / pill; (5) The pharmaceutical composition R is a solid preparation, such as a solid oral preparation; (6) The pharmaceutical composition R is a pharmaceutical composition for treating and / or preventing psychiatric disorders, neurological disorders, neurodegenerative disorders or renal diseases; Preferably, the psychiatric disorder, neurological disorder or neurodegenerative disorder is selected from the group consisting of disorders associated with dysregulated emotional processing (e.g., borderline personality disorder or depression, such as major depressive disorder, major depressive disorder, dysthymia, dysthymia and postpartum depression, and bipolar disorder), disorders associated with anxiety and fear (e.g., post-traumatic stress disorder, panic disorder, agoraphobia, social phobia, generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder and separation anxiety), memory disorders (e.g., Alzheimer's disease, amnesia, aphasia, brain injury, brain tumor, chronic fatigue syndrome, Creutzfeldt-Jakob disease, dissociative amnesia, fugue amnesia, Huntington's disease, learning disorders, sleep disorders, multiple personality disorder, pain, post-traumatic stress disorder, schizophrenia, sports injuries, stroke and Weil-Cohen syndrome), disorders associated with impaired impulse control, and the like. Control and addiction-related disorders, Parkinson's disease, amyotrophic lateral sclerosis, epilepsy, and other brain disorders caused by trauma or other damage including aging; or, the renal disease is focal segmental glomerulosclerosis, minimal change disease, diabetic nephropathy, Alport syndrome, hypertensive nephropathy, nephrotic syndrome, steroid-resistant nephrotic syndrome, membranous nephropathy, idiopathic membranous nephropathy, membranoproliferative glomerulonephritis, immune complex-mediated MPGN, complement-mediated MPGN, lupus nephritis, post-infectious glomerulonephritis, thin basement membrane disease, mesangial proliferative glomerulonephritis, amyloidosis nephropathy (preferably primary amyloidosis nephropathy), C1q nephropathy, rapidly progressive glomerulonephritis, anti-glomerular basement membrane disease, C3 glomerulonephritis, hypertensive nephrosclerosis, primary glomerular disease (preferably IgA nephropathy).

9. The pharmaceutical composition R according to claim 8, characterized in that The pharmaceutical composition R is selected from any one of the following groups: Pharmaceutical composition 1: 10% substance X, 56% lactose monohydrate, 29% microcrystalline cellulose, 3% croscarmellose sodium, 1% silicon dioxide, 1% magnesium stearate and the capsule shell; Pharmaceutical composition 2: 10% substance X, 64% lactose monohydrate, 21% microcrystalline cellulose, 3% croscarmellose sodium, 1% silicon dioxide, 1% magnesium stearate, and the capsule shell; Pharmaceutical composition 3: 10% substance X, 64% mannitol, 21% microcrystalline cellulose, 3% croscarmellose sodium, 1% silicon dioxide, 1% magnesium stearate and the capsule shell; Pharmaceutical composition 4: 10% substance X, 64% lactose, 21% microcrystalline cellulose, 3% croscarmellose sodium, 1% silicon dioxide, 1% magnesium stearate, and the capsule shell; Pharmaceutical composition 5: 10% substance X, 85% mannitol, 3% croscarmellose sodium, 1% silicon dioxide, 1% magnesium stearate and the capsule shell; Pharmaceutical composition 6: 10% crystalline form B of the compound represented by formula I, 56% lactose monohydrate GRANULAC200, 29% microcrystalline cellulose PH102, 3% cross-linked sodium carboxymethylcellulose SD711, 1% silicon dioxide, 1% magnesium stearate and the HPMC capsule shell; Pharmaceutical composition 7: 10% crystalline form B of the compound represented by formula I, 64% lactose monohydrate GRANULAC200, 21% microcrystalline cellulose PH102, 3% cross-linked carboxymethyl cellulose sodium SD711, 1% silicon dioxide, 1% magnesium stearate and the HPMC capsule shell; Pharmaceutical composition 8: 10% crystalline form B of the compound of formula I, 64% mannitol 200SD, 21% microcrystalline cellulose PH102, 3% croscarmellose sodium SD711, 1% silicon dioxide, 1% magnesium stearate, and the HPMC capsule shell; Pharmaceutical composition 9: 10% crystalline form B of the compound of formula I, 64% lactose Flowlac100, 21% microcrystalline cellulose PH102, 3% cross-linked sodium carboxymethylcellulose SD711, 1% silicon dioxide, 1% magnesium stearate and the HPMC capsule shell; Pharmaceutical composition 10: 10% crystalline form B of the compound represented by formula I, 85% mannitol 200SD, 3% cross-linked carboxymethylcellulose sodium SD711, 1% silicon dioxide, 1% magnesium stearate and the HPMC capsule shell; Pharmaceutical composition 11: 10% crystalline form B of the compound represented by formula I, 56% lactose monohydrate GRANULAC200, 29% microcrystalline cellulose PH102, 3% cross-linked sodium carboxymethyl cellulose SD711, 1% silicon dioxide, 1% magnesium stearate, and the gelatin capsule shell; Pharmaceutical composition 12: 10% crystalline form B of the compound represented by formula I, 64% lactose monohydrate GRANULAC200, 21% microcrystalline cellulose PH102, 3% cross-linked carboxymethyl cellulose sodium SD711, 1% silicon dioxide, 1% magnesium stearate, and the gelatin capsule shell; Pharmaceutical composition 13: 10% crystalline form B of the compound represented by formula I, 64% mannitol 200SD, 21% microcrystalline cellulose PH102, 3% croscarmellose sodium SD711, 1% silicon dioxide, 1% magnesium stearate, and the gelatin capsule shell; Pharmaceutical composition 14: 10% crystalline form B of the compound represented by formula I, 64% lactose Flowlac100, 21% microcrystalline cellulose PH102, 3% cross-linked carboxymethyl cellulose sodium SD711, 1% silicon dioxide, 1% magnesium stearate, and the gelatin capsule shell; Pharmaceutical composition 15: 10% crystalline form B of the compound represented by Formula I, 85% mannitol 200SD, 3% cross-linked carboxymethyl cellulose sodium SD711, 1% silicon dioxide, 1% magnesium stearate and the gelatin capsule shell; the percentages are the mass ratios of the pharmaceutical composition.

10. A method for preparing the pharmaceutical composition R according to claim 8 or 9, characterized in that: The method comprises filling the pharmaceutical composition Q according to any one of claims 1 to 6 into capsules; Preferably, the preparation method satisfies one or more of the following conditions: (1) In the preparation method of the pharmaceutical composition R, the capsule is an HPMC capsule shell or a gelatin capsule shell, for example, an HPMC capsule shell; (2) In the preparation method of the pharmaceutical composition R, the capsule filling is performed using a fully automatic capsule filling machine, for example, the model of the fully automatic capsule filling machine is In-Cap XL.

11. Use of a substance Y in the preparation of a medicament, wherein the substance Y is the pharmaceutical composition Q according to any one of claims 1 to 7 or the pharmaceutical composition R according to any one of claims 8 to 10; the medicament is a medicament for treating and / or preventing a TRPC5-mediated disease; Preferably, in the application, the TRPC5-mediated disease is a psychiatric disorder, a neurological disorder, a neurodegenerative disorder or kidney disease; Further, the psychiatric disorder, neurological disorder or neurodegenerative disorder is selected from the group consisting of disorders associated with dysregulated emotional processing (e.g., borderline personality disorder or depression, such as major depressive disorder, major depressive disorder, dysthymia, dysthymia and postpartum depression, and bipolar disorder), disorders associated with anxiety and fear (e.g., post-traumatic stress disorder, panic disorder, agoraphobia, social phobia, generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder and separation anxiety), memory disorders (e.g., Alzheimer's disease, amnesia, aphasia, brain injury, brain tumor, chronic fatigue syndrome, Creutzfeldt-Jakob disease, dissociative amnesia, fugue amnesia, Huntington's disease, learning disorders, sleep disorders, multiple personality disorder, pain, post-traumatic stress disorder, schizophrenia, sports injuries, stroke and Weil-Cohen syndrome), disorders associated with impaired impulse control, Control and addiction-related disorders, Parkinson's disease, amyotrophic lateral sclerosis, epilepsy, and other brain disorders caused by trauma or other damage including aging; or, the renal disease is focal segmental glomerulosclerosis, minimal change disease, diabetic nephropathy, Alport syndrome, hypertensive nephropathy, nephrotic syndrome, steroid-resistant nephrotic syndrome, membranous nephropathy, idiopathic membranous nephropathy, membranoproliferative glomerulonephritis, immune complex-mediated MPGN, complement-mediated MPGN, lupus nephritis, post-infectious glomerulonephritis, thin basement membrane disease, mesangial proliferative glomerulonephritis, amyloidosis nephropathy (preferably primary amyloidosis nephropathy), C1q nephropathy, rapidly progressive glomerulonephritis, anti-glomerular basement membrane disease, C3 glomerulonephritis, hypertensive nephrosclerosis or primary glomerular disease (preferably IgA nephropathy).

12. Use of a substance Y in the preparation of a medicament, wherein the substance Y is the pharmaceutical composition Q according to any one of claims 1 to 7 or the pharmaceutical composition R according to any one of claims 8 to 10, and the medicament is a medicament for treating and / or preventing psychiatric disorders, neurological disorders, neurodegenerative disorders, or renal diseases; Preferably, in the application, the psychiatric disorder, neurological disorder or neurodegenerative disorder is selected from the group consisting of: diseases associated with disordered emotional processing (e.g., borderline personality disorder or depression, such as major depressive disorder, major depressive disorder, dysthymia, dysthymia and postpartum depression and bipolar disorder), disorders associated with anxiety and fear (e.g., post-traumatic stress disorder, panic disorder, agoraphobia, social phobia, generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder and separation anxiety), memory disorders (e.g., Alzheimer's disease, amnesia, aphasia, brain injury, brain tumor, chronic fatigue syndrome, Creutzfeldt-Jakob disease, dissociative amnesia, fugue amnesia, Huntington's disease, learning disorders, sleep disorders, multiple personality disorder, pain, post-traumatic stress disorder, schizophrenia, sports injuries, stroke and Weil-Cohen syndrome), and disorders associated with Impaired impulse control and addiction-related disorders, Parkinson's disease, amyotrophic lateral sclerosis, epilepsy, and other brain disorders caused by trauma or other injuries including aging; or, the renal disease is focal segmental glomerulosclerosis, minimal change disease, diabetic nephropathy, Alport syndrome, hypertensive nephropathy, nephrotic syndrome, steroid-resistant nephrotic syndrome, membranous nephropathy, idiopathic membranous nephropathy, membranoproliferative glomerulonephritis, immune complex-mediated MPGN, complement-mediated MPGN, lupus nephritis, post-infectious glomerulonephritis, thin basement membrane disease, mesangial proliferative glomerulonephritis, amyloidosis nephropathy (preferably primary amyloidosis nephropathy), C1q nephropathy, rapidly progressive glomerulonephritis, anti-glomerular basement membrane disease, C3 glomerulonephritis, hypertensive nephrosclerosis, primary glomerular disease (preferably IgA nephropathy).

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