WO2018059531A1 - Crystal form of adenosine a2a receptor antagonist drug and preparation method and use thereof - Google Patents

Abstract

A crystal form of an adenosine A_2A receptor antagonist drug, tozadenant, and a preparation method and use thereof. The prepared tozadenant has crystal form CS1, can be used to prepare an adenosine A_2A receptor antagonist drug formulation, provides a new option for the preparation of a drug formulation containing tozadenant, and has a crucial value for drug development.

Description

Crystal form of adenosine A2A receptor antagonist drug, preparation method and use thereof Technical field

The invention relates to the field of pharmaceutical crystal technology. Specifically, it relates to a crystalline form of an adenosine A _2A receptor antagonist drug, a preparation method thereof and use thereof.

Background technique

Parkinson's disease (PD) is a chronic central nervous system degenerative disease that primarily affects the motor nervous system. Symptoms of Parkinson's disease usually appear slowly over time. The most obvious symptoms in the early stages are tremors, limb stiffness, motor dysfunction, and gait abnormalities. There may also be cognitive and behavioral problems; dementia is quite common in patients with severe conditions. Major depressive disorder and anxiety disorders can occur in more than one-third of cases. Other symptoms that may accompany include sensory, sleep, and emotional problems.

In 2015, approximately 6.2 million people worldwide suffered from Parkinson's disease and caused 117,000 deaths. Parkinson's disease usually occurs in elderly people over the age of 60, and about 1% of the elderly suffer from the disease; men are more likely to get Parkinson's disease than women. Parkinson's disease usually survives 7-14 years after diagnosis.

Levodopa is currently the most effective drug for controlling motor symptoms in patients with Parkinson's disease. However, most patients will eventually face the "off-term" problem, that is, the drug effect has subsided until the next time. Tozadenant, also known as 4-hydroxy-4-methyl-piperidine-1-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide, is a high Affinity, highly selective adenosine A _2A receptor antagonists act on brain regions affected by Parkinson's disease. Unlike levodopa, Tozadenant is not used to increase dopamine levels, but to help dopamine continue to work, thereby reducing the "department" time of patients with Parkinson's disease, and can be used as an adjuvant therapy with levodopa in the treatment of Parkinson's disease.

In addition, Tozadenant can also be used to treat or prevent other diseases associated with adenosine A _2A receptors, including Alzheimer's disease, Huntington's disease, attention deficit hyperactivity disorder, neuroprotection, schizophrenia, anxiety, depression. Wait. Its structural formula is as shown in formula (I):

The stability of the drug is an important aspect in the quality evaluation of the drug. It is of great significance to reduce the drug dissolution rate and bio-profitability due to the change of the crystal form, which is effective for ensuring the efficacy and safety of the drug and preventing the occurrence of adverse drug reactions. The thermodynamically more stable crystal form is more controllable during the crystallization process, and it is not easy to appear mixed crystals; it is not easy to be converted into other crystal forms during the preparation process and storage process, thereby ensuring consistent and controllable sample quality and ensuring the preparation of the product. The dissolution profile does not change as the storage time changes.

Solid chemical drugs have different crystal forms, which can cause differences in solubility, stability, moisture permeability, fluidity and compressibility, thus affecting the safety and effectiveness of pharmaceutical products containing the compound (see K.Knapman, Modern Drug Discovery, 3, 53-54, 57, 2000.), resulting in differences in clinical efficacy.

For 4-hydroxy-4-methyl-piperidine-1-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide, patent document WO2005116026A1 (which is incorporated by reference) The structure of Tozadenant and its preparation method are disclosed in the method of the present application. Experimentally, the sample obtained by the method is unstable and is not suitable for storage and production of the drug. Therefore, there is still a need in the art to systematically develop the crystal form of Tozadenant to find a crystal form which is stable and suitable for industrial production. After extensive experimental research, the applicant of the present invention discovered that the crystalline form CS1 of Tozadenant has good stability, simple preparation and repeatability, good solubility and low wettability, and meets medicinal requirements, including Tozadenant. The preparation of pharmaceutical preparations provides new and better choices and is of great importance for drug development.

Summary of the invention

The main object of the present invention is to provide a crystalline form of Tozadenant, a process for its preparation and its use.

According to an object of the present invention, the present invention provides a crystalline form CS1 of Tozadenant (hereinafter referred to as "crystal form" CS1"). The crystal form CS1 is an anhydride.

Using Cu-Kα radiation, the X-ray powder diffraction of the crystal form CS1 has characteristic peaks at diffraction angle 2θ values of 8.6°±0.2°, 9.4°±0.2°, and 17.4°±0.2°.

Further, the X-ray powder diffraction of the crystalline form CS1 has one or more of diffraction angle 2θ values of 15.0°±0.2°, 22.6°±0.2°, 16.4°±0.2°, and 19.9°±0.2°. Characteristic peaks. Preferably, the X-ray powder diffraction of the crystal form CS1 has characteristic peaks in the diffraction angle 2θ values of 15.0°±0.2°, 22.6°±0.2°, 16.4°±0.2°, and 19.9°±0.2°.

Further, the X-ray powder diffraction of the crystal form CS1 has a characteristic peak at a diffraction angle 2θ value of 11.7°±0.2°, 12.4°±0.2°, 19.1°±0.2° or two or three places. Preferably, the X-ray powder diffraction of the crystal form CS1 has characteristic peaks in the diffraction angle 2θ values of 11.7°±0.2°, 12.4°±0.2°, and 19.1°±0.2°.

In a preferred embodiment, the X-ray powder diffraction of the crystalline form CS1 has a diffraction angle 2θ of 8.6°±0.2°, 9.4°±0.2°, 17.4°±0.2°, 15.0°±0.2°, 22.6°. There are characteristic peaks at ±0.2°, 16.4°±0.2°, 19.9°±0.2°, 11.7°±0.2°, 12.4°±0.2°, and 19.1°±0.2°.

Without limitation, in one embodiment of the invention, the X-ray powder diffraction pattern of Form CS1 is shown in FIG.

Without limitation, in a specific embodiment of the present invention, the crystal form CS1 provided by the present invention has a mass loss of 1.0% when heated to 150 ° C when subjected to thermogravimetric analysis, and the TGA thereof is as shown in FIG. 2 . .

According to the object of the present invention, the present invention also provides a process for the preparation of the crystalline form CS1 of Tozadenant, which is characterized in that the Tozadenant solid is dissolved in a solvent of methanol or acetone or 1,4-dioxane or chloroform. It was volatilized at a temperature of 4 to 70 ° C to obtain a white solid.

among them:

Preferably, the temperature is from 25 to 50 °C.

The "volatilization" is accomplished by conventional methods in the art, such as fast swinging, slow swinging, and the like. The fast swing means that the compound is dissolved in a specific system, and after being filtered, the open mouth is rapidly volatilized at a specific temperature. The slow swing means that the compound is dissolved in a specific system, and after filtration, a sealing film is applied to the mouth of the container, and a small hole is marked on the needle by the needle to slowly evaporate.

In the present invention, "crystal" or "crystal form" refers to the characterization by the X-ray diffraction pattern shown. Those skilled in the art will appreciate that the physicochemical properties discussed herein can be characterized, with experimental error depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample. In particular, those skilled in the art It is known that the X-ray diffraction pattern usually varies with the conditions of the instrument. It is particularly important to note that the relative intensities of the X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor. In addition, the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ±0.2° is usually allowed. In addition, due to experimental factors such as sample height, the overall offset of the peak angle is caused, and a certain offset is usually allowed. Thus, it will be understood by those skilled in the art that the X-ray diffraction pattern of one crystal form in the present invention need not be identical to the X-ray diffraction pattern in the examples referred to herein. Any crystal form having a map identical or similar to the characteristic peaks in these maps is within the scope of the present invention. One skilled in the art will be able to compare the maps listed herein with a map of an unknown crystal form to verify whether the two sets of maps reflect the same or different crystal forms.

In some embodiments, the novel crystalline form CS1 of the present invention is pure, unitary, and substantially free of any other crystalline form. In the present invention, "substantially free" when used to refer to a new crystalline form means that the crystalline form contains less than 20% by weight of other crystalline forms, especially less than 10% by weight of other crystalline forms, more Other crystal forms of 5% by weight, more preferably less than 1% by weight of other crystal forms.

It should be noted that the numerical values and numerical ranges recited in the present invention are not to be construed as narrowly construed as a numerical value or a numerical range per se. It will be understood by those skilled in the art that they may vary depending on the specific technical environment without departing from the spirit of the invention. On the basis of the principle, there are fluctuations around specific numerical values. In the present invention, such a floating range which can be foreseen by those skilled in the art is often expressed by the term "about".

Furthermore, the invention provides a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a crystalline form CS1 of the invention, together with at least one pharmaceutically acceptable carrier, diluent or excipient.

Further, the present invention provides the use of the crystalline form CS1 of Tozadenant in the preparation of a pharmaceutical preparation of an adenosine A _2A receptor antagonist.

Further, the present invention provides the use of Tozadenant's crystalline form CS1 in the preparation of a pharmaceutical preparation for treating Parkinson's disease, Alzheimer's disease, Huntington's disease, attention deficit hyperactivity disorder, neuroprotection, schizophrenia, anxiety, depression .

The beneficial effects of the invention are:

At present, there is no patent or literature report on the available crystal forms of Tozadenant, and the inventors of the present invention have solved this problem through research and found a crystal form suitable for development.

The stability of the crystal form plays a crucial role in judging whether a crystal form has development value. The crystal form CS1 sample of the invention is placed in a constant temperature and humidity chamber of 25 ° C / 60% RH and 40 ° C / 75% RH for one year, and is not changed for one week at 80 ° C, and has good stability. And the preparation method of the crystalline form CS1 of the invention is simple, the particle size is uniform, the purity of the crystal form is high, the wettability is low, in SGF (simulated artificial gastric juice), FeSSIF (artificial intestinal juice in fed state), FaSSIF (artificial intestinal juice in fasting state) ) It has good solubility in solution and is suitable for drug development.

DRAWINGS

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is an XRPD pattern of a crystal form CS1 obtained according to Example 1 of the present invention.

2 is a TGA diagram of a crystalline form CS1 obtained according to Example 1 of the present invention.

Figure 3 is an XRPD overlay of the crystalline form CS1 obtained in Example 1 according to Example 1 of the present invention placed in a constant temperature and humidity chamber at 25 ° C / 60% RH, 40 ° C / 75% RH and placed in an oven at 80 ° C for a period of time (from Top to bottom is the X-ray pattern of Tozadenant crystal form CS1, placed at 25 ° C / 60% RH for one year, 40 ° C / 75% RH for one year and 80 ° C for one week.

4 is a DVS diagram of a crystal form CS1 obtained according to Example 1 of the present invention.

Fig. 5 is a PSD diagram of a crystal form CS1 in the fifth embodiment of the present invention.

Fig. 6 is a PLM diagram of a crystal form CS1 in the fifth embodiment of the present invention.

detailed description

The invention is further defined by the following examples which describe in detail the preparation and use of the crystalline forms of the invention. It will be apparent to those skilled in the art that many changes in the materials and methods can be practiced without departing from the scope of the invention.

The abbreviations used in the present invention are explained as follows:

XRPD: X-ray powder diffraction

TGA: Thermogravimetric Analysis

DVS: Dynamic moisture adsorption

PSD: particle size distribution

PLM: polarized light microscope

HPLC: high performance liquid chromatography

RH: relative humidity

Instruments and methods used to collect data:

The X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer. The method parameters of the X-ray powder diffraction described in the present invention are as follows:

X-ray reflection parameters: Cu, Kα

Kα1

1.540598; Kα2

1.544426

Kα2/Kα1 intensity ratio: 0.50

Voltage: 45 volts (kV)

Current: 40 milliamps (mA)

Scan range: from 3.0 to 40.0 degrees

Thermogravimetric analysis (TGA) data was taken from the TA Instruments Q500 TGA, the instrument control software was Thermal Advantage, and the analysis software was Universal Analysis.

The particle size distribution results described in the present invention were collected on a Microtrac S3500 laser particle size analyzer. The Microtrac S3500 is equipped with an SDC (Sample Delivery Controller) injection system. This test uses a wet method and the test dispersion medium is Isopar G. The method parameters of the laser particle size analyzer are as follows:

*: The flow rate is 60% of 60% of 65 ml/sec.

The following examples were operated at room temperature unless otherwise stated.

Tozadenant used in the following examples was prepared according to the method described in WO2005116026 A1.

Example 1

Preparation of Tozadenant Form CS1 by Volatilization:

A certain amount of Tozadenant solid was weighed, dissolved in a certain volume of solvent in Table 1, filtered and slowly/rapidly volatilized at a certain temperature to obtain a white solid crystal.

The solids obtained in the examples in Table 1 were respectively labeled as samples 1-a to 1-l, and after testing, samples 1-a to 1-l were both tested. For the Tozadenant crystal form CS1. Sample 1-a was selected for test characterization, and its XRPD data is shown in Figure 1, Table 2. When subjected to thermogravimetric analysis, it had a mass loss of 1.0% when heated to 150 ° C, and its TGA is shown in FIG. 2 .

Table 1

Table 2

Diffraction angle 2θ	d value	strength%
7.15	12.36	1.28
8.64	10.23	100.00
9.35	9.46	66.71
10.25	8.63	0.87
11.68	7.57	14.38
12.40	7.14	6.50
14.06	6.30	0.49
14.66	6.04	2.79
14.93	5.93	25.74
16.38	5.41	18.64
16.88	5.25	3.14
17.40	5.10	30.39
18.71	4.74	3.12
19.09	4.65	4.72

19.92	4.46	3.88
20.50	4.33	2.32
20.96	4.24	1.23
21.28	4.17	1.46
21.77	4.08	0.99
22.60	3.93	25.36
23.17	3.84	1.82
23.52	3.78	3.77
24.58	3.62	1.02
25.02	3.56	1.56
26.92	3.31	0.91
27.17	3.28	1.19
28.21	3.16	2.90
28.84	3.10	0.94
29.82	3.00	1.82
30.27	2.95	0.95
31.47	2.84	3.33
31.86	2.81	1.27
32.21	2.78	2.74
33.60	2.67	0.27
34.38	2.61	1.05
34.93	2.57	0.41
35.80	2.51	1.29
36.54	2.46	0.48
37.09	2.42	1.37
38.05	2.36	0.31

Example 2

Long-term and high-temperature stability studies of Tozadenant crystal form CS1:

Samples of Tozadenant crystal form CS1 were placed in a constant temperature and humidity chamber at 25 ° C / 60% RH, 40 ° C / 75% RH and placed in an oven at 80 ° C for a period of time, and then XRPD and purity were sampled. The results are shown in Figure 3 (from above) The next step is to place the Tozadenant crystal form CS1 before placing it at 25 ° C / 60% RH for one year, 40 ° C / 75% RH for one year and 80 ° C for one week of XRPD). The results show that Tozadenant crystal form CS1 is placed at 25 ° C / 60% RH, 40 ° C / 75% RH and 80 ° C for a period of time The crystal form and its purity were unchanged, and the purity was above 98%, indicating that the Tozadenant crystal form CS1 has good stability.

The crystalline form CS1 has good stability and can reduce the drug dissolution rate and bioavailability change of the drug due to the crystal form change, which is of great significance for ensuring the efficacy and safety of the drug and preventing the occurrence of adverse drug reactions.

Example 3

Solubility study of Tozadenant crystal form CS1:

The prepared Tozadenant crystal form CS1 sample was prepared into a saturated solution with SGF (simulated artificial gastric juice), pH 5.0 FeSSIF (artificial intestinal juice in fed state), pH 6.5 FaSSIF (artificial intestinal juice in fasting state), respectively, in 1 hour. The content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC) after 4 hours and 24 hours. The solubility data of the Tozadenant crystal form CS1 of the present invention is shown in Table 3.

table 3

The results show that the Tozadenant crystal form CS1 provided by the present invention has good solubility in SGF, FeSSIF and FaSSIF, especially in FeSSIF, which can reach 68 μg/mL. The high solubility of the crystalline form CS1 directly affects the absorption of the drug in the human body, and is of great significance for improving the efficacy and safety of the drug and reducing the drug load.

Example 4

Humidity test of crystal form CS1:

Approximately 10 mg of Tozadenant Form CS1 of the present invention was tested for its wettability using a dynamic moisture adsorption (DVS) instrument. The experimental results are shown in Table 4. The DVS pattern of the wettability test of Tozadenant crystal form CS1 is shown in Fig. 4.

Table 4

The results show that the Tozadenant crystal form CS1 of the present invention has a weight gain of 0.43% after being equilibrated at 80% humidity, and is slightly hygroscopic according to the definition of the wettability weight gain. The low moisture absorption of the crystalline form CS1 is beneficial to the long-term storage of the drug, and can greatly reduce the material storage and quality control cost, and has strong economic value.

Defining the characteristics of wettability and the definition of wetting weight gain (Chinese Pharmacopoeia 2015 General Principles 9103 Guidelines for Drug Wetness Test, Experimental Conditions: 25 °C ± 1 °C, 80% Relative Humidity):

Deliquescence: absorb enough water to form a liquid

Very hygroscopic: the wetting weight gain is not less than 15%

Humidity: Wet weight gain is less than 15% but not less than 2%

Slightly wettability: wetting gain is less than 2% but not less than 0.2%

No or almost no wettability: wetting gain is less than 0.2%

Example 5

Particle size distribution and morphology study of crystalline form CS1:

The crystal form CS1 of the present invention was tested for particle size distribution, and the results are shown in Table 5.

table 5

Crystal form	MV (μm)	D10 (μm)	D50 (μm)	D90 (μm)
CS1	33.64	10.04	21.37	60.31

The abbreviations used in the present invention are explained as follows:

MV: average particle size by volume

D10: indicates the particle size distribution (volume distribution) accounts for 10% of the particle size

D50: indicates the particle diameter corresponding to the particle size distribution (volume distribution), which is also called the median diameter.

D90: indicates the particle size distribution (volume distribution) accounts for 90% of the particle size

The PSD diagram and the PLM diagram of the crystal form CS1 of the present invention are shown in Figs. 5 and 6, respectively. The PSD diagram and Table 5 indicate that the volume average particle diameter of the crystal form CS1 is 33.64 μm, and the particle size distribution is narrow, showing almost a normal distribution. The particle size distribution is uniform. It can be seen from the PLM diagram that the crystal form CS1 is granular and has good dispersibility.

The crystal form CS1 has a small particle size and uniform distribution, and the smaller particle size can increase the specific surface area of the drug, increase the dissolution rate of the drug, facilitate drug absorption, thereby improving bioavailability, and is suitable for drug development.

The above embodiments are merely illustrative of the technical concept and the features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the present invention and to implement the present invention, and the scope of the present invention is not limited thereto. Equivalent variations or modifications made in accordance with the spirit of the invention are intended to be included within the scope of the invention.

Claims (9)

1. A crystal form CS1 of Tozadenant characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values of 8.6 ° ± 0.2 °, 9.4 ° ± 0.2 °, and 17.4 ° ± 0.2 °.
2. The crystal form CS1 according to claim 1, wherein the X-ray powder diffraction pattern has a 2θ value of 15.0 ° ± 0.2 °, 22.6 ° ± 0.2 °, 16.4 ° ± 0.2 °, and 19.9 ° ± 0.2 °. One or more of them have characteristic peaks.
3. The crystal form CS1 according to claim 1, further characterized in that the X-ray powder diffraction pattern is at one or two of 2θ values of 11.7°±0.2°, 12.4°±0.2°, and 19.1°±0.2°. Or three with characteristic peaks.
4. The crystal form CS1 according to claim 1, wherein the crystal form is an anhydrate.
5. A method for preparing a crystalline form CS1 according to claim 1, wherein the preparation method comprises: dissolving a Tozadenant solid in a solvent of methanol or acetone or 1,4-dioxane or chloroform, 4~ It is obtained by volatilization at 70 ° C.
6. The method according to claim 5, wherein the volatilization temperature is 25 to 50 °C.
7. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form CS1 of claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.
8. Use of the crystalline form CS1 as claimed in claim 1 for the manufacture of a pharmaceutical preparation for the preparation of an adenosine A _2A receptor antagonist.
9. The crystalline form CS1 according to claim 1 is produced for the preparation of a pharmaceutical preparation for treating Parkinson's disease, Alzheimer's disease, Huntington's disease, attention deficit hyperactivity disorder, neuroprotection, schizophrenia, anxiety, depression the use of.

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