Salts of benzothiazole compounds, their crystalline forms and uses

Abstract

The present invention relates to salts of benzothiazole compounds of formula I selected from pamoate and palmitate salts, their crystalline forms and uses, and further to the use of salts of the compound of formula I and its crystalline forms in the manufacture of medicaments for the treatment of Parkinson's disease and restless legs syndrome. JPEG2023550235000032.jpg28170

Description

[Technical Field]

[0001] This application claims priority to Chinese Patent Application No. 202011304450.1, filed on 19 November 2020, entitled “Salts of Benzothiazole Compounds, Crystal Forms and Uses thereof,” the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to a salt of (S)-2-amino-4,5,6,7-tetrahydro-6-propylamine-benzothiazole, its crystalline form, and its use. [Background technology]

[0003] Parkinson's disease (PD) is a neurological disorder affecting the motor system. It is characterized by its progressive nature, affecting movement and leading to the loss of dopamine-producing brain cells, causing tremors in the hands, arms, legs, jaw, and face, and / or rigidity or stiffness in the limbs and trunk. The main symptoms include muscle stiffness, bradykinesia (slowness of movement), resting tremor, and postural instability.

[0004] (S)-2-amino-4,5,6,7-tetrahydro-6-propylamine-benzothiazole (hereinafter referred to as "Compound I") is a non-ergot dopamine receptor agonist developed by Boehringer Ingelheim in Germany. Currently, the products marketed in China and overseas are mainly immediate-release hydrochloride tablets and sustained-release hydrochloride tablets used to treat Parkinson's disease and restless legs syndrome.

[0005] Studies show that most Parkinson's disease patients are middle-aged or elderly, and among them, the incidence of dysphagia is high at 70-90%, which increases the risk of aspiration pneumonia by 15-50%. Dysphagia appears in the early stages of the disease and develops throughout the entire course of Parkinson's disease, and because it is highly likely to cause choking, it increases the risk of aspiration pneumonia, which is one of the leading causes of death in Parkinson's disease patients. Current clinical drugs are mainly administered orally and require multiple doses per day, and the single dose is large, making it urgent to improve compliance. Furthermore, secondary pulsed stimulation due to fluctuations in dopamine blood concentration may further exacerbate abnormalities in dopamine receptor levels and function, and continuous and stable dopamine stimulation is necessary to control or reduce the occurrence of poor responses in motor complications. In addition, solutions with long-term release exceeding 24 hours are also helpful for patient adaptation, and because patients with progressive PD are generally not compliant, it is difficult to assess whether patients are receiving the appropriate dosage of medication.

[0006] Based on the above, it is proposed that long-acting sustained-release formulations, such as oral sustained-release formulations, long-acting transdermal patches, and long-acting injectable formulations, be used to maintain stable blood concentrations clinically and improve patient compliance. Therefore, there is an urgent need for salt forms and their crystalline forms that can be used in long-acting sustained-release formulations. [Overview of the project]

[0007] A first aspect of the present invention provides a salt of (S)-2-amino-4,5,6,7-tetrahydro-6-propylamine-benzothiazole (whose structural formula is as shown in Formula I), selected from pamoate and palmitate.

[0008] [ka] In some embodiments, the salt of the compound shown in formula I is a palmitate.

[0009] A second aspect of the present invention provides crystals of a salt of compound I, for example, pamoate crystals A to S and palmitate crystals T to V of compound I. A third aspect of the present invention provides a pharmaceutical composition comprising a salt of compound I selected from pamoate and palmitate, particularly pamoate crystals or palmitate crystals of compound I, and one or more pharmaceutically acceptable carriers.

[0010] A fourth aspect of the present invention provides the use of salts or crystals thereof of compound I, particularly pamoate crystals A-S and palmitate crystals T-V of compound I, or pharmaceutical compositions, in the manufacture of drugs used for the treatment of Parkinson's disease and restless legs syndrome.

[0011] A salt or crystal of compound I of the present invention has low solubility, achieves a sustained-release effect, and can be used to produce a long-acting sustained-release formulation. [Brief explanation of the drawing]

[0012] [Figure 1] This is the X-ray powder diffraction (XRPD) pattern of the pamoate crystal A of compound I. [Figure 2] This is the XRPD pattern of the pamoate crystal B of compound I. [Figure 3] This is the XRPD pattern of the pamoate crystal C of compound I. [Figure 4] This is the XRPD pattern of the pamoate crystal D of compound I. [Figure 5] This is the XRPD pattern of the pamoate crystal E of compound I. [Figure 6] This is the XRPD pattern of the pamoate crystal F of compound I. [Figure 7] This is the XRPD pattern of the pamoate crystal G of compound I. [Figure 8] This is the XRPD pattern of the pamoate crystal H of compound I. [Figure 9] This is the XRPD pattern of the pamoate crystal I of compound I. [Figure 10] This is the XRPD pattern of the pamoate crystal J of compound I. [Figure 11] The XRPD pattern of the pamoate crystal K of Compound I. [Figure 12] The XRPD pattern of the pamoate crystal L of Compound I. [Figure 13] The XRPD pattern of the pamoate crystal M of Compound I. [Figure 14] The XRPD pattern of the pamoate crystal N of Compound I. [Figure 15] The XRPD pattern of the pamoate crystal O of Compound I. [Figure 16] The XRPD pattern of the pamoate crystal P of Compound I. [Figure 17] The XRPD pattern of the pamoate crystal Q of Compound I. [Figure 18] The XRPD pattern of the pamoate crystal R of Compound I. [Figure 19] The XRPD pattern of the pamoate crystal S of Compound I. [Figure 20] The XRPD pattern of the palmitate crystal T of Compound I. [Figure 21] The XRPD pattern of the palmitate crystal U of Compound I. [Figure 22] The XRPD pattern of the palmitate crystal V of Compound I.

Mode for Carrying Out the Invention

[0013] Definition The meaning and intention of all technical terms and scientific terms used in this specification are the same as those generally understood by those skilled in the art, unless otherwise defined below. The technical intention used in this specification refers to the technology generally understood in this field and includes technical changes or substitutions of equivalent technologies that are obvious to those skilled in the art. The following terms are considered to be easily understood by those skilled in the art, but are still interpreted in order to better explain the present invention.

[0014] The terms “inclusive,” “includes,” “possess,” “contains,” or “concerns,” as used herein, and other variations thereof, are inclusive or open and do not exclude other unlisted elements or method steps.

[0015] As used herein, the term "about" means, as will be understood by those skilled in the art, being within an acceptable standard error, such as ±0.05, ±0.1, ±0.2, ±0.3, ±1, ±2, or ±3.

[0016] In this specification, "compound I" and "compound shown in formula I" both refer to the compound whose structural formula is formula I below, and are used interchangeably in this specification.

[0017] [ka] The term "pharmaceutical composition" refers to an active ingredient which can be optionally combined with one or more pharmaceutically acceptable chemical components (e.g., carriers and / or excipients). The active ingredient is, for example, Compound I or its pamoate or palmitate, one or more of the crystalline forms of the present invention, or one or more of the crystalline compositions of the present invention.

[0018] The terms "administration" or "medication" refer to methods that enable the delivery of a compound or composition to a desired biological site of action. These methods include, but are not limited to, oral administration, parenteral administration (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical administration, rectal administration, etc.

[0019] For drugs or pharmacological agents, the term "effective dose" refers to a sufficient amount of the drug or agent that is non-toxic but capable of achieving the desired effect. For oral dosage forms in this invention, the "effective dose" of one active substance in the composition may be the amount necessary to achieve the desired effect when used in combination with another active substance in the composition. Determining the effective dose varies from person to person, depends on the age and general circumstances of the receptor, and also depends on the specific active substance. An appropriate effective dose in each case can be determined by a person skilled in the art based on general testing.

[0020] The terms “active ingredient,” “therapeutic agent,” “active substance,” or “activator” refer to a chemical entity capable of effectively treating or preventing a target disorder, disease, or pathological condition. In this specification, these terms refer, for example, to the compounds shown in Formula I or their pamoate or palmitate, one or more of the crystalline forms of the present invention, or one or more of the crystalline compositions of the present invention.

[0021] As used herein, the term "amorphous" refers to any solid material that does not exhibit three-dimensional regularity. In some cases, amorphous solids can be characterized by known techniques, including XRPD crystallography, solid-state nuclear magnetic resonance (ssNMR) spectroscopy, DSC, or a combination of these techniques. As described below, amorphous solids generally produce broad XRPD patterns containing one or two broad peaks (i.e., peaks with a base width of about 5°2θ or more).

[0022] As used herein, the terms "crystalline form" or "crystal" refer to any solid material exhibiting three-dimensional regularity, which, unlike amorphous solid materials, produces a characteristic XRPD pattern with well-defined peaks.

[0023] As used herein, the term "X-ray powder diffraction pattern (XRPD pattern)" refers to the diffraction pattern observed in an experiment or the parameters derived therefrom. XRPD patterns are generally characterized by peak positions (horizontal coordinates) and / or peak intensities (vertical coordinates).

[0024] In X-ray powder diffraction (XRPD or XRD) spectra, the diffraction patterns obtained from crystalline compounds are often characteristic of a particular crystal form. Here, the relative intensity of the spectral band (especially at low angles) can vary due to dominant orientation effects resulting from differences in crystal conditions, grain size, and other measurement conditions. Therefore, the relative intensity of the diffraction peaks is not characteristic of a corresponding crystal form, and when determining whether it is the same as a known crystal form, more attention should be paid to the relative position of the peaks rather than the relative intensity of the peaks. Furthermore, it is known in the field of crystallography that there may be a small error in the position of the peaks for any given crystal form. For example, changes in temperature during sample analysis, sample movement, or instrument calibration can cause the position of the peaks to shift, and the measurement error of the 2θ value may be approximately ±0.2°. Therefore, this error should be taken into consideration when determining the structure of various crystal forms. When it is stated that the crystal form of the present invention is substantially as shown in the designated figure, the term "substantially" is also intended to include such differences in the position of the diffraction peaks.

[0025] In XRPD patterns, peak positions are generally indicated by either a 2θ angle or a lattice plane spacing d, with a simple conversion relationship between the two: d = λ / 2sinθ, where d represents the lattice plane spacing, λ represents the wavelength of the incident X-ray, and θ represents the diffraction angle. For identical compounds and identical crystal forms, the peak positions of their XRPD patterns show overall similarity, and the error in relative intensity may be relatively large. Furthermore, it should be noted that in the identification of mixtures, factors such as a decrease in content can cause the loss of some diffraction lines. In this case, it is not necessary to rely on all spectral bands observed from high-purity samples, and consequently, even just one spectral band may be characteristic of a given crystal.

[0026] As used herein, the term "2θ" refers to a peak position expressed in degrees based on the experimental setup of an X-ray diffraction experiment, and is generally the transverse coordinate unit in the diffraction pattern. If reflection is diffracted when the incident beam forms an angle θ with a certain lattice plane, the experimental setup requires recording the reflected beam at a 2θ angle. It should be understood that specific 2θ values ​​for specific crystal forms mentioned herein are intended to represent 2θ values ​​(expressed in degrees) measured using the X-ray diffraction experimental conditions described herein.

[0027] As used herein, the term "thermogravimetric analysis (TGA) pattern" refers to a curve recorded by a thermogravimetric analyzer.

[0028] As used herein, the term "differential scanning calorimetry (DSC) pattern" refers to a curve recorded by a differential scanning calorimetry.

[0029] The term "nuclear magnetic resonance" as used herein 1 A "H-NMR pattern" refers to a signal peak recorded by a nuclear magnetic resonance spectrometer.

[0030] As used herein, the term “substantially the same” with respect to X-ray diffraction peak position means taking into account typical peak positions and intensity variations. For example, a person skilled in the art will understand that the peak position (2θ) will also exhibit some variation, generally around 0.1 to 0.2 degrees, in the instruments used to measure diffraction. A person skilled in the art will also understand that the relative peak intensity will show variation between instruments, as well as variation due to crystallinity, preferred orientation, the surface of the prepared sample, and other factors known to a person skilled in the art, and that this should be considered merely a qualitative measurement.

[0031] As used herein, the term "room temperature" refers to 20°C ± 5°C.

[0032] Salts of compound I and their crystals The present invention provides salts of (S)-2-amino-4,5,6,7-tetrahydro-6-propylamine-benzothiazole (compound I), selected from pamoate and palmitate.

[0033] [ka] In some other embodiments, the salt of compound I of the formula is the palmitate of compound I of the formula.

[0034] In some embodiments, the salt of compound I of the formula is the pamoate of compound I of the formula.

[0035] Pamoate salt of compound I and its crystals (1:1) In some embodiments, the stoichiometric ratio of compound I to pamoic acid in the pamoate of compound I is 1:1.

[0036] Crystal A In some embodiments, in the pamoate crystal A of compound I according to the present invention, the stoichiometric ratio of compound I to pamoic acid is 1:1, and its XRPD pattern includes diffraction peaks at 2θ of approximately 4.76±0.2°, 7.07±0.2°, 8.32±0.2°, 10.7±0.2°, 11.73±0.2°, 13.29±0.2°, 16.25±0.2°, 18.45±0.2°, 21.51±0.2°, 24.81±0.2°, and 26.17±0.2°. Preferably, the XRPD pattern of the pamoate crystal A of compound I further includes diffraction peaks at 2θ of approximately 17.87±0.2°, 22.01±0.2°, and 25.17±0.2°.

[0037] In some embodiments, the XRPD pattern of the pamoate crystal A of compound I includes diffraction peaks at 2θ of approximately 4.76±0.2°, 7.07±0.2°, 8.32±0.2°, 10.7±0.2°, 11.73±0.2°, 13.29±0.2°, 16.25±0.2°, 17.87±0.2°, 18.45±0.2°, 21.51±0.2°, 22.01±0.2°, 24.81±0.2°, 25.17±0.2°, and 26.17±0.2°.

[0038] In some embodiments, the XRPD pattern of the pamoate crystal A of compound I includes the following diffraction peaks at 2θ.

[0039] [Table 1] In some embodiments, the XRPD pattern of the pamoate crystal A of compound I is substantially as shown in Figure 1. In some preferred embodiments, the XRPD pattern of the pamoate crystal A of compound I is as shown in Figure 1.

[0040] Crystal B In some embodiments, in the pamoate crystal B of compound I according to the present invention, the stoichiometric ratio of compound I to pamoic acid is 1:1, and its XRPD pattern includes diffraction peaks at 2θ of approximately 5.79±0.2°, 6.38±0.2°, 10.95±0.2°, 14.72±0.2°, 17.61±0.2°, 18.40±0.2°, 19.81±0.2°, and 22.18±0.2°. Preferably, the XRPD pattern of the pamoate crystal B of compound I further includes diffraction peaks at 2θ of approximately 10.61±0.2°, 12.51±0.2°, 17.61±0.2°, and 20.01±0.2°. More preferably, the XRPD pattern of the pamoate crystal B of compound I further includes diffraction peaks at 2θ of approximately 10.18±0.2°, 13.15±0.2°, and 13.36±0.2°.

[0041] In some embodiments, the XRPD pattern of the pamoate crystal B of compound I includes diffraction peaks at 2θ of approximately 5.79±0.2°, 6.38±0.2°, 10.61±0.2°, 10.95±0.2°, 12.51±0.2°, 14.72±0.2°, 17.61±0.2°, 18.40±0.2°, 19.81±0.2°, 20.01±0.2°, and 22.18±0.2°. In several other embodiments, the XRPD pattern of the pamoate crystal B of compound I includes diffraction peaks at 2θ of approximately 5.79±0.2°, 6.38±0.2°, 10.18±0.2°, 10.61±0.2°, 10.95±0.2°, 12.51±0.2°, 13.15±0.2°, 13.36±0.2°, 14.72±0.2°, 17.61±0.2°, 18.40±0.2°, 19.81±0.2°, 20.01±0.2°, and 22.18±0.2°.

[0042] In some embodiments, the XRPD pattern of the pamoate crystal B of compound I includes the following diffraction peaks at 2θ.

[0043] [Table 2] In some embodiments, the XRPD pattern of the pamoate crystal B of compound I is substantially as shown in Figure 2. In some preferred embodiments, the XRPD pattern of the pamoate crystal B of compound I is as shown in Figure 2.

[0044] crystal C In some embodiments, in the pamoate crystal C of compound I according to the present invention, the stoichiometric ratio of compound I to pamoic acid is 1:1, and its XRPD pattern includes diffraction peaks at 2θ of approximately 7.43±0.2°, 11.18±0.2°, 11.98±0.2°, 14.78±0.2°, 20.20±0.2°, 20.97±0.2°, and 23.30±0.2°. Preferably, the XRPD pattern of the pamoate crystal C of compound I further includes diffraction peaks at 2θ of approximately 16.90±0.2°, 19.73±0.2°, 22.12±0.2°, and 25.37±0.2°. More preferably, the XRPD pattern of the pamoate crystal C of compound I further includes diffraction peaks at 2θ of approximately 19.34±0.2° and 22.91±0.2°.

[0045] In some embodiments, the XRPD pattern of the pamoate crystal C of compound I includes diffraction peaks at 2θ of approximately 7.43±0.2°, 11.18±0.2°, 11.98±0.2°, 14.78±0.2°, 16.90±0.2°, 19.73±0.2°, 20.20±0.2°, 20.97±0.2°, 22.12±0.2°, 23.31±0.2°, and 25.37±0.2°. In several other embodiments, the XRPD pattern of the pamoate crystal C of compound I includes diffraction peaks at 2θ of approximately 7.43±0.2°, 11.18±0.2°, 11.98±0.2°, 14.78±0.2°, 16.90±0.2°, 19.34±0.2°, 19.73±0.2°, 20.20±0.2°, 20.97±0.2°, 22.12±0.2°, 22.91±0.2°, 23.31±0.2°, and 25.37±0.2°.

[0046] In some embodiments, the XRPD pattern of the pamoate crystal C of compound I includes the following diffraction peaks at 2θ.

[0047] [Table 3] In some embodiments, the XRPD pattern of the pamoate crystal C of compound I is substantially as shown in Figure 3. In some preferred embodiments, the XRPD pattern of the pamoate crystal C of compound I is as shown in Figure 3.

[0048] Crystal D In some embodiments, in the pamoate crystal D of compound I according to the present invention, the stoichiometric ratio of compound I to pamoic acid is 1:1, and its XRPD pattern includes diffraction peaks at 2θ of approximately 11.24±0.2°, 11.88±0.2°, 12.03±0.2°, 13.57±0.2°, 14.76±0.2°, 15.17±0.2°, 20.85±0.2°, 21.15±0.2°, and 23.26±0.2°. Preferably, the XRPD pattern of the pamoate crystal D of compound I further includes diffraction peaks at 2θ of approximately 15.17±0.2°, 16.92±0.2°, and 24.24±0.2°. More preferably, the XRPD pattern of the pamoate crystal D of compound I further includes diffraction peaks at 2θ of approximately 19.3709±0.2° and 20.2490±0.2°.

[0049] In some embodiments, the XRPD pattern of the pamoate crystal D of compound I includes diffraction peaks at 2θ of approximately 11.24±0.2°, 11.88±0.2°, 12.03±0.2°, 13.57±0.2°, 14.76±0.2°, 15.17±0.2°, 16.92±0.2°, 20.85±0.2°, 21.15±0.2°, 23.26±0.2°, and 24.24±0.2°. In several other embodiments, the XRPD pattern of the pamoate crystal D of compound I includes diffraction peaks at 2θ of approximately 11.24±0.2°, 11.88±0.2°, 12.03±0.2°, 13.57±0.2°, 14.76±0.2°, 15.17±0.2°, 16.92±0.2°, 19.37±0.2°, 20.85±0.2°, 21.15±0.2°, 23.26±0.2°, 24.24±0.2° and 20.25±0.2°.

[0050] In some embodiments, the XRPD pattern of the pamoate crystal D of compound I includes the following diffraction peaks at 2θ.

[0051] [Table 4] In some embodiments, the XRPD pattern of the pamoate crystal D of compound I is substantially as shown in Figure 4. In some preferred embodiments, the XRPD pattern of the pamoate crystal D of compound I is as shown in Figure 4.

[0052] Crystal E In some embodiments, in the pamoate crystal E of compound I according to the present invention, the stoichiometric ratio of compound I to pamoic acid is 1:1, and its XRPD pattern includes diffraction peaks at 2θ of approximately 7.32±0.2°, 11.26±0.2°, 12.04±0.2°, 14.77±0.2°, 15.24±0.2°, 16.95±0.2°, 20.28±0.2°, 21.26±0.2°, and 23.27±0.2°. Preferably, the XRPD pattern of the pamoate crystal E of compound I further includes diffraction peaks at 2θ of approximately 19.37±0.2° and 19.83±0.2°.

[0053] In some embodiments, the XRPD pattern of the pamoate crystal E of compound I includes the following diffraction peaks at 2θ.

[0054] [Table 5] In some embodiments, the XRPD pattern of the pamoate crystal E of compound I is substantially as shown in Figure 5. In some preferred embodiments, the XRPD pattern of the pamoate crystal E of compound I is as shown in Figure 5.

[0055] Crystal F In some embodiments, in the pamoate crystal F of compound I according to the present invention, the stoichiometric ratio of compound I to pamoic acid is 1:1, and its XRPD pattern includes diffraction peaks at 2θ of approximately 11.19±0.2°, 12.10±0.2°, 14.67±0.2°, 15.48±0.2°, 18.11±0.2°, 20.25±0.2°, and 23.33±0.2°. Preferably, the XRPD pattern of the pamoate crystal F of compound I further includes diffraction peaks at 2θ of approximately 11.92±0.2°, 14.67±0.2°, 16.71±0.2°, and 25.84±0.2°. More preferably, the XRPD pattern of the pamoate crystal F of compound I further includes diffraction peaks at 2θ of approximately 19.19±0.2° and 21.23±0.2°.

[0056] In some embodiments, the XRPD pattern of the pamoate crystal F of compound I includes diffraction peaks at 2θ of approximately 11.19±0.2°, 11.92±0.2°, 12.10±0.2°, 14.67±0.2°, 15.48±0.2°, 16.71±0.2°, 18.11±0.2°, 20.25±0.2°, 23.33±0.2°, and 25.84±0.2°. In several other embodiments, the XRPD pattern of the pamoate crystal F of compound I includes diffraction peaks at 2θ of approximately 11.19±0.2°, 11.92±0.2°, 12.10±0.2°, 14.67±0.2°, 15.48±0.2°, 16.71±0.2°, 18.11±0.2°, 19.19±0.2°, 20.25±0.2°, 21.23±0.2°, 23.33±0.2°, and 25.84±0.2°.

[0057] In some embodiments, the XRPD pattern of the pamoate crystal F of compound I includes the following diffraction peaks at 2θ.

[0058] [Table 6] In some embodiments, the XRPD pattern of the pamoate crystal F of compound I is substantially as shown in Figure 6. In some preferred embodiments, the XRPD pattern of the pamoate crystal F of compound I is as shown in Figure 6.

[0059] crystal G In some embodiments, in the pamoate crystal G of compound I according to the present invention, the stoichiometric ratio of compound I to pamoic acid is 1:1, and its XRPD pattern includes diffraction peaks at 2θ of approximately 6.13±0.2°, 11.24±0.2°, 11.86±0.2°, 13.15±0.2°, 14.79±0.2°, 20.27±0.2°, and 23.13±0.2°. Preferably, the XRPD pattern of the pamoate crystal G of compound I further includes diffraction peaks at 2θ of approximately 11.24±0.2°, 14.54±0.2°, 19.90±0.2°, 20.09±0.2°, 22.21±0.2°, 23.96±0.2°, and 24.76±0.2°. More preferably, the XRPD pattern of the pamoate crystal G of compound I further includes diffraction peaks at 2θ of approximately 16.88±0.2°, 19.35±0.2°, and 20.46±0.2°.

[0060] In some embodiments, the XRPD pattern of the pamoate crystal G of compound I includes diffraction peaks at 2θ of approximately 6.13±0.2°, 11.24±0.2°, 11.86±0.2°, 13.15±0.2°, 14.54±0.2°, 14.79±0.2°, 19.90±0.2°, 20.09±0.2°, 20.27±0.2°, 22.21±0.2°, 23.13±0.2°, 23.96±0.2°, and 24.76±0.2°. In several other embodiments, the XRPD pattern of the pamoate crystal G of compound I includes diffraction peaks at 2θ of approximately 6.13±0.2°, 11.24±0.2°, 11.86±0.2°, 13.15±0.2°, 14.54±0.2°, 14.79±0.2°, 16.88±0.2°, 19.35±0.2°, 19.90±0.2°, 20.09±0.2°, 20.27±0.2°, 20.46±0.2°, 22.21±0.2°, 23.13±0.2°, 23.96±0.2°, and 24.76±0.2°.

[0061] In some embodiments, the XRPD pattern of the pamoate crystal G of compound I includes the following diffraction peaks at 2θ.

[0062] [Table 7] In some embodiments, the XRPD pattern of the pamoate crystal G of compound I is substantially as shown in Figure 7. In some preferred embodiments, the XRPD pattern of the pamoate crystal G of compound I is as shown in Figure 7.

[0063] Crystal H In some embodiments, in the pamoate crystal H of compound I according to the present invention, the stoichiometric ratio of compound I to pamoic acid is 1:1, and its XRPD pattern includes diffraction peaks at 2θ of approximately 7.08±0.2°, 11.92±0.2°, 13.03±0.2°, 14.71±0.2°, 16.90±0.2°, 20.85±0.2°, 21.96±0.2°, 23.04±0.2°, and 23.56±0.2°. Preferably, the XRPD pattern of the pamoate crystal H of compound I further includes diffraction peaks at 2θ of approximately 11.76±0.2°, 13.03±0.2°, 20.27±0.2°, and 26.66±0.2°. More preferably, the XRPD pattern of the pamoate crystal H of compound I further includes diffraction peaks at 2θ of approximately 11.30±0.2°, 14.71±0.2°, and 19.97±0.2°.

[0064] In some embodiments, the XRPD pattern of the pamoate crystal H of compound I includes diffraction peaks at 2θ of approximately 7.08±0.2°, 11.76±0.2°, 11.92±0.2°, 13.03±0.2°, 14.71±0.2°, 16.90±0.2°, 20.27±0.2°, 20.85±0.2°, 21.96±0.2°, 23.04±0.2°, 23.56±0.2°, and 26.66±0.2°. In some embodiments, the XRPD pattern of the pamoate crystal H of compound I includes diffraction peaks at 2θ of approximately 7.08±0.2°, 11.76±0.2°, 11.30±0.2°, 11.92±0.2°, 13.03±0.2°, 14.71±0.2°, 16.90±0.2°, 19.97±0.2°, 20.27±0.2°, 20.85±0.2°, 21.96±0.2°, 23.04±0.2°, 23.56±0.2°, and 26.66±0.2°.

[0065] In some embodiments, the XRPD pattern of the pamoate crystal H of compound I includes the following diffraction peaks at 2θ.

[0066] [Table 8] In some embodiments, the XRPD pattern of the pamoate crystal H of compound I is substantially as shown in Figure 8. In some preferred embodiments, the XRPD pattern of the pamoate crystal H of compound I is as shown in Figure 8.

[0067] Crystal I In some embodiments, in the pamoate crystal I of compound I according to the present invention, the stoichiometric ratio of compound I to pamoic acid is 1:1, and its XRPD pattern includes diffraction peaks at 2θ of approximately 5.59±0.2°, 5.98±0.2°, 9.39±0.2°, 20.39±0.2°, 25.27±0.2°, and 26.01±0.2°. Preferably, the XRPD pattern of the pamoate crystal I of compound I further includes diffraction peaks at 2θ of approximately 7.62±0.2°, 8.22±0.2°, 11.59±0.2°, 18.09±0.2°, and 22.59±0.2°. More preferably, the XRPD pattern of the pamoate crystal I of compound I further includes diffraction peaks at 2θ of approximately 7.80±0.2°, 9.88±0.2°, and 23.40±0.2°.

[0068] In some embodiments, the XRPD pattern of the pamoate crystal I of compound I includes diffraction peaks at 2θ of approximately 5.59±0.2°, 5.98±0.2°, 7.62±0.2°, 8.22±0.2°, 9.39±0.2°, 11.59±0.2°, 18.09±0.2°, 20.39±0.2°, 22.59±0.2°, 25.27±0.2°, and 26.01±0.2°. In another embodiment, the XRPD pattern of the pamoate crystal I of compound I includes diffraction peaks at 2θ of approximately 5.59±0.2°, 5.98±0.2°, 7.62±0.2°, 7.80±0.2°, 8.22±0.2°, 9.39±0.2°, 9.88±0.2°, 11.59±0.2°, 18.09±0.2°, 20.39±0.2°, 22.59±0.2°, 23.40±0.2°, 25.27±0.2°, and 26.01±0.2°.

[0069] In some embodiments, the XRPD pattern of the pamoate crystal I of compound I includes the following diffraction peaks at 2θ.

[0070] [Table 9] In some embodiments, the XRPD pattern of the pamoate crystal I of compound I is substantially as shown in Figure 9. In some preferred embodiments, the XRPD pattern of the pamoate crystal I of compound I is as shown in Figure 9.

[0071] Crystal J In some embodiments, the pamoate crystal J of compound I according to the present invention has a stoichiometric ratio of compound I to pamoic acid of 1:1, and its XRPD pattern includes diffraction peaks at 2θ of approximately 5.33±0.2°, 7.13±0.2°, 10.90±0.2°, 14.57±0.2°, 16.62±0.2°, 19.80±0.2°, and 25.29±0.2°. Preferably, the XRPD pattern of the pamoate crystal J of compound I further includes diffraction peaks at 2θ of approximately 14.99±0.2°, 19.01±0.2°, and 20.74±0.2°. More preferably, the XRPD pattern of the pamoate crystal J of compound I further includes diffraction peaks at 2θ of approximately 19.32±0.2° and 22.24±0.2°.

[0072] In some embodiments, the XRPD pattern of the pamoate crystal J of compound I includes diffraction peaks at 2θ of approximately 5.33±0.2°, 7.13±0.2°, 10.90±0.2°, 14.57±0.2°, 14.99±0.2°, 16.62±0.2°, 19.01±0.2°, 19.80±0.2°, 20.74±0.2°, and 25.29±0.2°. In several other embodiments, the XRPD pattern of the pamoate crystal J of compound I includes diffraction peaks at 2θ of approximately 5.33±0.2°, 7.13±0.2°, 10.90±0.2°, 14.57±0.2°, 14.99±0.2°, 16.62±0.2°, 19.01±0.2°, 19.32±0.2°, 19.80±0.2°, 20.74±0.2°, 22.24±0.2°, and 25.29±0.2°.

[0073] In some embodiments, the XRPD pattern of the pamoate crystal J of compound I includes the following diffraction peaks at 2θ.

[0074] [Table 10] In some embodiments, the XRPD pattern of the pamoate crystal J of compound I is substantially as shown in Figure 10. In some preferred embodiments, the XRPD pattern of the pamoate crystal J of compound I is as shown in Figure 10.

[0075] Crystal K In some embodiments, in the pamoate crystal K of compound I according to the present invention, the stoichiometric ratio of compound I to pamoic acid is 1:1, and its XRPD pattern includes diffraction peaks at 2θ of approximately 5.57±0.2°, 5.97±0.2°, 7.73±0.2°, 11.55±0.2°, 18.01±0.2°, and 18.90±0.2°. Preferably, the XRPD pattern of the pamoate crystal K of compound I further includes diffraction peaks at 2θ of approximately 9.34±0.2°, 19.79±0.2°, and 25.84±0.2°. More preferably, the XRPD pattern of the pamoate crystal K of compound I further includes diffraction peaks at 2θ of approximately 23.25±0.2° and 25.10±0.2°.

[0076] In some embodiments, the XRPD pattern of the pamoate crystal K of compound I includes diffraction peaks at 2θ of approximately 5.57±0.2°, 5.97±0.2°, 7.73±0.2°, 9.34±0.2°, 11.55±0.2°, 18.01±0.2°, 18.90±0.2°, 19.79±0.2°, and 25.84±0.2°. In several other embodiments, the XRPD pattern of the pamoate crystal K of compound I includes diffraction peaks at 2θ of approximately 5.57±0.2°, 5.97±0.2°, 7.73±0.2°, 9.34±0.2°, 11.55±0.2°, 18.01±0.2°, 18.90±0.2°, 19.79±0.2°, 23.25±0.2°, 25.10±0.2°, and 25.84±0.2°.

[0077] In some embodiments, the XRPD pattern of the pamoate crystal K of compound I includes the following diffraction peaks at 2θ.

[0078] [Table 11] In some embodiments, the XRPD pattern of the pamoate crystal K of compound I is substantially as shown in Figure 11. In some preferred embodiments, the XRPD pattern of the pamoate crystal K of compound I is as shown in Figure 11.

[0079] crystal L In some embodiments, in the pamoate crystal L of compound I according to the present invention, the stoichiometric ratio of compound I to pamoic acid is 1:1, and its XRPD pattern includes diffraction peaks at 2θ of about 6.20±0.2°, 8.13±0.2°, 9.92±0.2°, 10.85±0.2°, 12.81±0.2°, and 21.82±0.2°. Preferably, the XRPD pattern of the pamoate crystal L of compound I further includes diffraction peaks at 2θ of about 15.29±0.2° and 25.86±0.2°. More preferably, the XRPD pattern of the pamoate crystal L of compound I further includes diffraction peaks at 2θ of about 19.29±0.2° and 25.63±0.2°.

[0080] In some embodiments, the XRPD pattern of the pamoate crystal L of compound I includes diffraction peaks at 2θ of approximately 6.20±0.2°, 8.13±0.2°, 9.92±0.2°, 10.85±0.2°, 12.81±0.2°, 15.29±0.2°, 21.82±0.2°, and 25.86±0.2°. In some other embodiments, the XRPD pattern of the pamoate crystal L of compound I includes diffraction peaks at 2θ of approximately 6.20±0.2°, 8.13±0.2°, 9.92±0.2°, 10.85±0.2°, 12.81±0.2°, 15.29±0.2°, 19.29±0.2°, 21.82±0.2°, 25.63±0.2°, and 25.86±0.2°.

[0081] In some embodiments, the XRPD pattern of the pamoate crystal L of compound I includes the following diffraction peaks at 2θ.

[0082] [Table 12] In some embodiments, the XRPD pattern of the pamoate crystal L of compound I is substantially as shown in Figure 12. In some preferred embodiments, the XRPD pattern of the pamoate crystal L of compound I is as shown in Figure 12.

[0083] Crystal M In some embodiments, in the pamoate crystal M of compound I according to the present invention, the stoichiometric ratio of compound I to pamoic acid is 1:1, and its XRPD pattern includes diffraction peaks at 2θ of approximately 6.31±0.2°, 11.55±0.2°, 14.49±0.2°, 15.94±0.2°, 19.58±0.2°, and 23.50±0.2°. Preferably, the XRPD pattern of the pamoate crystal M of compound I further includes diffraction peaks at 2θ of approximately 19.27±0.2°, 20.28±0.2°, and 25.88±0.2°. More preferably, the XRPD pattern of the pamoate crystal M of compound I further includes diffraction peaks at 2θ of approximately 22.27±0.2° and 24.88±0.2°.

[0084] In some embodiments, the XRPD pattern of the pamoate crystal M of compound I includes diffraction peaks at 2θ of approximately 6.31±0.2°, 11.55±0.2°, 14.49±0.2°, 15.94±0.2°, 19.58±0.2°, 19.27±0.2°, 20.28±0.2°, 23.50±0.2°, and 25.88±0.2°. In several other embodiments, the XRPD pattern of the pamoate crystal M of compound I includes diffraction peaks at 2θ of approximately 6.31±0.2°, 11.55±0.2°, 14.49±0.2°, 15.94±0.2°, 19.58±0.2°, 19.27±0.2°, 20.28±0.2°, 22.27±0.2°, 23.50±0.2°, 24.88±0.2°, and 25.88±0.2°.

[0085] In some embodiments, the XRPD pattern of the pamoate crystal M of compound I includes the following diffraction peaks at 2θ.

[0086] [Table 13] In some embodiments, the XRPD pattern of the pamoate crystal M of compound I is substantially as shown in Figure 13. In some preferred embodiments, the XRPD pattern of the pamoate crystal M of compound I is as shown in Figure 13.

[0087] Pamoate salt of compound I and its crystals (2:1) In some embodiments, the stoichiometric ratio of compound I to pamoic acid in the pamoate of compound I is 2:1.

[0088] Crystal N In some embodiments, in the pamoate crystal N of compound I according to the present invention, the stoichiometric ratio of compound I to pamoic acid is 2:1, and its XRPD pattern includes diffraction peaks at 2θ of approximately 5.87±0.2°, 6.42±0.2°, 10.11±0.2°, 12.58±0.2°, 13.38±0.2°, 16.12±0.2°, and 17.86±0.2°. Preferably, the XRPD pattern of the pamoate crystal N of compound I further includes diffraction peaks at 2θ of approximately 10.55±0.2°, 14.74±0.2°, 24.90±0.2°, and 26.45±0.2°. More preferably, the XRPD pattern of the pamoate crystal N of compound I further includes diffraction peaks at 2θ of approximately 10.87±0.2°, 23.55±0.2°, and 24.29±0.2°.

[0089] In some embodiments, the XRPD pattern of the pamoate crystal N of compound I includes diffraction peaks at 2θ of approximately 5.87±0.2°, 6.42±0.2°, 10.11±0.2°, 10.55±0.2°, 12.58±0.2°, 13.38±0.2°, 14.74±0.2°, 16.12±0.2°, 17.86±0.2°, 24.90±0.2°, and 26.45±0.2°. In several other embodiments, the XRPD pattern of the pamoate crystal N of compound I includes diffraction peaks at 2θ of approximately 5.87±0.2°, 6.42±0.2°, 10.11±0.2°, 10.55±0.2°, 10.87±0.2°, 12.58±0.2°, 13.38±0.2°, 14.74±0.2°, 16.12±0.2°, 17.86±0.2°, 23.55±0.2°, 24.29±0.2°, 24.90±0.2°, and 26.45±0.2°.

[0090] In some embodiments, the XRPD pattern of the pamoate crystal N of compound I includes the following diffraction peaks at 2θ.

[0091] [Table 14] In some embodiments, the XRPD pattern of the pamoate crystal N of compound I is substantially as shown in Figure 14. In some preferred embodiments, the XRPD pattern of the pamoate crystal N of compound I is as shown in Figure 14.

[0092] Crystal O In some embodiments, in the pamoate crystal O of compound I according to the present invention, the stoichiometric ratio of compound I to pamoic acid is 2:1, and its XRPD pattern includes diffraction peaks at 2θ of approximately 11.33±0.2°, 11.92±0.2°, 14.71±0.2°, 16.11±0.2°, 17.50±0.2°, and 20.86±0.2°. Preferably, the XRPD pattern of the pamoate crystal O of compound I further includes diffraction peaks at 2θ of approximately 20.27±0.2°, 23.04±0.2°, 23.57±0.2°, and 27.70±0.2°. More preferably, the XRPD pattern of the pamoate crystal O of compound I further includes diffraction peaks at 2θ of approximately 19.96±0.2°, 24.05±0.2°, 25.43±0.2°, and 26.66±0.2°. In some embodiments, the XRPD pattern of the pamoate crystal O of compound I includes diffraction peaks at 2θ of approximately 11.33±0.2°, 11.92±0.2°, 14.71±0.2°, 16.11±0.2°, 17.50±0.2°, 20.27±0.2°, 20.86±0.2°, 23.04±0.2°, 23.57±0.2°, and 27.70±0.2°. In some embodiments, the XRPD pattern of the pamoate crystal O of compound I includes diffraction peaks at 2θ of approximately 11.33±0.2°, 11.92±0.2°, 14.71±0.2°, 16.11±0.2°, 17.50±0.2°, 19.96±0.2°, 20.27±0.2°, 20.86±0.2°, 23.04±0.2°, 23.57±0.2°, 24.05±0.2°, 25.43±0.2°, 26.66±0.2°, and 27.70±0.2°.

[0093] In some embodiments, the XRPD pattern of the pamoate crystal O of compound I includes the following diffraction peaks at 2θ.

[0094] [Table 15] In some embodiments, the XRPD pattern of the pamoate crystal O of compound I is substantially as shown in Figure 15. In some preferred embodiments, the XRPD pattern of the pamoate crystal O of compound I is as shown in Figure 15.

[0095] Crystal P In some embodiments, in the pamoate crystal P of compound I according to the present invention, the stoichiometric ratio of compound I to pamoic acid is 2:1, and its XRPD pattern includes diffraction peaks at 2θ of approximately 5.79±0.2°, 6.36±0.2°, 10.58±0.2°, 10.90±0.2°, 13.32±0.2°, 14.69±0.2°, 17.61±0.2°, and 25.26±0.2°. Preferably, the XRPD pattern of the pamoate crystal P of compound I further includes diffraction peaks at 2θ of approximately 10.58±0.2°, 22.20±0.2°, 22.80±0.2°, and 23.47±0.2°. More preferably, the XRPD pattern of the pamoate crystal P of compound I further includes diffraction peaks at 2θ of approximately 23.76±0.2° and 24.08±0.2°.

[0096] In some embodiments, the XRPD pattern of the pamoate crystal P of compound I includes diffraction peaks at 2θ of approximately 5.79±0.2°, 6.36±0.2°, 10.58±0.2°, 10.90±0.2°, 13.32±0.2°, 14.69±0.2°, 17.61±0.2°, 22.20±0.2°, 22.80±0.2°, 23.47±0.2°, and 25.26±0.2°. In several other embodiments, the XRPD pattern of the pamoate crystal P of compound I includes diffraction peaks at 2θ of approximately 5.79±0.2°, 6.36±0.2°, 10.58±0.2°, 10.90±0.2°, 13.32±0.2°, 14.69±0.2°, 17.61±0.2°, 22.20±0.2°, 22.80±0.2°, 23.47±0.2°, 23.76±0.2°, 24.08±0.2°, and 25.26±0.2°.

[0097] In some embodiments, the XRPD pattern of the pamoate crystal P of compound I includes the following diffraction peaks at 2θ.

[0098] [Table 16] In some embodiments, the XRPD pattern of the pamoate crystal P of compound I is substantially as shown in Figure 16. In some preferred embodiments, the XRPD pattern of the pamoate crystal P of compound I is as shown in Figure 16.

[0099] Crystal Q In some embodiments, in the pamoate crystal Q of compound I according to the present invention, the stoichiometric ratio of compound I to pamoic acid is 2:1, and its XRPD pattern includes diffraction peaks at 2θ of approximately 5.75±0.2°, 6.20±0.2°, 10.46±0.2°, 14.54±0.2°, 15.26±0.2°, and 20.78±0.2°. Preferably, the XRPD pattern of the pamoate crystal Q of compound I further includes diffraction peaks at 2θ of approximately 16.16±0.2°, 17.51±0.2°, and 24.37±0.2°. More preferably, the XRPD pattern of the pamoate crystal Q of compound I further includes diffraction peaks at 2θ of approximately 17.98±0.2°, 21.74±0.2°, and 23.58±0.2°.

[0100] In some embodiments, the XRPD pattern of the pamoate crystal Q of compound I includes diffraction peaks at 2θ of approximately 5.75±0.2°, 6.20±0.2°, 10.46±0.2°, 14.54±0.2°, 15.26±0.2°, 16.16±0.2°, 17.51±0.2°, 20.78±0.2°, and 24.37±0.2°. In several other preferred embodiments, the XRPD pattern of the pamoate crystal Q of compound I includes diffraction peaks at 2θ of approximately 5.75±0.2°, 6.20±0.2°, 10.46±0.2°, 14.54±0.2°, 15.26±0.2°, 16.16±0.2°, 17.51±0.2°, 17.98±0.2°, 20.78±0.2°, 21.74±0.2°, 23.58±0.2°, and 24.37±0.2°.

[0101] In some embodiments, the XRPD pattern of the pamoate crystal Q of compound I includes the following diffraction peaks at 2θ.

[0102] [Table 17] In some embodiments, the XRPD pattern of the pamoate crystal Q of compound I is substantially as shown in Figure 17. In some preferred embodiments, the XRPD pattern of the pamoate crystal Q of compound I is as shown in Figure 17.

[0103] Crystal R In some embodiments, in the pamoate crystal R of compound I according to the present invention, the stoichiometric ratio of compound I to pamoic acid is 2:1, and its XRPD pattern includes diffraction peaks at 2θ of approximately 5.97±0.2°, 11.45±0.2°, 12.06±0.2°, 13.41±0.2°, 17.75±0.2°, and 18.77±0.2°. Preferably, the XRPD pattern of the pamoate crystal R of compound I further includes diffraction peaks at 2θ of approximately 19.42±0.2°, 21.64±0.2°, 23.89±0.2°, 27.10±0.2°, and 28.76±0.2°. More preferably, the XRPD pattern of the pamoate crystal R of compound I further includes diffraction peaks at 2θ of approximately 21.64±0.2°, 23.09±0.2°, and 26.18±0.2°.

[0104] In some embodiments, the XRPD pattern of the pamoate crystal R of compound I includes diffraction peaks at 2θ of approximately 5.97±0.2°, 11.45±0.2°, 12.06±0.2°, 13.41±0.2°, 17.75±0.2°, 18.77±0.2°, 19.42±0.2°, 21.64±0.2°, 23.89±0.2°, 27.10±0.2°, and 28.76±0.2°. In several other embodiments, the XRPD pattern of the pamoate crystal R of compound I includes diffraction peaks at 2θ of approximately 5.97±0.2°, 11.45±0.2°, 12.06±0.2°, 13.41±0.2°, 17.75±0.2°, 18.77±0.2°, 19.42±0.2°, 21.64±0.2°, 23.09±0.2°, 23.89±0.2°, 26.18±0.2°, 27.10±0.2°, and 28.76±0.2°.

[0105] In some embodiments, the XRPD pattern of the pamoate crystal R of compound I includes the following diffraction peaks at 2θ.

[0106] [Table 18] In some embodiments, the XRPD pattern of the pamoate crystal R of compound I is substantially as shown in Figure 18. In some preferred embodiments, the XRPD pattern of the pamoate crystal R of compound I is as shown in Figure 18.

[0107] Crystal S In some embodiments, in the pamoate crystal S of compound I according to the present invention, the stoichiometric ratio of compound I to pamoic acid is 2:1, and its XRPD pattern includes diffraction peaks at 2θ of approximately 5.84±0.2°, 6.34±0.2°, 10.06±0.2°, 11.14±0.2°, 13.25±0.2°, 14.65±0.2°, 18.26±0.2°, and 25.25±0.2°. Preferably, the XRPD pattern of the pamoate crystal S of compound I further includes diffraction peaks at 2θ of approximately 19.33±0.2°, 21.53±0.2°, 22.68±0.2°, and 24.06±0.2°. More preferably, the XRPD pattern of the pamoate crystal S of compound I further includes diffraction peaks at 2θ of approximately 20.20±0.2°, 22.09±0.2°, and 24.06±0.2°.

[0108] In some embodiments, the XRPD pattern of the pamoate crystal S of compound I includes diffraction peaks at 2θ of approximately 5.84±0.2°, 6.34±0.2°, 10.06±0.2°, 11.14±0.2°, 13.25±0.2°, 14.65±0.2°, 18.26±0.2°, 19.33±0.2°, 21.53±0.2°, 22.68±0.2°, 24.06±0.2°, and 25.25±0.2°. In several other embodiments, the XRPD pattern of the pamoate crystal S of compound I includes diffraction peaks at 2θ of approximately 5.84±0.2°, 6.34±0.2°, 10.06±0.2°, 11.14±0.2°, 13.25±0.2°, 14.65±0.2°, 18.26±0.2°, 19.33±0.2°, 20.20±0.2°, 21.53±0.2°, 22.09±0.2°, 22.68±0.2°, 24.06±0.2° and 25.25±0.2°.

[0109] In some embodiments, the XRPD pattern of the pamoate crystal S of compound I includes the following diffraction peaks at 2θ.

[0110] [Table 19] In some embodiments, the XRPD pattern of the pamoate crystal S of compound I is substantially as shown in Figure 19. In some preferred embodiments, the XRPD pattern of the pamoate crystal S of compound I is as shown in Figure 19.

[0111] Palmitate of compound I and its crystals (1:1) In some embodiments, the stoichiometric ratio of compound I to palmitic acid in the palmitate of compound I is 1:1.

[0112] Crystal T In some embodiments, the palmitate crystal T of compound I according to the present invention has a stoichiometric ratio of compound I to palmitic acid of 1:1, and its XRPD pattern includes diffraction peaks at 2θ of approximately 6.17±0.2°, 9.73±0.2°, 10.20±0.2°, 11.52±0.2°, 12.44±0.2°, 15.16±0.2°, and 21.40±0.2°. Preferably, the XRPD pattern of the palmitate crystal T of compound I further includes diffraction peaks at 2θ of approximately 13.82±0.2°, 16.36±0.2°, and 16.65±0.2°. More preferably, the XRPD pattern of the palmitate crystal T of compound I further includes diffraction peaks at 2θ of approximately 16.89±0.2°, 19.88±0.2°, and 20.18±0.2°.

[0113] In some embodiments, the XRPD pattern of the palmitate crystal T of compound I includes diffraction peaks at 2θ of approximately 6.17±0.2°, 9.73±0.2°, 10.20±0.2°, 11.52±0.2°, 12.44±0.2°, 13.82±0.2°, 15.16±0.2°, 16.36±0.2°, 16.65±0.2°, and 21.40±0.2°. In several other embodiments, the XRPD pattern of the palmitate crystal T of compound I includes diffraction peaks at 2θ of approximately 6.17±0.2°, 9.73±0.2°, 10.20±0.2°, 11.52±0.2°, 12.44±0.2°, 13.82±0.2°, 15.16±0.2°, 16.36±0.2°, 16.65±0.2°, 16.89±0.2°, 19.88±0.2°, 20.18±0.2°, and 21.40±0.2°.

[0114] In some embodiments, the XRPD pattern of the palmitate crystal T of compound I includes the following diffraction peaks at 2θ.

[0115] [Table 20] In some embodiments, the XRPD pattern of the palmitate crystal T of compound I is substantially as shown in Figure 20. In some preferred embodiments, the XRPD pattern of the palmitate crystal T of compound I is as shown in Figure 20.

[0116] crystal U In some embodiments, in the palmitate crystal U of compound I according to the present invention, the stoichiometric ratio of compound I to palmitic acid is 1:1, and its XRPD pattern includes diffraction peaks at 2θ of approximately 5.95±0.2°, 15.15±0.2°, 17.90±0.2°, 20.57±0.2°, 21.44±0.2°, 21.83±0.2°, and 25.82±0.2°. Preferably, the XRPD pattern of the palmitate crystal U of compound I further includes diffraction peaks at 2θ of approximately 10.81±0.2°, 14.47±0.2°, 18.20±0.2°, 22.63±0.2°, and 26.63±0.2°. More preferably, the XRPD pattern of the palmitate crystal U of compound I further includes diffraction peaks at 2θ of approximately 11.27±0.2° and 26.03±0.2°.

[0117] In some embodiments, the XRPD pattern of the palmitate crystal U of compound I includes diffraction peaks at 2θ of approximately 5.95±0.2°, 10.81±0.2°, 14.47±0.2°, 15.15±0.2°, 17.90±0.2°, 18.20±0.2°, 20.57±0.2°, 21.44±0.2°, 21.83±0.2°, 22.63±0.2°, 25.82±0.2°, and 26.63±0.2°. In several other embodiments, the XRPD pattern of the palmitate crystal U of compound I includes diffraction peaks at 2θ of approximately 5.95±0.2°, 10.81±0.2°, 11.27±0.2°, 14.47±0.2°, 15.15±0.2°, 17.90±0.2°, 18.20±0.2°, 20.57±0.2°, 21.44±0.2°, 21.83±0.2°, 22.63±0.2°, 25.82±0.2°, 26.03±0.2°, and 26.63±0.2°.

[0118] In some embodiments, the XRPD pattern of the palmitate crystal U of compound I includes the following diffraction peaks at 2θ.

[0119] [Table 21] In some embodiments, the XRPD pattern of the palmitate crystal U of compound I is substantially as shown in Figure 21. In some preferred embodiments, the XRPD pattern of the palmitate crystal U of compound I is as shown in Figure 21.

[0120] Crystal V In some embodiments, in the palmitate crystal V of compound I according to the present invention, the stoichiometric ratio of compound I to palmitic acid is 1:1, and its XRPD pattern includes diffraction peaks at 2θ of approximately 5.56±0.2°, 12.99±0.2°, 13.21±0.2°, 13.59±0.2°, 14.02±0.2°, 14.71±0.2°, and 19.90±0.2°. Preferably, the XRPD pattern of the palmitate crystal V of compound I further includes diffraction peaks at 2θ of approximately 11.19±0.2°, 19.66±0.2°, 22.61±0.2°, 22.80±0.2°, and 23.43±0.2°. More preferably, the XRPD pattern of the palmitate crystal V of compound I further includes diffraction peaks at 2θ of approximately 11.38±0.2°, 19.48±0.2°, 20.26±0.2°, and 22.96±0.2°.

[0121] In some embodiments, the XRPD pattern of the palmitate crystal V of compound I includes diffraction peaks at 2θ of approximately 5.56±0.2°, 11.19±0.2°, 12.99±0.2°, 13.21±0.2°, 13.59±0.2°, 14.02±0.2°, 14.71±0.2°, 19.90±0.2°, 19.66±0.2°, 22.61±0.2°, 22.80±0.2°, and 23.43±0.2°. In several other embodiments, the XRPD pattern of the palmitate crystal V of compound I includes diffraction peaks at 2θ of approximately 5.56±0.2°, 11.19±0.2°, 11.38±0.2°, 12.99±0.2°, 13.21±0.2°, 13.59±0.2°, 14.02±0.2°, 14.71±0.2°, 19.48±0.2°, 19.90±0.2°, 19.66±0.2°, 20.26±0.2°, 22.61±0.2°, 22.80±0.2°, 22.96±0.2°, and 23.43±0.2°.

[0122] In some embodiments, the XRPD pattern of the palmitate crystal V of compound I includes the following diffraction peaks at 2θ.

[0123] [Table 22] In some embodiments, the XRPD pattern of the palmitate crystal V of compound I is substantially as shown in Figure 22. In some preferred embodiments, the XRPD pattern of the palmitate crystal V of compound I is as shown in Figure 22.

[0124] Pharmaceutical composition and use Another object of the present invention is to provide a pharmaceutical composition comprising a salt of compound I selected from pamoates and palmitates, particularly pamoate crystals or palmitate crystals of compound I, and one or more pharmaceutically acceptable carriers.

[0125] Another object of the present invention is the use of salts of compound I of the present invention (e.g., pamoate and palmitate of compound I, particularly pamoate crystals or palmitate crystals of compound I, or any combination thereof) or pharmaceutical compositions in the manufacture of drugs used for the treatment of Parkinson's disease and restless legs syndrome.

[0126] Another object of the present invention is to provide the use of salts of compound I of the present invention (e.g., pamoate and palmitate of compound I, particularly pamoate crystals or palmitate crystals of compound I, or any combination thereof) or pharmaceutical compositions in the treatment of Parkinson's disease and restless legs syndrome.

[0127] Another object of the present invention is to provide a method for treating Parkinson's disease and restless legs syndrome, comprising the step of administering a salt of compound I of the present invention (e.g., pamoate and palmitate of compound I, particularly pamoate crystals or palmitate crystals of compound I, or any combination thereof) or a pharmaceutical composition to an individual in need of treatment in a therapeutically effective amount.

[0128] As used herein, “pharmaceutically acceptable carrier” means a diluent, adjuvant, excipient, or vehicle administered with a therapeutic agent that, within reasonable medical judgment, is free from excessive toxicity, irritation, allergic reactions, or other problems or complications that do not outweigh the reasonable benefit-to-risk ratio, and is suitable for contact with human and / or other animal tissues.

[0129] The compounds of the present invention can be administered in pure form or in the form of a suitable pharmaceutical composition by any acceptable mode of administration that provides a drug for similar use. Pharmaceutical compositions of the present invention can be prepared by combining the compounds of the present invention or salts thereof with a suitable pharmaceutically acceptable carrier.

[0130] The pharmaceutical composition of the present invention can be manufactured by methods well known in the art, such as conventional mixing methods.

[0131] Typical routes for administering the compounds of the present invention or their pharmaceutical compositions include, but are not limited to, oral, rectal, mucosal, intra-intestinal, topical, transdermal, inhalation, parenteral, sublingual, vaginal, nasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0132] In preferred embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with a drug-acceptable carrier, excipient, and / or medium known in the art. These carriers, excipients, and mediums allow the compounds of the present invention to be formulated for oral administration to patients in the form of tablets, pills, lozenges, sugar-coated preparations, capsules, liquids, gels, slurries, suspensions, etc.

[0133] Solid oral compositions can be manufactured by conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable adjuvants if necessary, and then processing the mixture into particles to obtain a tablet or sugar-coated core.

[0134] Beneficial effects The pamoate and palmitate salts of Compound I of the present invention have advantages such as high purity and high stability. Furthermore, they have lower solubility and can be used in long-acting sustained-release formulations. The pamoate and palmitate salts of Compound I of the present invention are used in extended T max and T 1 / 2 By having a longer duration and maintaining effective blood concentrations for a longer period, it is possible to demonstrate that a long-acting release effect can be achieved.

[0135] The crystals of the present invention (e.g., crystal forms A-S and T-V) have advantages such as high purity and high stability. Furthermore, they have lower solubility and can be used in long-acting sustained-release formulations. The crystals of the present invention are extended T max and T 1 / 2By having a longer duration and maintaining effective blood concentrations for a longer period, it is possible to demonstrate that a long-acting release effect can be achieved.

[0136] Examples X-ray powder diffraction (XRPD) The XRPD patterns of each crystal were collected using an X′Pert3 Powder Diffractometer. The apparatus was irradiated with Cu-palladium and performed continuous projection scanning using Absolute scan at room temperature. The scanning 2θ range was 3.5° to 40°, the step size was 0.013°, the residence time was 50 s, and one scan was performed.

[0137] All solvents used in this invention are commercially available and can be used without further purification.

[0138] Example 1: Preparation of pamoate crystal A of compound I 50 mg of compound I and 92 mg of pamoic acid were placed in 2 mL of methanol and suspended by shaking in a 40-10°C heating-cooling cycle (the 40-10°C heating-cooling cycle involves holding at 40°C for 1 hour, then cooling to 10°C and holding for 1 hour, then heating to 40°C and holding for 1 hour, then cooling to 10°C and holding for 1 hour, and repeating the cycle). After 24 hours, the mixture was centrifuged to obtain pamoic acid crystal A of compound I, which was then subjected to XRPD detection, and the resulting XRPD pattern is shown in Figure 1.

[0139] Example 2: Preparation of pamoate crystal B of compound I 50 mg of compound I and 92 mg of pamoic acid were placed in 2 mL of acetonitrile, and the mixture was suspended by shaking under a heating-cooling cycle of 40-10°C. After 24 hours, the mixture was centrifuged to obtain pamoic acid crystal B of compound I, and XRPD detection was performed on it. The resulting XRPD pattern is shown in Figure 2.

[0140] Example 3: Preparation of pamoate crystals C of compound I 50 mg of compound I and 92 mg of pamoic acid were placed in 2 mL of acetone, and the mixture was suspended by shaking under a heating-cooling cycle of 40-10°C. After 24 hours, the mixture was centrifuged to obtain pamoic acid crystal C of compound I, and XRPD detection was performed on it. The resulting XRPD pattern is shown in Figure 3.

[0141] Example 4: Preparation of pamoate crystals D of compound I 50 mg of compound I and 92 mg of pamoic acid were placed in 2 mL of methanol, suspended by shaking under a heating-cooling cycle of 40-10°C, centrifuged after 24 hours, and then dried at 60°C to obtain pamoate crystal D of compound I. XRPD detection was performed on this crystal, and the resulting XRPD pattern is shown in Figure 4.

[0142] Example 5: Preparation of pamoate crystals E of compound I 50 mg of compound I and 92 mg of pamoic acid were placed in a mixed solvent of 1 mL of acetonitrile and 1 mL of water, suspended by shaking under a heating-cooling cycle of 40-10°C, and centrifuged after 24 hours to obtain pamoic acid crystal E of compound I. XRPD detection was performed on this crystal, and the resulting XRPD pattern is shown in Figure 5.

[0143] Example 6: Preparation of pamoate crystals F of compound I 50 mg of compound I and 92 mg of pamoic acid were placed in 3 mL of acetonitrile, suspended by shaking under a heating-cooling cycle of 40-10°C, centrifuged after 24 hours, and then dried at 60°C to obtain pamoate crystals F of compound I. XRPD detection was performed on these crystals, and the resulting XRPD pattern is shown in Figure 6.

[0144] Example 7: Preparation of pamoate crystals G of compound I 50 mg of compound I and 92 mg of pamoic acid were placed in 4 mL of acetonitrile, shaken at 50°C to suspend, and after 4 hours, centrifuged to obtain pamoic acid crystals G of compound I. XRPD detection was performed on these crystals, and the resulting XRPD pattern is shown in Figure 7.

[0145] Example 8: Preparation of pamoate crystal H of compound I 50 mg of compound I and 92 mg of pamoic acid were placed in 4 mL of methanol, shaken at 50°C to suspend, and after 4 hours, centrifuged to obtain pamoate crystal H of compound I. XRPD detection was performed on this crystal, and the resulting XRPD pattern is shown in Figure 8.

[0146] Example 9: Preparation of Pamoate Crystal I of Compound I 50 mg of compound I and 92 mg of pamoic acid were placed in a mixed solvent of 1 mL of methanol and 1 mL of water, and the mixture was shaken at 25°C to suspend the compound. After 24 hours, the mixture was centrifuged to obtain pamoic acid crystal I of compound I, and XRPD detection was performed on it. The resulting XRPD pattern is shown in Figure 9.

[0147] Example 10: Preparation of pamoate crystals J of compound I 50 mg of compound I and 92 mg of pamoic acid were placed in 2 mL of THF, and the mixture was suspended by shaking under a heating-cooling cycle of 40-10°C. After 24 hours, the mixture was centrifuged to obtain pamoic acid crystals J of compound I, and XRPD detection was performed on these crystals. The resulting XRPD pattern is shown in Figure 10.

[0148] Example 11: Preparation of pamoate crystal K of compound I 50 mg of compound I and 92 mg of pamoic acid were placed in a mixed solution of 1 mL of methanol and 3 mL of water, suspended by shaking under a heating-cooling cycle of 40-10°C, and centrifuged after 24 hours to obtain pamoate crystal K of compound I. XRPD detection was performed on this crystal, and the resulting XRPD pattern is shown in Figure 11.

[0149] Example 12: Preparation of pamoate crystals L of compound I 50 mg of compound I and 92 mg of pamoic acid were placed in a mixed solution of 0.4 mL of methanol and 1.6 mL of MTBE, and the mixture was suspended by shaking under a heating-cooling cycle of 40-10°C. After 24 hours, the mixture was centrifuged to obtain pamoic acid crystals L of compound I, and XRPD detection was performed on these crystals. The resulting XRPD pattern is shown in Figure 12.

[0150] Example 13: Preparation of pamoate crystals M of compound I 50 mg of compound I and 92 mg of pamoic acid were placed in a mixed solution of 1 mL of THF and 1 mL of water, and suspended by shaking under a heating-cooling cycle of 40-10°C. After 24 hours, the mixture was centrifuged to obtain pamoic acid crystals M of compound I, and XRPD detection was performed on them. The resulting XRPD pattern is shown in Figure 13.

[0151] Example 14: Preparation of Pamoate Crystals N of Compound I 50 mg of compound I and 46 mg of pamoic acid were placed in 2 mL of acetone, and the mixture was suspended by shaking under a heating-cooling cycle of 40-10°C. After 24 hours, the mixture was centrifuged to obtain pamoate crystal N of compound I, and XRPD detection was performed on it. The resulting XRPD pattern is shown in Figure 14.

[0152] Example 15: Preparation of pamoate crystals O of compound I 50 mg of compound I and 46 mg of pamoic acid were placed in 2 mL of methanol, and the mixture was suspended by shaking under a heating-cooling cycle of 40-10°C. After 24 hours, the mixture was centrifuged to obtain pamoate crystals O of compound I, and XRPD detection was performed on these crystals. The resulting XRPD pattern is shown in Figure 15.

[0153] Example 16: Preparation of pamoate crystals P of compound I 50 mg of compound I and 46 mg of pamoic acid were placed in 2 mL of acetonitrile, and the mixture was suspended by shaking under a heating-cooling cycle of 40-10°C. After 24 hours, the mixture was centrifuged to obtain pamoic acid crystals P of compound I, which were then subjected to XRPD detection. The resulting XRPD pattern is shown in Figure 16.

[0154] Example 17: Preparation of pamoate crystal Q of compound I 50 mg of compound I and 46 mg of pamoic acid were placed in 2 mL of isopropanol, and the mixture was suspended by shaking under a heating-cooling cycle of 40-10°C. After 24 hours, the mixture was centrifuged to obtain pamoate crystal Q of compound I, and XRPD detection was performed on it. The resulting XRPD pattern is shown in Figure 17.

[0155] Example 18: Preparation of pamoate crystals R of compound I 50 mg of compound I and 46 mg of pamoic acid were placed in 2 mL of THF, and the mixture was suspended by shaking under a heating-cooling cycle of 40-10°C. After 24 hours, the mixture was centrifuged to obtain pamoic acid crystals R of compound I, and XRPD detection was performed on these crystals. The resulting XRPD pattern is shown in Figure 18.

[0156] Example 19: Preparation of pamoate crystals S of compound I 50 mg of compound I and 46 mg of pamoic acid were placed in a mixed solvent of 0.4 mL of ethanol and 1.6 mL of n-heptane, suspended by shaking under a heating-cooling cycle of 40-10°C, and centrifuged after 24 hours to obtain pamoate crystal S of compound I. XRPD detection was performed on the crystal, and the resulting XRPD pattern is shown in Figure 19.

[0157] Example 20: Preparation of palmitate crystals T of compound I 2.0 g of compound I and 2.4 g of palmitic acid were placed in 30 mL of ethyl acetate, stirred at 25°C, and filtered after 2 hours to obtain palmitate crystal T of compound I. XRPD detection was performed on this crystal, and the resulting XRPD pattern is shown in Figure 20.

[0158] Example 21: Preparation of palmitate crystals U of compound I 20 mg of palmitate crystal T of compound I (produced in Example 20) was placed in 1 mL of ethanol, suspended by shaking under a heating-cooling cycle of 40-10°C, and centrifuged after 24 hours to obtain palmitate crystal U of compound I. XRPD detection was performed on this crystal, and the resulting XRPD pattern is shown in Figure 21.

[0159] Example 22: Preparation of Compound I palmitate crystals V 20 mg of palmitate crystal T of compound I (prepared in Example 20) was placed in 1 mL of acetone, suspended by shaking under a heating-cooling cycle of 40-10°C, and centrifuged after 24 hours to obtain palmitate crystal V of compound I. XRPD detection was performed on this crystal, and the resulting XRPD pattern is shown in Figure 22.

[0160] Test Example 1: Solubility Test 1-1 Solubility of crystal T, crystal U, crystal V and compound I The sample was placed in pure water, an excess of the sample was added, and the mixture was shaken at room temperature for 15 hours. The solution was then filtered and detected by HPLC. The HPLC test conditions were as follows: the mobile phase was sodium octanesulfonate-potassium dihydrogen phosphate buffer (5.0 g of sodium octanesulfonate and 9.1 g of potassium dihydrogen phosphate dissolved in 1000 ml of water, with the pH adjusted to 3.0 with phosphoric acid)-acetonitrile (72:28); the detection wavelength was 264 nm; the flow rate was 1.5 ml / min; the column temperature was 40°C; the sample injection volume was 10 μl; and the chromatography column was packed with octadecylsilane-bonded silica (CAPCELL PAK MG II C18, 4.6 mm × 250 mm, 5 μm).

[0161] [Table 23] As can be seen from the data in the table above, the crystals of the present invention have lower solubility compared to the free base of compound I and can be used in long-acting sustained-release formulations.

[0162] 1-2 Solubility of Crystalline D and Crystalline N According to the test method described in 1-1, pamoate crystals D and N were tested, and the results of their solubility tests are shown in the table below.

[0163] [Table 24] As can be seen from the data in the above table, the crystal of the present invention has lower solubility compared to the free base of Compound I and can be used in a long-acting sustained-release preparation.

[0164] Test Example 2 Rat Pharmacokinetics Test 2-1 Rat Pharmacokinetics Test of Pamoate Using 4 female rats, the rats are administered only once with 5 mg / kg of pamoate crystal D of Compound I by intramuscular injection. At 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 24 h, 48 h, 72 h, 96 h, 120 h, 144 h, and 168 h before and after administration, 0.3 ml of venous blood samples (EDTA-K2 anticoagulated) are collected respectively. Next, the blood concentration after administration is measured, and the pharmacokinetic parameters are calculated by fitting the blood concentration-time curve. Refer to the following table for related data.

[0165] Pharmacokinetic Data of Pamoate Crystal

Table 25

[0166] 2-2 Rat Pharmacokinetics Test of Palmitate Four female rats were administered a single dose of compound I palmitate crystal T at a dose of 5 mg / kg via intramuscular injection. Venous blood samples (EDTA-K2 anticoagulant) of 0.3 ml were collected before administration and at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 24 h, 48 h, 72 h, 96 h, 120 h, 144 h, and 168 h after administration. Pharmacokinetic parameters were then calculated by measuring post-administration blood concentrations and fitting blood concentration-time curves. See the table below for relevant data.

[0167] Pharmacokinetic data of palmitate [Table 26] FDA document (FDA.Mirapex(registered trademark) ER) TM As can be seen from (pramipexole dihydrochloride), NDA 22-421, Serial 000 received 10 / 24 / 08), when compound I (pramipexole) was orally administered to rats, the T max It is 0.5h, and T 1 / 2 The duration is 3.18h. As can be seen from this, compared to compound I itself, the palmitate crystal of compound I of the present invention can maintain an effective blood concentration for a longer period of time, and the duration is longer. max and T 1 / 2 It has a long duration and achieves a sustained-release effect that acts over a long period of time.

[0168] The above-described specific embodiments further illustrate the present invention. However, this should not be understood as limiting the scope of the subject matter of the present invention to the examples listed above; any technical means implemented based on the content of the present invention falls within the scope of the present invention.

Claims

1. Palmitate of the compound of formula I. 【Chemistry 1】

2. The palmitate salt of the compound of formula I according to claim 1, wherein the stoichiometric ratio of the compound of formula I to palmitic acid is 1:

1.

3. A palmitate crystal T of the compound of formula I according to claim 2, having an XRPD pattern including diffraction peaks at 2θ of 6.17±0.2°, 9.73±0.2°, 10.20±0.2°, 11.52±0.2°, 12.44±0.2°, 15.16±0.2° and 21.40±0.2°.

4. A palmitate crystal T of the compound of formula I according to claim 3, wherein the XRPD pattern further includes diffraction peaks at 2θ of 13.82±0.2°, 16.36±0.2°, and 16.65±0.2°.

5. A palmitate crystal T of the compound of formula I according to claim 4, wherein the XRPD pattern further includes diffraction peaks at 2θ of 16.89±0.2°, 19.88±0.2°, and 20.18±0.2°.

6. A palmitate crystal U of the compound of formula I according to claim 2, having an XRPD pattern including diffraction peaks at 2θ of 5.95±0.2°, 15.15±0.2°, 17.90±0.2°, 20.57±0.2°, 21.44±0.2°, 21.83±0.2° and 25.82±0.2°.

7. A palmitate crystal U of the compound of formula I according to claim 6, wherein the XRPD pattern further includes diffraction peaks at 2θ of 10.81±0.2°, 14.47±0.2°, 18.20±0.2°, 22.63±0.2° and 26.63±0.2°.

8. The palmitate crystal U of the compound of formula I according to claim 7, wherein the XRPD pattern further includes diffraction peaks at 2θ of 11.27±0.2° and 26.03±0.2°.

9. A palmitate crystal V of the compound of formula I according to claim 2, having an XRPD pattern including diffraction peaks at 2θ of 5.56±0.2°, 12.99±0.2°, 13.21±0.2°, 13.59±0.2°, 14.02±0.2°, 14.71±0.2° and 19.90±0.2°.

10. A palmitate crystal V of the compound of formula I according to claim 9, wherein the XRPD pattern further includes diffraction peaks at 2θ of 11.19±0.2°, 19.66±0.2°, 22.61±0.2°, 22.80±0.2° and 23.43±0.2°.

11. A palmitate crystal V of the compound of formula I according to claim 10, wherein the XRPD pattern further includes diffraction peaks at 2θ of 11.38±0.2°, 19.48±0.2°, 20.26±0.2°, and 22.96±0.2°.

12. i) Palmitate of the compound of formula I according to claim 1 or 2, and Palmitate crystals of the compound of formula I according to any one of claims 3 to 11 One or more of the following, ii) A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers.

13. The pharmaceutical composition according to claim 12 for the treatment of Parkinson's disease and restless legs syndrome.

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