WO2024140425A1 - Crystal form of aprocitentan, preparation method therefor and use thereof - Google Patents

Abstract

The present invention relates to a novel crystal form of aprocitentan (referred to as "compound I"), a preparation method therefor, a pharmaceutical composition containing the crystal form, and the use of the crystal form in the preparation of dual endothelin receptor antagonist drugs and drugs for treating resistant hypertension.

Description

A kind of aprexitentan crystal form and its preparation method and use Technical Field

The present invention relates to the field of crystal chemistry, and in particular to a crystal form of aprexitentan, a preparation method thereof and a use thereof.

Background technique

Refractory hypertension (RH) is the main cause of heart failure, renal failure, and multiple cardiovascular diseases. When patients take three antihypertensive drugs at the highest tolerated dose, one of which is a diuretic, but still cannot control their blood pressure at the target value, this condition is called refractory hypertension. In other words, patients with refractory hypertension need to take four or more drugs at the same time to control their blood pressure.

Aprocitentan is a dual endothelin receptor antagonist developed by Idorsia Pharmaceuticals for the treatment of diseases related to vasoconstriction, hyperplasia or inflammation caused by increased endothelin levels, such as hypertension, pulmonary hypertension, coronary heart disease, heart failure, renal and myocardial ischemia, renal failure, etc. The results of the study showed that aprocitentan achieved good results in the Phase III clinical trial of refractory hypertension.

The chemical name of Aprexitentan is {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfonamide (hereinafter referred to as "Compound I"), and its structural formula is as follows:

A crystal is a solid in which the molecules of a compound are arranged in a three-dimensional orderly manner in a microscopic structure to form a crystal lattice. Polymorphism refers to the phenomenon that a compound exists in multiple crystal forms. A compound may exist in one or more crystal forms, but its existence and characteristics cannot be specifically predicted. APIs of different crystal forms have different physical and chemical properties, which may lead to different dissolution and absorption of the drug in the body, thereby affecting the clinical efficacy of the drug to a certain extent. In particular, for some poorly soluble oral solid or semi-solid preparations, the crystal form is crucial to the product performance. In addition, the physical and chemical properties of the crystal form are crucial to the production process. Therefore, polymorphism is an important part of drug research and drug quality control.

WO2018154101A1 discloses Compound I crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form J, crystal form K, crystal form L and an amorphous form of Compound I. The specification discloses that crystal form A and/or crystal form C are preferred, and crystal form A is particularly preferred.

CN112679441A discloses crystal forms I-VI of compound I. Among them, crystal form I is the same as crystal form A of WO2018154101A1, crystal form II is the same as crystal form B of WO2018154101A1, and crystal form III is the same as crystal form C of WO2018154101A1. The inventors of the present application have found that crystal forms V and VI are crystal forms of degradation products of compound I.

WO2021088645A1 discloses Compound I crystalline form CSI, which discloses that crystalline form CSI is a more thermodynamically stable crystalline form than WO2018154101A1 crystalline form A.

WO2021237004A1 discloses compound I crystalline forms T9, T10, T12, P1, P2, methanesulfonic acid cocrystal, ethanesulfonic acid cocrystal Crystal form T1 is a methyl acetate solvate, crystal form T10 is an ether solvate, crystal form T12 is an anhydrous form, and crystal forms P1 and P2 are piperazine cocrystals.

The inventors of the present application have devoted a lot of creative work and accidentally discovered a crystalline form of CSVI that is different from all crystalline forms in the prior art. The crystalline form of CSVI has advantages in physical and chemical properties, formulation processing performance and bioavailability, especially high solubility, good stability and low hygroscopicity, which provides a new and better choice for the development of drugs containing compound I and is of great significance.

Summary of the invention

The main purpose of the present invention is to provide a new crystal form of compound I and a preparation method and use thereof.

The present invention provides a new crystal form of Compound I and a preparation method thereof, as well as a pharmaceutical composition comprising the new crystal form.

According to the purpose of the present invention, the present invention provides a crystalline form of Compound I, which is a benzyl alcohol solvate (hereinafter referred to as "crystalline form CSVI").

On the one hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSVI has characteristic peaks at one, two, or three of the diffraction angles 2θ of 18.2°±0.2°, 20.9°±0.2°, and 23.6°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSVI has characteristic peaks at diffraction angles 2θ of 18.2°±0.2°, 20.9°±0.2°, and 23.6°±0.2°.

Further, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSVI has characteristic peaks at one, two, or three of the diffraction angles 2θ of 17.2°±0.2°, 20.5°±0.2°, and 26.5°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSVI has characteristic peaks at diffraction angles 2θ of 17.2°±0.2°, 20.5°±0.2°, and 26.5°±0.2°.

Further, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSVI has characteristic peaks at one, two, or three of the diffraction angles 2θ of 15.0°±0.2°, 18.7°±0.2°, and 30.7°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSVI has characteristic peaks at diffraction angles 2θ of 15.0°±0.2°, 18.7°±0.2°, and 30.7°±0.2°.

On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSVI has characteristic peaks at any one, any two, any three, or four, or five, or six, or seven, or eight, or nine of the diffraction angle 2θ values of 15.0°±0.2°, 17.2°±0.2°, 18.2°±0.2°, 18.7°±0.2°, 20.5°±0.2°, 20.9°±0.2°, 23.6°±0.2°, 24.6°±0.2°, 25.8°±0.2°, 26.5°±0.2°, and 30.7°±0.2°.

Without limitation, using Cu-Kα radiation, the X-ray powder diffraction pattern of Form CSVI is substantially as shown in FIG. 1 .

Without limitation, the TGA graph of the crystalline form CSVI is substantially as shown in FIG. 2 , and when heated to 150° C., it has a mass loss of about 10.1%.

Without limitation, Form CSVI is a benzyl alcohol solvate containing about 0.5 molar equivalents of benzyl alcohol.

According to the purpose of the present invention, the present invention also provides a method for preparing the crystalline form CSVI, which comprises: mixing the solid compound I with benzyl alcohol and stirring to obtain the crystalline form CSVI.

Furthermore, the stirring temperature is preferably -20°C to 10°C, and more preferably 4°C.

According to the purpose of the present invention, the present invention provides the use of the crystalline form CSVI for preparing other crystalline forms or co-crystals of compound I and its salts.

According to the purpose of the present invention, the present invention provides a pharmaceutical composition, which comprises an effective therapeutic amount of crystalline CSVI and a pharmaceutically acceptable excipient.

According to the purpose of the present invention, the present invention provides use of crystalline CSVI in preparing a dual endothelin receptor antagonist drug.

According to the purpose of the present invention, the present invention provides use of crystalline CSVI in preparing a drug for treating refractory hypertension.

The crystalline form CSVI provided by the present invention has the following beneficial effects:

(1) Crystalline CSVI has higher solubility.

Compared with the prior art, the crystalline form CSVI of the present invention has higher solubility, especially in FaSSIF, the solubility is The crystal form CSVI provided by the present invention has higher solubility, which is beneficial to improve the absorption of the drug in the human body and improve the bioavailability; in addition, higher solubility can reduce the dosage of the drug while ensuring the efficacy of the drug, thereby reducing the side effects of the drug and improving the safety of the drug.

(2) Crystalline CSVI has good stability.

Crystal form CSVI has better humidity stability. After experiencing humidity changes from 0% RH to 95% RH to 0% RH, the crystal form of crystal form CSI remains unchanged.

The crystalline CSVI API provided by the present invention has good stability. The crystalline CSVI API was placed under 25°C/60%RH conditions, and the crystal form did not change for 6 months, and the chemical purity was maintained at more than 99.7%. This indicates that the crystalline CSVI API has good stability under long-term conditions. At the same time, the crystalline CSVI API was placed under 40°C/75%RH conditions, and the crystal form did not change for 6 months, and the chemical purity was more than 99.7%, and the purity remained basically unchanged during storage. This indicates that the crystalline CSVI API has good stability under accelerated conditions.

High humidity conditions caused by seasonal differences, climate differences in different regions, and environmental factors can affect the storage, transportation, and production of APIs. Crystalline CSVI has good stability, which helps to avoid the impact of crystal transformation on drug quality during drug storage, transportation, and production, thereby ensuring consistent and controllable quality of APIs and reducing changes in drug quality, bioavailability, and toxic side effects caused by changes in crystal form.

(3) Crystalline CSVI has low hygroscopicity.

The crystalline CSVI provided by the present invention has low hygroscopicity. Test results show that the weight gain of the crystalline CSVI under 80% RH is 0.07%, and it is almost non-hygroscopic. The low hygroscopic crystal form has no strict requirements on the environment, reduces the cost of material production, storage and quality control, and has strong economic value.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is the XRPD diagram of crystalline form CSVI

Figure 2 is the TGA graph of crystalline CSVI

Figure 3 is a comparison of XRPD images of crystalline form CSVI placed under different conditions for a certain period of time (from top to bottom: initial, 25°C/60%RH sealed for 6 months, 25°C/60%RH open for 6 months, 40°C/75%RH sealed for 6 months)

Figure 4 is a comparison of XRPD images of CSVI before and after the 0%RH-95%RH-0%RH change (from top to bottom: before DVS, after DVS)

Detailed ways

The present invention is described in detail with reference to the following examples, which describe in detail the preparation and use of the crystalline forms of the present invention. It will be apparent to those skilled in the art that many changes in both materials and methods may be made without departing from the scope of the present invention.

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

XRPD: X-ray powder diffraction

TGA: Thermogravimetric analysis

DVS: Dynamic Water Sorption

¹ H NMR: liquid nuclear magnetic hydrogen spectrum

HPLC: High Performance Liquid Chromatography

Instruments and methods used to collect data:

The X-ray powder diffraction pattern of the present invention was collected on a Bruker D8 ADVANCE X-ray powder diffractometer. The method parameters of the X-ray powder diffraction are as follows:

X-ray source: Cu, Kα

1.54060; 1.54439

Kα2/Kα1 intensity ratio: 0.50

Voltage: 40 kilovolts (kV)

Current: 40 milliamperes (mA)

Scanning range: from 4.0 to 40.0 degrees

The thermogravimetric analysis (TGA) graph of the present invention is collected on TA Q500. The method parameters of the thermogravimetric analysis (TGA) of the present invention are as follows:

Scan rate: 10℃/min

Protective gas: _N2

The dynamic moisture adsorption (DVS) graph of the present invention is collected on an Intrinsic dynamic moisture adsorption instrument produced by SMS (Surface Measurement Systems Ltd.). The instrument control software is DVS-Intrinsic control software. The method parameters of the dynamic moisture adsorption instrument are as follows:

Temperature: 25℃

Carrier gas, flow rate: N ₂ , 200mL/min

Relative humidity range: 0%RH-95%RH

The nuclear magnetic resonance hydrogen spectrum data ( ¹ H NMR) were collected from a Bruker Avance II DMX 400M HZ nuclear magnetic resonance spectrometer. 1-5 mg of sample was weighed and dissolved in 0.5 mL of deuterated chloroform to prepare a 2-10 mg/mL solution.

The solubility test method is shown in Table 1.

Table 1

The detection methods of relevant substances are shown in Table 2.

Table 2

In the present invention, the "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, with a stirring speed of 50-1800 rpm, wherein the magnetic stirring is preferably 300-900 rpm, and the mechanical stirring is preferably 100-300 rpm.

The "separation" is accomplished by conventional methods in the art, such as centrifugation or filtration. The "centrifugation" operation is: placing the sample to be separated in a centrifuge tube and centrifuging at a rate of 10,000 rpm until all the solids sink to the bottom of the centrifuge tube.

The "drying" can be carried out at room temperature or higher. The drying temperature is from room temperature to about 80°C, or to 60°C, or to 40°C. The drying time can be more than 0.5 hours, or overnight. The drying is carried out in a fume hood, a forced air oven, or a vacuum oven.

In the present invention, "crystal" or "crystal form" can be characterized by X-ray powder diffraction. Those skilled in the art will understand that the X-ray powder diffraction pattern is affected by the conditions of the instrument, the preparation of the sample and the purity of the sample. The relative intensity of the diffraction peaks in the X-ray powder diffraction pattern may also change with the change of the experimental conditions, so the diffraction peak intensity cannot be used as the only or decisive factor for determining the crystal form. In fact, the relative intensity of the diffraction peaks in the X-ray powder diffraction pattern is related to the preferred orientation of the crystal, and the diffraction peak intensity shown in the present invention is illustrative rather than for absolute comparison. Therefore, those skilled in the art will understand that the X-ray powder diffraction pattern of the crystal form protected by the present invention does not have to be completely consistent with the X-ray powder diffraction pattern in the embodiments referred to herein, and any crystal form having an X-ray powder diffraction pattern that is the same or similar to the characteristic peaks in these patterns belongs to the scope of the present invention. Those skilled in the art can compare the X-ray powder diffraction pattern listed in the present invention with the X-ray powder diffraction pattern of an unknown crystal form to confirm whether the two sets of patterns reflect the same or different crystal forms.

The term "about" in the present invention, when used to refer to a measurable value, such as mass, time, temperature, etc., means that there is a certain floating range around the specific value, which can be ±10%, ±5%, ±1%, ±0.5%, or ±0.1%.

The “characteristic peak” refers to a representative diffraction peak used to identify crystals. When Cu-Kα radiation is used for testing, the 2θ value of the characteristic peak can usually have an error of ±0.2°.

The "solvate" is a crystalline form containing stoichiometric or non-stoichiometric amounts of solvent.

In some embodiments, the crystalline form CSVI of the present invention is pure and substantially free of any other crystalline forms. 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, particularly less than 10% (by weight) of other crystalline forms, more preferably less than 5% (by weight) of other crystalline forms, and more preferably less than 1% (by weight) of other crystalline forms.

Unless otherwise specified, the following examples were all operated at room temperature.

According to the present invention, the compound I and/or its salt as a raw material includes but is not limited to solid form (crystalline or amorphous), oily, liquid form and solution. Preferably, the compound I and/or its salt as a raw material is in solid form.

The compound I used in the following examples can be prepared according to the prior art, for example, according to the method described in WO2018154101A1.

Example 1: Preparation method of crystalline form CSVI

About 10 mg of the solid compound I was mixed with 0.2 mL of benzyl alcohol and stirred at 4°C for 3 hours, and about 5 mg of the solid compound I was added again, and the stirring was continued at 4°C for about 2 days. The solid was separated and vacuum dried at 25°C for about 3.5 hours to obtain a solid. According to XRPD detection, the obtained solid was the crystalline form CSVI of the present invention, and its X-ray powder diffraction pattern was shown in FIG1 , and the X-ray powder diffraction data were shown in Table 3. Its TGA was shown in FIG2 , and when it was heated to 150°C, it had a mass loss of about 10.1%.

¹ H NMR results showed that crystalline CSVI was a benzyl alcohol solvate, and about 0.5 molar equivalents of benzyl alcohol were detected. NMR data were: ¹ H NMR (400 MHz, Chloroform-d) δ8.50 (s, 1H), 8.49 (s, 2H), 7.62–7.53 (m, 2H), 7.41–7.27 (m, 2.5H), 7.19–7.08 (m, 3H), 5.56 (s, 2H), 4.76–4.68 (m, 3H), 4.65–4.57 (m, 2H), 1.65 (t, 0.5H).

table 3

Example 2 Solubility of Crystalline Form CSVI

About 10 mg of each of the crystalline form CSI of the present invention, the crystalline form A of the prior art, and the crystalline form CSI of the prior art were dispersed in 1.0 mL of FaSSIF, 1.0 mL of FeSSIF, and 1.0 mL of water at 37°C to prepare a suspension, and after 15 minutes of equilibration, the saturated solution was obtained by filtration, and the content of the sample in the saturated solution was tested by high performance liquid chromatography (μg/mL). The results are shown in Table 4. The results show that the crystalline form CSVI has higher solubility in the above three media, especially in FaSSIF, the solubility of the crystalline form CSVI is 6-8 times that of the prior art.

Table 4

Example 3 Stability of Crystalline Form CSVI

An appropriate amount of the crystalline CSVI prepared by the present invention was placed under 25°C/60%RH and 40°C/75%RH conditions, and the purity and crystalline form were determined by HPLC and XRPD. The results are shown in Table 5, and the XRPD comparison chart is shown in Figure 3. The results show that the crystalline CSVI can be stable for at least 6 months under 25°C/60%RH and 40°C/75%RH conditions. It can be seen that the crystalline CSVI can maintain good stability under both long-term and accelerated conditions.

table 5

Open: Place the sample in a glass vial, cover the vial with a layer of aluminum foil and make a hole in the foil.

Sealing: Place the sample in a glass vial, cover the bottle mouth with a layer of aluminum foil and make a hole in the aluminum foil, and seal the glass bottle containing the sample together with 1g of silica gel desiccant in an aluminum foil bag.

Example 4 Hygroscopicity of Crystalline Form CSVI

About 10 mg of the crystal form CSVI of the present invention was taken and its hygroscopicity was tested by a dynamic moisture sorption (DVS) instrument. After undergoing a change from 0% RH to 95% RH to 0% RH, the mass change at each humidity was recorded, and the crystal form of the sample before and after the humidity cycle was tested by XRPD. The XRPD comparison diagram is shown in Figure 4. The results show that the weight gain of the crystal form CSVI at 0-80% RH is only 0.07%, and the crystal form remains unchanged after experiencing humidity changes, and has good humidity stability.

The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims (9)

1. A crystalline form of Compound I, characterized in that it is a benzyl alcohol solvate,
   
2. The crystalline form according to claim 1, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has a characteristic peak at at least one of the 2θ values of 18.2°±0.2°, 20.9°±0.2°, and 23.6°±0.2°.
3. The crystalline form according to claim 2 is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has a characteristic peak at at least one of the 2θ values of 17.2°±0.2°, 20.5°±0.2°, and 26.5°±0.2°.
4. The crystalline form according to claim 2 is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has a characteristic peak at at least one of the 2θ values of 15.0°±0.2°, 18.7°±0.2°, and 30.7°±0.2°.
5. The crystalline form according to claim 1 is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern is substantially as shown in Figure 1.
6. A preparation method, characterized in that the solid compound I is mixed with benzyl alcohol and then stirred to obtain the crystalline form according to claim 1.
7. A pharmaceutical composition comprising an effective therapeutic amount of the crystal form described in claim 1 and a pharmaceutically acceptable excipient.
8. Use of the crystal form described in claim 1 in the preparation of a dual endothelin receptor antagonist drug.
9. Use of the crystal form described in claim 1 in the preparation of a drug for treating refractory hypertension.