Eutectic of Afiicamten and preparation method and application thereof

Abstract

The invention relates to a co-crystal of Aficamten and tartaric acid, a preparation method of the co-crystal, a pharmaceutical composition containing the co-crystal, and application of the co-crystal in preparation of a cardiac myosin inhibitor drug and a drug for treating hypertrophic cardiomyopathy.

Description

Aficamten cocrystal and its preparation method and use Technical Field

[0001] The present invention relates to the field of crystal chemistry, and in particular to a cocrystal of Aficamten, a preparation method thereof, and uses thereof. Background Art

[0002] Cardiac sarcomeres are composed of a network of contractile proteins and structural proteins that regulate myocardial function. Abnormalities in cardiac sarcomeres have been identified as the cause of a variety of heart diseases, such as hypertrophic cardiomyopathy (HCM). HCM is a disease in which the myocardium thickens or enlarges abnormally, primarily due to abnormalities in cardiac sarcomeres. Thickening of the myocardium can cause the interior of the left ventricle to become smaller and harder, and its ability to relax and fill with blood becomes worse, which ultimately limits the heart's ability to pump blood, leading to chest pain, dizziness, shortness of breath, or fainting. Existing drugs that target cardiac sarcomeres are not selective enough for heart tissue, and thus produce side effects, thereby limiting their use. In view of the limitations of existing drugs, new drugs are still needed for the treatment of heart disease.

[0003] Aficamten is an oral, novel, small molecule cardiac myosin inhibitor developed by Cytokinetics for the treatment of hypertrophic cardiomyopathy, with positive Phase 3 clinical results. Aficamten's chemical name is (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide (hereinafter referred to as "Compound I"), and the structural formula of Compound I is as follows:

[0004] In small molecule drug development, drug polymorphism is a common phenomenon and a significant factor affecting drug quality. Crystals are solids whose compound molecules are arranged in an orderly three-dimensional microstructure, forming a lattice. Polymorphism refers to the phenomenon of a single compound existing in multiple crystalline forms. A compound may exist in one or more crystalline forms, but their existence and properties cannot be precisely predicted.

[0005] Different solid forms of active pharmaceutical ingredients (APIs) have different physicochemical properties, including chemical stability, thermal stability, solubility, and hygroscopicity. This can lead to varying dissolution and absorption of the drug in the body, thereby impacting the drug's clinical efficacy to a certain extent. Furthermore, different solid forms of active pharmaceutical ingredients (APIs) have different manufacturability characteristics, including yield, purification, filtration, drying, milling, and stability to pressure during tableting, which can affect the processing of the active pharmaceutical ingredient during production. Therefore, different solid forms of active pharmaceutical ingredients may have different properties, providing opportunities to improve drug performance.

[0006] WO2021011807A1 discloses free forms I-VI of compound I, and form IV is the most stable crystal form. The applicant of the present invention has found that form IV has low solubility. In order to find a new solid form that can improve drug performance, the inventors of the present application accidentally discovered the co-crystal of compound I and tartaric acid provided by the present invention. According to the FDA drug co-crystal guidelines, drug co-crystals are crystalline materials formed by two or more different molecules (one of which is an active pharmaceutical ingredient (API)) in the same crystal lattice in a certain stoichiometric ratio through non-ionic bonds and non-covalent bonds. One advantage of drug co-crystals is that they can be used to improve the bioavailability and stability of drugs and to improve the processing performance of raw materials during drug production. Another advantage of drug co-crystals is that for some active pharmaceutical ingredients that are difficult to form salts due to the lack of ionizable functional groups, drug co-crystals can provide them with more solid forms. The inventors of the present application unexpectedly discovered a co-crystal of Compound I and tartaric acid, which has advantages in at least one aspect of solubility, hygroscopicity, purification effect, stability, adhesion, compressibility, fluidity, in vitro and in vivo dissolution, and bioavailability, especially high solubility, good fluidity, low hygroscopicity, and good stability, which solves the problems existing in the prior art and is of great significance to the development of drugs containing Compound I.

[0007] Summary of the Invention

[0008] The present invention provides a co-crystal of Compound I, a method for preparing the same, and a pharmaceutical composition comprising the co-crystal.

[0009] According to the purpose of the present invention, the present invention provides a co-crystal of Compound I and tartaric acid.

[0010] According to the purpose of the present invention, the present invention provides a co-crystal CSI of Compound I and tartaric acid (hereinafter referred to as "crystal form CSI").

[0011] On the one hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at diffraction angles 2θ of 12.2°±0.2°, 14.7°±0.2°, and 19.1°±0.2°.

[0012] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at one, or two, or three of the diffraction angles 2θ of 7.3°±0.2°, 8.9°±0.2°, and 15.6°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at diffraction angles 2θ of 7.3°±0.2°, 8.9°±0.2°, and 15.6°±0.2°.

[0013] Further, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at one, two, or three of the diffraction angles 2θ of 10.9°±0.2°, 12.6°±0.2°, and 22.8°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at diffraction angles 2θ of 10.9°±0.2°, 12.6°±0.2°, and 22.8°±0.2°.

[0014] On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at any one, or two, or three, or four, or five, or six, or seven, or eight, or nine of the diffraction angle 2θ values ​​of 12.2°±0.2°, 14.7°±0.2°, 19.1°±0.2°, 7.3°±0.2°, 8.9°±0.2°, 15.6°±0.2°, 10.9°±0.2°, 12.6°±0.2°, 22.8°±0.2°, 10.2°±0.2°, and 18.0°±0.2°.

[0015] Without limitation, Form CSI is an anhydrous co-crystal of Compound 1 and tartaric acid.

[0016] Without limitation, the crystalline form CSI is preferably an L-tartaric acid cocrystal, a DL-tartaric acid cocrystal or a D-tartaric acid cocrystal of Compound 1, more preferably an L-tartaric acid cocrystal.

[0017] Without limitation, the molar ratio of tartaric acid to Compound I in the crystalline form CSI is preferably 0.4-0.6, more preferably 0.5.

[0018] Without limitation, using Cu-Kα radiation, the X-ray powder diffraction pattern of Form CSI is substantially as shown in FIG1 .

[0019] Without limitation, the thermogravimetric analysis of Form CSI is substantially as shown in FIG2 , and there is substantially no mass loss when heated to about 100° C.

[0020] Without limitation, the differential scanning calorimetry analysis chart of Form CSI is substantially as shown in FIG3 , which has an endothermic peak with an onset temperature of about 163° C. and a peak temperature of about 166° C.

[0021] According to the purpose of the present invention, the present invention also provides a method for preparing the crystalline form CSI, which comprises: placing Compound I and tartaric acid in a ketone solvent and stirring to obtain the crystalline form CSI.

[0022] Furthermore, the ketone solvent is preferably methyl isobutyl ketone; the tartaric acid is preferably L-tartaric acid, DL-tartaric acid or D-tartaric acid, more preferably L-tartaric acid.

[0023] According to the purpose of the present invention, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a co-crystal of Compound I and tartaric acid and a pharmaceutically acceptable excipient.

[0024] Furthermore, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of crystalline CSI and pharmaceutically acceptable excipients.

[0025] According to the purpose of the present invention, the present invention provides use of a co-crystal of Compound I and tartaric acid in preparing a cardiac myosin inhibitor drug.

[0026] Furthermore, the present invention provides use of crystalline CSI in the preparation of cardiac myosin inhibitor drugs.

[0027] According to the purpose of the present invention, the present invention provides use of a co-crystal of Compound I and tartaric acid in preparing a medicament for treating hypertrophic cardiomyopathy.

[0028] Furthermore, the present invention provides use of crystalline CSI in the preparation of drugs for treating hypertrophic cardiomyopathy.

[0029] The crystalline CSI provided by the present invention has the following unexpected technical effects:

[0030] (1) Crystalline CSI has higher solubility. Compared with existing technologies, crystalline CSI has higher solubility in FaSSGF, FaSSIF, FeSSIF, and water, which is beneficial for improving drug absorption in the human body and enhancing bioavailability.

[0031] (2) Crystalline CSI has better fluidity. Compared with existing technologies, the better fluidity of crystalline CSI can avoid clogging of production equipment and improve production efficiency; ensure the content uniformity of the preparation, reduce weight variation, and improve product quality.

[0032] (3) Crystalline CSI is almost non-hygroscopic and has low hygroscopicity. Test results show that the weight gain of crystalline CSI due to moisture absorption at 80% RH is 0.18%. Crystalline CSI has low hygroscopicity and is not demanding on drug production and storage, thus reducing the cost of drug production, storage, and quality control, and possesses strong economic value.

[0033] (4) Crystalline CSI has good stability.

[0034] Crystalline CSI has good humidity stability. After experiencing humidity changes from 0% RH to 95% RH and then to 0% RH, the crystal form of CSI remains unchanged.

[0035] Crystalline CSI exhibits excellent physical and chemical stability. When stored at 25°C / 60% RH and 40°C / 75% RH, the crystal form remains unchanged for at least nine months, and its purity remains essentially unchanged. When stored at 60°C / 75% RH, the crystal form remains unchanged for at least three months, and its purity remains essentially unchanged.

[0036] Crystalline CSI has good stability under mechanical force and its crystal form remains unchanged after ball milling.

[0037] High humidity conditions caused by seasonal variations, regional climate differences, and environmental factors can affect the storage, transportation, and production of APIs. Furthermore, APIs often require grinding or pulverization during the pharmaceutical manufacturing process. The excellent stability of the CSI crystal form helps prevent the effects of crystal transformation during storage, transportation, and production on drug quality. It also reduces the risk of API crystallinity loss and crystal transformation during pharmaceutical manufacturing. This ensures consistent and controllable API quality and minimizes variations in drug quality, bioavailability, and toxic side effects caused by changes in crystal form. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 is the XRPD pattern of crystal form CSI

[0039] Figure 2 is the TGA diagram of crystal form CSI

[0040] Figure 3 is the DSC diagram of crystal form CSI

[0041] Figure 4 is the DVS diagram of crystal form CSI

[0042] Figure 5 shows the XRPD patterns of the crystal form CSI before and after DVS testing (from top to bottom: before DVS testing, after DVS testing)

[0043] Figure 6 shows the XRPD patterns of crystal form CSI before and after ball milling (from top to bottom: before ball milling, after ball milling)

[0044] Figure 7 shows the XRPD patterns of Form CSI before and after storage under different conditions (from top to bottom: before storage, after storage at 25°C / 60% RH for 9 months, after storage at 40°C / 75% RH for 9 months, and after storage at 60°C / 75% RH for 3 months) DETAILED DESCRIPTION

[0045] 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 variations in both materials and methods may be made without departing from the scope of the present invention.

[0046] The abbreviations used in the present invention are explained as follows:

[0047] XRPD: X-ray powder diffraction

[0048] DSC: Differential Scanning Calorimetry

[0049] TGA: Thermogravimetric analysis

[0050] DVS: Dynamic Water Sorption

[0051] HPLC: High Performance Liquid Chromatography

[0052] 1 H NMR: hydrogen nuclear magnetic resonance

[0053] RH: relative humidity

[0054] Instruments and methods used to collect data:

[0055] The X-ray powder diffraction patterns of the present invention were collected on a Bruker D8 ADVANCE X-ray powder diffractometer. The X-ray powder diffraction method parameters of the present invention are as follows:

[0056] X-ray source: Cu, Kα

[0057] 1.54060; 1.54439

[0058] Kα2 / Kα1 intensity ratio: 0.50

[0059] Voltage: 40kV

[0060] Current: 40mA

[0061] Scanning range: from 4.0 to 40.0 degrees

[0062] The TGA images of the present invention were collected on a TA Q500. The method parameters of the TGA of the present invention are as follows:

[0063] Scan rate: 10℃ / min

[0064] Shielding gas: N2

[0065] The differential scanning calorimetry (DSC) graphs of the present invention were collected on a TA Q2000. The method parameters of the differential scanning calorimetry (DSC) of the present invention are as follows:

[0066] Scan rate: 10℃ / min

[0067] Shielding gas: N2

[0068] The dynamic moisture sorption (DVS) graphs described herein were collected using an Intrinsic dynamic moisture sorption instrument manufactured by SMS (Surface Measurement Systems Ltd.). The instrument control software was DVS-Intrinsic control software. The method parameters for the dynamic moisture sorption instrument were as follows:

[0069] Temperature: 25℃

[0070] Carrier gas, flow rate: N2, 200mL / min

[0071] Relative humidity range: 0%RH-95%RH

[0072] 1 H NMR spectra were acquired on a Bruker Avance II DMX 400M HZ NMR spectrometer. 1-5 mg of sample was weighed and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to prepare a 2-10 mg / mL solution.

[0073] The test method for dynamic solubility of the present invention is shown in Table 1.

[0074] Table 1

[0075] The purity test method of the present invention is shown in Table 2.

[0076] Table 2

[0077] 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 speed is preferably 300-900 rpm, and the mechanical stirring speed is preferably 100-300 rpm.

[0078] The separation is accomplished by conventional methods in the art, such as centrifugation or filtration. The centrifugation operation is as follows: the sample to be separated is placed in a centrifuge tube and centrifuged at a rate of 10,000 rpm until all solids settle to the bottom of the centrifuge tube.

[0079] The drying process is accomplished using conventional methods in the art, such as vacuum drying, forced air drying, or air drying. The drying temperature can be room temperature or higher, preferably room temperature to about 60°C, or to 50°C, or to 40°C. The drying time can be 2-48 hours, or overnight. Drying is performed in a fume hood, forced air oven, or vacuum oven.

[0080] The "eutectic of Compound I and tartaric acid" refers to a crystalline material formed by Compound I and tartaric acid being bonded in a certain stoichiometric ratio in the same crystal lattice through non-ionic bonds and non-covalent bonds.

[0081] 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°.

[0082] In the present invention, "crystals" or "crystal forms" can be characterized by X-ray powder diffraction. Those skilled in the art will appreciate that X-ray powder diffraction patterns can vary depending on instrument conditions, sample preparation, and sample purity. The relative intensities of diffraction peaks in an X-ray powder diffraction pattern may also vary with experimental conditions, so the diffraction peak intensities cannot be the sole or decisive factor in determining a crystal form. In fact, the relative intensities of diffraction peaks in an X-ray powder diffraction pattern are related to the preferred orientation of the crystal. The diffraction peak intensities shown herein are illustrative and not intended for absolute comparison. Therefore, those skilled in the art will appreciate that the X-ray powder diffraction patterns of the crystal forms claimed by the present invention do not necessarily have to be identical to those in the Examples described herein; any crystal form having X-ray powder diffraction patterns that are identical or similar to the characteristic peaks in these patterns falls within the scope of the present invention. Those skilled in the art can compare the X-ray powder diffraction patterns listed herein with those of an unknown crystal form to determine whether the two patterns reflect the same or different crystal forms.

[0083] In some embodiments, the crystalline form CSI of the present invention is pure and substantially free of any other crystalline form. As used herein, "substantially free" when referring to a new crystalline form means that the crystalline form contains less than 20% (by weight) of any other crystalline form, particularly less than 10% (by weight) of any other crystalline form, more particularly less than 5% (by weight) of any other crystalline form, and even more particularly less than 1% (by weight) of any other crystalline form.

[0084] 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%.

[0085] Unless otherwise specified, the following examples are all operated at room temperature and ambient humidity. The "room temperature" is not a specific temperature value, but refers to a temperature range of 10-30°C.

[0086] According to the present invention, the compound I and / or its salt as a raw material include but are not limited to solid form (crystalline or amorphous), oily, liquid form and solution. Preferably, the compound I as a raw material is in solid form. The compound I and / or its salt used in the following examples can be prepared according to the prior art, for example, according to the method described in WO2021011807A1.

[0087] Example 1 Preparation method of crystal form CSI

[0088] 203.4 mg of Compound I and 45.5 mg of L-tartaric acid were weighed into a glass bottle, and 6 mL of methyl isobutyl ketone was added. The mixture was stirred at room temperature for 1 day, and the solid was separated and dried in vacuo at 30° C. for about 2 hours to obtain a dry solid.

[0089] The obtained dry solid was tested to be the crystalline form CSI of the present invention. Its X-ray powder diffraction pattern is shown in FIG1 , and the X-ray powder diffraction data are shown in Table 3.

[0090] The TGA graph is shown in Figure 2. When heated to approximately 100° C., there is essentially no mass loss. Form CSI is an anhydrous cocrystal of Compound I and L-tartaric acid.

[0091] The DSC graph is shown in FIG3 , which has an endothermic peak with an onset temperature of about 163° C. and a peak temperature of about 166° C.

[0092] 1 The H NMR data are: 1 H NMR(400MHz,DMSO-d6)δ8.44(d,J=8.4Hz,1H),8.18(s,1H),7.89(s,2H),7.8 5(dd,J=7.9,1.5Hz,1H),7.35(d,J=7.8Hz,1H),5.54(q,J=8.3Hz,1H),4.31( s,1H),3.85(s,3H),3.11-3.04(m,1H),3.00(q,J=7.5Hz,2H),2.96-2.85(m, 1H), 2.48-2.42 (m, 1H), 1.96 (dq, J = 12.5, 9.0Hz, 1H), 1.34 (t, J = 7.5Hz, 3H). The signal at 4.31 ppm corresponds to the two hydrogen atoms on the α-carbon of the carboxyl group of L-tartaric acid, corresponding to 0.5 molar equivalents of L-tartaric acid.

[0093] Table 3

[0094] Example 2 Dynamic Solubility of Crystalline Form CSI

[0095] Suspensions were prepared by dispersing sufficient amounts of the crystalline Form CSI of the present invention and the prior art Form IV in 1.0 mL of FaSSGF, FaSSIF, FeSSIF, and water, respectively. After equilibration at 37°C for 1 hour, the concentration of Compound I (μg / mL) in the solution was measured by HPLC. The results are shown in Table 4. The results demonstrate that the crystalline Form CSI has higher solubility in various media.

[0096] Table 4

[0097] Example 3 Fluidity of Crystalline Form CSI

[0098] Weigh about 400 mg of sample and add it to a 5 mL graduated cylinder. Measure its volume before compaction (V0). Vibrate it 1250 times using a ZS-2E vibrator and record the volume after compaction (V). f According to the formula c=(V0-V f ) / V0*100% to calculate the compressibility coefficient (c). The smaller the compressibility coefficient, the better the fluidity. The test results are shown in Table 5. The results show that the crystal form CSI has better fluidity.

[0099] Table 5

[0100] Example 4 Hygroscopicity and humidity stability of crystalline form CSI

[0101] An appropriate amount of the present invention's crystalline form CSI was tested for hygroscopicity using a DVS instrument. The sample was cycled from 0% RH to 95% RH and then back to 0% RH. The mass change at each humidity level was recorded. XRPD was then used to determine the crystal form of the sample before and after the DVS test. The DVS pattern of the crystalline form CSI is shown in Figure 4, and the XRPD patterns of the sample before and after the DVS test are shown in Figure 5. The results demonstrate that the crystalline form CSI exhibits virtually no hygroscopicity, with a weight gain of 0.18% after equilibrium at 80% relative humidity. Furthermore, the crystalline form CSI exhibits excellent humidity stability, maintaining its crystal form after undergoing humidity cycles from 0% RH to 95% RH and then back to 0% RH.

[0102] Example 5 Stability of Crystalline Form CSI under Mechanical Force

[0103] An appropriate amount of crystalline CSI was ball-milled at 500 rpm for 5 minutes. XRPD was used to confirm the sample's crystal form before and after ball milling. The XRPD patterns before and after ball milling are shown in Figure 6. The results indicate that the crystal form of crystalline CSI remained unchanged before and after ball milling, demonstrating good stability under mechanical stress.

[0104] Example 6 Physicochemical Stability of Crystalline Form CSI

[0105] An appropriate amount of the crystalline form CSI prepared by the present invention was taken, sealed and packaged, and placed under 25°C / 60% RH, 40°C / 75% RH, and 60°C / 75% RH conditions, respectively. The purity and crystalline form were determined by HPLC and XRPD. The results are shown in Table 6, and the XRPD comparison chart is shown in Figure 7. The results show that the crystalline form CSI is stable for at least 9 months under 25°C / 60% RH and 40°C / 75% RH conditions. It can be seen that the crystalline form CSI maintains good stability under both long-term and accelerated conditions. The crystalline form CSI is stable for at least 3 months under 60°C / 75% RH conditions, which shows that the stability is also very good under more stringent conditions.

[0106] Table 6

[0107] The above embodiments are intended only to illustrate the technical concepts and features of the present invention. Their purpose is to enable those skilled in the art to understand the contents of the present invention and implement them accordingly. They are not intended to limit the scope of protection of the present invention. Any equivalent changes or modifications made in accordance with the spirit of the present invention are intended to be covered by the scope of protection of the present invention.

Claims

1. A co-crystal of Compound I and tartaric acid, 2. The eutectic according to claim 1, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 12.2°±0.2°, 14.7°±0.2°, and 19.1°±0.2°.

3. The eutectic according to claim 2, characterized in that Using Cu—Kα radiation, its X-ray powder diffraction pattern has a characteristic peak at at least one of 2θ values ​​of 7.3°±0.2°, 8.9°±0.2°, and 15.6°±0.2°.

4. The eutectic according to claim 2, characterized in that The X-ray powder diffraction pattern thereof has a characteristic peak at at least one of 2θ values ​​of 10.9°±0.2°, 12.6°±0.2°, and 22.8°±0.2° using Cu—Kα radiation.

5. The eutectic according to claim 3, characterized in that The X-ray powder diffraction pattern thereof has a characteristic peak at at least one of 2θ values ​​of 10.9°±0.2°, 12.6°±0.2°, and 22.8°±0.2° using Cu—Kα radiation.

6. The eutectic according to claim 1, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern is basically as shown in Figure 1.

7. The eutectic according to claim 1, characterized in that It is an anhydrous eutectic.

8. A pharmaceutical composition comprising a therapeutically effective amount of the co-crystal according to claim 1 and a pharmaceutically acceptable excipient.

9. Use of the co-crystal according to claim 1 in preparing a drug for treating hypertrophic cardiomyopathy.

10. Use of the co-crystal according to claim 1 in the preparation of cardiac myosin inhibitor drugs.

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