Crystal form of triazinyl methyl naphthenic carboxylic acid derivative and application thereof

Abstract

The invention relates to solvate solid forms of triazinyl methyl naphthenic carboxylic acid derivatives as shown in formula (I), crystal forms of solvate solid forms, pharmaceutical compositions containing solvate solid forms, preparation methods of solvate solid forms and crystal forms, and application of solvate and polymorphic forms in prevention and / or treatment of diseases related to P2X3 activity or P2X2 / 3 activity, # imgabs0 #, as well as application of solvate solid forms and crystal forms of triazinyl methyl naphthenic carboxylic acid derivatives in prevention and / or treatment of diseases related to P2X3 activity or P2X2 / 3 activity.

Description

Crystal form and application of triazine methylcycloalkyl carboxylic acid derivatives

[0001] This application claims priority to the Chinese patent application filed with the China Patent Office on November 30, 2022, with application number 202211540134.3 and invention name “Crystal form of triazinemethylcycloalkylcarboxylic acid derivatives and their applications”, the entire contents of which are incorporated by reference into this application. Technical Field

[0002] The present application relates to the field of medical technology, and in particular to a solvate solid form of a triazinylmethylcycloalkylcarboxylic acid derivative and its crystal form, a pharmaceutical composition containing the solvate solid form, a preparation method thereof, and an application thereof. Background Art

[0003] P2X purinergic receptors are a family of ion channels activated by extracellular adenosine triphosphate (ATP). Purinergic receptors are involved in a variety of biological functions, particularly related to pain sensitivity. The P2X3 receptor is one of the members of this family, originally cloned from rat dorsal root ganglia (Chen et al., Nature, Vol. 377, pp. 428-431 (1995)). The nucleotide sequence and amino acid sequence of both rat P2X3 and human P2X3 are now known (Lewis et al., Nature, Vol. 377, pp. 432-435 (1995); and Garcia-Guzman et al., Brain Res. Mol. Brain Res., Vol. 47, pp. 59-66 (1997)).

[0004] P2X3 is reported to be involved in the afferent pathway that controls the bladder capacity reflex, and therefore, inhibition of P2X3 may treat storage and voiding-related disorders, such as overactive bladder (Cockayne et al., Nature, Vol. 407, pp. 1011-1015 (2000)).

[0005] P2X3 is also selectively expressed on nociceptive neurons, small-diameter sensory neurons (i.e., neurons stimulated by pain or injury), which is consistent with its role in pain sensitivity. In addition, it has also been reported that blocking P2X3 receptors has analgesic effects in animal models of chronic inflammatory and neuropathic pain (Jarvis et al., PNAS, 99, 17179-17184 (2002)). Therefore, methods for reducing P2X3 levels or activity can be used to modulate pain perception in subjects with pain.

[0006] P2X3 can also form P2X2 / 3 heterodimer with P2X2, and the P2X2 is another member of P2X purinergic ligand-gated ion channel family.P2X2 / 3 is highly expressed (Chen etc., Nature, vol. 377, pp. 428-431 (1995)) on the terminal (center and periphery) of sensory neurons.Research result also shows that P2X2 / 3 is mainly expressed (more than P2X3) in bladder sensory neurons, and is likely to work in the sensation of bladder filling and nociception (Zhong etc., Neuroscience, vol. 120, pp. 667-675 (2003)).

[0007] Currently, multiple P2X3 inhibitors are in the preclinical or clinical development stage. Since the solubility, stability, hygroscopicity, etc. of the active ingredients of the drug have a significant impact on the drugability research, and the development of crystal forms is more conducive to product quality control, this application has conducted in-depth research and exploration on the crystal form of the active ingredient based on the early development, and developed a new crystal form suitable for product development, providing more options for further drug development.

[0008] Summary of the Invention

[0009] Based on this, the purpose of the present application is to provide a solid form of a solvate of a triazinylmethylcycloalkylcarboxylic acid derivative and its application. Specifically, the solid form is a hemihydrate and a cyclohexane / water solvate. The triazinylmethylcycloalkylcarboxylic acid derivative is a P2X3 antagonist, and its molecular structure is (1S,2S)-2-((3-(4-chlorobenzyl)-4-((4-((5-fluoropyridin-2-yl)oxy)phenyl)amino)-2,6-dioxo-3,6-dihydro-1,3,5-triazine-1(2H)-yl)methyl)cyclopropane-1-carboxylic acid shown in formula (I).

[0010] In the first aspect of the present application, a solvate solid form of a compound of formula (I) is provided:

[0011] The solvate is a hemihydrate or a cyclohexane / water solvate.

[0012] In some embodiments, the solvate is a hemihydrate of the compound of formula (I).

[0013] In some embodiments, the solvate solid form is a hemihydrate crystalline form of the compound of Formula (I).

[0014] Hemihydrate of the compound of formula (I)

[0015] In some embodiments, the hemihydrate crystalline form of the compound of formula (I) has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following diffraction angle 2θ (°) values: 16.763±0.2, 20.034±0.2 and 22.072±0.2.

[0016] In some embodiments, the X-ray powder diffraction pattern of the hemihydrate crystalline form of the compound of formula (I) has characteristic diffraction peaks at the following diffraction angle 2θ (°) values: 16.763±0.2, 20.034±0.2, 22.072±0.2, and further includes 2 or more (such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21) characteristic diffraction peaks at diffraction angle 2θ (°) values ​​selected from the following group: 2.093±0.2, 5.868±0.2, 8.8 77±0.2, 11.561±0.2, 11.988±0.2, 13.078±0.2, 15.323±0.2, 16.04±0.2, 17.872±0.2, 18.861±0.2, 21.024±0.2, 23.39±0.2, 24.166±0.2, 25.185±0.2, 25.85±0.2, 27.146±0.2, 28.583±0.2, 29.419±0.2, 30.898±0.2, 31.132±0.2 and 33.496±0.2.

[0017] In some embodiments, the hemihydrate crystalline form of the compound of formula (I) has an X-ray powder diffraction pattern having characteristic diffraction peaks at 3 or more (such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23) or all of the following diffraction angle 2θ (°) values: 2.093 ± 0.2, 5.868 ± 0.2, 8.877 ± 0.2, 11.561 ± 0.2, 11.988 ± 0.2, 13.078 ± 0.2, 15. 323±0.2, 16.04±0.2, 16.763±0.2, 17.872±0.2, 18.861±0.2, 20.034±0.2, 21.024±0.2, 22.072±0.2, 23.39±0.2, 24.166±0.2, 25.185±0.2, 25.85±0.2, 27.146±0.2, 28.583±0.2, 29.419±0.2, 30.898±0.2, 31.132±0.2 and 33.496±0.2.

[0018] In some embodiments, the hemihydrate crystalline form of the compound of formula (I) has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following diffraction angles 2θ (°): 5.868±0.2, 15.323±0.2, 16.763±0.2, 17.872±0.2, 18.861±0.2, 20.034±0.2, 22.072±0.2, 23.39±0.2, 25.185±0.2, 25.85±0.2 and 27.146±0.2.

[0019] In some embodiments, the hemihydrate crystalline form of the compound of formula (I) has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following diffraction angle 2θ (°) values: 5.868±0.2, 8.877±0.2, 11.561±0.2, 11.988±0.2, 13.078±0.2, 15.323±0.2, 16.04±0.2, 16.763±0.2, 17.872±0.2, 18.861±0.2, 20.034±0.2, 21.024±0.2, 22.072±0.2, 23.39±0.2, 24.166±0.2, 25.185±0.2, 25.85±0.2, 27.146±0.2, 28.583±0.2, 29.419±0.2, 30.898±0.2, 31.132±0.2 and 33.496±0.2.

[0020] In some embodiments, the hemihydrate crystalline form of the compound of formula (I) has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following diffraction angle 2θ (°) values: 2.093±0.2, 5.868±0.2, 8.877±0.2, 11.561±0.2, 11.988±0.2, 13.078±0.2, 15.323±0.2, 16.04±0.2, 16.763±0.2, 17.872 ±0.2, 18.861±0.2, 20.034±0.2, 21.024±0.2, 22.072±0.2, 23.39±0.2, 24.166±0.2, 25.185±0.2, 25.85±0.2, 27.146±0.2, 28.583±0.2, 29.419±0.2, 30.898±0.2, 31.132±0.2 and 33.496±0.2.

[0021] In some embodiments, the hemihydrate crystalline form of the compound of formula (I) has an X-ray powder diffraction pattern expressed in 2θ (°) values ​​and interplanar spacing (d) values ​​having characteristic diffraction peaks shown in Table 1, and the relative intensities of the peaks are shown in Table 1:

[0022] Table 1 2θ(°), d value and relative intensity I / I0 of hemihydrate crystal form

[0023] In some embodiments, the X-ray powder diffraction pattern (XRPD) of the hemihydrate crystalline form of the compound of formula (I) is substantially as shown in FIG3 .

[0024] In some embodiments, the onset temperature in the differential scanning calorimetry curve of the hemihydrate crystalline form of the compound of formula (I) is 114.76°C±3°C, 114.76°C±2°C, 114.76°C±1°C or 114.76°C±0.5°C, and the peak temperature is 128.52°C±3°C, 128.52°C±2°C, 128.52°C±1°C or 128.52°C±0.5°C.

[0025] In some embodiments, the differential scanning calorimetry spectrum (DSC spectrum) of the hemihydrate crystalline form of the compound of formula (I) is substantially as shown in Figure 4. In the embodiment shown in Figure 4, the melting point of the hemihydrate crystalline form is approximately 114.76°C ± 0.5°C.

[0026] In some embodiments, the thermogravimetric analysis pattern (TGA pattern) of the hemihydrate crystalline form of the compound of formula (I) is substantially as shown in FIG5 .

[0027] In some embodiments, the TGA spectrum of the hemihydrate crystalline form of the compound of formula (I) shows a weight loss of 0.156% from 37.16°C to 100.00°C and a weight loss of 1.306% from 100°C to 160°C.

[0028] In some embodiments, the dynamic water absorption curve (DVS diagram) of the hemihydrate crystalline form of the compound of formula (I) is substantially as shown in Figure 6;

[0029] In some embodiments, the DVS diagram of the hemihydrate crystalline form of the compound of formula (I) shows that at 25°C, the weight change during the change from 60% to 0% RH is less than 0.2%, the weight change during the change from 0% to 95% RH is less than 0.2%, and the weight change during the change from 95% to 0% RH is less than 0.2%.

[0030] In some embodiments, the hemihydrate crystalline form of the compound of formula (I) is substantially non-hygroscopic.

[0031] In some embodiments, the H NMR spectrum of the hemihydrate crystalline form of the compound of formula (I) is ( 1 H-NMR) is basically as shown in Figure 7.

[0032] In some embodiments, the hemihydrate crystalline form of the compound of formula (I) 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 12.12 (s, 1H), 10.64 (s, 1H), 9.36 (s, 1H), 8.15 (d, J = 3.1Hz, 1H), 7.81 (ddd, J = 8.9, 8.0, 3.2Hz, 1H ),7.58-7.22(m,5H),7.19-6.95(m,2H),5.55-4.96(m,2H),3.94-3.50(m,2H),1.59(td,J=6.7,5.1,2.7Hz,2H),1.35-0.50(m,3H).

[0033] In some embodiments, the solvate is a cyclohexane / water solvate of a compound of formula (I).

[0034] In some embodiments, the solvate solid form is a cyclohexane / water solvate crystalline form of the compound of Formula (I).

[0035] In some embodiments, the X-ray powder diffraction pattern of the cyclohexane / water solvate crystalline form of the compound of formula (I) has characteristic diffraction peaks at the following diffraction angle 2θ (°) values: 16.372±0.2, 19.825±0.2, 20.483±0.2, 21.561±0.2 and 23.121±0.2.

[0036] In some embodiments, the X-ray powder diffraction pattern of the cyclohexane / water solvate crystalline form of the compound of formula (I) has characteristic diffraction peaks at the following diffraction angle 2θ (°) values: 16.372±0.2, 19.825±0.2, 20.483±0.2, 21.561±0.2 and 23.121±0.2, further includes characteristic diffraction peaks at 2 or more (such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28) selected from the following group: 2.095±0.2, 8.651±0.2, 9.106±0.2, 10.366±0 .2, 11.072±0.2, 12.144±0.2, 13.735±0.2, 15.743±0.2, 16.909±0.2, 17.484±0.2, 18.111±0.2, 19.431±0.2, 22.232±0.2, 23.878±0.2, 24.508±0.2, 25.764±0. 2, 26.391±0.2, 26.901±0.2, 27.707±0.2, 28.555±0.2, 29.333±0.2, 30.418±0.2, 30.713±0.2, 31.314±0.2, 31.994±0.2, 32.264±0.2, 33.296±0.2 and 35.596±0.2.

[0037] In some embodiments, the X-ray powder diffraction pattern of the cyclohexane / water solvate of the compound of formula (I) has characteristic diffraction peaks at 3 or more (such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or 32) or all selected from the following diffraction angle 2θ (°) values: 2.095±0.2, 8.651±0.2, 9.106±0.2, 10.366±0.2, 11.072±0.2, 12.144±0.2, 13.735±0.2, 15.743±0.2, 16.372±0.2, 16.90 9±0.2, 17.484±0.2, 18.111±0.2, 19.431±0.2, 19.825±0.2, 20.483±0.2, 21.561±0.2, 22.232±0.2, 23.121±0.2, 23.878±0.2, 24.508±0.2, 25.764±0.2, 26 .391±0.2, 26.901±0.2, 27.707±0.2, 28.555±0.2, 29.333±0.2, 30.418±0.2, 30.713±0.2, 31.314±0.2, 31.994±0.2, 32.264±0.2, 33.296±0.2 and 35.596±0.2.

[0038] In some embodiments, the X-ray powder diffraction pattern of the cyclohexane / water solvate crystalline form of the compound of formula (I) has characteristic diffraction peaks at the following diffraction angle 2θ (°) values: 12.144±0.2, 13.735±0.2, 15.743±0.2, 16.372±0.2, 16.909±0.2, 17.484±0.2, 18.111±0.2, 19 .431±0.2, 19.825±0.2, 20.483±0.2, 21.561±0.2, 22.232±0.2, 23.121±0.2, 23.878±0.2, 24.508±0.2, 25.764±0.2, 26.391±0.2, 26.901±0.2, 27.707±0.2 and 30.713±0.2.

[0039] In some embodiments, the X-ray powder diffraction pattern of the cyclohexane / water solvate crystalline form of the compound of formula (I) has characteristic diffraction peaks at the following diffraction angle 2θ (°) values: 8.651±0.2, 9.106±0.2, 10.366±0.2, 11.072±0.2, 12.144±0.2, 13.735±0.2, 15.743±0.2, 16.372±0.2, 16.909±0.2, 17.484±0.2, 18.111±0.2, 19.431±0.2, 19.825±0.2, 20. 483±0.2, 21.561±0.2, 22.232±0.2, 23.121±0.2, 23.878±0.2, 24.508±0.2, 25.764±0.2, 26.391±0.2, 26.901±0.2, 27.707±0.2, 28.555±0.2, 29.333±0.2, 30.418±0.2, 30.713±0.2, 31.314±0.2, 31.994±0.2, 32.264±0.2, 33.296±0.2 and 35.596±0.2.

[0040] In some embodiments, the X-ray powder diffraction pattern of the cyclohexane / water solvate of the compound of formula (I) has characteristic diffraction peaks at the following diffraction angle 2θ (°) values: 2.095±0.2, 8.651±0.2, 9.106±0.2, 10.366±0.2, 11.072±0.2, 12.144±0.2, 13.735±0.2, 15.743±0.2, 16.372±0.2, 16.909±0.2, 17.484±0.2, 18.111±0.2, 19.431±0.2, 19.825±0.2 2, 20.483±0.2, 21.561±0.2, 22.232±0.2, 23.121±0.2, 23.878±0.2, 24.508±0.2, 25.764±0.2, 26.391±0.2, 26.901±0.2, 27.707±0.2, 28.555±0.2, 29.333±0.2, 30.418±0.2, 30.713±0.2, 31.314±0.2, 31.994±0.2, 32.264±0.2, 33.296±0.2 and 35.596±0.2.

[0041] In some embodiments, the cyclohexane / water solvate crystalline form of the compound of formula (I) has an X-ray powder diffraction pattern expressed in 2θ (°) values ​​and d values ​​having characteristic diffraction peaks shown in Table 2, and the relative intensities of the peaks are shown in Table 2:

[0042] Table 2 2θ (°), d value and relative intensity I / I0 of cyclohexane / water solvate crystal form

[0043] In some embodiments, the X-ray powder diffraction pattern of the cyclohexane / water solvate of the compound of formula (I) is substantially as shown in FIG8 .

[0044] In some embodiments, the onset temperature in the differential scanning calorimetry curve of the cyclohexane / water solvate crystalline form of the compound of formula (I) is 120.01°C±3°C, 120.01°C±2°C, 120.01°C±1°C or 120.01°C±0.5°C, and the peak temperature is 131.72°C±3°C, 131.72°C±2°C, 131.72°C±1°C or 131.72°C±0.5°C.

[0045] In some embodiments, the DSC spectrum of the cyclohexane / water solvate of the compound of formula (I) is substantially as shown in Figure 9. In the embodiment shown in Figure 9, the melting point of the cyclohexane / water solvate is approximately 120.01°C ± 0.5°C.

[0046] In some embodiments, the TGA chart of the cyclohexane / water solvate crystalline form of the compound of formula (I) is substantially as shown in FIG10 .

[0047] In some embodiments, the TGA spectrum of the cyclohexane / water solvate of the compound of formula (I) shows a 0.208% weight loss from 23.54°C to 100°C and a 2.098% weight loss from 100.0°C to 177°C.

[0048] In some embodiments, the DVS diagram of the cyclohexane / water solvate of the compound of formula (I) shows that the weight change is less than 0.2% during the change of relative humidity from 0% to 95% RH at 25°C.

[0049] In some embodiments, the cyclohexane / water solvate crystalline form of the compound of formula (I) is substantially non-hygroscopic.

[0050] In some embodiments, the cyclohexane / water solvate crystalline form of the compound of formula (I) 1 The H-NMR is basically as shown in FIG11 .

[0051] In some embodiments, the cyclohexane / water solvate crystalline form of the compound of formula (I) 1H-NMR (400MHz, DMSO-d6) δ12.11(s,1H),10.65(s,1H),9.36(s,1H),8.15(d,J=3.1Hz,1H),7.81(td,J=8.6,3.2Hz,1H),7. 46-7.28(m,5H),7.11(td,J=6.2,2.8Hz,2H),5.34-5.08(m,2H),3.92-3.48(m,2H),1.74-1.49(m,2H),1.27-0.74(m,3H).

[0052] The water content of the hemihydrate of the compound of formula (I) of the present application or its crystals may be no more than 1.65±0.5 wt% (the theoretical water content of the hemihydrate is 1.65 wt%, but due to the influence of water attached to the crystals, the water content may be higher, or part of the water in the crystals may be desorbed before measurement, causing the water content to be lower).

[0053] The second aspect of the present application provides a method for preparing a hemihydrate crystalline form of the compound of formula (I) according to the first aspect.

[0054] The following steps are involved:

[0055] (I-1) dispersing the compound of formula (I) in a solvent to obtain a first liquid;

[0056] (I-2) Crystallizing the first liquid to obtain a hemihydrate crystalline form of the compound of formula (I).

[0057] In some embodiments, the solvent in step (I-1) is water, an organic solvent, or a combination thereof.

[0058] In some embodiments, the organic solvent is one or more of methanol, ethanol, isopropanol, acetone, acetonitrile, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, 2-butanone, tetrahydrofuran, dichloromethane, 1,4-dioxane, and toluene; preferably one or more of methanol, ethanol, isopropanol, acetonitrile, acetone, ethyl acetate, 2-butanone, isopropyl acetate, and 1,4-dioxane; more preferably one or more of methanol, ethanol, isopropanol, acetonitrile, and acetone; further preferably one or more of methanol, ethanol, and acetonitrile.

[0059] In some embodiments, the solvent in step (I-1) is water, preferably pure water.

[0060] In some embodiments, the mass volume ratio (w / v) of the compound of formula (I) to the solvent in step (I-1) is 200:1-10:1; preferably 150:1-20:1; more preferably 100:1-25:1; further preferably 100:1 or 25:1.

[0061] In some embodiments, the crystallization treatment in step (I-2) is selected from one or more of suspension shaking, stirring, suspension centrifugation, slow volatilization, cooling crystallization and / or adding an anti-solvent.

[0062] In some embodiments, the crystallization treatment in step (I-2) is carried out at -10°C to 80°C. For example, the temperature can be any range consisting of any two values ​​selected from -10°C, -5°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C and 80°C as end values, without specific limitation.

[0063] In some embodiments, the crystallization treatment in step (I-2) is stirring.

[0064] In some embodiments, the stirring is performed at -10°C to 55°C. In some embodiments, the stirring is performed at 20°C to 55°C.

[0065] In some embodiments, the stirring time is 0.5-10 days.

[0066] In some embodiments, the stirring time is 1-7 days; more preferably 1-5 days; further preferably 1-3 days.

[0067] In some embodiments, the stirring is at 20-55° C. for 1-3 days.

[0068] In some embodiments, the crystallization treatment in step (I-2) further includes separation and / or drying steps.

[0069] In some embodiments, the separation is performed by filtration, centrifugation, or a combination thereof.

[0070] In some embodiments, the drying is vacuum drying or evaporation of the solvent.

[0071] In some embodiments, the method for preparing the hemihydrate crystalline form of the compound of formula (I) comprises the following steps:

[0072] (II-1) dispersing the compound of formula (I) in a solvent to obtain a first liquid;

[0073] (II-2) adding an anti-solvent to the first liquid, followed by stirring, to obtain a hemihydrate crystalline form of the compound of formula (I).

[0074] In some embodiments, the stirring in step (II-2) is at -10-40°C; preferably -5-35°C; more preferably 0-30°C; further preferably 20-30°C.

[0075] In some embodiments, the stirring time in step (II-2) is 12-48 h; preferably 20-40 h; more preferably 20-30 h; further preferably 24 h.

[0076] In some embodiments, the anti-solvent is selected from one or more of n-heptane, isopropyl ether, petroleum ether, and pure water, preferably pure water.

[0077] In some embodiments, the step (II-2) further comprises a crystallization treatment of cooling crystallization after adding the anti-solvent.

[0078] In some embodiments, the cooling crystallization is performed by standing at -5°C to 5°C.

[0079] In some embodiments, the standing time is 0.5-3 h; preferably 0.5-2 h; more preferably 0.75-1.5 h; further preferably 1 h.

[0080] In some embodiments, step (II-2) further comprises separation and / or drying steps after the stirring.

[0081] In some embodiments, the separation is performed by filtration, centrifugation, or a combination thereof.

[0082] In some embodiments, the drying is vacuum drying or evaporation of the solvent.

[0083] The third aspect of the present application provides a method for preparing a cyclohexane / water solvate crystalline form of the compound of formula (I) according to the first aspect, comprising the following steps:

[0084] (III-1) dispersing the compound of formula (I) in a good solvent to obtain a first liquid;

[0085] (III-2) adding an anti-solvent to the first liquid, and performing a second crystallization treatment to obtain a cyclohexane / water solvate crystalline form of the compound of formula (I).

[0086] In some embodiments, the compound of formula (I) described in step (III-1) is a hemihydrate crystalline form of the compound of formula (I).

[0087] In some embodiments, the first liquid in step (III-1) is a solution.

[0088] In some embodiments, the good solvent in step (III-1) is selected from one or more of acetone, ethyl acetate, and ethanol.

[0089] In some embodiments, the mass volume ratio (w / v, mg / ml) of the compound of formula (I) described in step (III-1) to the good solvent is 200:1-50:1; preferably 150:1-50:1; more preferably 120:1-75:1; further preferably 100:1.

[0090] In some embodiments, the anti-solvent in step (III-2) is cyclohexane.

[0091] In some embodiments, the second crystallization treatment in step (III-2) is selected from one or more of suspension shaking, stirring, suspension centrifugation, slow volatilization, and cooling crystallization.

[0092] In some embodiments, the second crystallization treatment in step (III-2) is stirring and / or slow volatilization.

[0093] In some embodiments, the second crystallization treatment in step (III-2) is stirring, cooling crystallization and slow volatilization.

[0094] In some embodiments, the stirring is carried out at 5-40°C, for example, it can be any range consisting of any two values ​​selected from 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C and 40°C as end values, without specific limitation.

[0095] In some embodiments, the stirring time is 1-24 h. For example, it can be any range consisting of any two values ​​selected from 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h, 20 h, 21 h, 22 h, 23 h and 24 h as end values, without specific limitation.

[0096] In some embodiments, the temperature of the cooling crystallization is -20-5°C. For example, it can be any range consisting of any two values ​​selected from -20°C, -15°C, -10°C, -5°C, 0°C, 1°C, 2°C, 3°C, 4°C and 5°C as end values, without specific limitation.

[0097] In some embodiments, the slow volatilization is carried out at 0-40°C. For example, it can be any range consisting of any two values ​​selected from 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C and 40°C as end values, without specific limitation.

[0098] In some embodiments, step (III-2) further comprises a separation step after the second crystallization treatment.

[0099] In some embodiments, the separation is performed by filtration, centrifugation, or a combination thereof.

[0100] In some embodiments, step (III-2) further comprises a drying step after the second crystallization treatment.

[0101] In some embodiments, the drying is vacuum drying or evaporation of the solvent.

[0102] In a fourth aspect, the present application provides a pharmaceutical composition comprising a solid form of a solvate of the compound of formula (I) above; and a pharmaceutically acceptable carrier.

[0103] In a fifth aspect, the present application provides the use of a solid solvate form of the compound of formula (I) in the preparation of a medicament for preventing and / or treating diseases associated with P2X3 activity or P2X2 / 3 activity.

[0104] In some embodiments, the disease associated with P2X3 activity or with P2X2 / 3 activity is pain, urinary tract disorders, gastrointestinal diseases, cancer, immune-related diseases, cough, depression, anxiety or stress-related disorders.

[0105] The sixth aspect of the present application provides the use of the pharmaceutical composition described in the fourth aspect in the preparation of a medicament for preventing and / or treating diseases related to P2X3 activity or P2X2 / 3 activity.

[0106] In some embodiments, the disease associated with P2X3 activity or with P2X2 / 3 activity is pain, urinary tract disorders, gastrointestinal diseases, cancer, immune-related diseases, cough, depression, anxiety or stress-related disorders.

[0107] In the seventh aspect of the present application, there is provided a method for preventing and / or treating diseases associated with P2X3 activity or P2X2 / 3 activity, comprising administering to a patient a therapeutically effective amount of a solid form of a solvate of the compound of formula (I) described in the first aspect of the present application, or the pharmaceutical composition described in the fourth aspect of the present application.

[0108] In some embodiments, the disease associated with P2X3 activity or P2X2 / 3 activity is pain, urinary tract disease, gastrointestinal disease, cancer, immune-related disease, cough, depression, anxiety or stress-related disease. Further, the disease associated with P2X3 activity or P2X2 / 3 activity is P2X3 or P2X2 / 3-mediated pain, urinary tract disease, gastrointestinal disease, cancer, immune-related disease, cough, depression, anxiety or stress-related disease.

[0109] In an eighth aspect, the present application provides a solid solvate form of a compound of formula (I) for preventing and / or treating diseases associated with P2X3 activity or P2X2 / 3 activity, wherein the solvate is a hemihydrate or a cyclohexane / water solvate.

[0110] In a ninth aspect, the present application provides a pharmaceutical composition for preventing and / or treating diseases related to P2X3 activity or P2X2 / 3 activity, the pharmaceutical composition comprising a solvate solid form of the compound of formula (I) above; and a pharmaceutically acceptable carrier.

[0111] In the present application, the hemihydrate crystalline form of the compound of formula (I) is stable in a variety of solvents, and the XRPD pattern of the crystalline form remains essentially unchanged under high temperature and accelerated conditions, demonstrating good physical stability. The impurity content does not change significantly under high temperature and accelerated conditions, demonstrating good chemical stability. Furthermore, the hemihydrate crystalline form is virtually non-hygroscopic. The cyclohexane / water solvate crystalline form of the compound of formula (I) is stable in a variety of solvents, demonstrating good physical stability. Furthermore, the cyclohexane / water solvate crystalline form is virtually non-hygroscopic. The solvate solid form of the present application is more suitable for further drug development. BRIEF DESCRIPTION OF THE DRAWINGS

[0112] In order to more clearly illustrate the embodiments of the present application or the technical solutions in the related technologies, the following briefly introduces the drawings required for use in the embodiments or related technical descriptions. Obviously, the drawings described below are only embodiments of the present application. For ordinary technicians in this field, other drawings can also be obtained based on the drawings of the application.

[0113] FIG1 is an ellipsoid diagram of the molecular stereostructure of a single crystal compound of formula (I);

[0114] FIG2 is an XRPD pattern of the compound of formula (I) obtained in Preparation Example 1;

[0115] FIG3 is an XRPD pattern of the hemihydrate crystalline form of the compound of formula (I);

[0116] FIG4 is a DSC spectrum of the hemihydrate crystalline form of the compound of formula (I);

[0117] FIG5 is a TGA spectrum of the hemihydrate crystalline form of the compound of formula (I);

[0118] FIG6 is a DVS spectrum of the hemihydrate crystalline form of the compound of formula (I);

[0119] Figure 7 is a hemihydrate crystal of the compound of formula (I) 1 H-NMR spectrum;

[0120] FIG8 is an XRPD pattern of a cyclohexane / water solvate of the compound of formula (I);

[0121] FIG9 is a DSC spectrum of a cyclohexane / water solvate crystalline form of the compound of formula (I);

[0122] FIG10 is a TGA spectrum of a cyclohexane / water solvate crystalline form of the compound of formula (I);

[0123] Figure 11 is a cyclohexane / water solvate crystal of the compound of formula (I) 1 H-NMR spectrum;

[0124] Figure 12 is a crystalline form of the hemihydrate of the compound of formula (I) and the cyclohexane / water solvate 1 H-NMR superposition spectrum (wherein, the upper figure is the hemihydrate (solvent DMSO-d6), and the lower figure is the cyclohexane / water solvate (solvent DMSO-d6);

[0125] FIG13 shows the effects of different treatment groups on paw withdrawal thresholds 2 hours after administration, where * and *** indicate P<0.05 and P<0.001, respectively, compared between the test compound group and the solvent group;

[0126] FIG14 shows the effects of different treatment groups on paw withdrawal thresholds 4 hours after administration, where ** indicates P < 0.01 compared between the test compound group and the solvent group;

[0127] FIG15 is a unit cell diagram of a single crystal of a hemihydrate of the compound of formula (I). DETAILED DESCRIPTION

[0128] To make the objectives, technical solutions, and advantages of this application more clearly understood, the present application is further described below with reference to the accompanying drawings and examples. It is apparent that the described examples are only a portion of the embodiments of this application, and not all of them. All other embodiments derived by persons of ordinary skill in the art based on the examples in this application are intended to fall within the scope of protection of this application.

[0129] As used in this application, "crystal" and "crystal form" may be used interchangeably; "cyclohexane / water solvate", "cyclohexane / water solvate", "cyclohexane hydrate", and "cyclohexane hydrate of the compound of formula (I)" may be used interchangeably; "cyclohexane hydrate crystal form", "cyclohexane hydrate crystal form of the compound of formula (I)", and "cyclohexane / water solvate crystal form" may be used interchangeably; "hemihydrate", and "hemihydrate of the compound of formula (I)" may be used interchangeably; "hemihydrate crystal form", and "hemihydrate crystal form of the compound of formula (I)" may be used interchangeably; the above interchangeable usage does not affect the meaning thereof.

[0130] In the present application, the compound of formula (I) is (1S,2S)-2-((3-(4-chlorobenzyl)-4-((4-((5-fluoropyridin-2-yl)oxy)phenyl)amino)-2,6-dioxo-3,6-dihydro-1,3,5-triazin-1(2H)-yl)methyl)cyclopropane-1-carboxylic acid.

[0131] In addition, the compounds of formula (I) of the present application also include tautomers, which refer to mutually balanced isomeric forms of a compound. The imine-enamine tautomers in the structure of the compound of formula (I) are as follows. The present application includes these tautomers and mixtures thereof, that is, the compounds of formula (I) of the present application include the imine tautomers, enamine tautomers and mixtures thereof in their structures.

[0132] Polymorphs: Solids can exist in either amorphous or crystalline forms. In the crystalline form, the molecules are arranged in a three-dimensional lattice. When a compound crystallizes from a solution or slurry, it can crystallize in different spatial arrangements (a property known as "polymorphism"), forming crystals with different crystalline forms, known as "polymorphs." Different polymorphs of a given substance can differ from one another in one or more physical properties, such as solubility and dissolution rate, true specific gravity, crystal shape, packing pattern, flowability, and / or solid-state stability.

[0133] Crystallization: Production-scale crystallization can be accomplished by manipulating the solution so that the solubility limit of the compound of interest is exceeded. This can be accomplished in a variety of ways, for example, by dissolving the compound at a relatively high temperature and then cooling the solution to below the saturation limit. Alternatively, the liquid volume can be reduced by boiling, atmospheric evaporation, vacuum drying, or other methods. The solubility of the compound of interest can be reduced by adding an antisolvent or a solvent or mixture of such solvents in which the compound has low solubility. Another alternative is to adjust the pH to reduce solubility. For a detailed description of crystallization, see Crystallization, 3rd edition, J.W. Mullens, Butterworth-Heineman Ltd., 1993, ISBN 0750611294.

[0134] The meanings of the parameters in the crystal data are as follows:

[0135] The "suspension shaking" mentioned in the present application refers to a method of mixing the compound of formula (I) in a suitable solvent to form a turbid solution and then shaking to obtain crystals. The suitable solvent may be water or an organic solvent.

[0136] The "suspension centrifugation" mentioned herein refers to a method in which the compound of formula (I) is mixed in a suitable solvent to form a turbid solution and then centrifuged to obtain crystals. The suitable solvent may be water or an organic solvent.

[0137] The "slow volatilization" mentioned in the present application refers to a method in which a solution containing the compound of formula (I) is placed at a certain temperature to slowly volatilize the solvent to obtain crystals.

[0138] The "anti-solvent addition" or "addition of anti-solvent" mentioned in the present application refers to a method of adding another suitable solvent to a solution of the compound of formula (I) and then precipitating the resulting crystals.

[0139] Optimization of crystallization can include seeding the crystallization medium with crystals of the desired form. In addition, many crystallization methods use a combination of the above strategies. One example is to dissolve the compound of interest in a solvent at an elevated temperature, followed by the controlled addition of an appropriate volume of antisolvent to bring the system just below saturation. At this point, seeds of the desired form can be added (while maintaining the integrity of the seeds) and the system cooled to complete crystallization. As used herein, unless otherwise specified, the term "about" means ±5 based on the given value.

[0140] In this document, when referring to a data range, if the unit is followed only by the right endpoint, it means that the units for both the left and right endpoints are the same. For example, 3-5h means that the units for both the left endpoint "3" and the right endpoint "5" are h (hours); 1-7d means that the units for both the left endpoint "1" and the right endpoint "7" are d (days).

[0141] Herein, the terms "preferred," "better," "more preferred," and "suitable" are used solely to describe preferred implementations or examples and should not be construed as limiting the scope of protection of this application. If multiple "preferred" terms appear in a technical solution, each "preferred" term is considered independent unless otherwise specified and there are no contradictions or mutual constraints.

[0142] The terms "and / or", "or / and", and "and / or" used herein include any one of two or more related listed items, and also include any and all combinations of the related listed items, wherein the any and all combinations include any combination of two related listed items, any more related listed items, or all related listed items. It should be noted that when at least three items are connected by at least two conjunctions selected from "and / or", "or / and", and "and / or", it should be understood that in this application, the technical solution undoubtedly includes technical solutions connected by "logical AND" and technical solutions connected by "logical OR".

[0143] As used herein, "plurality," "multiple," "multiple times," etc., unless otherwise specified, refer to a quantity greater than or equal to 2. For example, "multiple" means greater than or equal to two.

[0144] In this article, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0145] As used herein, the term "crystalline form of the present application" includes but is not limited to the hemihydrate crystalline form of the compound of formula (I) and the cyclohexane / water solvate crystalline form of the compound of formula (I).

[0146] Pharmaceutical composition and its application

[0147] Generally, the solid form of the solvate of the compound of formula (I) of the present application can be used as an active ingredient and can be combined with one or more pharmaceutically acceptable carriers to form a suitable dosage form for administration.

[0148] "Pharmaceutically acceptable carrier" refers to a non-toxic, inert, solid, semi-solid substance or liquid filling machine, diluent, encapsulating material or auxiliary formulation or any type of excipient, which is compatible with the subject to be administered (preferably a mammal, more preferably a human), and is suitable for delivering the active substance of the present application to the target site without terminating its activity.

[0149] The pharmaceutical compositions of the present application are formulated, dosed, and administered in a manner consistent with standard medical practice. The "therapeutically effective amount" of the active ingredient administered is determined by factors such as the specific condition to be treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.

[0150] The present application provides a solvate solid form of the compound of formula (I) described in the first aspect of the present application and a pharmaceutical composition described in the fourth aspect of the present application, which can be used to prepare drugs for treating and / or preventing diseases related to P2X3 activity or P2X2 / 3 activity or mediated by P2X3 or P2X2 / 3 activity.

[0151] The present application provides a method for treating and / or preventing diseases related to P2X3 activity or P2X2 / 3 activity or mediated by P2X3 or P2X2 / 3 activity, comprising administering to a subject a therapeutically effective amount of a solid form of a solvate of a compound of formula (I) as described in the first aspect of the present application, or the pharmaceutical composition as described in the fourth aspect of the present application.

[0152] As used herein, "therapeutically effective amount" refers to the amount of the compound of formula (I) of the present application that will induce a biological or medical response in an individual, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, relieving or delaying disease progression, or preventing disease.

[0153] As used herein, "subject" refers to an animal, preferably a mammal, more preferably a human. The term "mammal" refers to warm-blooded vertebrate mammals, including cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs and humans.

[0154] "Treatment" refers to alleviating, slowing the progression of, attenuating, preventing, or maintaining an existing disease or condition (eg, cancer). Treatment also includes curing, preventing the development of, or alleviating to some extent, one or more symptoms of a disease or condition.

[0155] Example

[0156] The present application will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present application only and are not intended to limit the scope of the present application. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight. Unless otherwise defined, the terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to the described contents may be applied to the present application.

[0157] Reagents and instruments

[0158] In this application, the structure and purity of the compound were determined by nuclear magnetic resonance (1 H-NMR) and / or liquid chromatography-mass spectrometry (LC-MS).

[0159] 1 H-NMR: Bruker AVANCE-400 nuclear magnetism analyzer, internal standard is tetramethylsilane (TMS).

[0160] LC-MS: Agilent 1290 HPLC System / 6130 / 6150MS liquid chromatography-mass spectrometer (manufacturer: Agilent), column: Waters BEH / CHS, 50×2.1 mm, 1.7 μm.

[0161] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent 1260 Infinity HPLC, OpenLAB CDS Chemstation workstation, an XBridge C18 4.6*250 mm column, ID 5 μm column, and a DAD detector.

[0162] Elemental analysis was performed using an inductively coupled plasma optical emission spectrometer (ICP 500) with a power of 1300 W and a flow rate of 1 mL / min.

[0163] Known starting materials can be synthesized by methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.

[0164] As used herein, room temperature in the following examples refers to about 20-30°C, and overnight refers to about 10 hours to 16 hours.

[0165] General Methods

[0166] X-ray powder diffraction (XRPD): In the present application, the X-ray powder diffraction pattern of the above-mentioned crystalline form or amorphous form is obtained by a method known in the art using an ARL Equinox 3000 X-ray powder diffraction analyzer. The XRPD test parameters are shown in Table 3 below:

[0167] Table 3

[0168] In an X-ray powder diffraction pattern, the position of each peak is determined by the 2θ (°) value. It will be appreciated that different instruments and / or conditions may result in slightly different data, and the position and relative intensity of each peak may vary.

[0169] The peak intensity classification only reflects the approximate size of the peaks at each location. In this application, the diffraction peak with the highest peak height for each crystal form is defined as the base peak, and its relative intensity is defined as 100% (the peak with a 2θ(°) value of 16.763 for the hemihydrate crystal form is the base peak; the peak with a 2θ(°) value of 19.825 for the cyclohexane hydrate crystal form is the base peak). The relative intensity of each other peak is defined as the ratio of its peak height to the base peak height, I / I0. The classification of the relative intensity of each peak is defined as shown in Table 4 below:

[0170] Table 4

[0171] Single Crystal X-ray Diffraction (SXRD): In this application, single crystal X-ray diffraction patterns of the compound of Formula (I) were obtained using a D8 Venture diffractometer using methods known in the art. The SXRD test parameters are shown in Table 5 below. After collecting the relevant data, the crystal structure was further analyzed using a direct method (SHELXT2014 software) to confirm the absolute configuration and obtain relevant unit cell or lattice parameters.

[0172] Table 5

[0173] Karl Fischer Moisture Analyzer: A Mettler V30 Karl Fischer Moisture Analyzer was used to determine the moisture content.

[0174] High Performance Liquid Chromatography: In this application, high performance liquid chromatography (HPLC) was acquired on an Agilent 1260 HPLC.

[0175] Differential Scanning Calorimetry (DSC): In the present application, the differential scanning calorimetry spectrum of the above-mentioned crystal form was obtained by a method known in the art using a DSC25A differential scanning calorimeter. The DSC test parameters are shown in Table 6 below:

[0176] Table 6

[0177] Thermogravimetric analysis (TGA): In the present application, the thermogravimetric analysis spectrum of the above-mentioned crystal form was obtained by a known method in the art using a TGA550 thermogravimetric analyzer. The TGA test parameters are shown in Table 7 below:

[0178] Table 7

[0179] Dynamic moisture sorption (DVS) curves were collected on a DVS Intrinsic dynamic moisture sorption instrument from SMS (Surface Measurement Systems, UK). Relative humidity at 25°C was calibrated using the deliquescent points of LiCl, Mg(NO3)2, and KCl. Instrument test conditions are shown in Table 8 below:

[0180] Table 8

[0181] The "Guidelines for Hygroscopicity Tests of Drugs" No. 9103 of the "Chinese Pharmacopoeia" (2020) stipulates the description of hygroscopic characteristics and the definition of hygroscopic weight gain: (1) Deliquescent: absorbing sufficient water to form a liquid; (2) Extremely hygroscopic: hygroscopic weight gain is not less than 15%; (3) Hygroscopic: hygroscopic weight gain is less than 15% but not less than 2%; (4) Slightly hygroscopic: hygroscopic weight gain is less than 2% but not less than 0.2%; (5) No or almost no hygroscopic: hygroscopic weight gain is less than 0.2%.

[0182] The Pharmacopoeia of the People's Republic of China (2020) contains a note on solubility: "Solubility is a physical property of a drug." The selected solvents for each drug category and their solubility in those solvents provide a reference for purification or solution preparation. The approximate solubility of a drug is expressed in the following terms: (1) Very soluble: refers to the solute 1g (ml) being soluble in less than 1ml of solvent; (2) Easily soluble: refers to the solute 1g (ml) being soluble in 1 to less than 10ml of solvent; (3) Soluble: refers to the solute 1g (ml) being soluble in 10 to less than 30ml of solvent; (4) Slightly soluble: refers to the solute 1g (ml) being soluble in 30 to less than 100ml of solvent; (5) Slightly soluble: refers to the solute 1g (ml) being soluble in 100 to less than 1000ml of solvent; (6) Very slightly soluble: refers to the solute 1g (ml) being soluble in 1000 to less than 10000ml of solvent; (7) Almost insoluble or insoluble: refers to the solute 1g (ml) being incompletely soluble in 10000ml of solvent.

[0183] It is understood that other types of instruments having the same function as the above-mentioned instruments or using test conditions different from those used in this application may result in different values. Therefore, the quoted values ​​should not be regarded as absolute values.

[0184] Due to instrument errors or differences in operators, those skilled in the art will understand that the above parameters used to characterize the physical properties of the crystals may have slight differences, so the above parameters are only used to assist in characterizing the crystal form provided in this application and cannot be regarded as a limitation on the crystal form provided in this application.

[0185] The abbreviations of the reagents used in this application have the following meanings: DMF: dimethylformamide; CDI: N,N-carbonyldiimidazole; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; THF: tetrahydrofuran; MTBE: methyl tert-butyl ether; KHSO4: potassium hydrogen sulfate; DEAD: diethyl azodicarboxylate, MeOH: methanol, DCM: dichloromethane, LiOH: lithium hydroxide, HCOOH: formic acid, H2O: water, DMSO: dimethyl sulfoxide, EA: ethyl acetate, PE: petroleum ether.

[0186] Unless otherwise specified, the stirring in the present invention refers to stirring under sealed conditions.

[0187] Preparation Example 1. Preparation of (1S,2S)-2-((3-(4-chlorobenzyl)-4-((4-((5-fluoropyridin-2-yl)oxy)phenyl)amino)-2,6-dioxo-3,6-dihydro-1,3,5-triazin-1(2H)-yl)methyl)cyclopropane-1-carboxylic acid (Compound of Formula (I))

[0188] Step 1: Dissolve (±)-dimethyl trans-1,2-cyclopropanedicarboxylate (25 g, 0.158 mol) in methanol (90 mL) / water (10 mL), cool in an ice bath, add sodium hydroxide (6.65 g, 0.166 mol), and stir at room temperature overnight. The reaction mixture was concentrated, diluted with 40 mL of water, and adjusted to pH 6 with 3 M (mol / L) hydrochloric acid. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate, and concentrated to afford (±)-trans-2-(methoxycarbonyl)cyclopropane-1-carboxylic acid (22 g). MS m / z (ESI): 145.0 [M+1]. + .

[0189] Step 2: (±) trans-2-(methoxycarbonyl)cyclopropane-1-carboxylic acid (22 g, 0.153 mol) was dissolved in dry THF (100 mL). Borane solution in tetrahydrofuran (1 M, 183 mL, 0.183 mol) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 2 hours. Water was added dropwise to the reaction solution to quench the reaction. After no bubbles were generated, the reaction solution was filtered and the filtrate was concentrated. The residue was diluted with ethyl acetate (250 mL), washed with water and saturated sodium chloride solution, dried, and concentrated to give (±) trans-2-(hydroxymethyl)cyclopropane-1-carboxylic acid methyl ester (20 g). MS m / z (ESI): 131.1 [M+1] + .

[0190] Step 3: (±) trans-2-(hydroxymethyl)cyclopropane-1-carboxylic acid methyl ester (7 g, 53.85 mmol), 1-(4-chlorobenzyl)-6-(ethylthio)-1,3,5-triazine-2,4(1H,3H)-dione (16 g, 53.85 mmol, CAS.NO.1239691-22-5) and triphenylphosphine (22.6 g, 86.16 mmol) were suspended in dry dichloromethane and DEAD (15 g, 86.16 mmol) was added dropwise under ice-cooling. The reaction solution gradually became clear and was stirred at room temperature for 3 hours. The reaction solution was concentrated and the residue was diluted with ethyl acetate (90 mL). Petroleum ether (150 mL) was slowly added under stirring. A large amount of solid precipitated and the product was filtered. The filtrate was concentrated and the residue was purified by column chromatography (EA / PE=1 / 1.8) to give (±) trans-2-((3-(4-chlorobenzyl)-4-ethylsulfanyl-2,6-dioxo-3,6-dihydro-1,3,5-triazin-1(2H)-yl)methyl)cyclopropane-1-carboxylate (25 g). MS m / z(ESI):410.1[M+1] + .

[0191] Step 4: Dissolve (±)-methyl trans-2-((3-(4-chlorobenzyl)-4-ethylthio-2,6-dioxo-3,6-dihydro-1,3,5-triazin-1(2H)-yl)methyl)cyclopropane-1-carboxylate (1.9 g, 4.64 mmol) and 4-((5-fluoropyridin-2-yl)oxy)aniline (947 mg, 4.64 mmol) in pivalic acid (10 mL). The reaction was stirred at 120°C for 3 hours, neutralized with saturated sodium bicarbonate, extracted with dichloromethane, and dried over anhydrous sodium sulfate. The product was dried under reduced pressure and then separated by column chromatography (20 g silica gel, 0-5% MeOH / DCM) to give (±) trans-methyl 2-((3-(4-chlorobenzyl)-4-((4-((5-fluoropyridin-2-yl)oxy)phenyl)amino)-2,6-dioxo-3,6-dihydro-1,3,5-triazin-1(2H)-yl)methyl)cyclopropane-1-carboxylate (2 g). MS m / z (ESI): 551.4 [M+H] + .

[0192] Step 5: (±)trans-methyl 2-((3-(4-chlorobenzyl)-4-((4-((5-fluoropyridin-2-yl)oxy)phenyl)amino)-2,6-dioxo-3,6-dihydro-1,3,5-triazin-1(2H)-yl)methyl)cyclopropane-1-carboxylate (2.00 g, 3.62 mmol) was dissolved in methanol (10 mL) and water (10 mL). LiOH (433.91 mg, 18.12 mmol) was then added. The reaction was stirred at room temperature for 16 hours, the solvent was evaporated, and the residue was purified by preparative liquid chromatography (preparative column: 21.2×250 mm C18 column; system: 10 mM HCOOH H2O and acetonitrile; wavelength: 254 / 214 nm; gradient: 30% to 60% acetonitrile) to obtain (±) trans-2-((3-(4-chlorobenzyl)-4-((4-((5-fluoropyridin-2-yl)oxy)phenyl)amino)-2,6-dioxo-3,6-dihydro-1,3,5-triazin-1(2H)-yl)methyl)cyclopropane-1-carboxylic acid (Compound A) (1.2 g). MS m / z (ESI): 538.1 [M+1]. + .

[0193] Step 6: (±)trans-2-((3-(4-chlorobenzyl)-4-((4-((5-fluoropyridin-2-yl)oxy)phenyl)amino)-2,6-dioxo-3,6-dihydro-1,3,5-triazin-1(2H)-yl)methyl)cyclopropane-1-carboxylic acid was separated via a chiral HPLC column (system: Waters UPCC; column: IG 4.6×100mm 5μm; solvent: methanol; flow rate: 3.0mL / min) to give enantiomer A-1 (defined as the compound of formula (I) in this application) (retention time: 1.960min) and enantiomer A-2 (retention time: 2.678min), respectively.

[0194] The obtained compound of formula (I) was subjected to XRPD detection, and its XRPD pattern was substantially as shown in Figure 2, indicating amorphous. The absolute configuration of the compound of formula (I) can be determined by the single crystal structure of the hemihydrate prepared in Example 1 below.

[0195] Example 1. Preparation of hemihydrate of compound of formula (I)

[0196] Approximately 50 mg of the compound of formula (I) (prepared as described in Preparation Example 1) was weighed into a 5 mL glass vial, followed by the addition of 2 mL of purified water. The sample was stirred at room temperature for 3 days to obtain a suspension, and the wet solid was collected by centrifugation. The collected solid was further dried under reduced pressure and vacuum (60°C, -0.09 MPa). The XRPD pattern of the dried solid was then measured. The XRPD pattern is substantially as shown in Figure 3. The XRPD pattern exhibits peaks at the 2θ (°) values ​​shown in Table 1 above, and the relative intensities of each peak are as shown in Table 1 above.

[0197] Its DSC graph is shown in Figure 4 , with an onset temperature of 114.76°C and a peak temperature of 128.52°C, indicating good crystallinity, indicating that the melting point of the obtained solid is approximately 114.76°C;

[0198] Its TGA graph is shown in Figure 5. The weight loss from 37.16°C to 100.00°C is 0.156%, and the weight loss from 100°C to 160°C is 1.306%. The moisture content was measured by Karl Fischer titrator and was 1.643%. The theoretical value of the moisture content of hemihydrate is 1.65%, indicating that the obtained solid is a hemihydrate.

[0199] Its DVS diagram is shown in Figure 6. At 25°C, the weight change during the relative humidity change from 60% to 0% RH is less than 0.2%, the weight change during the relative humidity change from 0% to 95% RH is less than 0.2%, and the weight change during the relative humidity change from 95% to 0% RH is less than 0.2%, indicating that the obtained solid has almost no hygroscopicity.

[0200] 1 g of the obtained solid was dissolved in 3 mL of methanol. After the solution was clear, the solution was allowed to stand to obtain colorless transparent crystals. The obtained crystals were subjected to single crystal X-ray diffraction (SXRD) analysis. The molecular three-dimensional structure ellipsoid diagram of the compound of formula (I) in the single crystal was basically as shown in Figure 1, indicating that the absolute configuration of the compound of formula (I) is (1S, 2S), that is, (1S, 2S)-2-((3-(4-chlorobenzyl)-4-((4-((5-fluoropyridin-2-yl)oxy)phenyl)amino)-2,6-dioxo-3,6-dihydro-1,3,5-triazin-1(2H)-yl)methyl)cyclopropane-1-carboxylic acid, that is, the compound of formula (I) in the present application.

[0201] SXRD analysis data were collected to obtain unit cell data, as shown in Tables 9 and 10. The unit cell data in Table 9 indicate that the resulting single crystal is a hemihydrate. The resulting unit cell diagram is substantially as shown in Figure 15, with the framed portion in the figure also indicating that it is a hemihydrate. The resulting solid is defined herein as the hemihydrate crystalline form of the compound of Formula (I).

[0202] Table 9 Crystal data of single crystal

[0203] Table 10 Positional parameters of the single crystal structure at 170K

[0204] The obtained hemihydrate crystal 1 The H-NMR diagram is shown in Figure 7. 1 H-NMR (400MHz, DMSO-d6) δ12.12(s,1H),10.64(s,1H),9.36(s,1H),8.15(d,J=3.1Hz,1H),7.81(ddd,J=8.9,8.0,3.2Hz,1H),7 .58-7.22(m,5H),7.19-6.95(m,2H),5.55-4.96(m,2H),3.94-3.50(m,2H),1.59(td,J=6.7,5.1,2.7Hz,2H),1.35-0.50(m,3H).

[0205] Example 2. Preparation of hemihydrate of compound of formula (I)

[0206] Approximately 50 mg of the compound of formula (I) (prepared according to Preparation Example 1) was weighed into a 5 mL glass vial, and 2 mL of water was added. The sample was stirred at 50°C for 3 days to obtain a suspension, and the wet solid was collected by centrifugation. The collected solid was further dried under reduced pressure and vacuum (60°C, -0.09 MPa). The XRPD pattern of the dried solid was measured, which is substantially as shown in Figure 3. The moisture content was 1.686% as measured by Karl Fischer titrator, while the theoretical moisture content for a hemihydrate is 1.65%. This indicates that the obtained solid is the hemihydrate crystalline form of the compound of formula (I).

[0207] Example 3. Preparation of hemihydrate of compound of formula (I)

[0208] Approximately 50 mg of the compound of formula (I) (prepared as described in Preparation Example 1) was weighed into a 5 ml glass vial, and 0.5 ml of a good solvent was added to completely dissolve the mixture. 2.5 ml of an antisolvent was then added dropwise to allow sufficient solid to precipitate. The mixture was refrigerated at 4°C for 1 hour, stirred at room temperature for 24 hours, and then the wet solid was collected by centrifugation. The collected solid was further dried under reduced pressure (60°C, -0.09 MPa), and the XRPD and TGA patterns of the dried solid were measured. The XRPD pattern is generally shown in Figure 3, and the TGA pattern is generally shown in Figure 5. The solvent system and the resulting solid are shown in Table 11:

[0209] Table 11

[0210] Example 4. Preparation of cyclohexane / water solvate of compound of formula (I)

[0211] Approximately 50 mg of the hemihydrate crystalline form (prepared according to Example 1) was weighed into a 5 mL glass vial, and 0.5 mL of acetone was added to completely dissolve the mixture. 4 mL of cyclohexane was then added dropwise to precipitate the solid. The mixture was magnetically stirred at room temperature for 6 h, and the solid was collected by centrifugation. The collected solid was further dried under reduced pressure and vacuum, and the XRPD pattern of the dried solid was measured. The XRPD pattern is substantially as shown in Figure 8. The XRPD pattern exhibits peaks at the 2θ (°) values ​​shown in Table 2 above, and the relative intensities of each peak are shown in Table 2 above.

[0212] Its DSC graph is shown in Figure 9 , with an onset temperature of 120.01°C and a peak temperature of 131.72°C, indicating good crystallinity, indicating that the melting point of the obtained solid is approximately 120.01°C;

[0213] Its TGA graph is shown in FIG10 , which shows a weight loss of 0.208% from 23.54° C. to 100° C. and a weight loss of 2.098% from 100.0° C. to 177° C.

[0214] That 1 The H-NMR spectrum is shown in Figure 11. 1 H-NMR (400MHz, DMSO-d6) δ12.11(s,1H),10.65(s,1H),9.36(s,1H),8.15(d,J=3.1Hz,1H),7.81(td,J=8.6,3.2Hz,1H),7. 46-7.28(m,5H),7.11(td,J=6.2,2.8Hz,2H),5.34-5.08(m,2H),3.92-3.48(m,2H),1.74-1.49(m,2H),1.27-0.74(m,3H).

[0215] The obtained solid was heated to 110°C and dried for 20 minutes without changing its crystalline form; the hemihydrate and the solid obtained in this example 1 The H-NMR results overlay shows that the solid obtained in this example has a cyclohexane solvent peak at approximately 1.40 ppm on the abscissa and a water peak at approximately 3.33 ppm (see Figure 12), indicating that the obtained solid is a cyclohexane / water solvate of the compound of formula (I). The obtained solid is defined in this application as a cyclohexane / water solvate crystalline form of the compound of formula (I).

[0216] Example 5. Preparation of cyclohexane / water solvate of compound of formula (I)

[0217] Approximately 50 mg of the hemihydrate crystalline form (prepared as described in Example 2) was weighed into a 5 mL glass vial. 0.5 mL of ethanol was then added to completely dissolve the crystalline form. 4 mL of cyclohexane was then added dropwise to allow sufficient solid precipitation. The sample was magnetically stirred for 6 hours and refrigerated at 4°C for 3 hours. The sample was then transferred to room temperature and the cap of the sample vial was loosened to allow the solvent to evaporate slowly. The collected solid was further dried under reduced pressure and then its XRPD pattern was measured. The XRPD pattern is shown in Figure 8, indicating that the obtained solid is a cyclohexane / water solvate crystalline form.

[0218] Example 6. Preparation of cyclohexane / water solvate of compound of formula (I)

[0219] Approximately 50 mg of the hemihydrate crystalline form (prepared as described in Example 2) was weighed into a 5 mL glass vial, and 0.5 mL of ethyl acetate was added to completely dissolve the mixture. 4 mL of cyclohexane was then added dropwise to precipitate the solid. The mixture was magnetically stirred at room temperature for 6 h, and the solid was collected by centrifugation. The collected solid was further dried under reduced pressure and vacuum, and the XRPD pattern of the dried solid was measured. The XRPD pattern of the obtained solid is substantially as shown in Figure 8, indicating that the obtained solid is a cyclohexane / water solvate crystalline form.

[0220] Test Example 1. Solubility Test

[0221] The solubility of the hemihydrate was tested in pure water, a pH 1.0 solution (0.1 mol / L hydrochloric acid solution), a pH 4.5 solution (acetic acid-sodium acetate buffer), and a pH 6.8 solution (phosphate buffer). Approximately 5 mg of the hemihydrate crystalline form was weighed into each vial, 5 mL of medium (target concentration 1 mg / mL) was added, and the mixture was shaken at 200 rpm at 37°C for 24 hours. Samples were taken at 1 hour, 4 hours, and 24 hours, and then centrifuged at 10,000 rpm for 10 minutes. The supernatant was filtered through a 0.45 μm filter and its concentration was determined by HPLC. The results are shown in Table 12.

[0222] Table 12 Hemihydrate solubility test results

[0223] The test results in Table 12 show that the hemihydrate is easily soluble in pH 6.8 buffer and has good solubility.

[0224] Test Example 2. Stability Test

[0225] 2.1 Stability test in solvent

[0226] Approximately 50 mg of the hemihydrate crystalline form sample was weighed into a 5 mL glass vial. 2 mL of solvent was then added. The sample was stirred at a constant temperature for 6 hours to obtain a suspension. The wet solid was collected by centrifugation and further dried under reduced pressure (40°C, -0.09 MPa). The XRPD pattern of the dried solid was then measured. The solvents used, stirring temperatures, and the resulting solids are shown in Table 13.

[0227] Table 13 Stability test results of hemihydrate crystal form in solvent

[0228] The test results in Table 13 indicate that the hemihydrate can exist stably in a variety of solvents.

[0229] 2.2 Stability test under high temperature / accelerated conditions

[0230] About 100 mg of the hemihydrate crystalline form of the compound of formula (I) and the compound of formula (I) (prepared as described in Preparation Example 1) were weighed separately and placed under high temperature (60°C sealed) conditions and accelerated (40°C-75% RH-sealed) conditions. The changes in crystalline form and impurities were detected on 5 days (d), 10 days, and 16 days, respectively. The impurity content was detected by HPLC, and the total impurity content was the sum of the contents of each single impurity.

[0231] The XRPD of the hemihydrate crystal form showed little change, indicating that the hemihydrate crystal form had good physical stability under both high temperature and accelerated conditions.

[0232] HPLC analysis revealed that the hemihydrate exhibited good purity and low impurity levels, both within acceptable ranges. Furthermore, the impurity levels of the hemihydrate remained within acceptable limits, maintaining stable chemical stability under both elevated temperature and accelerated conditions.

[0233] Table 14 Stability test results

[0234] Note: Impurities above 0.01% are reported.

[0235] Test Example 3. Hygroscopicity test

[0236] The DVS test was performed on the hemihydrate crystal form and the cyclohexane / water solvate crystal form of the compound of formula (I):

[0237] The DVS diagram of the hemihydrate crystalline form of the compound of formula (I) is shown in Figure 6. The DVS diagram shows that at 25°C, the weight change during the relative humidity change from 60% to 0% RH is less than 0.2%, the weight change during the relative humidity change from 0% to 95% RH is less than 0.2%, and the weight change during the relative humidity change from 95% to 0% RH is less than 0.2%, indicating that the hemihydrate crystalline form of the compound of formula (I) is almost non-hygroscopic.

[0238] A DVS measurement was performed on the cyclohexane / water solvate crystalline form of the compound of formula (I) (prepared with reference to Example 4). The DVS graph of the cyclohexane / water solvate crystalline form of the compound of formula (I) showed that the weight change was less than 0.2% during the relative humidity change from 0% to 95% RH at 25°C, indicating that the cyclohexane / water solvate crystalline form of the compound of formula (I) is almost non-hygroscopic.

[0239] Test Example 4: FLIPR assay to screen compounds for hP2X3 / hP2X 2 / 3 Receptor antagonist activity

[0240] The materials are shown in Table 15:

[0241] Table 15

[0242] Cell preparation: Cells 1321N1 / hP2X3 and 1321N1 / hP2X2 / 3 (supplier Chempartner) were stably transfected with Versene digestion solution, centrifuged, resuspended in plating medium (DMEM + 10% DFBS), and counted. The cell count was adjusted to 3 × 10 5 cells / mL, 50 μL of cells were plated per well in a 384-well test plate, and cultured in a 5% CO2, 37°C incubator for 16-24 h.

[0243] The cell culture medium formula is shown in Table 16:

[0244] Table 16

[0245] The experimental dye solution (Dye) formula is shown in Table 17:

[0246] Table 17

[0247] Compound preparation: 1. Test sample: Prepare the test compound at 180 times the required concentration in DMSO (54 mM DMSO stock solution) in a 384-well polypropylene microplate that meets the Echo standard. Add 500 nL per well to the 384-well compound plate and supplement with 30 μL of assay buffer (containing 1.26 mM Ca 2+1× HBSS+2mM CaCl2+20mM HEPES) and shake for 20-40min to mix.

[0248] 2. Agonist: Prepare agonist (α, β-meATP) at 3 times the required concentration in assay buffer (the final concentration for hP2X3 and hP2X2 / 3 cells is 3000 nM) and add 45 μL of agonist to each well of a 384-well compound plate.

[0249] Dye incubation: Take out the cell plate, remove the cell supernatant, and add 30 μL Dye ( Calcium 4 Assay Kit, diluted in assay buffer) and incubated for 1 h.

[0250] FLIPR assay: Add 15 μL of compound to each well of the cell plate (FLIPR instrument loading). After 15 minutes, add 22.5 μL of agonist to each well and detect the fluorescence signal (excitation wavelength 470 nm-495 nm, emission wavelength 515 nm-575 nm).

[0251] Data processing: The difference between the peak and valley values ​​of the signal was taken as the basic data. The highest concentration data of the positive drug was taken as 100% inhibition rate, and the DMSO data was taken as 0% inhibition rate. The inhibitory effect curve of the compound was fitted by (log (inhibitor) vs. response--Variable slope) on the software Graphpad Prism 6 and the IC was calculated. 50 value.

[0252] Assay uniformity criteria: Perform ≥12 max values ​​(DMSO treatment results) and ≥12 min values ​​(maximum concentration of the positive drug treatment results) on each plate. Calculate the Z score. If Z ≥ 0.5, the replicate wells are considered uniform and the data reliable. The Z score calculation formula is: Z = 1 - 3 * (SDmax + SDmin) / (MEANmax - MEANmin). The test results are shown in Tables 18 and 19.

[0253] Table 18 Inhibitory activity of compounds against P2X3

[0254] Table 19 The multiple of the inhibitory activity of the compounds on P2X2 / 3 and on P2X3

[0255] As can be seen from Tables 18 and 19, the compound of formula (I) of the present application has a high inhibitory activity against P2X3, a low inhibitory activity against P2X2 / 3, and a high inhibitory selectivity.

[0256] Test Example 5: Evaluation of analgesic effect in rat CFA inflammatory pain model

[0257] Experimental Animals: 50 male Sprague-Dawley rats, weighing 230-260 g, were purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd. After purchase, animals were provided with food and water ad libitum at a temperature of 20-25°C and a humidity of 40-70%. They were housed in individual cages and tail-tagged. The experimental design, group assignments, and drug treatments are shown in Table 20.

[0258] Table 20 Experimental design, grouping and drug treatment

[0259] Complete Freund's adjuvant (CFA) and saline were mixed in equal amounts to create an emulsion, which was then injected subcutaneously into rats. Animals were placed in a custom-designed pain test multi-unit metal mesh cage and allowed to acclimate for 15 minutes. After the animals had completed their grooming and exploratory activities and had adapted to the testing environment, a series of calibrated von Frey filaments (0.4, 0.6, 1.0, 1.4, 2, 4, 6, 8, 10, and 15 g) were applied to the hind paw for 6-8 seconds. A withdrawal reflex was recorded as a pain response, and pain was assessed using the paw withdrawal threshold (PWT). The experiment was conducted blindly, and results are presented as mean ± standard deviation. Data were analyzed using GraphPad Prism 5-point t-tests. P < 0.05 was considered statistically significant.

[0260] The specific experimental results are shown in Figures 13 and 14. It can be seen from Figures 13 and 14 that 2 hours after administration, the compound of formula (I) significantly inhibited mechanical allodynia in the rat CFA inflammatory pain model. The effective dose in the rat CFA inflammatory pain model was 30 mg / kg, and the medium and high doses (60 mg / kg) still had a good analgesic effect 4 hours after administration.

[0261] Test Example 6: Pharmacokinetic study in rats after single administration

[0262] Experimental Animals: 24 male Sprague-Dawley rats, SPF grade, weighing 200-240 g, were purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd. After purchase, animals were provided with food and water ad libitum at a temperature of 20-25°C and a humidity of 40-70%. They were housed in individual cages and marked using tail tagging. The experimental design, group assignments, and drug treatments are shown in Table 21.

[0263] Table 21 Experimental design, grouping and drug treatment

[0264] Animals were randomly divided into groups based on body weight. Each group received a single oral dose according to the dose design in Table 21. The drug vehicle consisted of a 1 / 3 0.5% HPC (pH 7.5) and 2 / 3 20% captisol (pH 7.4) aqueous solution (HPC manufacturer: Sigma-Aldrich, batch number: MKBJ6793V; captisol manufacturer: Bidex Pharmaceuticals, batch number: DQP029). Animals were fasted overnight before dosing. Food was resumed 4 hours after dosing, with free access to water. A certain amount of whole blood was collected from each dose group at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 7 hours, and 24 hours after dosing. Plasma samples were obtained by centrifugation and quantitatively analyzed by LC-MS / MS. The pharmacokinetic profile of each group in SD rats was investigated. The results are shown in Table 22. The exposure of the compound of formula (I) at each dose was comparable to that of D1.

[0265] Table 22 Pharmacokinetic parameters in rats

[0266] Test Example 7: Toxicity Test

[0267] Experimental Animals: 16 male and 16 female Sprague-Dawley rats (SPF grade). Male Sprague-Dawley rats weighed approximately 240 g and were 6-9 weeks old; female Sprague-Dawley rats weighed approximately 200 g and were 6-9 weeks old. All experimental animals were purchased from Zhejiang Weitonglihua Experimental Animal Technology Co., Ltd. and provided with food and water ad libitum. The animals were housed at a temperature of 20-26°C, a humidity of 40-70%, and 100% fresh air with 15 or more air changes per hour. The lighting was automated, with a 12-hour light-dark cycle. Males and females were housed in separate cages, with no more than five animals per cage.

[0268] Animals were randomly divided into groups based on sex and body weight. Each group received oral administration of the drug according to the dosage design shown in Table 23, once daily for 14 consecutive days. The drug solvent was a 5 wt% polyethylene glycol stearate (Solutol) + 1 wt% RC591 (Solutol manufacturer: BASF, lot number: BCCD3924; RC591 manufacturer: Du Pont, USA, lot number: DN19833862) aqueous solution. Blood samples were collected before the first and last doses, and 30 minutes, 1 hour, 4 hours, 7 hours, 10 hours, and 24 hours after each dose. The toxicokinetic process of each group in SD rats was investigated. The results are shown in Table 24.

[0269] Table 23 Experimental dosage design

[0270] Safety window calculation basis: According to Test Example 6, the onset dose of the compound of formula (I) in the rat pain model is 30 mg / kg, the peak concentration (Cmax) at this dose is about 18.4 μg / mL, and the area under the drug concentration-time curve (AUC) is about 249hr*μg / mL. Synchronous test example 6 experiments show that the onset dose of the D1 compound in the rat pain model is 60 mg / kg, the Cmax at this dose is about 141 μg / mL, and the AUC is about 1566hr*μg / mL. Safety window (Cmax) = Cmax at the last dose ÷ Cmax at the onset dose, safety window (AUC 0-t ) = AUC at the last dose ÷ AUC at the effective dose.

[0271] Table 24 Toxicokinetic analysis of rat toxicity study

[0272] During the test period, no significant abnormalities were observed in the body weight of the animals in each group, and no animals died or were dying. The data in Table 24 also show that the compound of formula (I) has a relatively high safety window.

[0273] The structure of compound D1 (CAS: 1640808-39-4) in Test Example 6 and Test Example 7 is shown below, and it can be obtained from commercial sources or prepared according to existing techniques.

[0274] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above disclosure, those skilled in the art may make various changes or modifications to this application, and that such equivalents also fall within the scope of the claims appended hereto.

[0275] The technical features of the above-mentioned embodiments can be combined arbitrarily. In order to make the description concise, not all possible combinations of the technical features in the above-mentioned embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0276] The above-described embodiments merely represent several implementation methods of the present application, and their descriptions are relatively specific and detailed, but they should not be construed as limiting the scope of the patent application. It should be noted that a person of ordinary skill in the art may make a number of variations and improvements without departing from the concept of the present application, and these variations and improvements fall within the scope of protection of the present application. Therefore, the scope of protection of the patent application shall be based on the appended claims, and the description and drawings may be used to interpret the content of the claims.

[0277] The above description is only a preferred embodiment of the present application and is not intended to limit the present application. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present application shall be included in the scope of protection of the present application.

Claims

1. A solid form of a solvate of a compound of formula (I), The solvate is a hemihydrate or a cyclohexane / water solvate.

2. The solid form of claim 1, wherein The solid form is a hemihydrate crystal form of the compound of formula (I), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following diffraction angle 2θ (°) values: 16.763±0.2, 20.034±0.2 and 22.072±0.

2.

3. The solid form of claim 2, wherein The X-ray powder diffraction pattern of the solid form further comprises characteristic diffraction peaks at two or more diffraction angle 2θ (°) values ​​selected from the group consisting of: 2.093±0.2, 5.868±0.2, 8.877±0.2, 11.561±0.2, 11.988±0.2, 13.078±0.2, 15.323±0.2, 16.04±0.2, 17.87 2±0.2, 18.861±0.2, 21.024±0.2, 23.39±0.2, 24.166±0.2, 25.185±0.2, 25.85±0.2, 27.146±0.2, 28.583±0.2, 29.419±0.2, 30.898±0.2, 31.132±0.2 and 33.496±0.

2.

4. The solid form of claim 1, wherein The solid form is a hemihydrate crystalline form of the compound of formula (I), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following diffraction angle 2θ (°) values: 2.093±0.2, 5.868±0.2, 8.877±0.2, 11.561±0.2, 11.988±0.2, 13.078±0.2, 15.323±0.2, 16.04±0.2, 16.763±0.2, 17.872±0 .2, 18.861±0.2, 20.034±0.2, 21.024±0.2, 22.072±0.2, 23.39±0.2, 24.166±0.2, 25.185±0.2, 25.85±0.2, 27.146±0.2, 28.583±0.2, 29.419±0.2, 30.898±0.2, 31.132±0.2 and 33.496±0.

2.

5. The solid form of claim 1, wherein The solid form is a cyclohexane / water solvate crystalline form of the compound of formula (I), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following diffraction angles 2θ (°): 16.372±0.2, 19.825±0.2, 20.483±0.2, 21.561±0.2 and 23.121±0.

2.

6. The solid form of claim 5, wherein The X-ray powder diffraction pattern of the solid form further comprises characteristic diffraction peaks at two or more diffraction angle 2θ (°) values ​​selected from the group consisting of: 2.095±0.2, 8.651±0.2, 9.106±0.2, 10.366±0.2, 11.072±0.2, 12.144±0.2, 13.735±0.2, 15.743±0.2, 16.909±0.2, 17.484±0.2, 18.111±0.2, 19.431±0.2 , 22.232±0.2, 23.878±0.2, 24.508±0.2, 25.764±0.2, 26.391±0.2, 26.901±0.2, 27.707±0.2, 28.555±0.2, 29.333±0.2, 30.418±0.2, 30.713±0.2, 31.314±0.2, 31.994±0.2, 32.264±0.2, 33.296±0.2 and 35.596±0.

2.

7. The solid form of claim 1, wherein The solid form is a cyclohexane / water solvate crystalline form of the compound of formula (I), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following diffraction angle 2θ (°) values: 2.095±0.2, 8.651±0.2, 9.106±0.2, 10.366±0.2, 11.072±0.2, 12.144±0.2, 13.735±0.2, 15.743±0.2, 16.372±0.2, 16.909±0.2, 17.484±0.2, 18.111±0.2, 19.431±0.2, 19.825±0.2, 20.483±0.2, 21.561±0.2, 22.232±0.2, 23.121±0.2, 23.878±0.2, 24.508±0.2, 25.764±0.2, 26.391±0.2, 26.901±0.2, 27.707±0.2, 28.555±0.2, 29.333±0.2, 30.418±0.2, 30.713±0.2, 31.314±0.2, 31.994±0.2, 32.264±0.2, 33.296±0.2 and 35.596±0.

2.

8. The solid form of claim 1, wherein The solid form is a hemihydrate crystal form of the compound of formula (I), which has one, more or all of the technical features selected from the following groups: (1) Its X-ray powder diffraction pattern is basically as shown in Figure 3; (2) Its differential scanning calorimetry analysis spectrum is basically as shown in Figure 4; (3) Its thermogravimetric analysis spectrum is basically as shown in Figure 5; (4) Its dynamic water absorption curve is substantially as shown in FIG6; and / or (5) Its H NMR spectrum is basically as shown in Figure 7.

9. The solid form of claim 1, wherein The solid form is a cyclohexane / water solvate crystalline form of the compound of formula (I), which has one, more or all of the technical features selected from the following groups: (1) Its X-ray powder diffraction pattern is basically as shown in Figure 8; (2) Its differential scanning calorimetry analysis spectrum is basically as shown in Figure 9; (3) Its thermogravimetric analysis spectrum is substantially as shown in FIG10; and / or (4) Its H NMR spectrum is basically as shown in Figure 11.

10. A method for preparing a hemihydrate crystalline form of the compound of formula (I) according to any one of claims 2 to 4 or claim 8, comprising the following steps: (I-1) dispersing the compound of formula (I) in a solvent to obtain a first liquid; (I-2) Crystallizing the first liquid to obtain a hemihydrate crystalline form of the compound of formula (I).

11. A pharmaceutical composition comprising: The solid form of any one of claims 1 to 9, and a pharmaceutically acceptable carrier.

12. Use of the solid form according to any one of claims 1 to 9 or the pharmaceutical composition according to claim 11 in the preparation of a medicament for preventing and / or treating diseases associated with P2X3 activity or P2X2 / 3 activity.

13. The use according to claim 12, wherein: The disease associated with P2X3 activity or P2X2 / 3 activity is pain, urinary tract disease, gastrointestinal disease, cancer, immune-related disease, cough, depression, anxiety or stress-related disease.

14. A method for preventing and / or treating a disease associated with P2X3 activity or P2X2 / 3 activity, comprising administering to a patient a therapeutically effective amount of the solid form according to any one of claims 1 to 9, or the pharmaceutical composition according to claim 11.

15. A solid form of a solvate of a compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutical composition according to claim 11, for use in preventing and / or treating diseases associated with P2X3 activity or P2X2 / 3 activity.

Images