WO2024046279A1 - Polymorph of mao-b inhibitor prodrug, and preparation method therefor and use thereof - Google Patents

Abstract

The present invention relates to a compound of formula (I), which has a plurality of crystal forms. The crystal forms of the compound show good stability in addition to higher purity, especially crystal form I, crystal form II and crystal form III. In addition, the crystal forms of the compound can be released more stably after being injected, thereby ensuring that the plasma concentration is kept at a certain concentration stably for a long time.

Description

A polymorphic form of MAO-B inhibitor prodrug and its preparation method and use Technical field

The present invention relates to the technical field of pharmaceutical crystal forms, and more specifically, to the polymorphic forms of MAO-B inhibitor derivatives, including crystal form I, crystal form II, crystal form III and crystal form IV, and their preparation methods and uses.

Background technique

Parkinson's disease (PD), also known as paralysis shaking, is a common neurodegenerative disease characterized by progressiveness, multiple occurrence, and insidious onset. It mainly manifests as slowness of movement, myotonia, and Resting tremor and postural instability. PD rarely occurs in people before the age of 50, and its incidence increases rapidly after the age of 60. It is estimated that there are more than 2 million PD patients in China, and the incidence rate among people over 65 years old is about 1.7%. As China gradually ages, this number has an upward trend.

Rasagiline (English name: rasagiline) is an irreversible monoamine oxidase inhibitor. By selectively inhibiting monoamine oxidase, it can reduce the decomposition of dopamine and increase the extracellular level of dopamine in the high striatum of the brain. The increased dopamine level can alleviate the symptoms of Parkinson's disease. . This drug is used as a monotherapy (without levodopamine) or as an adjuvant therapy (combined with levodopamine) to treat idiopathic Parkinson's disease. It is well tolerated and has a long maintenance time. It is a first-line drug for the early treatment of PD.

Parkinson's disease is a progressive, incurable neurological disease that requires long-term medication, and rasagiline requires daily dosing. Since Parkinson's disease mainly affects the elderly, and patients have poor memory and are prone to forgetting things, the development of long-acting Parkinson's disease drugs will have a huge market. The inventor's early patent CN109422668B provides a method for The long-acting rasagiline prodrug for the treatment of Parkinson's disease has a good long-acting effect.

Since different crystal forms of the drug have a certain relationship with the dissolution and absorption of the drug in the body, in order to ensure the stable blood concentration of the rasagiline prodrug in the body, it is necessary to study the polymorphic form of the long-acting prodrug to obtain the A stable crystalline form that is pharmaceutically available to facilitate the long-acting effect of the drug.

Contents of the invention

On the basis of the previous research results, the present invention further studies multiple crystal forms of long-acting rasagiline prodrugs, with the purpose of providing multiple stable crystal forms of the compound described in formula (I) with better pharmaceutical properties. Specifically, they are crystal form I, crystal form II, crystal form III and crystal form IV, among which crystal form I, crystal form II and crystal form III show good stability.

Another object of the present invention is to provide methods for preparing multiple stable crystal forms of the compound described in formula (I).

Another object of the present invention is to provide the use of multiple stable crystal forms of the compound described in formula (I).

The compound described in formula (I) is an MAO-B inhibitor derivative and belongs to the rasagiline prodrug. By modifying the structure of rasagiline, the inventor finally obtained a prodrug with long-acting properties. After the compound of formula (I) passes through the subcutaneous or muscle, it forms a drug reservoir in the body, is continuously released and converted into rasagiline, which not only ensures the curative effect, but also has a long-lasting effect. However, injectable long-acting drugs have problems with unstable drug release speed and incomplete release. The unstable drug release speed is manifested by sudden release or too slow release within a short time after drug injection, resulting in increased side effects or inability to Reach the effective blood drug concentration; incomplete release means that the drug is not completely released in the body at a later stage, resulting in reduced bioavailability of the drug. This is closely related to the physical stability of crystalline drugs.

The above objects of the present invention are achieved through the following solutions:

One of the objects of the present invention is to provide a crystal form I of a compound of formula (I). The X-ray powder diffraction pattern of the crystal form I has diffraction peaks at 3.72, 7.32, 10.92, 21.54 and 23.10, and the 2θ value error range is ± 0.2.

In one of the specific embodiments, the 2θ of the X-ray powder diffraction pattern of Form I has diffraction peaks at 3.72, 7.32, 10.92, 12.06, 14.52, 21.54, 23.10, 24.72, 25.48, and 26.36, where the 2θ value error range is ±0.2. The X-ray powder diffraction pattern of Form I is shown in Figure 1.

The present invention also provides a method for preparing crystal form I of the compound of formula (I), which is obtained by dissolving the compound of formula (I) in a solvent and crystallizing it by cooling;

Wherein, the solvent is selected from ethanol, ethanol/water, acetone/water, isopropyl alcohol, isopropyl alcohol/water, isopropyl alcohol/n-heptane, dichloromethane/n-heptane, methyl tert-butyl ether/ Dichloromethane, methyl tert-butyl ether/cyclohexane, methyl tert-butyl ether/n-heptane or tetrahydrofuran/n-heptane.

"Solvent 1/Solvent 2" means a mixture of two solvents.

Preferably, the solvent is selected from ethanol, the volume ratio of ethanol/water is 3:1, the volume ratio of acetone/water is 4:1, isopropyl alcohol, the volume ratio of isopropyl alcohol/water is 4:1, isopropyl alcohol/ The volume ratio of n-heptane is 3:1, the volume ratio of dichloromethane/n-heptane is 1:3, the volume ratio of methyl tert-butyl ether/dichloromethane is 5:1, and the volume ratio of methyl tert-butyl ether/cyclohexane The volume ratio of alkane is 1:2, the volume ratio of methyl tert-butyl ether/n-heptane is 3:1, or the volume ratio of tetrahydrofuran/n-heptane is 1:2.

Preferably, when the solvent is selected from ethanol or isopropyl alcohol, after heating to dissolve, water is added to mix and then rapidly cooled to obtain crystal I.

Preferably, the solvent is selected from ethanol/water, acetone/water, isopropyl alcohol/water, isopropyl alcohol/n-heptane, dichloromethane/n-heptane, methyl tert-butyl ether/dichloromethane, methane When using methyl tert-butyl ether/cyclohexane, methyl tert-butyl ether/n-heptane or tetrahydrofuran/n-heptane, after heating and dissolving, directly cool quickly to obtain crystal Ⅰ.

The second object of the present invention is to provide a crystalline form II of the compound of formula (I). The 2θ of the X-ray powder diffraction pattern of the crystalline form II has diffraction peaks at 3.32, 13.88, 15.52, 21.68 and 23.12, wherein the 2θ value error range is ± 0.2.

In one of the specific embodiments, the 2θ of the X-ray powder diffraction pattern of Form II has diffraction peaks at 3.32, 6.80, 10.30, 13.88, 15.52, 21.68, 23.12, and 24.62, and the 2θ value error range is ±0.2. The X-ray powder diffraction pattern of Form II is shown in Figure 2.

The present invention also provides a method for preparing crystal form II of the compound of formula (I), which is obtained by dissolving the compound of formula (I) in a solvent and crystallizing it by cooling;

Wherein, the solvent is selected from acetone, acetonitrile, methyl tert-butyl ether, isopropyl acetate, butyl acetate/n-heptane, dichloromethane/acetonitrile, acetone/acetonitrile, acetone/n-heptane, acetone/tetrahydrofuran , acetone/isopropyl acetate, acetone/ethyl acetate, acetone/methylene chloride, acetone/methyl tert-butyl ether, methyl tert-butyl ether/ethyl acetate, methyl tert-butyl ether/methyl ring Hexane, toluene/n-heptane, methyl tert-butyl ether/acetonitrile, or methyl tert-butyl ether/tetrahydrofuran.

Preferably, when the solvent is a mixture of two solvents, the volume ratio of butyl acetate/n-heptane is 3:1, the volume ratio of methylene chloride/acetonitrile is 1:3, and the volume ratio of acetone/acetonitrile is 3. :1. The volume ratio of acetone/n-heptane is 3:1, the volume ratio of acetone/tetrahydrofuran is 10:1, the volume ratio of acetone/isopropyl acetate is 5:1, and the volume ratio of acetone/ethyl acetate is 5:1, the volume ratio of acetone/methylene chloride is 10:1, the volume ratio of acetone/methyl tert-butyl ether is 3:1, the volume ratio of methyl tert-butyl ether/ethyl acetate is 5:1 , the volume ratio of methyl tert-butyl ether/methylcyclohexane is 1:2, the volume ratio of toluene/n-heptane is 3:1, and the volume ratio of methyl tert-butyl ether/acetonitrile is 5:1, Or the volume ratio of methyl tert-butyl ether/tetrahydrofuran is 5:1.

The third object of the present invention is to provide crystal form III of the compound of formula (I). The X-ray powder diffraction pattern of crystal form III has diffraction peaks at 3.60, 11.54, 19.62, 22.12, 23.04, and 25.30, and the 2θ value error range is is ±0.2. The X-ray powder diffraction pattern of Form III is shown in Figure 3.

The present invention also provides a method for preparing crystal form III of the compound of formula (I), which is obtained by crystallizing the compound of formula (I) through anti-solvent crystallization; wherein the good solvent is selected from n-butanol, ethyl acetate or sec-butanol, and the poor solvent is selected from Methylcyclohexane or n-heptane;

Or the compound of formula (I) is dissolved in a solvent and evaporated to crystallize at room temperature. The solvent used is selected from chloroform/acetone, tetrahydrofuran/dichloromethane or isopropyl ether/dichloromethane.

The fourth object of the present invention is to provide a crystalline form IV of the compound of formula (I). The 2θ of the X-ray powder diffraction pattern of the crystalline form IV has diffraction peaks at 3.60, 7.18, 10.74, 14.32, 22.10, and 25.18, and the 2θ value error range is is ±0.2. The X-ray powder diffraction pattern of Form IV is shown in Figure 4.

The present invention also provides a method for preparing crystal form IV of the compound of formula (I), which is obtained by crystallizing the compound of formula (I) through anti-solvent crystallization; wherein the good solvent is selected from isopropanol or n-propanol, and the poor solvent is selected from water;

Or, the compound of formula (I) is dissolved in dioxane/water and crystallized by cooling.

The fifth object of the present invention is to provide a composition comprising crystal form I, crystal form II, crystal form III or crystal form IV of the aforementioned compound of formula (I), and pharmaceutically acceptable carriers and/or excipients.

The sixth object of the present invention is to provide crystal form I, crystal form II, crystal form III or crystal form IV of the aforementioned compound of formula (I), and the use of the aforementioned composition in preparing drugs for preventing and/or treating neurodegenerative diseases. .

Preferably, the drug is a long-acting drug.

Preferably, the drug is administered subcutaneously, intramuscularly or intravenously.

Preferably, the neurodegenerative disease is Parkinson's disease.

The compound of formula (I) of the present invention has multiple crystal forms. In addition to higher purity, its crystal form compounds also show good stability, especially crystal form I, crystal form II and crystal form III; in addition , its crystalline compound can be released more smoothly after injection, ensuring that the blood drug concentration can be maintained stably at a certain concentration for a long time.

Description of drawings

Figure 1 shows the X-ray powder diffraction pattern of Form I.

Figure 2 shows the X-ray powder diffraction pattern of Form II.

Figure 3 is the X-ray powder diffraction pattern of Form III.

Figure 4 is the X-ray powder diffraction pattern of Form IV.

Detailed ways

The present invention will be further described in detail below with reference to specific examples. The examples are only used to explain the present invention and are not intended to limit the scope of the present invention. The test methods used in the following examples are conventional methods unless otherwise stated; the materials and reagents used, unless otherwise stated, are commercially available reagents and materials.

The compound of formula (I) is a prodrug with long-acting properties that was finally obtained by the inventor by modifying the structure of rasagiline in the early stage. Based on the early research, the inventor further conducted research on its crystal form. researched. The compounds of formula (I) used in the following experiments were all prepared according to the method described in patent CN109422668B.

In order to study the various crystal forms of the compound of formula (I), various crystallization methods have been tried, and many experiments have been carried out on different solvent types and process temperature conditions. The experimental conditions for preparing the relevant crystal forms are as follows. Non-exhaustive forms are listed in the examples.

Testing instruments used in experiments

1.X-ray powder diffraction (XRPD)

Model: Bruker D8Advance Diffractometer

Ray: The copper target wavelength is Kα

Step size: 0.02°2θ

Speed: 0.2s.step ^-1 .

Example 1 Preparation of Crystal Form I

Weigh 1.5g of the compound of formula (Ⅰ), add 14.4mL of isopropyl alcohol, heat to reflux to dissolve, add 3.6mL of water while hot, stir, quickly cool to 5°C, filter, and dry the solid under vacuum to obtain 1.4g of product. After testing , its X-ray powder diffraction pattern is shown in Figure 1, which is called crystal form I.

Example 2 Preparation of Crystal Form I

Weigh 1.5g of the compound of formula (I), add 12.0mL of ethanol, heat to reflux to dissolve, add 4.0mL of water while hot, stir, quickly cool to 5°C, filter, and dry the solid in vacuum to obtain 1.3g of product, which is powdered by X-ray Diffraction detection showed that it was crystal form I.

Example 3 Preparation of Crystal Form I

Weigh 0.8g of the compound of formula (Ⅰ), add 7.5mL of isopropanol and 2.5mL of n-heptane, heat to reflux to dissolve, stir, quickly cool to 5°C, filter, and dry the solid in vacuum to obtain 0.73g of product, which is powdered by X-ray Diffraction detection showed that it was crystal form I.

Example 4 Preparation of Crystal Form I

Weigh 0.8g of the compound of formula (I), add 2.5mL of dichloromethane and 7.5mL of n-heptane, heat to reflux to dissolve, stir, quickly cool to 5°C, filter, and dry the solid in vacuum to obtain 0.72g of product. Powder diffraction detection showed that it was crystal form I.

The products of Examples 1-4 have been tested and their X-ray powder diffraction patterns are basically the same, with minimal differences within the error range. The patterns are shown in Figure 1, designated as crystalline form I, and the 2θ of the pattern is at 3.72 , 7.32, 10.92, 12.06, 14.52, 21.54, 23.10, 24.72, 25.48, 26.36 have diffraction peaks, in which the 2θ value error range is ±0.2.

Example 5 Preparation of Crystal Form II

Weigh 0.8g of the compound of formula (I), add 8.0mL of methyl tert-butyl ether and 1.6mL of ethyl acetate, heat to reflux to dissolve, stir, slowly cool to 5°C, filter, and dry the solid in vacuum to obtain 0.70g of product. After testing, its X-ray powder diffraction pattern is shown in Figure 2, which is called crystal form II.

Example 6 Preparation of Form II

Weigh 0.8g of the compound of formula (I), add 9.6 mL of acetonitrile, heat to reflux to dissolve, stir, slowly cool to 5°C, filter, and dry the solid in vacuum to obtain 0.75g of product. After X-ray powder diffraction detection, it is crystal form II. .

Example 7 Preparation of Form II

Weigh 0.8g of the compound of formula (I), add 7.2mL toluene and 2.4mL n-heptane, heat to reflux to dissolve, stir, slowly cool to 5°C, filter, and dry the solid in vacuum to obtain 0.73g of product, which is analyzed by X-ray powder diffraction It was detected as crystal form II.

Example 8 Preparation of Form II

Weigh 0.8g of the compound of formula (I), add 9.6mL of isopropyl acetate, heat to reflux to dissolve, stir, cool to 5°C, filter, and dry the solid in vacuum to obtain 0.72g of product. After X-ray powder diffraction detection, it is crystalline Type II.

Example 9 Preparation of Form II

Weigh 0.8g of the compound of formula (I), add 5.4mL of acetone and 1.8mL of acetonitrile, heat to reflux to dissolve, stir, cool to 5°C, filter, and dry the solid in vacuum to obtain 0.74g of product. After X-ray powder diffraction detection, it is Crystal form II.

The products of Examples 5-9 have been tested and their X-ray powder diffraction patterns are basically the same, with minimal differences within the error range. The patterns are shown in Figure 2, designated as crystal form II, and the 2θ of the pattern is at 3.32 , there are diffraction peaks at 6.80, 10.30, 13.88, 15.52, 21.68, 23.12, and 24.62, and the 2θ value error range is ±0.2.

Example 10 Preparation of Form III

Weigh 15 mg of the compound of formula (I), add 2.0 mL of n-butanol and heat to dissolve, cool to room temperature, slowly add 3.0 mL of methylcyclohexane while stirring, continue to cool to 4°C, and centrifuge to obtain a solid. The solid is detected. The X-ray powder diffraction pattern is shown in Figure 3 and is called crystal form III.

Example 11 Preparation of Form III

Weigh 15 mg of the compound of formula (I), add 0.6 mL of ethyl acetate, stir to dissolve, and spin to dryness under reduced pressure at room temperature. The product is detected by X-ray powder diffraction and is crystalline form III.

The products of Examples 10 and 11 have been tested and their X-ray powder diffraction patterns are basically the same, with minimal differences within the error range. The patterns are shown in Figure 3, designated as crystal form III, and the 2θ of the pattern is at 3.60 , there are diffraction peaks at 11.54, 19.62, 22.12, 23.04, and 25.30, and the 2θ value error range is ±0.2.

Example 12 Preparation of Form IV

Weigh 15 mg of the compound of formula (I), add 0.5 mL of dioxane and 0.5 mL of water, heat to dissolve, cool down and stir to crystallize. The product is tested and its X-ray powder diffraction pattern is shown in Figure 3, which is called the crystal form. Ⅳ.

Example 13 Preparation of Form IV

Weigh 15 mg of the compound of formula (Ⅰ), add 2.0 mL of isopropyl alcohol and stir to dissolve. Add 3.0 mL of water at room temperature. After the product is centrifuged, it is detected by X-ray powder diffraction and is crystal form IV.

The products of Examples 12 and 13 have been tested and their X-ray powder diffraction patterns are basically the same, with minimal differences within the error range. The patterns are shown in Figure 4, designated as crystalline form IV, and the 2θ of the pattern is at 3.60 , there are diffraction peaks at 7.18, 10.74, 14.32, 22.10, and 25.18, and the 2θ value error range is ±0.2.

Example 14 Stability investigation of multiple crystal forms

1. Competition test of different crystal forms

Take equal amounts of crystal forms I, II, III and IV, mix them well, add them to methanol or pure water system respectively, stir at room temperature for 3 days, and take samples for XRPD detection.

The test results show that: after the mixed crystals are stirred in methanol for three days, they all transform into crystal form II; after the mixed crystals are stirred in pure water for three days, they transform into a mixed crystal form of crystal forms I and II.

2. Stability in dry state

Take appropriate amounts of crystal forms I, II, III and IV and divide them into several packages. The inner packaging material is low-density polyethylene and the outer material is aluminum-plastic composite film. Place it in a constant temperature stable box at 25°C and take samples for testing according to the set time nodes. The stability of the crystal form was investigated, and the test results are shown in Table 1.

The results show that crystalline forms I and II have good stability within the 12-month node, and crystalline form III has good stability at the 12-month node. At 3 months, some parts were converted to crystal form I, and crystal form IV was converted to crystal form I during the 3-month test.

Table 1 Stability investigation results of the dry state of the crystalline form of the present invention

3. Stability of crystal forms in preparation samples

Take an appropriate amount of crystal form I and II samples respectively and place them in an agate ball mill jar. Add 0.3% Tween 80, 0.3% CMC-Na and water. Add zirconia beads (0.6~0.8mm) and ball-mill to form a suspension. Distribute Put it in a 7mL vial, add a stopper, cap it and place it in a constant temperature stabilization box at 25°C. Take samples for testing according to the set time points to examine the stability of the crystal form. The test results are shown in Table 2. The results show that crystalline forms I and II have good stability within the 12-month node.

Table 2 Stability investigation results of the crystal form of the present invention in suspension

Example 15 In vivo pharmacokinetic test of crystalline forms I and II

One ordinary male beagle dog was used in this experiment. They were fasted for 12 hours before administration and had free access to water. Make crystal forms I and II into injection suspensions and inject them intramuscularly at a dosage of 0.47 mg/kg rasagiline (1.72 mg/kg converted into prodrug crystal form) before and after administration. 1h, 2h, 4h, 8h, 12h, 18h, 24h, 48h, 96h, 144h, 192h, 240h, 288h, 360h, collect about 1.0mL of whole blood from the beagle dog through the forelimb vein, place it in a heparinized centrifuge tube, and keep at 4℃ , centrifuge at 6000 rpm for 10 min, separate the plasma, and store at -80°C for testing.

Plasma sample processing: The sample was processed in an ice bath. Take 30 μL of methanol and 20 μL of internal standard (apigenin 2 μg/mL, dissolved in 50% methanol). Add 300 μL of plasma sample and vortex to mix. Add 4 mL of ethyl acetate and vortex to mix. Centrifuge at 9000g for 2 minutes, evaporate the organic phase to dryness under vacuum, redissolve in 150 μL of methanol, and inject 30 μL of sample for analysis.

Data analysis: Samples are detected by LC-MS/MS. Based on the blood concentration data of the drug, DAS 2.0 software is used to calculate pharmacokinetic parameters, providing AUC (0-t), AUC (0-∞), MRT (0 -t), MRT(0-∞), Cmax, Tmax, and t1/2 and other parameters.

It can be seen from the experimental results that the crystalline compound of the present invention can be slowly, continuously and stably released and converted into rasagiline in the body, thereby exerting a long-acting effect, and can well meet the requirements of long-acting injection suspension.

Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and do not limit the protection scope of the present invention. For those of ordinary skill in the art, based on the above descriptions and ideas, they can also make There are other variations or modifications in different forms, and it is not necessary and impossible to exhaustively enumerate all implementations here. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention shall be included in the protection scope of the claims of the present invention.

Claims (19)

A crystal form I of a compound of formula (I), characterized in that the structure of the compound of formula (I) is as follows:
The 2θ of the X-ray powder diffraction pattern of Form I has diffraction peaks at 3.72, 7.32, 10.92, 21.54 and 23.10, and the 2θ value error range is ±0.2. The crystal form I of the compound of formula (I) according to claim 1, characterized in that the X-ray powder diffraction pattern 2θ of the crystal form I is at 3.72, 7.32, 10.92, 12.06, 14.52, 21.54, 23.10, 24.72, 25.48, 26.36 There are diffraction peaks, and the 2θ value error range is ±0.2. The crystal form I of the compound of formula (I) according to claim 1 or 2, characterized in that the X-ray powder diffraction pattern of the crystal form I is as shown in Figure 1. The preparation method of crystal form I of the compound of formula (I) according to any one of claims 1 to 3, characterized in that the compound of formula (I) is added to a solvent, heated to dissolve, and then rapidly cooled or mixed with water and then cooled rapidly , obtained by crystallization; Wherein, the solvent is selected from ethanol, ethanol/water, acetone/water, isopropyl alcohol, isopropyl alcohol/water, isopropyl alcohol/n-heptane, dichloromethane/n-heptane, methyl tert-butyl ether/ Dichloromethane, methyl tert-butyl ether/cyclohexane, methyl tert-butyl ether/n-heptane or tetrahydrofuran/n-heptane. A crystal form II of a compound of formula (I) is characterized in that the 2θ of the X-ray powder diffraction pattern of the crystal form II has diffraction peaks at 3.32, 13.88, 15.52, 21.68 and 23.12, in which the 2θ value error range is ±0.2. The crystal form II of the compound of formula (I) according to claim 5, characterized in that the X-ray powder diffraction pattern 2θ of the crystal form II has diffraction peaks at 3.32, 6.80, 10.30, 13.88, 15.52, 21.68, 23.12, 24.62, The 2θ value error range is ±0.2. The crystal form II of the compound of formula (I) according to claim 5 or 6, characterized in that the X-ray powder diffraction pattern of the crystal form I is as shown in Figure 2. The preparation method of crystal form II of the compound of formula (I) according to any one of claims 5 to 7, characterized in that the compound of formula (I) is dissolved in a solvent, heated to dissolve, and cooled to crystallize; Wherein, the solvent is selected from acetone, acetonitrile, methyl tert-butyl ether, isopropyl acetate, butyl acetate/n-heptane, dichloromethane/acetonitrile, acetone/acetonitrile, acetone/n-heptane, acetone/tetrahydrofuran , acetone/isopropyl acetate, acetone/ethyl acetate Ethyl acid ester, acetone/methylene chloride, acetone/methyl tert-butyl ether, methyl tert-butyl ether/ethyl acetate, methyl tert-butyl ether/methylcyclohexane, toluene/n-heptane, methane Methyl tert-butyl ether/acetonitrile, or methyl tert-butyl ether/tetrahydrofuran. A crystal form III of the compound of formula (I), characterized in that the 2θ of the X-ray powder diffraction pattern of the crystal form III has diffraction peaks at 3.60, 11.54, 19.62, 22.12, 23.04, and 25.30, wherein the 2θ value error range is ± 0.2. The crystal form III of the compound of formula (I) according to claim 9, characterized in that the X-ray powder diffraction pattern of the crystal form III is as shown in Figure 3. The preparation method of crystal form III of the compound of formula (I) according to claim 9 or 10, characterized in that the compound of formula (I) is obtained by anti-solvent crystallization; wherein the benign solvent is selected from n-butanol, ethyl acetate or secondary Butanol, the poor solvent is selected from methylcyclohexane or n-heptane; Or the compound of formula (I) is dissolved in a solvent, and is evaporated and crystallized at room temperature. The solvent used is selected from chloroform/acetone, tetrahydrofuran/dichloromethane, or isopropyl ether/dichloromethane. A crystal form IV of a compound of formula (I), characterized in that the 2θ of the X-ray powder diffraction pattern of the crystal form IV has diffraction peaks at 3.60, 7.18, 10.74, 14.32, 22.10, and 25.18, and the 2θ value error range is ± 0.2. The crystal form IV of the compound of formula (I) according to claim 12, wherein the X-ray powder diffraction pattern of the crystal form IV is as shown in Figure 4. The preparation method of crystal form IV of the compound of formula (I) according to claim 12 or 13, characterized in that the compound of formula (I) is obtained by antisolvent crystallization; wherein the good solvent is selected from isopropanol or n-propanol, and the bad solvent is The solvent is selected from water; Or, the compound of formula (I) is dissolved in dioxane/water and crystallized by cooling. A composition, characterized in that it contains the crystalline form I, crystalline form II, crystalline form III or Crystalline Form IV, and pharmaceutically acceptable carriers and/or excipients. The crystalline form I, the crystalline form II, the crystalline form III or the crystalline form IV of the formula (I) compound in any one of claims 1-3, 5-7, 9, 10, 12 or 13, and claim 15 Use of the composition in the preparation of a medicament for the prevention and or treatment of neurodegenerative diseases. The use according to claim 16, characterized in that the drug is a long-acting drug. The use according to claim 16, characterized in that the drug is administered by subcutaneous, intramuscular or intravenous injection. The use according to claim 16, characterized in that the neurodegenerative disease is Parkinson's disease.