Solid forms of naphthylamine mitochondrial autophagy inducers, methods of making, pharmaceutical compositions, and uses thereof

Abstract

Disclosed herein are solid forms of a naphthylamine mitochondrial autophagy inducer, methods of making the same, pharmaceutical compositions, and uses thereof. Various solid forms of the compound of Formula (I) were prepared, such as sodium, potassium, calcium, tromethamine, lysine, tert-butylamine, diisopropylamine, ethanolamine, and diethanolamine salts of the compound of Formula (I).

Description

[0001] Cross-referencing related applications

[0002] This application claims priority to Chinese Patent Application No. 2023102800439, filed on March 21, 2023, entitled "Solid Form of Naphthylamine Mitophagy Inducer, Preparation Method Thereof, Pharmaceutical Composition and Uses thereof", the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates to the solid form of naphthylamine-based mitochondrial autophagy inducers, their preparation methods, pharmaceutical compositions, and uses. Background Technology

[0004] Mitochondria are vital organelles regulating various cellular processes and functions. They are not only the energy source of cells but also play a crucial role in cell survival and death. Therefore, the quality control of mitochondria is extremely important for cells. Mitochondrial quality control mainly involves clearing damaged mitochondria and regulating newly formed mitochondria. Mitophagy, as a selective autophagy process, plays a key role in clearing damaged mitochondria. The primary purpose of mitophagy is to identify and eliminate dysfunctional mitochondria. Since mitochondria play a central role in energy supply through oxidative phosphorylation and have other important functions including energy metabolism, amino acid production, lipid synthesis, and ion homeostasis, they are essential for maintaining the function of aerobic-dependent cell types such as neurons, muscle cells, and liver cells. The homeostasis regulation of mitochondrial formation and autophagy is a crucial link in maintaining cellular function. Dysfunction of mitophagy leads to the accumulation of damaged mitochondria, decreased ATP+ synthesis capacity, and the production of large amounts of peroxides, resulting in changes in cellular intermediate metabolites and triggering a series of pathological consequences. Enhancing mitophagy to clear aging or dysfunctional mitochondria can protect cells. Therefore, developing mitophagy inducers that can effectively induce autophagy in damaged mitochondria, especially selectively induce autophagy in damaged mitochondria, is crucial for inhibiting or alleviating various acute and chronic diseases caused by mitochondrial dysfunction.

[0005] The applicant has previously developed several compounds with a naphthylamine structure as inducers of mitophagy. The applicant subsequently investigated the effects of these compounds and selected those with good therapeutic efficacy to prepare various solid forms. This application describes the solid forms of the compounds with the greatest drug potential and their uses. Summary of the Invention

[0006] The object of the present invention is to provide a solid form of the compound of formula (I).

[0007] Another object of the present invention is to provide a method for preparing the solid form of the compound of formula (I).

[0008] Another object of the present invention is to provide a pharmaceutical composition in solid form containing a compound of formula (I).

[0009] Another object of the present invention is to provide the use of a pharmaceutical composition containing a compound of formula (I) in solid form or in solid form.

[0010] To solve the above-mentioned technical problems, in a first aspect, the present invention provides a pharmaceutically acceptable salt of a compound of formula (I) in solid form.

[0011]

[0012] In some preferred embodiments, the pharmaceutically acceptable salt is a sodium salt, potassium salt, calcium salt, tromethamine salt, lysine salt, tert-butylamine salt, diisopropylamine salt, ethanolamine salt, or diethanolamine salt.

[0013] In some preferred embodiments, the solid form is the solid form (D crystal form) of the sodium salt of the compound of formula (I), and the X-ray powder diffraction pattern of the solid form of the sodium salt of the compound of formula (I) shows characteristic peaks (Cu Kα rays) at 7.06° (±0.2°) and 20.87° (±0.2°) 2θ.

[0014] In some preferred embodiments, the solid form of the sodium salt of the compound of formula (I) has a structure as shown in formula (II).

[0015]

[0016] Where x is selected from 0.5 to 2, for example 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2.0.

[0017] In some preferred embodiments, the solid form of the sodium salt of the compound of formula (I) has at least one of the following characteristics:

[0018] The differential scanning calorimetry (DSC) curve of the sodium salt of the compound of formula (I) in solid form shows an endothermic peak at 183.79 °C (±3 °C) and an exothermic peak at 210.79 °C (±3 °C); and

[0019] The sodium salt of the compound of formula (I) is shown in solid form as... Figure 12 The thermogravimetric analysis curves are roughly the same.

[0020] In some preferred embodiments, the X-ray powder diffraction pattern of the sodium salt of the compound of formula (I) in solid form exhibits at least one characteristic peak selected from 7.06° (±0.2°), 18.07° (±0.2°), 25.02° (±0.2°), and 20.87° (±0.2°)2θ.

[0021] In some preferred embodiments, the X-ray powder diffraction pattern of the sodium salt of the compound of formula (I) in solid form exhibits at least one characteristic peak selected from 7.06° (±0.2°), 18.07° (±0.2°), 25.02° (±0.2°), 17.58° (±0.2°), 20.87° (±0.2°), 10.54° (±0.2°), 23.91° (±0.2°)2θ.

[0022] In some preferred embodiments, the X-ray powder diffraction pattern of the sodium salt of the compound of formula (I) in solid form exhibits at least one characteristic peak selected from 7.06° (±0.2°), 18.07° (±0.2°), 25.02° (±0.2°), 17.58° (±0.2°), 20.87° (±0.2°), 10.54° (±0.2°), 23.91° (±0.2°), 27.65° (±0.2°), 27.05° (±0.2°), 21.68° (±0.2°), and 25.91° (±0.2°)2θ.

[0023] In some preferred embodiments, the solid form of the sodium salt of the compound of formula (I) exhibits the same characteristics as... Figure 10 The X-ray powder diffraction patterns are roughly the same.

[0024] In some preferred embodiments, the solid form of the sodium salt of the compound of formula (I) exhibits the same characteristics as... Figure 11 The differential scanning calorimetry curves are roughly the same.

[0025] In some preferred embodiments, the X-ray powder diffraction pattern of the sodium salt of the compound of formula (I) in solid form (A crystal form) shows characteristic peaks at 6.85° (±0.2°) and 19.43° (±0.2°) 2θ.

[0026] In some preferred embodiments, the solid form (A crystal form) of the sodium salt of the compound of formula (I) has at least one of the following characteristics:

[0027] The differential scanning calorimetry (DSC) curve of the sodium salt of the compound of formula (I) in solid form (crystal form A) shows endothermic peaks at 144.89 °C (±3 °C) and 150.40 °C (±3 °C), and an exothermic peak at 214.79 °C (±3 °C).

[0028] In some preferred embodiments, the X-ray powder diffraction pattern of the sodium salt of the formula (I) in solid form (A crystal form) exhibits at least one characteristic peak selected from 6.85° (±0.2°), 19.43° (±0.2°), 21.47° (±0.2°) and 4.70° (±0.2°) 2θ.

[0029] In some preferred embodiments, the solid form of the sodium salt of the compound of formula (I) exhibits the same characteristics as... Figure 1 The X-ray powder diffraction patterns are roughly the same.

[0030] In some preferred embodiments, the solid form of the sodium salt of the compound of formula (I) exhibits the same characteristics as... Figure 2 The differential scanning calorimetry curves are roughly the same.

[0031] In some preferred embodiments, the solid form of the sodium salt of the compound of formula (I) exhibits the same characteristics as... Figure 3 The thermogravimetric analysis curves are roughly the same.

[0032] In some preferred embodiments, the X-ray powder diffraction pattern of the sodium salt of the compound of formula (I) in solid form (Crystal B) shows characteristic peaks of 7.88° (±0.2°) and 19.29° (±0.2°) 2θ.

[0033] In some preferred embodiments, the solid form (B crystal form) of the sodium salt of the compound of formula (I) has at least one of the following characteristics:

[0034] The differential scanning calorimetry (DSC) curve of the sodium salt of the compound of formula (I) in solid form shows endothermic peaks at 72.14 °C (±3 °C) and 145.82 °C (±3 °C), and an exothermic peak at 184.61 °C (±3 °C); and

[0035] The thermogravimetric analysis curve of the sodium salt of the compound of formula (I) in solid form shows a weight loss peak at 73.50 °C (±3 °C) (preferably, the weight loss is 6.78% (±0.2%) relative to the total weight of the solid form).

[0036] In some preferred embodiments, the X-ray powder diffraction pattern of the sodium salt of the compound of formula (I) in solid form exhibits at least one characteristic peak selected from 7.88° (±0.2°), 9.64° (±0.2°), 14.42° (±0.2°), 19.29° (±0.2°) and 22.65° (±0.2°)2θ.

[0037] In some preferred embodiments, the solid form of the sodium salt of the compound of formula (I) exhibits the same characteristics as... Figure 4 The X-ray powder diffraction patterns are roughly the same.

[0038] In some preferred embodiments, the solid form of the sodium salt of the compound of formula (I) exhibits the same characteristics as... Figure 5 The differential scanning calorimetry curves are roughly the same.

[0039] In some preferred embodiments, the solid form of the sodium salt of the compound of formula (I) exhibits the same characteristics as... Figure 6 The thermogravimetric analysis curves are roughly the same.

[0040] In some preferred embodiments, the X-ray powder diffraction pattern of the sodium salt of the formula (I) compound in solid form (C crystal form) shows characteristic peaks of 8.56° (±0.2°) and 19.96° (±0.2°) 2θ.

[0041] In some preferred embodiments, the solid form (C crystal form) of the sodium salt of the compound of formula (I) has at least one of the following characteristics:

[0042] The differential scanning calorimetry (DSC) curve of the sodium salt of the compound of formula (I) in solid form shows endothermic peaks at 59.75 °C (±3 °C) and 140.91 °C (±3 °C), and an exothermic peak at 185.61 °C (±3 °C); and

[0043] The thermogravimetric analysis curve of the sodium salt of the compound of formula (I) in solid form shows a weight loss peak at 70.15 °C (±3 °C) (preferably, the weight loss is 4.96% (±0.2%) relative to the total weight of the solid form).

[0044] In some preferred embodiments, the X-ray powder diffraction pattern of the sodium salt of the compound of formula (I) in solid form exhibits at least one characteristic peak selected from 8.56° (±0.2°), 13.24° (±0.2°), 14.62° (±0.2°), 19.96° (±0.2°), and 24.542° (±0.2°)2θ.

[0045] In some preferred embodiments, the solid form of the sodium salt of the compound of formula (I) exhibits the same characteristics as... Figure 7 The X-ray powder diffraction patterns are roughly the same.

[0046] In some preferred embodiments, the solid form of the sodium salt of the compound of formula (I) exhibits the same characteristics as... Figure 8 The differential scanning calorimetry curves are roughly the same.

[0047] In some preferred embodiments, the solid form of the sodium salt of the compound of formula (I) exhibits the same characteristics as... Figure 9 The thermogravimetric analysis curves are roughly the same.

[0048] In some preferred embodiments, the solid form is the solid form of the potassium salt of the compound of formula (I), and the X-ray powder diffraction pattern of the solid form of the potassium salt of the compound of formula (I) shows at least one characteristic peak selected from 9.67° (±0.2°) and 19.63° (±0.2°) 2θ.

[0049] In some preferred embodiments, the potassium salt of the compound of formula (I) in solid form has a structure as shown in formula (III), (F crystal form).

[0050]

[0051] Where x is between 0.5 and 2.0. For example, x can be 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2.0.

[0052] In some preferred embodiments, the solid form of the potassium salt of the compound of formula (I) has at least one of the following characteristics:

[0053] The differential scanning calorimetry (DSC) curve of the potassium salt of compound (I) in solid form is shown below. Figure 17 The differential scanning calorimetry (DSC) curves are roughly the same; and

[0054] The thermogravimetric analysis curves of the potassium salt of compound (I) in solid form are shown below. Figure 18 The thermogravimetric analysis curves are roughly the same.

[0055] In some preferred embodiments, the potassium salt of the compound of formula (I) is presented in solid form as... Figure 16 The X-ray powder diffraction patterns are roughly the same.

[0056] In some preferred embodiments, the solid form of the potassium salt of the compound of formula (I) exhibits at least one characteristic peak selected from 9.67° (±0.2°), 11.34° (±0.2°), 16.68° (±0.2°), 19.63° (±0.2°) and 22.46° (±0.2°)2θ in the X-ray powder diffraction pattern.

[0057] In some preferred embodiments, the solid form is the solid form of the calcium salt of formula (I), and the X-ray powder diffraction pattern of the solid form of the calcium salt of formula (I) shows at least one characteristic peak selected from 11.53° (±0.2°) and 21.54° (±0.2°) 2θ.

[0058] In some preferred embodiments, the solid form of the calcium salt of the compound of formula (I) has the structure shown in formula (IV), (G crystal form).

[0059]

[0060] Where x is 0.5-2.0. For example, x is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0. Preferably, x is 0.8, 0.9, 1, or 1.1. (G crystal form)

[0061] In some preferred embodiments, the solid form of the calcium salt of the compound of formula (I) has at least one of the following characteristics:

[0062] The differential scanning calorimetry curve of the calcium salt of the compound of formula (I) in solid form is shown below. Figure 20 The differential scanning calorimetry (DSC) curves are roughly the same; and

[0063] The thermogravimetric analysis curves of the calcium salt of compound (I) in solid form are shown below. Figure 21 The thermogravimetric analysis curves are roughly the same.

[0064] In some preferred embodiments, the solid form of the calcium salt of the compound of formula (I) exhibits the same characteristics as... Figure 19 The X-ray powder diffraction patterns are roughly the same.

[0065] In some preferred embodiments, the X-ray powder diffraction pattern of the calcium salt of formula (I) in solid form exhibits at least one characteristic peak selected from 11.53° (±0.2°), 21.54° (±0.2°), 12.46° (±0.2°), 18.56° (±0.2°), 20.92° (±0.2°), 25.20° (±0.2°), and 26.06° (±0.2°)2θ.

[0066] In some preferred embodiments, the solid form is the solid form of the tromethamine salt of formula (I), and the X-ray powder diffraction pattern of the solid form of the tromethamine salt of formula (I) shows at least one characteristic peak selected from 8.94° (±0.2°) and 14.35° (±0.2°) 2θ.

[0067] In some preferred embodiments, the solid form of the aminobutadiene triol salt of the compound of formula (I) has the structure shown in formula (V), (H crystal form).

[0068]

[0069] Where x is between 0.5 and 2.0. For example, x is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0. Preferably, x is 0.8, 0.9, 1, or 1.1.

[0070] In some preferred embodiments, the solid form of the aminobutadiene triol salt of the compound of formula (I) has at least one of the following characteristics:

[0071] The differential scanning calorimetry (DSC) curve of the solid form of the aminobutyrate of compound (I) is shown below. Figure 23 The differential scanning calorimetry (DSC) curves are roughly the same; and

[0072] The thermogravimetric analysis curve of the solid form of the aminobutyric acid glycerol salt of compound (I) is shown below. Figure 24 The thermogravimetric analysis curves are roughly the same.

[0073] In some preferred embodiments, the solid form of the aminobutadiene triol salt of the compound of formula (I) exhibits the same characteristics as... Figure 22 The X-ray powder diffraction patterns are roughly the same.

[0074] In some preferred embodiments, the X-ray powder diffraction pattern of the solid form of the tromethamine salt of the compound of formula (I) exhibits at least one characteristic peak selected from 8.94° (±0.2°), 14.35° (±0.2°), 17.09° (±0.2°), 18.69° (±0.2°), 19.76° (±0.2°), 22.19° (±0.2°), 22.59° (±0.2°), 22.99° (±0.2°), 25.40° (±0.2°), and 26.58° (±0.2°)2θ.

[0075] In some preferred embodiments, the solid form is the solid form of the lysine salt of the compound of formula (I), and the X-ray powder diffraction pattern of the solid form of the lysine salt of the compound of formula (I) shows at least one characteristic peak selected from 12.31° (±0.2°) and 19.66° (±0.2°) 2θ.

[0076] In some preferred embodiments, the solid form of the lysine salt of the compound of formula (I) has the structure shown in formula (VI), (I crystal form).

[0077]

[0078] Where x is between 0.5 and 2.0. For example, x is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0. Preferably, x is 0.8, 0.9, 1, or 1.1.

[0079] In some preferred embodiments, the solid form of the lysine salt of the compound of formula (I) has at least one of the following characteristics:

[0080] The thermogravimetric analysis curve of the lysine salt of compound (I) in solid form is shown below. Figure 27 The thermogravimetric analysis curves are roughly the same.

[0081] In some preferred embodiments, the solid form of the lysine salt of the compound of formula (I) exhibits the same characteristics as... Figure 25 The X-ray powder diffraction patterns are roughly the same.

[0082] In some preferred embodiments, the X-ray powder diffraction pattern of the solid form of the lysine salt of the compound of formula (I) exhibits at least one characteristic peak selected from 12.31° (±0.2°), 17.72° (±0.2°), 21.16° (±0.2°), 24.13° (±0.2°), and 19.66° (±0.2°)2θ.

[0083] In some preferred embodiments, the solid form is the solid form of the tert-butylamine salt of formula (I), and the X-ray powder diffraction pattern of the solid form of the tert-butylamine salt of formula (I) shows at least one characteristic peak selected from 7.15° (±0.2°) and 10.14° (±0.2°) 2θ.

[0084] In some preferred embodiments, the solid form of the tert-butylamine salt of the compound of formula (I) has the structure shown in formula (VII), (J crystal form).

[0085]

[0086] Where x is between 0.5 and 2.0. For example, x is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0. Preferably, x is 0.8, 0.9, 1, or 1.1.

[0087] In some preferred embodiments, the solid form of the tert-butylamine salt of the compound of formula (I) has at least one of the following characteristics:

[0088] The differential scanning calorimetry (DSC) curve of the solid form of the tert-butylamine salt of compound (I) is shown below. Figure 29The differential scanning calorimetry (DSC) curves are roughly the same; and

[0089] The thermogravimetric analysis curve of the tert-butylamine salt of the compound of formula (I) in solid form is shown below. Figure 30 The thermogravimetric analysis curves are roughly the same.

[0090] In some preferred embodiments, the solid form of the tert-butylamine salt of the compound of formula (I) exhibits the same characteristics as... Figure 28 The X-ray powder diffraction patterns are roughly the same.

[0091] In some preferred embodiments, the X-ray powder diffraction pattern of the solid form of the tert-butylamine salt of the compound of formula (I) exhibits at least one characteristic peak selected from 7.15° (±0.2°), 17.85° (±0.2°), 18.28° (±0.2°), 19.19° (±0.2°), 20.51° (±0.2°), 22.03° (±0.2°) and 10.14° (±0.2°) 2θ.

[0092] In some preferred embodiments, the solid form is the solid form of the diisopropylamine salt of formula (I), and the X-ray powder diffraction pattern of the solid form of the diisopropylamine salt of formula (I) shows at least one characteristic peak selected from 8.87° (±0.2°) and 17.20° (±0.2°) 2θ.

[0093] In some preferred embodiments, the solid form of the diisopropylamine salt of the compound of formula (I) has the structure shown in formula (VIII), (K crystal form).

[0094]

[0095] Where x is between 0.5 and 2.0. For example, x is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0. Preferably, x is 0.8, 0.9, 1, or 1.1.

[0096] In some preferred embodiments, the solid form of the diisopropylamine salt of the compound of formula (I) has at least one of the following characteristics:

[0097] The differential scanning calorimetry (DSC) curve of the diisopropylamine salt of compound (I) in solid form is shown below. Figure 32 The differential scanning calorimetry (DSC) curves are roughly the same; and

[0098] The thermogravimetric analysis curve of the diisopropylamine salt of compound (I) in solid form is shown below. Figure 33 The thermogravimetric analysis curves are roughly the same.

[0099] In some preferred embodiments, the solid form of the diisopropylamine salt of the compound of formula (I) exhibits the same characteristics as... Figure 31 The X-ray powder diffraction patterns are roughly the same.

[0100] In some preferred embodiments, the X-ray powder diffraction pattern of the solid form of the diisopropylamine salt of the compound of formula (I) exhibits at least one characteristic peak selected from 8.87° (±0.2°), 9.25° (±0.2°), 9.65° (±0.2°), 15.07° (±0.2°), 16.97° (±0.2°), 18.06° (±0.2°), 19.31° (±0.2°), 20.01° (±0.2°), 22.65° (±0.2°), 27.29° (±0.2°), and 17.20° (±0.2°)2θ.

[0101] In some preferred embodiments, the solid form is the solid form of the ethanolamine salt of formula (I), and the X-ray powder diffraction pattern of the solid form of the ethanolamine salt of formula (I) shows at least one characteristic peak selected from 7.62° (±0.2°) and 19.70° (±0.2°) 2θ.

[0102] In some preferred embodiments, the solid form of the ethanolamine salt of the compound of formula (I) has the structure shown in formula (IX), (L crystal form).

[0103]

[0104] Where x is between 0.5 and 2.0. For example, x is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0. Preferably, x is 0.8, 0.9, 1, or 1.1.

[0105] In some preferred embodiments, the solid form of the ethanolamine salt of the compound of formula (I) has at least one of the following characteristics:

[0106] The differential scanning calorimetry (DSC) curve of the solid form of the ethanolamine salt of compound (I) is shown below. Figure 35 The differential scanning calorimetry (DSC) curves are roughly the same; and

[0107] The thermogravimetric analysis curves of the solid form of the ethanolamine salt of compound (I) are shown below. Figure 36 The thermogravimetric analysis curves are roughly the same.

[0108] In some preferred embodiments, the solid form of the ethanolamine salt of the compound of formula (I) exhibits the same characteristics as... Figure 34 The X-ray powder diffraction patterns are roughly the same.

[0109] In some preferred embodiments, the X-ray powder diffraction pattern of the solid form of the ethanolamine salt of the compound of formula (I) exhibits at least one characteristic peak selected from 7.62° (±0.2°), 9.72° (±0.2°), 14.98° (±0.2°), 19.34° (±0.2°) and 19.70° (±0.2°)2θ.

[0110] In some preferred embodiments, the solid form is the solid form of the diethanolamine salt of formula (I), and the X-ray powder diffraction pattern of the solid form of the diethanolamine salt of formula (I) shows at least one characteristic peak selected from 6.33° (±0.2°) and 19.87° (±0.2°) 2θ.

[0111] In some preferred embodiments, the solid form of the diethanolamine salt of the compound of formula (I) has the structure shown in formula (X), (M crystal form).

[0112]

[0113] Where x is between 0.5 and 2.0. For example, x is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0. Preferably, x is 0.8, 0.9, 1, or 1.1.

[0114] In some preferred embodiments, the solid form of the diethanolamine salt of the compound of formula (I) has at least one of the following characteristics:

[0115] The differential scanning calorimetry (DSC) curve of the diethanolamine salt of compound (I) in solid form is shown below. Figure 38 The differential scanning calorimetry (DSC) curves are roughly the same; and

[0116] The thermogravimetric analysis curve of the diethanolamine salt of compound (I) in solid form is shown below. Figure 39 The thermogravimetric analysis curves are roughly the same.

[0117] In some preferred embodiments, the solid form of the diethanolamine salt of the compound of formula (I) exhibits the same characteristics as... Figure 37 The X-ray powder diffraction patterns are roughly the same.

[0118] In some preferred embodiments, the X-ray powder diffraction pattern of the solid form of the diethanolamine salt of the compound of formula (I) exhibits at least one characteristic peak selected from 6.33° (±0.2°), 7.41° (±0.2°), 12.46° (±0.2°), 22.02° (±0.2°), 28.45° (±0.2°), and 19.87° (±0.2°)2θ.

[0119] In a second aspect, the present invention provides a solid form (E crystal form) of a free acid of formula (I); the X-ray powder diffraction pattern of the solid form of the free acid of formula (I) shows at least one characteristic peak selected from 8.92° (±0.2°) and 23.31° (±0.2°) 2θ.

[0120]

[0121] In some preferred embodiments, the solid form of the free acid of the compound of formula (I) also has at least one of the following characteristics:

[0122] The differential scanning calorimetry (DSC) curve of the solid form of the ethanolamine salt of compound (I) is shown below. Figure 14 The differential scanning calorimetry (DSC) curves are roughly the same; and

[0123] The thermogravimetric analysis curves of the solid form of the ethanolamine salt of compound (I) are shown below. Figure 15 The thermogravimetric analysis curves are roughly the same.

[0124] In some preferred embodiments, the X-ray powder diffraction pattern of the free acid of formula (I) in solid form exhibits at least one characteristic peak selected from 8.92° (±0.2°), 23.31° (±0.2°), 27.41° (±0.2°), 19.70° (±0.2°), 16.51° (±0.2°), 12.27° (±0.2°), 21.50° (±0.2°), 18.23° (±0.2°), and 18.37° (±0.2°)2θ.

[0125] In a third aspect, the present invention provides a pharmaceutical composition comprising a solid form of a compound of formula (I) as described in any one of the first to ninth aspects of the present invention, and a pharmaceutically acceptable carrier or excipient.

[0126] In a fourth aspect, the present invention provides a method for preparing a solid form of a sodium salt of a compound of formula (I), the method comprising the steps of: dissolving the compound of formula (I) in a reaction medium and reacting it with a sodium-containing base.

[0127] In some preferred embodiments, the reaction medium is selected from at least one of methanol, ethanol, isopropanol, tert-butanol, acetone, acetonitrile, and ethyl acetate, or a mixture of at least one of methanol, ethanol, isopropanol, tert-butanol, acetone, acetonitrile, and ethyl acetate and water. For example, a mixture of acetone, acetone, and water, or a mixture of acetonitrile and water.

[0128] In some preferred embodiments, the sodium-containing base is selected from at least one of sodium bicarbonate, sodium carbonate, sodium hydroxide, sodium acetate, sodium formate, sodium methoxide, sodium ethoxide, and sodium tert-butoxide.

[0129] In some preferred embodiments, the molar ratio of the compound of formula (I) to the sodium-containing base in the reaction system is 1:(0.9-1.1).

[0130] In some preferred embodiments, the compound of formula (I) is dissolved in acetone at 35-55°C (preferably 40-50°C), and a sodium bicarbonate solution is added. After the solid precipitates, the mixture is kept at this temperature and allowed to stand for at least 20 minutes (preferably at least 30 minutes), and then cooled to room temperature to obtain the solid form of the sodium salt of the compound of formula (I).

[0131] In some preferred embodiments, the compound of formula (I) is dissolved in acetone at 35-55°C, cooled to room temperature, sodium bicarbonate solution is added and stirred, and after the solid precipitates, it is kept at the temperature and allowed to stand for at least 20 minutes (preferably at least 30 minutes) to obtain the solid form of the sodium salt of the compound of formula (I).

[0132] In some preferred embodiments, the compound of formula (I) is dissolved in acetone at 35-55°C, a sodium bicarbonate solution is added and stirred, and after the solid precipitates, it is kept at the temperature and stirred for at least 20 minutes (preferably at least 30 minutes), and then cooled to room temperature to obtain the solid form of the sodium salt of the compound of formula (I).

[0133] In some preferred embodiments, the compound of formula (I) is dissolved in acetone at 35-55°C, a sodium methoxide methanol solution is added and stirred, and after the solid precipitates, it is kept at the temperature and allowed to stand for at least 50 minutes (preferably at least 60 minutes), and then cooled to room temperature and stirred for at least 50 minutes (preferably at least 60 minutes) to obtain the solid form of the sodium salt of the compound of formula (I).

[0134] In some preferred embodiments, the compound of formula (I) is dissolved in acetone at 35-55°C, sodium bicarbonate solution is added and stirred, and after the solid precipitates, it is kept at the temperature and allowed to stand for at least 50 minutes (preferably at least 60 minutes) to obtain the solid form of the sodium salt of the compound of formula (I).

[0135] A fifth aspect of the present invention provides the use of a compound of formula (I) as described in the first or second aspect of the present invention, or a pharmaceutical composition as described in the third aspect of the present invention, for: (i) preparing a medicament for the prevention and / or treatment of diseases related to kidney injury; and / or

[0136] (ii) Prevention and / or treatment of diseases associated with kidney injury; and / or

[0137] (iii) Prevention and / or treatment of diseases associated with mitochondrial dysfunction; and / or

[0138] (iv) To prepare drugs for the prevention and / or treatment of diseases associated with mitochondrial dysfunction.

[0139] Compared with the prior art, the present invention has at least the following advantages:

[0140] (1) Various solid forms of the compound of formula (I) were prepared in this invention, such as free acid, sodium salt, potassium salt, calcium salt, tromethamine salt, lysine salt, tert-butylamine salt, diisopropylamine salt, ethanolamine salt, and diethanolamine salt, and corresponding identification methods were provided.

[0141] (2) The sodium salt of compound (I) prepared in the preferred embodiment of the present invention has excellent effects in terms of crystal stability, biological activity, safety and bioavailability. In addition, it has low hygroscopicity, good water solubility and good drug development prospects.

[0142] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0143] One or more embodiments are illustrated by way of example with reference to the accompanying drawings, and these illustrative descriptions do not constitute a limitation on the embodiments.

[0144] Figure 1 This is the X-ray powder diffraction pattern of crystal type A according to an embodiment of the present invention;

[0145] Figure 2 This is the differential scanning calorimetry curve of crystal form A according to an embodiment of the present invention;

[0146] Figure 3 This is the thermogravimetric analysis curve of crystal form A according to an embodiment of the present invention;

[0147] Figure 4 This is an X-ray powder diffraction pattern of crystal type B according to an embodiment of the present invention;

[0148] Figure 5 This is a differential scanning calorimetry curve of crystal form B according to an embodiment of the present invention;

[0149] Figure 6 This is a thermogravimetric analysis curve of crystal form B according to an embodiment of the present invention;

[0150] Figure 7 This is an X-ray powder diffraction pattern of C-type crystal according to an embodiment of the present invention;

[0151] Figure 8 This is a differential scanning calorimetry curve of the C-type crystal form according to an embodiment of the present invention;

[0152] Figure 9 This is a thermogravimetric analysis curve of the C-type crystal form according to an embodiment of the present invention;

[0153] Figure 10 This is an X-ray powder diffraction pattern of crystal type D according to an embodiment of the present invention;

[0154] Figure 11 This is a differential scanning calorimetry curve of crystal form D according to an embodiment of the present invention;

[0155] Figure 12 This is a thermogravimetric analysis curve of crystal form D according to an embodiment of the present invention;

[0156] Figure 13 This is an E-type X-ray powder diffraction pattern according to an embodiment of the present invention;

[0157] Figure 14 This is a differential scanning calorimetry curve of the E-crystal form according to an embodiment of the present invention;

[0158] Figure 15 This is a thermogravimetric analysis curve of the E-type crystal according to an embodiment of the present invention;

[0159] Figure 16 This is an X-ray powder diffraction pattern of the F-crystal type according to an embodiment of the present invention;

[0160] Figure 17 This is a differential scanning calorimetry curve of the F-type crystal form according to an embodiment of the present invention;

[0161] Figure 18 This is a thermogravimetric analysis curve of the F-type crystal form according to an embodiment of the present invention;

[0162] Figure 19 This is an X-ray powder diffraction pattern of the G-type crystal according to an embodiment of the present invention;

[0163] Figure 20 This is a differential scanning calorimetry curve of crystal form G according to an embodiment of the present invention;

[0164] Figure 21 This is a thermogravimetric analysis curve of crystal form G according to an embodiment of the present invention;

[0165] Figure 22 This is an H-type X-ray powder diffraction pattern according to an embodiment of the present invention;

[0166] Figure 23 This is a differential scanning calorimetry curve of the H-type crystal according to an embodiment of the present invention;

[0167] Figure 24 This is a thermogravimetric analysis curve of the H-type crystal form according to an embodiment of the present invention;

[0168] Figure 25 This is the X-ray powder diffraction pattern of crystal type I according to the embodiment of the present invention;

[0169] Figure 26 This is a diagram showing the interconversion relationship of sodium salt polymorphs according to an embodiment of the present invention;

[0170] Figure 27 This is a thermogravimetric analysis curve of crystal form I according to an embodiment of the present invention;

[0171] Figure 28 This is the J-type X-ray powder diffraction pattern according to an embodiment of the present invention;

[0172] Figure 29 This is a differential scanning calorimetry curve of crystal form J according to an embodiment of the present invention;

[0173] Figure 30 This is a thermogravimetric analysis curve of the J-type crystal according to an embodiment of the present invention;

[0174] Figure 31 This is an X-ray powder diffraction pattern of K-type crystal according to an embodiment of the present invention;

[0175] Figure 32 This is a differential scanning calorimetry curve of K crystal form according to an embodiment of the present invention;

[0176] Figure 33 This is a thermogravimetric analysis curve of K crystal form according to an embodiment of the present invention;

[0177] Figure 34 This is an X-ray powder diffraction pattern of the L-crystal form according to an embodiment of the present invention;

[0178] Figure 35 This is a differential scanning calorimetry curve of the L-type crystal form according to an embodiment of the present invention;

[0179] Figure 36 This is a thermogravimetric analysis curve of the L-type crystal form according to an embodiment of the present invention;

[0180] Figure 37 This is an M-type X-ray powder diffraction pattern according to an embodiment of the present invention;

[0181] Figure 38 This is a differential scanning calorimetry curve of crystal form M according to an embodiment of the present invention;

[0182] Figure 39 This is a thermogravimetric analysis curve of crystal form M according to an embodiment of the present invention;

[0183] Figure 40 This is the DVS spectrum of the D crystal form sample according to an embodiment of the present invention;

[0184] Figure 41 This is a solubility diagram of D-type FaSSIF buffer, FeSSIF buffer, water and SGF according to an embodiment of the present invention;

[0185] Figure 42 These are heatmaps of the level of mitophagy induced by different concentrations of D crystal form according to embodiments of the present invention;

[0186] Figure 43 This is a graph showing the changes in serum creatinine before and after administration of D crystal form in a rat model of kidney injury caused by unilateral renal ischemia-reperfusion according to an embodiment of the present invention.

[0187] Figure 44 This is a graph showing the changes in blood urea nitrogen before and after administration of D crystal form in a rat model of kidney injury caused by unilateral renal ischemia-reperfusion according to an embodiment of the present invention.

[0188] Figure 45 This is a graph showing the change in serum creatinine clearance rate before and after administration of D crystal form in a rat model of kidney injury caused by unilateral renal ischemia-reperfusion according to an embodiment of the present invention.

[0189] Figure 46 This is a diagram showing the changes in Caspase 9 in renal tissue before and after administration of D crystal form in a rat model of renal injury caused by unilateral renal ischemia-reperfusion according to an embodiment of the present invention.

[0190] Figure 47 This is a diagram showing the changes in IL-6 in kidney tissue before and after administration of D crystal form in a rat model of kidney injury caused by unilateral renal ischemia-reperfusion according to an embodiment of the present invention.

[0191] Figure 48 This is a diagram showing the changes in IL-1β in kidney tissue before and after administration of D crystal form in a rat model of kidney injury caused by unilateral renal ischemia-reperfusion according to an embodiment of the present invention.

[0192] Figure 49 This is a diagram showing the changes in TUNEL in kidney tissue before and after administration of D crystal form in a rat model of kidney injury caused by unilateral renal ischemia-reperfusion injury according to an embodiment of the present invention. Detailed Implementation

[0193] This invention prepared various solid forms of compound TJ01-013 (as shown in Formula I), and studied the stability, solubility, safety, and bioavailability of each crystal form. Ultimately, it was found that the D crystal form of sodium salt of compound TJ01-013 has the best drug development potential.

[0194] Solid form of compound TJ01-013

[0195] This invention relates to various solid forms of compound TJ01-013 (as shown in Formula I). ​​These include: sodium salts of compound (I), potassium salts of compound (I), calcium salts of compound (I), tromethamine salts of compound (I), lysine salts of compound (I), tert-butylamine salts of compound (I), diisopropylamine salts of compound (I), ethanolamine salts of compound (I), and diethanolamine salts of compound (I).

[0196]

[0197] In this invention, the term "solid form" refers to solid material types, including amorphous and crystalline forms. The term "crystalline form" refers to polymorphs, solvates, hydrates, etc. The term "polymorph" refers to a specific crystal structure with specific physical properties (e.g., X-ray diffraction, melting point, and the like).

[0198] In this invention, the aforementioned solid forms are characterized using methods conventional in the art, such as X-ray powder diffraction, differential scanning calorimetry, and thermogravimetric analysis. It should be understood that the positions and relative intensities of peaks in X-ray powder diffraction patterns can vary slightly due to various factors known to those skilled in the art. For example, shifts in peak positions or relative intensities may occur due to the equipment used, the method of sample preparation, preferred packaging and orientation, the source of radiation, and the method and length of data collection. However, those skilled in the art will be able to compare the X-ray powder diffraction patterns shown in the accompanying drawings with those of unknown solid forms to confirm the identity of the solid form. In this invention, the terms "generally," "substantially," and "essentially" mean a measurement uncertainty of ±0.3 (in 2θ degrees), preferably ±0.2 (in 2θ degrees), or a measurement uncertainty of ±0.3 °C when applied to DSC curves, or a variation of ±2% in weight loss when applied to TGA thermal analysis patterns.

[0199] (1) Sodium salt of compound (I)

[0200] In this invention, the sodium salt of compound (I) refers to the salt obtained by reacting compound (I) with a sodium-containing base (sodium-containing bases include sodium-containing organic bases, such as sodium ethoxide; sodium-containing inorganic bases, such as sodium hydroxide; and sodium-containing strong base weak acid salts, such as sodium bicarbonate, sodium dihydrogen carbonate, etc.). The sodium salt of compound (I) preferably has the structure shown in formula (II) below, where x is selected from 0.5-2, for example 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2.0.

[0201]

[0202] Depending on the preparation method, at least four different crystal forms (crystal AD) of the sodium salt of compound (I) are obtained in this invention.

[0203] In some embodiments, the sodium salt of compound (I) is prepared in solid form by the following method, including the steps of:

[0204] The compound of formula (I) is dissolved in acetone at 40-50°C and reacted with a sodium-containing base.

[0205] In some embodiments, at 40-50°C, the compound of formula (I) is dissolved in acetone and sodium bicarbonate solution is added. After the solid precipitates, the mixture is kept at the temperature and allowed to stand for at least 30 minutes. Then, it is cooled to room temperature and filtered to obtain the solid form (crystal form A) of the sodium salt of the compound of formula (I).

[0206] In some embodiments, the compound of formula (I) is dissolved in acetone at 40-50°C, cooled to room temperature, sodium bicarbonate solution is added and stirred, and after the solid precipitates, it is kept at the temperature and allowed to stand for at least 30 minutes to obtain the solid form (crystal form B) of the sodium salt of the compound of formula (I).

[0207] In some embodiments, the compound of formula (I) is dissolved in acetone at 40-50°C, sodium bicarbonate solution is added and stirred, and after the solid precipitates, it is kept at the temperature and stirred for at least 30 minutes, and then cooled to room temperature and filtered to obtain the solid form (crystal form C) of the sodium salt of the compound of formula (I).

[0208] In some preferred embodiments, the compound of formula (I) is dissolved in acetone at 40-50°C, a sodium methoxide methanol solution is added and stirred, and after the solid precipitates, it is kept at the temperature and allowed to stand for at least 60 minutes. Then it is cooled to room temperature and stirred for at least 60 minutes. The sodium salt of the compound of formula (I) is obtained by filtration (crystal form D).

[0209] In some preferred embodiments, the compound of formula (I) is dissolved in acetone at 40-50°C, sodium bicarbonate solution is added and stirred, and after the solid precipitates, it is kept at the temperature and allowed to stand for at least 60 minutes. After the solid precipitates, it is kept at the temperature and allowed to stand for at least 60 minutes. The solid form (crystal form D) of the sodium salt of the compound of formula (I) is obtained by filtration.

[0210] As a solid form (crystal form D) of the sodium salt of formula (I), its X-ray powder diffraction pattern has at least the following characteristics: the X-ray powder diffraction pattern displays characteristic peaks at 7.06° (±0.2°) and 20.87° (±0.2°) 2θ; more preferably, the X-ray powder diffraction pattern displays characteristic peaks at 7.06° (±0.2°) and 20.87° (±0.2°) 2θ, and at least one characteristic peak selected from 18.07° (±0.2°) and 25.02° (±0.2°) 2θ; even more preferably, the X-ray powder diffraction pattern displays characteristic peaks at 7.06° (±0.2°) and 20.87° (±0.2°) 2θ, and at least one characteristic peak selected from 18.07° (±0.2°), 17.58° (±0.2°), and 10.54° (±0.2°) 2θ. The X-ray powder diffraction pattern shows characteristic peaks of 7.06° (±0.2°) and 20.87° (±0.2°), and at least one characteristic peak selected from 18.07° (±0.2°), 17.58° (±0.2°), 10.54° (±0.2°), 23.91° (±0.2°), 27.65° (±0.2°), 27.05° (±0.2°), 21.68° (±0.2°), 25.91° (±0.2°), and 25.02° (±0.2°) 2θ; more preferably, the X-ray powder diffraction pattern shows characteristic peaks of 2θ as shown in Table 1-1 below; the solid form of the sodium salt of the compound of formula (I) shows the same characteristics as... Figure 10 The X-ray powder diffraction patterns are roughly the same.

[0211] Table 1-1

[0212]

[0213] As a solid form (crystal form D) of the sodium salt of compound (I), its differential scanning calorimetry curve shows an endothermic peak at 183.79℃ (±3℃), an enthalpy of 3.9256 J / g, an initial temperature of 175.04℃, and an exothermic peak at 210.79℃ (±3℃); more preferably, the solid form of the sodium salt of compound (I) exhibits the same characteristics as... Figure 11 The differential scanning calorimetry curves are roughly the same.

[0214] As a solid form (crystal form D) of the sodium salt of compound (I), its thermogravimetric analysis curve shows that the sample does not lose weight before decomposition; more preferably, the solid form of the sodium salt of compound (I) exhibits the same characteristics as... Figure 12 The thermogravimetric analysis curves are roughly the same.

[0215] (2) Potassium salts of compound (I)

[0216] In this invention, the solid form of the sodium salt of compound (I) refers to the salt obtained by reacting compound (I) with a potassium-containing base. It preferably has the structure shown in formula (III), where x is selected from 0.5-2, for example 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0.

[0217]

[0218] As a solid form of the potassium salt of formula (I), its X-ray powder diffraction pattern exhibits characteristic peaks at 9.67° (±0.2°) and 19.63° (±0.2°) 2θ; more preferably, its X-ray powder diffraction pattern exhibits characteristic peaks at 9.67° (±0.2°) and 19.63° (±0.2°) 2θ, and at least one characteristic peak selected from 11.34° (±0.2°), 16.68° (±0.2°), and 22.46° (±0.2°) 2θ; more preferably, the solid form of the potassium salt of formula (I) exhibits characteristic peaks at 9.67° (±0.2°) and 19.63° (±0.2°) 2θ, and at least one characteristic peak selected from 11.34° (±0.2°), 16.68° (±0.2°), and 22.46° (±0.2°) 2θ; even more preferably, the solid form of the potassium salt of formula (I) exhibits characteristic peaks at 9.67° (±0.2°) and 19.63° (±0.2°) 2θ. Figure 16 The X-ray powder diffraction patterns are roughly the same.

[0219] As a solid form of the potassium salt of compound (I), its differential scanning calorimetry curve is shown in the figure. Figure 17 The differential scanning calorimetry curves are roughly the same.

[0220] As a solid form of the potassium salt of compound (I), its thermogravimetric analysis curve is shown in the figure. Figure 18 The thermogravimetric analysis curves are roughly the same.

[0221] (3) Calcium salts of compound (I)

[0222] In this invention, the solid form of the calcium salt of formula (I) refers to the salt obtained by reacting the compound of formula (I) with a calcium-containing base. It preferably has the structure shown in formula (IV), where x is selected from 0.5-2, for example 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0.

[0223]

[0224] As a solid form of the calcium salt of formula (I), its X-ray powder diffraction pattern exhibits characteristic peaks at 11.53° (±0.2°) and 21.54° (±0.2°) 2θ; more preferably, its X-ray powder diffraction pattern exhibits characteristic peaks at 11.53° (±0.2°) and 21.54° (±0.2°) 2θ, and at least one characteristic peak selected from 12.46° (±0.2°), 18.56° (±0.2°), 20.92° (±0.2°), 25.20° (±0.2°), and 26.06° (±0.2°) 2θ; more preferably, the solid form of the calcium salt of formula (I) exhibits characteristic peaks at 11.53° (±0.2°) and 21.54° (±0.2°) 2θ. Figure 19 The X-ray powder diffraction patterns are roughly the same.

[0225] As a solid form of the calcium salt of compound (I), its differential scanning calorimetry curve is shown in the figure. Figure 20 The differential scanning calorimetry curves are roughly the same.

[0226] As a solid form of the calcium salt of compound (I), its thermogravimetric analysis curve is shown in the figure. Figure 21 The thermogravimetric analysis curves are roughly the same.

[0227] (4) The aminobutane triol salt of compound (I)

[0228] In this invention, the solid form of the tromethamine salt of formula (I) refers to the salt obtained by reacting the compound of formula (I) with a base containing tromethamine. It preferably has the structure shown in formula (V), where x is selected from 0.5-2, for example 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0.

[0229]

[0230] As a solid form of the tromethamine salt of formula (I), its X-ray powder diffraction pattern exhibits characteristic peaks at 8.94° (±0.2°) and 14.35° (±0.2°) 2θ; more preferably, its X-ray powder diffraction pattern exhibits characteristic peaks at 8.94° (±0.2°) and 14.35° (±0.2°) 2θ, and at least one characteristic peak selected from 17.09° (±0.2°), 18.69° (±0.2°), 19.76° (±0.2°), 22.19° (±0.2°), 22.59° (±0.2°), 22.99° (±0.2°), 25.40° (±0.2°), and 26.58° (±0.2°) 2θ; more preferably, the solid form of the tromethamine salt of formula (I) exhibits the same characteristic peaks as... Figure 22 The X-ray powder diffraction patterns are roughly the same.

[0231] As a solid form of the aminobutanetriol salt of compound (I), its differential scanning calorimetry curve is shown with Figure 23 The differential scanning calorimetry curves are roughly the same.

[0232] As a solid form of the aminobutanetriol salt of compound (I), its thermogravimetric analysis curve is shown with Figure 24 The thermogravimetric analysis curves are roughly the same.

[0233] (5) Lysine salt of compound (I)

[0234] In this invention, the solid form of the lysine salt of formula (I) refers to the salt obtained by reacting the compound of formula (I) with a lysine-containing base. It preferably has the structure shown in formula (VI), where x is 0.5-2.0. For example, x is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0. Preferably, x is 0.8, 0.9, 1, or 1.1.

[0235]

[0236] As a solid form of the lysine salt of formula (I), its X-ray powder diffraction pattern exhibits characteristic peaks at 12.31° (±0.2°) and 19.66° (±0.2°) 2θ; more preferably, its X-ray powder diffraction pattern exhibits characteristic peaks at 12.31° (±0.2°) and 19.66° (±0.2°) 2θ, and at least one characteristic peak selected from 17.72° (±0.2°), 21.16° (±0.2°), and 24.13° (±0.2°) 2θ; more preferably, the solid form of the lysine salt of formula (I) exhibits characteristic peaks at 12.31° (±0.2°) and 19.66° (±0.2°) 2θ, and at least one characteristic peak selected from 17.72° (±0.2°), 21.16° (±0.2°), and 24.13° (±0.2°) 2θ; even more preferably, the solid form of the lysine salt of formula (I) exhibits characteristic peaks at 12.31° (±0.2°) and 19.66° (±0.2°) 2θ. Figure 25 The X-ray powder diffraction patterns are roughly the same.

[0237] As a solid form of the lysine salt of compound (I), its thermogravimetric analysis curve is shown in the figure. Figure 27 The thermogravimetric analysis curves are roughly the same.

[0238] (6) Tert-butylamine salt of compound (I)

[0239] In this invention, the solid form of the tert-butylamine salt of formula (I) refers to the salt obtained by reacting the compound of formula (I) with a base containing tert-butylamine. It preferably has the structure shown in formula (VII), where x is 0.5-2.0. For example, x is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0. Preferably, x is 0.8, 0.9, 1, or 1.1.

[0240]

[0241] As a solid form of the tert-butylamine salt of formula (I), its X-ray powder diffraction pattern exhibits characteristic peaks at 7.15° (±0.2°) and 10.14° (±0.2°) 2θ; more preferably, its X-ray powder diffraction pattern exhibits characteristic peaks at 7.15° (±0.2°) and 10.14° (±0.2°) 2θ, and at least one characteristic peak selected from 17.85° (±0.2°), 18.28° (±0.2°), 19.19° (±0.2°), 20.51° (±0.2°), and 22.03° (±0.2°) 2θ; more preferably, the solid form of the tert-butylamine salt of formula (I) exhibits the same characteristic peaks as those of the tert-butylamine salt of formula (I). Figure 28 The X-ray powder diffraction patterns are roughly the same.

[0242] As a solid form of the tert-butylamine salt of compound (I), its differential scanning calorimetry curve is shown with... Figure 29 The differential scanning calorimetry curves are roughly the same.

[0243] As a solid form of the tert-butylamine salt of compound (I), its thermogravimetric analysis curve is shown with Figure 30 The thermogravimetric analysis curves are roughly the same.

[0244] (7) Diisopropylamine salt of compound (I)

[0245] In this invention, the solid form of the diisopropylamine salt of formula (I) refers to the salt obtained by reacting the compound of formula (I) with a base containing diisopropylamine. It preferably has the structure shown in formula (VIII), where x is 0.5-2.0. For example, x is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0. Preferably, x is 0.8, 0.9, 1, or 1.1.

[0246]

[0247] As a solid form of the diisopropylamine salt of formula (I), its X-ray powder diffraction pattern exhibits characteristic peaks at 8.87° (±0.2°) and 17.20° (±0.2°) 2θ; more preferably, its X-ray powder diffraction pattern exhibits characteristic peaks at 8.87° (±0.2°) and 17.20° (±0.2°) 2θ, and at least one characteristic peak selected from 9.25° (±0.2°), 9.65° (±0.2°), 15.07° (±0.2°), 16.97° (±0.2°), 18.06° (±0.2°), 19.31° (±0.2°), 20.01° (±0.2°), 22.65° (±0.2°), and 27.29° (±0.2°) 2θ; more preferably, the solid form of the diisopropylamine salt of formula (I) exhibits the same characteristic peaks as... Figure 31 The X-ray powder diffraction patterns are roughly the same.

[0248] As a solid form of the diisopropylamine salt of compound (I), its differential scanning calorimetry curve is shown with... Figure 32 The differential scanning calorimetry curves are roughly the same.

[0249] As a solid form of the diisopropylamine salt of compound (I), its thermogravimetric analysis curve is shown to be consistent with... Figure 33 The thermogravimetric analysis curves are roughly the same.

[0250] (8) Ethanolamine salt of compound (I)

[0251] In this invention, the solid form of the ethanolamine salt of formula (I) refers to the salt obtained by reacting the compound of formula (I) with a base containing ethanolamine. It preferably has the structure shown in formula (IX), where x is 0.5-2.0. For example, x is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0. Preferably, x is 0.8, 0.9, 1, or 1.1.

[0252]

[0253] As a solid form of the ethanolamine salt of formula (I), its X-ray powder diffraction pattern exhibits characteristic peaks at 7.62° (±0.2°) and 19.70° (±0.2°) 2θ; more preferably, its X-ray powder diffraction pattern exhibits characteristic peaks at 7.62° (±0.2°) and 19.70° (±0.2°) 2θ, and at least one characteristic peak selected from 9.72° (±0.2°), 14.98° (±0.2°), and 19.34° (±0.2°) 2θ; more preferably, the solid form of the ethanolamine salt of formula (I) exhibits the same characteristic peaks as... Figure 34The X-ray powder diffraction patterns are roughly the same.

[0254] As a solid form of the ethanolamine salt of compound (I), its differential scanning calorimetry curve is shown with... Figure 35 The differential scanning calorimetry curves are roughly the same.

[0255] As a solid form of the ethanolamine salt of compound (I), its thermogravimetric analysis curve is shown in the figure. Figure 36 The thermogravimetric analysis curves are roughly the same.

[0256] (9) Diethanolamine salt of compound (I)

[0257] In this invention, the solid form of the diethanolamine salt of compound (I) refers to the salt obtained by reacting compound (I) with a base containing diethanolamine. It preferably has the structure shown in formula (X), where x is 0.5-2.0. For example, x is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0. Preferably, x is 0.8, 0.9, 1, or 1.1.

[0258]

[0259] As a solid form of the diethanolamine salt of formula (I), its X-ray powder diffraction pattern exhibits characteristic peaks at 6.33° (±0.2°) and 19.87° (±0.2°) 2θ; more preferably, its X-ray powder diffraction pattern exhibits characteristic peaks at 6.33° (±0.2°) and 19.87° (±0.2°) 2θ, and at least one characteristic peak selected from 7.41° (±0.2°), 12.46° (±0.2°), 22.02° (±0.2°), and 28.45° (±0.2°) 2θ; more preferably, the solid form of the diethanolamine salt of formula (I) exhibits the same characteristic peaks as... Figure 37 The X-ray powder diffraction patterns are roughly the same.

[0260] As a solid form of the diethanolamine salt of compound (I), its differential scanning calorimetry curve is shown in the figure. Figure 38 The differential scanning calorimetry curves are roughly the same.

[0261] As a solid form of the diethanolamine salt of compound (I), its thermogravimetric analysis curve is shown in the figure. Figure 39 The thermogravimetric analysis curves are roughly the same.

[0262] (10) The solid form of the free acid of compound (I)

[0263] In this invention, the solid form of the free acid of compound (I) refers to the solid form of compound (I). As a solid form of the free acid of formula (I), its X-ray powder diffraction pattern exhibits at least one characteristic peak selected from 8.92° (±0.2°) and 23.31° (±0.2°) 2θ; more preferably, the X-ray powder diffraction pattern of the solid form of the free acid of formula (I) exhibits at least one characteristic peak selected from 8.92° (±0.2°), 23.31° (±0.2°), 27.41° (±0.2°), 19.70° (±0.2°), 16.51° (±0.2°), 12.27° (±0.2°), 21.50° (±0.2°), 18.23° (±0.2°), and 18.37° (±0.2°) 2θ; more preferably, the solid form of the free acid of formula (I) exhibits the same characteristic peak as... Figure 13 The X-ray powder diffraction patterns are roughly the same.

[0264] As a solid form of the free acid of compound (I), its differential scanning calorimetry curve is shown in relation to... Figure 14 The differential scanning calorimetry curves are roughly the same.

[0265] As a solid form of the free acid of compound (I), its thermogravimetric analysis curve is shown in... Figure 15 The thermogravimetric analysis curves are roughly the same.

[0266] Pharmaceutical Composition

[0267] The present invention also relates to pharmaceutical compositions comprising a compound of formula (I) in solid form, comprising a compound of formula (I) in solid form, and a pharmaceutically acceptable carrier or excipient.

[0268] As used herein, the term "composition" refers to a pharmaceutical preparation suitable for administration to a given individual for therapeutic purposes, containing at least one pharmaceutically active compound, including in any solid or amorphous form. The composition may include at least one pharmaceutically acceptable component to provide a modified formulation of the compound, such as a suitable carrier or excipient.

[0269] The term "pharmaceutically acceptable" indicates that, taking into account the disease or condition to be treated and the individual route of administration, the indicated material does not possess characteristics that would cause a reasonably cautious medical practitioner to avoid administering the material to a patient. For example, such materials are typically required to be substantially sterile, such as for injectable formulations.

[0270] use

[0271] This invention also relates to the use of compounds of formula (I) in solid form or pharmaceutical compositions for (i) the preparation of medicaments for the prevention and / or treatment of diseases associated with kidney damage; and / or

[0272] (ii) Prevention and / or treatment of diseases associated with kidney injury; and / or

[0273] (iii) Prevention and / or treatment of diseases associated with mitochondrial dysfunction; and / or

[0274] (iv) To prepare drugs for the prevention and / or treatment of diseases associated with mitochondrial dysfunction.

[0275] In some preferred embodiments, the kidney injury-related diseases include acute kidney injury and chronic kidney injury, preferably chronic kidney injury.

[0276] In some preferred embodiments, the kidney injury-related diseases are selected from acute renal ischemia-reperfusion injury, septic nephropathy, nephrotoxicosis, primary glomerulonephritis, hypertensive nephrotic arteriosclerosis, diabetic nephropathy, secondary glomerulonephritis, tubulointerstitial nephropathy, ischemic nephropathy, and hereditary nephropathy.

[0277] In some preferred embodiments, the tubulointerstitial lesion is selected from chronic pyelonephritis, chronic uric acid nephropathy, obstructive nephropathy, and drug-induced nephropathy.

[0278] In some preferred embodiments, the hereditary kidney disease is selected from polycystic kidney disease and hereditary nephritis.

[0279] In some preferred embodiments, the disease associated with mitochondrial dysfunction is selected from at least one of the following: inflammatory bowel disease; lung injury; fibrotic disease; sepsis; prostate disease; cardiovascular disease; neurological disease; and age-related disease.

[0280] In some preferred embodiments, the inflammatory bowel disease is selected from at least one of ulcerative colitis and Crohn's disease.

[0281] In some preferred embodiments, the fibrotic disease is selected from at least one of renal tubulointerstitial fibrosis, interstitial lung disease (ILD), idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease fibrosis, tissue fibrosis, joint fibrosis, liver fibrosis, skin fibrosis, fibromatosis, myelofibrosis, cardiac fibrosis, and cystic fibrosis.

[0282] In some preferred embodiments, the cardiovascular disease is selected from at least one of atherosclerosis, heart failure, myocardial ischemia / reperfusion injury, and hypertension, cardiomyopathy, and diabetic cardiovascular complications.

[0283] In some preferred embodiments, the neurological disease is selected from at least one of the following: sensorineural hearing loss, brain developmental abnormalities, congenital hydrocephalus, congenital cranial nerve diseases, congenital malformations of the brain's perforation pathway, metabolic dysfunction, congenital auditory aphasia, congenital visual aphasia, cerebral palsy, autism, depression, schizophrenia, bipolar disorder, paranoid personality disorder, mania, obsessive-compulsive disorder, Parkinson's disease, Alzheimer's disease, brain injury, amyotrophic lateral sclerosis, epilepsy, Huntington's disease, spinocerebellar ataxia, and cerebral ischemia.

[0284] In some preferred embodiments, the age-related disease is progeria.

[0285] In some preferred embodiments, the age-related disease is skin aging, and more preferably, the age-related disease is skin aging or damage caused by radiation.

[0286] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the present invention is further described below in conjunction with specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight. Unless otherwise specified, the experimental materials and reagents used in the following embodiments are commercially available.

[0287] Unless otherwise specified, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains. It should be noted that the terms used herein are for the purpose of describing particular embodiments only and are not intended to limit the exemplary embodiments of this application.

[0288] Example 1

[0289] In this embodiment, crystal form A of compound TJ01-013 (the sodium salt of compound TJ) was prepared. The specific steps are as follows:

[0290] Weigh 0.300 g of compound (I) into a 20 mL vial and add 12 mL of acetone. Heat to about 45 °C. The sample dissolves and becomes clear. Add 0.520 g of 10% sodium bicarbonate aqueous solution dropwise without stirring. The solid precipitates and settles to the bottom. Keep warm for 30 minutes, then slowly cool to room temperature (about 20 °C). Filter and rinse with a small amount of acetone. Dry under vacuum at room temperature to obtain crystal form A sample.

[0291] Example 2

[0292] In this embodiment, compound TJ01-013 crystal form B was prepared. The specific steps are as follows:

[0293] Weigh 0.300 g of compound (I) into a 20 mL vial and add 12 mL of acetone. Heat to about 45 °C. The sample dissolves and becomes clear. Cool to room temperature (about 20 °C) and add 0.520 g of 10% sodium bicarbonate aqueous solution dropwise. Stir magnetically (1000 rpm). After the solid precipitates, keep warm for 30 minutes, filter, and rinse with a small amount of acetone to obtain crystal form B sample.

[0294] Example 3

[0295] In this embodiment, crystal form C of compound TJ01-013 was prepared. The specific steps are as follows:

[0296] Weigh 0.100g of compound (I) into a 20mL vial and add 4mL of acetone. Heat to about 45℃. The sample dissolves and becomes clear. Add 0.173g of 10% sodium bicarbonate aqueous solution. Stir magnetically. After the solid precipitates, increase the stirring speed and keep warm for 30 minutes. Cool to room temperature (about 20℃), filter, and rinse with a small amount of acetone. Dry under vacuum at room temperature to obtain crystal form C sample.

[0297] Example 4

[0298] In this embodiment, the crystal form D of compound TJ01-013 was prepared by the following two methods.

[0299] (1) Method 1

[0300] Weigh 0.100 g of compound (I) and add 4 ml of acetone. Heat to approximately 45°C and stir until dissolved. Add 0.223 g of sodium methoxide methanol solution dropwise at approximately 45°C. A small amount of solid is added initially, but dissolves completely after stirring. A solid slowly precipitates after stirring. Maintain the temperature at approximately 45°C for 1 hour. After maintenance, cool to approximately 20°C and stir for 1 hour. Filter and wash with a small amount of acetone. Dry under vacuum at room temperature (without heating) for approximately 20 hours. The discharged product is identified as crystal form D.

[0301] Table 2-1 Feeding Ratio Table

[0302]

[0303]

[0304] (2) Method Two

[0305] Weigh 3.00 g of compound (I) and add 120 ml of acetone. Heat to approximately 45°C and stir until dissolved. Add 5.20 g of 10% sodium bicarbonate aqueous solution dropwise at approximately 45°C. A small amount of solid is added initially, but dissolves upon stirring. Solid slowly precipitates after stirring. Maintain the temperature at approximately 45°C for 1 hour. After maintenance, cool to approximately 20°C and stir for 1 hour. Filter and wash with a small amount of acetone. Dry under vacuum at room temperature (without heating) for approximately 20 hours. The discharged product is identified as crystal form D.

[0306] Table 2-2 Feeding Ratio Table

[0307] Compound of formula (I) 3.00 484.34 E020388-103-15 10% sodium bicarbonate aqueous solution 5.20 84 Self-configured acetone 120ml N / A 5055R220201M

[0308] Example 5

[0309] In this embodiment, potassium salt crystal form F of compound TJ01-013 was prepared. The specific steps are as follows:

[0310] Weigh 0.3g of compound (I), add 12mL of acetone, heat to about 45℃ to dissolve and clarify, add 0.62g of 10% potassium bicarbonate, dissolve and clarify, precipitate solid (a small amount of seed crystals may be added), cool to about 20℃, and filter.

[0311] Example 6

[0312] In this embodiment, calcium salt crystal form G of compound TJ01-013 was prepared. The specific steps are as follows:

[0313] Weigh 0.3g of compound (I), add 12mL of acetone, heat to about 45℃ to dissolve and clarify, add 0.98g of 10% calcium acetate, dissolve and clarify, no crystals precipitate, blow the solvent dry with nitrogen, add 12mL of isopropanol, precipitate solid, cool to about 20℃, and filter.

[0314] Example 7

[0315] In this embodiment, the crystal form H of compound TJ01-013 aminobutadiene triol salt was prepared. The specific steps are as follows:

[0316] Weigh 0.3g of compound (I), add 10mL of methanol, heat to about 45℃ to dissolve and clarify, add 1.5g of 5% tromethamine aqueous solution and keep warm for 0.5-1h, blow the solvent dry with nitrogen, add 10mL of ethyl acetate to precipitate the solid, cool to about 20℃ and filter.

[0317] Example 8

[0318] In this embodiment, lysine salt crystal form I of compound TJ01-013 was prepared. The specific steps are as follows:

[0319] Weigh 0.05g of compound (I), add 3mL of acetone, heat to about 45℃ to dissolve and clarify, add 0.30g of 5% lysine aqueous solution, dissolve and clarify, cool to precipitate solid, cool to about 20℃, and filter.

[0320] Example 9

[0321] In this embodiment, the crystal form J of compound TJ01-013 tert-butylamine salt was prepared. The specific steps are as follows:

[0322] Weigh 0.3g of compound (I), add 12mL of acetone, heat to about 45℃ to dissolve and clarify, add 0.906g of 5% tert-butylamine acetone solution, dissolve and clarify, precipitate solid, cool to about 20℃, and filter.

[0323] Example 10

[0324] In this embodiment, the diisopropylamine salt K of compound TJ01-013 was prepared. The specific steps are as follows:

[0325] Weigh 0.3g of compound (I), add 12mL of acetone, heat to about 45℃ to dissolve and clarify, add 1.253g of 5% diisopropylamine acetone solution, dissolve and clarify, precipitate solid, cool to about 20℃, and filter.

[0326] Example 11

[0327] In this embodiment, the ethanolamine salt crystal form L of compound TJ01-013 was prepared. The specific steps are as follows:

[0328] Weigh 0.3g of compound (I), add 12mL of acetone, heat to about 45℃ to dissolve and clarify, add 0.756g of 5% ethanolamine acetone solution, dissolve and clarify, precipitate solid, cool to about 20℃, and filter.

[0329] Example 12

[0330] In this embodiment, the diethanolamine salt crystal form M of compound TJ01-013 was prepared. The specific steps are as follows:

[0331] Weigh 0.3g of compound (I), add 12mL of acetone, heat to about 45℃ to dissolve and clarify, add 1.302g of 5% diethanolamine acetone solution, dissolve and clarify, precipitate solid, cool to about 20℃, and filter.

[0332] Example 13

[0333] In this embodiment, free acid crystal form E of compound TJ01-013 was prepared. The specific steps are as follows:

[0334]

[0335] UMI-77 (15 mg, 0.032 mmol) was suspended in DCM (0.5 mL) and stirred in an ice-water bath. 85% mCPBA (6.5 mg, 0.032 mmol) was added, followed by slow restoration to room temperature. The mixture was filtered, the filter cake was washed with DCM, and dried to obtain product TJ01-013 (crystal form E, 6 mg).

[0336] In this invention, X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis were used to characterize the crystal form samples prepared in the above embodiments.

[0337] X-ray diffraction method

[0338] The prepared crystal forms were analyzed using a PANalytacal Empyrean X-ray powder diffractometer. The scanning parameters are shown in Table 3 below.

[0339] Table 3

[0340]

[0341] The peak positions and intensities of the characteristic peaks in the X-ray powder diffraction pattern of crystal form A are shown in Table 4-1 below. The XRPD pattern is as follows: Figure 1 As shown.

[0342] Table 4-1

[0343]

[0344] The peak positions and intensities of the characteristic peaks in the X-ray powder diffraction pattern of B-type crystal are shown in Table 4-2 below. The XRPD pattern is as follows: Figure 4 As shown.

[0345] Table 4-2

[0346]

[0347] The peak positions and intensities of the characteristic peaks in the X-ray powder diffraction pattern of the C-type crystal are shown in Table 4-3 below. The XRPD pattern is as follows: Figure 7 As shown.

[0348] Table 4-3

[0349]

[0350] The peak positions and intensities of the characteristic peaks in the X-ray powder diffraction pattern of the D crystal form are shown in Table 4-4 below. The XRPD pattern is as follows: Figure 10 As shown.

[0351] Table 4-4

[0352]

[0353] The peak positions and intensities of the characteristic peaks in the X-ray powder diffraction patterns of the E-type crystal are shown in Table 4-5 below. The XRPD patterns are as follows: Figure 13 As shown.

[0354] Table 4-5

[0355]

[0356] The peak positions and intensities of the characteristic peaks in the X-ray powder diffraction patterns of the F-type crystal are shown in Table 4-6 below. The XRPD patterns are as follows: Figure 16 As shown.

[0357] Table 4-6

[0358]

[0359] The peak positions and intensities of the characteristic peaks in the X-ray powder diffraction patterns of the G crystal form are shown in Table 4-7 below. The XRPD patterns are as follows: Figure 19 As shown.

[0360] Table 4-7

[0361]

[0362] The peak positions and intensities of the characteristic peaks in the X-ray powder diffraction patterns of the H-type crystal are shown in Table 4-8 below. The XRPD patterns are as follows: Figure 22 As shown.

[0363] Table 4-8

[0364]

[0365] The peak positions and intensities of the characteristic peaks in the X-ray powder diffraction patterns of crystal form I are shown in Table 4-9 below. The XRPD patterns are as follows: Figure 25 As shown.

[0366] Table 4-9

[0367]

[0368] The peak positions and intensities of the characteristic peaks in the X-ray powder diffraction patterns of crystal form I are shown in Table 4-10 below. The XRPD patterns are as follows: Figure 28 As shown.

[0369] Table 4-10

[0370]

[0371] The peak positions and intensities of the characteristic peaks in the X-ray powder diffraction pattern of the K-type crystal are shown in Table 4-11 below. The XRPD pattern is as follows: Figure 31 As shown.

[0372] Table 4-11

[0373]

[0374] The peak positions and intensities of the characteristic peaks in the X-ray powder diffraction patterns of the L-type crystal are shown in Table 4-12 below. The XRPD patterns are as follows: Figure 34 As shown.

[0375] Table 4-12

[0376]

[0377] The peak positions and intensities of the characteristic peaks in the X-ray powder diffraction patterns of the M-type crystal are shown in Table 4-13 below. The XRPD patterns are as follows: Figure 37 As shown.

[0378] Table 4-13

[0379]

[0380] Differential scanning calorimetry

[0381] The crystals prepared in the above embodiments were tested using a TA Q200 / 2000 differential scanning calorimeter. The test parameters are shown in Table 5 below.

[0382] Table 5

[0383] method linear heating Sample tray Aluminum crucible, cover, and poke holes in the cover. Temperature range 30℃-250℃ Scan rate (°C / min) 10 Protective gas Nitrogen

[0384] The DSC spectrum of crystal form A is as follows: Figure 2 As shown, the differential scanning calorimetry curve of crystal form A has endothermic peaks at 144.89℃±3℃ and 150.40℃±3℃, and an exothermic peak at 214.79℃±3℃.

[0385] The DSC pattern of the B crystal form is as follows: Figure 5 As shown, the differential scanning calorimetry curve of crystal form B has endothermic peaks at 72.14℃±3℃ and 145.82℃±3℃, and an exothermic peak at 184.61℃±3℃.

[0386] The DSC pattern of the C-type crystal is as follows: Figure 8 As shown, the differential scanning calorimetry curve of the C crystal form has endothermic peaks at 59.75℃±3℃ and 140.91℃±3℃, and an exothermic peak at 185.61℃±3℃.

[0387] The DSC pattern of the D crystal form is as follows: Figure 11 As shown, the differential scanning calorimetry curve of the D crystal form has an endothermic peak at 183.79℃ (±3℃) and an exothermic peak at 210.79℃ ±3℃.

[0388] The DSC spectrum of the E crystal form is as follows: Figure 14 As shown, the differential scanning calorimetry curve of the E crystal form has an endothermic peak at 184.18±3℃ and an exothermic peak at 198.31℃±3℃.

[0389] The DSC spectrum of the F crystal form is as follows: Figure 17 As shown.

[0390] DSC spectrum of G crystal form as follows Figure 20As shown.

[0391] DSC spectrum of H crystal form as follows Figure 23 As shown.

[0392] The DSC spectrum of the J-type crystal is as follows: Figure 29 As shown.

[0393] DSC spectrum of K crystal form as follows Figure 32 As shown.

[0394] DSC spectrum of L-type crystal as follows Figure 35 As shown.

[0395] DSC pattern of M crystal form as follows Figure 38 As shown.

[0396] Thermogravimetric Analysis

[0397] The crystals prepared in the above embodiments were tested using a TA Q500 / 5000 thermogravimetric analyzer. The test parameters are shown in Table 6 below.

[0398] Table 6

[0399] method linear heating Sample tray Aluminum crucible, cover, and poke holes in the cover. Temperature range 30℃-250℃ Scan rate (°C / min) 10 Protective gas Nitrogen

[0400] TGA spectra of B-type crystals are as follows Figure 6 As shown, the thermogravimetric analysis curve of crystal form B shows a weight loss of 6.78±0.2% at 73.50±3℃.

[0401] The TGA spectrum of C-type crystal is as follows: Figure 9 As shown, the thermogravimetric analysis curve of the C crystal form shows a weight loss of 4.96±0.2% at 70.15±3℃.

[0402] TGA spectra of D crystal form are as follows Figure 12 As shown, the thermogravimetric analysis curve of the D crystal form indicates that the sample did not lose weight before decomposition.

[0403] TGA spectra of E-type crystals are as follows Figure 15 As shown.

[0404] TGA spectra of F-type crystals are as follows Figure 18 As shown.

[0405] TGA spectra of G crystal form are as follows Figure 21 As shown.

[0406] TGA spectra of H-type crystals are as follows Figure 24 As shown.

[0407] TGA spectra of crystal form I are as follows Figure 27 As shown.

[0408] TGA spectra of J-type crystals are as follows Figure 30 As shown.

[0409] TGA spectra of K crystal form are as follows Figure 33 As shown.

[0410] TGA spectra of L-type crystals are as follows Figure 36 As shown.

[0411] TGA spectra of M-type crystals are as follows Figure 39 As shown.

[0412] In addition, the performance of the crystal form samples prepared in the above embodiments is also studied in this invention.

[0413] Hygroscopicity

[0414] The hygroscopic properties of individual crystal form samples of compound TJ01-013 were tested using a Waters moisture adsorption analyzer. A dried sample pan was prepared, and the individual crystal form samples were laid flat inside, filling approximately 1 / 3 to 2 / 3 of the pan's volume. The instrument parameters were set as follows: temperature: 25℃; equilibration: dm / dt = 0.01% / min (minimum: 10 minutes, maximum: 180 minutes); drying: 120 minutes at 0% RH; RH (%) test gradient: 10%; RH (%) test gradient range: 0%-90%-0%. The hygroscopicity of each crystal form sample was tested at 90% relative humidity, and the results are shown in Table 7 below.

[0415] Table 7

[0416] Example 4 Sodium salt, compound TJ01-013, D crystal form 2.13％ Example 5 Potassium salt, compound TJ01-013, F crystal form 2.655％ Example 6 Calcium salt, compound TJ01-013, G crystal form 7.275％ Example 9 tert-Butylamine salt, compound TJ01-013, J crystal form 0.7884％ Example 10 Diisopropylamine salt, compound TJ01-013, K crystal form 0.2033％ Example 11 Ethanolamine salt, compound TJ01-013, L-crystal form 1.897％ Example 12 Diethanolamine salt, compound TJ01-013, M crystal form 6.026％ Example 7 Tromethamine triol salt, compound TJ01-013, H crystal form 2.313％ Example 13 E-crystal form of compound (I) 0.439％

[0417] According to Table 7, the sodium salt D crystal form of compound TJ01-013, the potassium salt F crystal form of compound TJ01-013, the tert-butylamine salt J crystal form of compound TJ01-013, the diisopropylamine salt K crystal form of compound TJ01-013, the ethanolamine salt L crystal form of compound TJ01-013, the tromethamine salt H crystal form of compound TJ01-013, and the E crystal form of compound (I) are slightly hygroscopic, while the other crystal forms are more hygroscopic.

[0418] Figure 40 The dvs spectrum of the sodium salt D crystal form of compound TJ01-013 is shown as an example.

[0419] Solubility

[0420] Equal amounts of sample were placed in FaSSIF buffer, FeSSIF buffer, water, and SGF, respectively, and their solubility was tested at 0.5, 2, and 24 hours. The results for the D-crystal form of compound TJ01-013 are shown in Table 8.

[0421] Table 8

[0422]

[0423] according to Figure 41 The D crystal form of compound TJ01-013 has high solubility in water, FaSSIF, and FeSSIF, but low solubility in SGF.

[0424] Crystal form transformation

[0425] In this embodiment, the interconversion relationships among the various crystal forms of sodium salts ABCD were further investigated through heat treatment under nitrogen protection and suspension competition experiments. Experimental results showed that crystal form B, heated to 106℃ and then cooled to room temperature, can be transformed into crystal form C. A stirring competition experiment was conducted on equal amounts of the four crystal form samples at different temperatures (RT / 50). The results showed that after approximately 20 hours of magnetic stirring (about 1000 rpm), mixing crystal form A and crystal form B into a pulp could transform into crystal form A; mixing crystal form A and crystal form C into a pulp could transform into crystal form A; mixing crystal form B and crystal form D into a pulp could transform into crystal form D; and mixing crystal form C and crystal form D could transform into crystal form D. That is, crystal forms B and C can be transformed into crystal forms A and D, meaning that crystal forms A and D are more stable than crystal forms B and C. The transformation relationships among the crystal forms are as follows: Figure 26 As shown.

[0426] However, heating, suspension pulping, and grinding methods cannot determine the thermodynamic transformation relationship between crystal form A and crystal form D. To further investigate this relationship, DSC analysis was performed on the DSC spectra of crystal form A. Figure 2 DSC of crystal form D, such as Figure 11 As shown, the melting point of crystal form A is higher than that of crystal form D, while the enthalpy of fusion of crystal form A is much lower than that of crystal form D. From the thermodynamic stability table, it can be determined that if TA > TD, ΔHf, A > ΔHf, D, crystal forms A and D have a single-variable relationship, and crystal form A is stable. If TA > TD, ΔHf, A < ΔHf, D, crystal forms A and D have an intervariable relationship. If the temperature is higher than the crystal transition temperature, crystal form A is stable, and if the temperature is lower than the crystal transition temperature, crystal form D is stable. From the DSC data of crystal forms A and D in Tables 9 and 10 below, it can be seen that TA > TD, ΔHf, A < ΔHf, D, that is, crystal form D is more stable at lower temperatures.

[0427] Table 9. Thermodynamic Stability Relationships

[0428]

[0429] Table 10 Summary of DSC data for sodium salt crystal forms A and D

[0430] A TJA-II-033-1 144.89，150.40 214.79 307.91mJ D TJA-I-057-1 ND 210.79 1225.67mJ

[0431] [Affinity test for recombinant Mcl-1 protein]

[0432] The binding affinity of the sodium salt D crystal form of TJ01-013 to Mcl-1 protein was studied using an in vitro surface plasmon resonance (SPR) assay with a Biacore analyzer and a CM5 chip-coupled protein assay. The experimental results are shown in Table 11 below.

[0433] Table 11 shows the binding affinity of the sodium salt D crystal form of TJ01-013 to Mcl-1 protein.

[0434]

[0435] Experimental conclusion: In the SPR assay, the sodium salt D crystal form of TJ01-013 can specifically bind to Mcl-1 protein.

[0436] [Testing of selective induction of disrupted mitophagy in a Keima HEK293 cell model]

[0437] In HEK293T cells in vitro, the Keima fluorescent protein derived from coral was fused with the mitochondrial localization sequence of cytochrome C oxidase subunit IV to form mtKeima protein. Nuclear staining was performed using Hoechst 33342 nuclear dye, and the cells were analyzed using Thermo CellInsight. TM CX7 LZR High Content Screening (HCS) platform, in E X / E M Mitochondrial autophagy levels were assessed at 594 nm / 620 nm. Mitochondrial membrane potential was disrupted using 3 μM Carbonyl cyanide 3-chlorophenylhydrazone (CCCP), causing mitochondrial damage, and the autophagy level of the damaged mitochondria was measured. Results are as follows: Figure 42 The results showed that different concentrations of sodium salt D crystal form of TJ01-013 (0 μM, 2.5 μM, 5 μM, 10 μM) selectively induced mitochondrial autophagy (T test two-tails test P = 0.0425), with good dose-relatedness and selectivity.

[0438] [Rat Pharmacokinetic Test]

[0439] Pharmacokinetic assays in rats of sodium salt D crystal form of compound TJ01-013

[0440] Healthy SD rats were administered three single-dose doses of TJ01-013 sodium salt D crystal form via gavage, a single-dose dose administered via multiple consecutive gavages, and a single-dose dose administered via intravenous injection. The plasma pharmacokinetic characteristics of the parent drug in rats were analyzed, including the absorption rate and exposure level of TJ01-013 D crystal form, individual variability, dose-response relationship, elimination rate, steady-state attainment, and potential accumulation. SD rats were administered TJ01-013 D crystal form at single gavage doses of 10, 30, and 90 mg / kg, 30 mg / kg via gavage once daily for 7 consecutive days, and 10 mg / kg via single intravenous injection. The plasma concentrations of the parent drug at different time points for each animal were calculated using WinNonlin software. The mean pharmacokinetic parameters for each group of 6 rats (half male and half female) are summarized in Table 12 below.

[0441] Table 12 Summary of Average Pharmacokinetic Parameters for D Crystal Form of TJ01-013

[0442]

[0443]

[0444] Note: *: T max The statistics are based on the median (minimum, maximum).

[0445] According to Table 12 above, SD rats administered TJ01-013 D crystal form via single gavage and intravenous administration exhibited pharmacokinetic characteristics of rapid absorption, low apparent volume of distribution, and moderate elimination rate.

[0446] Following single oral administration of 10, 30, and 90 mg / kg to SD rats, the plasma exposure C of the original TJ01-013 D crystal form was determined. max The concentrations were 3.13±1.66, 4.73±1.20, and 9.98±1.85 μg / mL, respectively, with AUC... 0-24h The concentrations were 10.7±4.44, 22.1±6.66, and 49.9±12.2 h·μg / mL, respectively, which increased with increasing dose, but the increase rate was less than the increase rate of dose.

[0447] After rats were administered 30 mg / kg by gavage once daily for 7 consecutive days, they reached steady state on day 4; compared with the gavage administration on day 1, the C-value on day 7 was significantly higher. max AUC 0-24h and T max Basically unchanged, t 1 / 2 The decrease suggests that once-daily, seven-day oral gavage administration did not result in significant accumulation, but rather a trend of faster elimination.

[0448] Following a single intravenous injection in SD rats, V ssThe concentration was 184 mL / kg, indicating a low tissue distribution of the D crystal form of TJ01-013. Compared with intravenous injection of the D crystal form of TJ01-013 at the same dose, the absolute bioavailability of the original TJ01-013 D crystal form was 9.55% after a single oral gavage administration of 10 mg / kg to SD rats.

[0449] In SD rats, after a single intravenous injection, a single gavage administration, and multiple gavage administrations, the plasma pharmacokinetic parameters of the original TJ01-013 D crystal form were similar between male and female animals, with no significant differences between them.

[0450] [In vivo efficacy study: Acute kidney injury model induced by unilateral renal ischemia-reperfusion in rats]

[0451] The pharmacodynamic effects of the D crystal form of TJ01-013 were investigated in a renal ischemia-reperfusion (I / R) model in SD rats. Twelve male rats (280-300g) were used in each group. The rats were administered the drug by gavage once daily for 3 consecutive days. They were divided into three dosage groups: 3 mg / kg, 10 mg / kg, and 30 mg / kg. The sham-operated group and the model control group received the same volume of 0.5% CMC-Na solvent. One hour after administration on day 4, left renal artery ligation was performed. After 45 minutes of ischemia, right nephrectomy was performed before reperfusion was restored. The drug was then administered daily until day 3. The endpoint was day 3. Results are shown below. Figures 43-49 .

[0452] Compared with the model control group, the 3, 10, and 30 mg / kg groups had no significant effect on body weight 72 h after reperfusion. Compared with the model control group, the creatinine levels in the 10 mg / kg group were significantly lower at 24 h, 48 h, and 72 h after ischemia-reperfusion (P < 0.05–0.01). The creatinine levels in the 30 mg / kg group were also significantly lower at 24 h and 72 h after reperfusion (P < 0.05). The blood urea nitrogen levels in the 10 mg / kg and 30 mg / kg groups showed a significant decreasing trend at 72 h after ischemia-reperfusion. Compared with the model control group, the creatinine clearance rate was improved to varying degrees in the 3 mg / kg, 10 mg / kg, and 30 mg / kg groups, with the creatinine clearance rate in the 10 mg / kg group being statistically significant compared with the model control group (P < 0.05). Compared with the model control group, the expression levels of apoptosis factor caspase 9 in renal tissue of the 10 mg / kg and 30 mg / kg groups were significantly decreased (P<0.001); the expression levels of inflammatory factors IL-6 and IL-1β in renal tissue of the 3 mg / kg, 10 mg / kg, and 30 mg / kg groups were significantly decreased (P<0.05–0.001). Compared with the model control group, the apoptotic cell rate in renal tissue of the 10 mg / kg and 30 mg / kg groups was significantly decreased (P<0.001). Compared with the model control group, the 10 mg / kg group significantly reduced the severity of renal tubular dilatation, necrosis, glomerular atrophy, interstitial inflammatory cell infiltration, edema, fibrosis, glomerular capillary dilatation, Bowman's capsule dilatation, and renal tubular mineralization, while the 30 mg / kg group showed a trend of alleviating the above-mentioned lesions.

[0453] [In vivo efficacy study: PAN-induced rat kidney injury model]

[0454] The effects of TJ01-013 D crystal form on renal function were investigated in an SD rat model of aminonucleoside puromycin (PAN). Twelve male rats (160-180g) were used in each group. On day 1 of the experiment, except for the normal control group, all other groups received a single intraperitoneal injection of 100 mg / kg PAN to induce proteinuria. After modeling, rats were randomly divided into a model control group, three TJ01-013 D crystal form dosage groups (3 mg / kg, 10 mg / kg, and 30 mg / kg), and a normal control group. Simultaneously with the intraperitoneal injection for PAN modeling, TJ01-013 was administered via gavage once daily at a volume of 10 mL / kg for four consecutive weeks.

[0455] Compared with the model control group, the 3, 10, and 30 mg / kg groups showed varying degrees of reduction in urinary protein concentration and 24-hour urinary protein level at 7 and 12 days after drug administration, with a certain downward trend in 24-hour urinary protein level at 12 days. Compared with the model control group, the 3, 10, and 30 mg / kg groups showed varying degrees of increase in serum albumin at 7 and 12 days after drug administration, with the 3 mg / kg group showing a statistically significant increase (P < 0.05). The 3, 10, and 30 mg / kg groups showed varying degrees of reduction in urinary protein concentration and 24-hour urinary protein level at 7 days after drug administration, with a certain downward trend in 24-hour urinary protein level at 12 days. Simultaneously, they caused varying degrees of increase in serum albumin at 7 and 12 days after drug administration.

[0456] It was observed that gavage administration of 3, 10, and 30 mg / kg of TJ01-013 (D crystal form) significantly treated PAN-induced kidney injury in rats. Pathological microscopic results showed that the low, medium, and high doses of the test drug reduced the severity of lesions including renal tubular dilatation, basophilic degeneration, hyaline casts, glomerular atrophy, Bowman's capsule dilatation, capsule wall thickening, and interstitial inflammatory cell infiltration.

[0457] Those skilled in the art will understand that the above embodiments are specific examples of implementing the present invention, and in practical applications, various changes in form and detail may be made without departing from the spirit and scope of the present invention.

Claims

1. A pharmaceutically acceptable salt of a compound of formula (I) in solid form; ； in, The solid form is the D crystal form of the sodium salt of compound (I), and the D crystal form of the sodium salt of compound (I) has the structure shown in formula (II). Where x is selected from 0.5-2, its X-ray powder diffraction pattern shows characteristic peaks of 7.06°±0.2° and 20.87°±0.2° 2θ, as well as characteristic peaks selected from 18.07°±0.2°, 17.58°±0.2°, 10.54°±0.2°, 23.91°±0.2° and 25.02°±0.2° 2θ.

2. The solid form according to claim 1, characterized in that, The X-ray powder diffraction pattern of the sodium salt of formula (I) in its D crystal form shows characteristic peaks at 7.06°±0.2° and 20.87°±0.2° 2θ, as well as characteristic peaks selected from 18.07°±0.2°, 17.58°±0.2°, 10.54°±0.2°, 23.91°±0.2°, 27.65°±0.2°, 27.05°±0.2°, 21.68°±0.2°, 25.91°±0.2° and 25.02°±0.2° 2θ.

3. The solid form according to claim 1, characterized in that, The characteristic peak of 2θ shown in Table 1-1 is displayed in the X-ray powder diffraction pattern of the D crystal form of the sodium salt of compound (I).

4. The solid form according to claim 1, characterized in that, The D crystal form of the sodium salt of the compound of formula (I) shows an X-ray powder diffraction pattern that is approximately the same as that in Figure 10.

5. The solid form according to claim 1, characterized in that, The D crystal form of the sodium salt of the compound of formula (I) also has at least one of the following characteristics: The differential scanning calorimetry (DSC) curve of the sodium salt of the compound of formula (I) in its D crystal form shows an endothermic peak at 183.79℃±3℃ and an exothermic peak at 210.79℃±3℃; and The thermogravimetric analysis (TGA) curves of the sodium salt of the compound of formula (I) in crystal form D are shown in a TGA curve pattern that is approximately the same as that in Figure 12.

6. A method for preparing the D-crystal form of the sodium salt of compound (I), characterized in that, The method includes the steps of: dissolving a compound of formula (I) in a reaction medium and reacting it with a sodium-containing base; the sodium salt of the compound of formula (I) has a D-crystal form as shown in formula (II). Where x is selected from 0.5-2; Furthermore, at 40-50°C, compound (I) is dissolved in acetone, sodium methoxide methanol solution is added and stirred. After the solid precipitates, it is kept at this temperature and allowed to stand for at least 60 minutes. Then, it is cooled to room temperature and stirred for at least 60 minutes. The sodium salt of compound (I) is obtained by filtration, yielding crystal form D; or Dissolve the compound of formula (I) in acetone at 40-50℃, add sodium bicarbonate solution and stir. After the solid precipitates, keep it warm and stand for at least 60 minutes. Filter to obtain the crystal form D of the sodium salt of the compound of formula (I).

7. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises a solid form of a compound of formula (I) as described in any one of claims 1 to 5, and a pharmaceutically acceptable carrier or excipient.

8. The use of the solid form of the compound of formula (I) as claimed in any one of claims 1 to 5, or the use of the pharmaceutical composition as claimed in claim 7, characterized in that, Used for: (i) To prepare medicines for the prevention and / or treatment of diseases related to kidney injury; and / or (iv) To prepare drugs for the prevention and / or treatment of diseases associated with mitochondrial dysfunction.

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