Crystal forms of niroxostat and dihydrobromide thereof, and preparation method and application of crystal forms of niroxostat and dihydrobromide thereof

Abstract

The invention relates to a novel crystal form of a compound I and dihydrobromide thereof, a preparation method of the novel crystal form, a pharmaceutical composition containing the crystal form, and application of the crystal form in preparation of gamma secretase inhibitor drugs and drugs for treating sclerofibroma.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of crystal chemistry. In particular, it relates to crystalline forms of nirogacestat and its dihydrobromide salt, and methods of preparation and uses thereof. BACKGROUND

[0002] Desmoid tumors, also known as aggressive fibromatosis, are a rare, locally aggressive, slow-growing soft tissue tumor. Although desmoid tumors cannot metastasize and are considered benign tumors, they can still cause serious complications in patients and occasionally lead to patient death, so there is an urgent need for drugs.

[0003] Surprisingly, the gamma secretase inhibitor nirogacestat developed by Spring Works Therapeutics has been marketed in the United States in the form of a dihydrobromide salt and is used to treat desmoid tumors. Nirogacestat can bind to gamma secretase and block the hydrolytic activation of Notch receptors. Existing clinical research data shows that Notch signaling plays an important role in cancer development. Therefore, inhibiting Notch signaling is an important strategy for treating desmoid tumors.

[0004] The chemical name of nirogacestat is (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide (hereinafter referred to as "Compound I"), and the structural formula of Compound I is as follows:

[0005]

[0006] The structural formula of Compound I dihydrobromide salt is as follows:

[0007]

[0008] A crystal form is a solid in which the molecules of a compound are arranged in a three-dimensional order in the microstructure to form a crystal lattice. Different crystal forms of a drug substance have different physicochemical properties, which can lead to different dissolution and absorption of the drug in the body, and thus to some extent affect the clinical efficacy of the drug. In particular, for some poorly soluble oral solid or semi-solid preparations, the crystal form is crucial to the performance of the product. In addition, the physical properties of the crystal form are crucial to the production process, for example, a certain compound can be more prone to form solvates, or it can be difficult to remove impurities. Therefore, polymorphism is an important part of drug research and drug quality control.

[0009] The inventors of the present application unexpectedly found that the crystal form of compound I provided by the present application has obvious advantages in purification effect, and can be used for preparing dihydrobromide raw material drug, which has very important significance for the development of drug containing compound I. In addition, the inventors of the present application unexpectedly found that the crystal form of compound I dihydrobromide provided by the present application has advantages in at least one of solubility, hygroscopicity, purification effect, stability, adhesion, compressibility, flowability, in-vivo and in-vitro dissolution, bioavailability, etc., solves the problems existing in the prior art, and has very important significance for the development of drug containing compound I. SUMMARY

[0010] The present application provides a new crystal form of compound I and dihydrobromide thereof, a preparation method thereof, and a pharmaceutical composition comprising the new crystal form.

[0011] According to the purposes of the present application, the present application provides a crystal form of compound I, which is non-limitingly crystal form K1 (hereinafter referred to as "crystal form K1").

[0012] Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form K1 has characteristic peaks at any 1, any 2, any 3, or 4, or 5, or 6, or 7, or 8, or 9 of the diffraction angle 2θ values of 4.3°±0.2°, 4.6°±0.2°, 5.4°±0.2°, 6.5°±0.2°, 7.3°±0.2°, 8.1°±0.2°, 8.9°±0.2°, 9.3°±0.2°, 11.9°±0.2°.

[0013] Non-limitingly, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form K1 is substantially as shown in Figure 1 .

[0014] According to the purposes of the present application, the present application also provides a preparation method of the crystal form K1, which comprises: dissolving compound I in an alcohol solvent, performing anti-solvent addition to obtain the crystal form K1.

[0015] Further, the alcohol is preferably ethanol; the anti-solvent is preferably water; and the temperature of the anti-solvent addition is preferably 5-25°C.

[0016] According to the purposes of the present application, the present application provides a crystal form of compound I, which is non-limitingly crystal form K3 (hereinafter referred to as "crystal form K3").

[0017] The X-ray powder diffraction pattern of the crystalline Form K1 has characteristic peaks at any one, any two, any three, or four, or five, or six, or seven of the diffraction angle 2Q values of 4.9°±0.2°, 5.1°±0.2°, 6.1°±0.2°, 6.5°±0.2°, 8.6°±0.2°, 9.9°±0.2°, 17.4°±0.2° using Cu-Ka radiation.

[0018] Without limitation, the X-ray powder diffraction pattern of the crystalline Form K3 is substantially as shown in Figure 2

[0019] According to the purposes of the present application, the present application also provides a preparation method of the crystalline Form K3, which comprises drying the crystalline Form K1 to obtain the crystalline Form K3.

[0020] According to the purposes of the present application, the present application provides the use of the crystalline Form K1 and the crystalline Form K3 for preparing the crystalline form or co-crystal of Compound I and salts thereof.

[0021] According to the purposes of the present application, the present application provides a crystalline form of Compound I dihydrobromide, without limitation, which is the crystalline Form CSVII (hereinafter referred to as “crystalline Form CSVII”).

[0022] In one aspect, the crystalline Form CSVII is a formate solvate.

[0023] Further, the X-ray powder diffraction pattern of the crystalline Form CSVII has characteristic peaks at one, or two, or three of the diffraction angle 2Q values of 4.3°±0.2°, 13.1°±0.2°, 20.9°±0.2° using Cu-Ka radiation; preferably, the X-ray powder diffraction pattern of the crystalline Form CSVII has characteristic peaks at the diffraction angle 2Q values of 4.3°±0.2°, 13.1°±0.2°, 20.9°±0.2°.

[0024] Further, the X-ray powder diffraction pattern of the crystalline Form CSVII has characteristic peaks at one, or two, or three of the diffraction angle 2Q values of 4.3°±0.2°, 13.1°±0.2°, 20.9°±0.2° using Cu-Ka radiation; preferably, the X-ray powder diffraction pattern of the crystalline Form CSVII has characteristic peaks at the diffraction angle 2Q values of 4.3°±0.2°, 13.1°±0.2°, 20.9°±0.2°.

[0025] ​Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form CSVII has characteristic peaks at one, two, or three of the following diffraction angles 2θ: 7.8°±0.2°, 12.1°±0.2°, and 15.6°±0.2°; preferably, the X-ray powder diffraction pattern of the crystal form CSVII has characteristic peaks at the following diffraction angles 2θ: 7.8°±0.2°, 12.1°±0.2°, and 15.6°±0.2°.

[0026] On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form CSVII has characteristic peaks at any one, two, three, four, five, six, seven, eight, or nine locations with diffraction angles of 2θ values ​​of 9.2°±0.2°, 9.9°±0.2°, 25.3°±0.2°, 4.3°±0.2°, 13.1°±0.2°, 20.9°±0.2°, 7.8°±0.2°, 12.1°±0.2°, and 15.6°±0.2°.

[0027] Without limitation, using Cu-Kα radiation, the X-ray powder diffraction pattern of crystal form CSVII is essentially as follows: Figure 4 As shown.

[0028] According to the purpose of this invention, the present invention also provides a method for preparing the crystal form CSVII, the method comprising:

[0029] The solid dihydrobromide of compound I was dissolved in a mixed solvent of formic acid and antisolvent, and the antisolvent was added dropwise to obtain the crystal form CSVII.

[0030] Furthermore, the antisolvent is preferably an ether or an ester; more preferably methyl tert-butyl ether, 2-methyltetrahydrofuran or isopropyl acetate.

[0031] According to the purpose of this invention, the present invention provides the use of crystal form CSVII for preparing crystal forms or eutectics of compound I and its salts.

[0032] According to the purpose of this invention, a pharmaceutical composition is provided, the pharmaceutical composition comprising an effective therapeutic amount of crystalline CSVII and pharmaceutically acceptable excipients.

[0033] According to the purpose of this invention, the present invention provides the use of crystalline CSVII in the preparation of γ-secretase inhibitor drugs or drugs for the treatment of desmoidoma. Attached Figure Description

[0034] Figure 1 XRPD diagram of crystal form K1

[0035] Figure 2 XRPD diagram of crystal form K3

[0036] Figure 3 TGA pattern for Form K3

[0037] Figure 4 XRPD pattern for Form CSVII obtained according to Example 4 DETAILED DESCRIPTION

[0038] The present application is described in detail below with reference to the following Examples, which describe in detail the preparation and use of the crystalline forms of the present application. It will be apparent to those skilled in the art that many modifications, both to materials and methods, can be practiced without departing from the scope of the present application.

[0039] The following abbreviations are used in the present application:

[0040] XRPD: X-ray powder diffraction

[0041] TGA: thermogravimetric analysis

[0042] HPLC: high performance liquid chromatography

[0043] RH: relative humidity

[0044] Instruments and methods used to collect data:

[0045] The X-ray powder diffraction patterns described in the Examples of the present application were collected on a Bruker D8 ADVANCE X-ray powder diffractometer. The method parameters for the X-ray powder diffraction are as follows:

[0046] X-ray source: Cu, K alpha

[0047] K alpha 1 1.54060; K alpha 2 1.54439

[0048] K alpha 2 / K alpha 1 intensity ratio: 0.50

[0049] Voltage: 40 kV

[0050] Current: 40 mA

[0051] Scan range: from 4.0 to 40.0 degrees

[0052] The TGA patterns described in the present application were collected on a TA Q5000. The method parameters for the TGA described in the present application are as follows:

[0053] Scan rate: 10 °C / min

[0054] Protective gas: N2

[0055] The "characteristic peaks" refer to representative diffraction peaks for identifying the crystal, and the 2Θ values of the characteristic peaks can generally have an error of ±0.2° when tested using Cu-Kα radiation.

[0056] In the present application, the "crystal" or "crystalline form" 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 the conditions of the instrument, the preparation of the sample, and the purity of the sample. The relative intensities of the diffraction peaks in an X-ray powder diffraction pattern can also vary with experimental conditions, and therefore the intensities of the diffraction peaks cannot be used as the sole or determining factor in identifying a crystalline form. In fact, the relative intensities of the diffraction peaks in an X-ray powder diffraction pattern are related to the preferred orientation of the crystals, and the intensities of the diffraction peaks shown in the present application are illustrative and not for absolute comparison. Thus, those skilled in the art will appreciate that the X-ray powder diffraction pattern of the crystalline forms claimed in the present application need not be identical to the X-ray powder diffraction patterns of the examples shown herein, and any crystalline form having an X-ray powder diffraction pattern substantially the same as, or similar to, the characteristic peaks of these patterns is within the scope of the present application. Those skilled in the art can compare the X-ray powder diffraction patterns of the present application with the X-ray powder diffraction pattern of an unknown crystalline form to determine whether the two sets of patterns reflect the same or different crystalline forms.

[0057] In some embodiments, the crystalline form K1, the crystalline form K3, and the crystalline form CSVII of the present application are pure, substantially free of any other crystalline form. In the present application, "substantially free" when used in reference to a new crystalline form means that the crystalline form contains less than about 20% by weight of another crystalline form, more preferably less than about 10% by weight of another crystalline form, more preferably less than about 5% by weight of another crystalline form, and more preferably less than about 1% by weight of another crystalline form.

[0058] In the present application, the term "about", when used in reference to a measurable quantity, such as an amount of mass, time, temperature, and the like, is meant to encompass a range of values around the recited value, which range can be ±10%, ±5%, ±1%, ±0.5%, or ±0.1%.

[0059] Unless otherwise specified, the following examples were performed at room temperature. The "room temperature" is not a specific temperature value, but refers to a temperature range of 10-30 °C.

[0060] According to the present application, the compound I and / or a salt thereof as a starting material includes, but is not limited to, a solid form (crystalline or amorphous), an oily form, a liquid form, and a solution. Preferably, the compound I as a starting material is in a solid form.

[0061] The compound I and / or a salt thereof used in the following examples can be prepared according to the prior art, for example, according to the method described in WO2005092864A1.

[0062] Example 1: Preparation method of crystal form K1

[0063] Weigh 49.7 mg of compound I into a vial, then add 0.75 mL of ethanol to obtain a clear solution. Slowly add 0.75 mL of water to the clear solution while stirring, stir at room temperature for 1 hour, transfer to 5°C and stir for 1 hour, then transfer to room temperature and stir overnight to obtain crystal form K1.

[0064] Example 2: Preparation method of crystal form K1

[0065] Approximately 200 mg of compound I was weighed into a vial, followed by the addition of 1 mL of ethanol, resulting in a clear solution. The solution was filtered, and 0.36 mL of water was added to the filtrate. An appropriate amount of K1 crystal seeds was added, followed by 0.04 mL of water. The mixture was stirred at room temperature until a large amount of solid precipitated. Then, 1.4 mL of ethanol / water (5:2, v / v) was added, and the mixture was stirred at room temperature to obtain K1 crystal. The XRPD data for K1 crystal are shown in Table 1, and the XRPD plot is shown in [Figure number missing]. Figure 1 As shown.

[0066] Table 1

[0067]

[0068]

[0069] Example 3: Preparation method of crystal form K3

[0070] Crystal form K1 was air-dried at room temperature to obtain crystal form K3 of the present invention. The XRPD data of crystal form K3 are shown in Table 2, and the XRPD plot is shown in... Figure 2 As shown.

[0071] Thermogravimetric analysis (TGA) was performed on crystal form K3, and its TGA curve is shown below. Figure 3 As shown, there is a weight loss of approximately 0.3% when heated from room temperature to 100°C.

[0072] Table 2

[0073]

[0074]

[0075] Example 4: Preparation method of crystal form CSVII

[0076] Weigh 500.2 mg of Compound I dihydrobromide solid into a glass bottle, add 4 mL of formic acid / methyl tert-butyl ether (1:1, v / v) mixed solvent to dissolve, and then filter into a 5°C reaction kettle. Add 1.25 mL of methyl tert-butyl ether, and then add 0.4 mL of a crystal seed suspension of formic acid / methyl tert-butyl ether (1:3, v / v), and the amount of crystal seed is about 2% (w / w) of the starting material. After aging for 15 min, add 6.75 mL of methyl tert-butyl ether into the kettle at a constant speed, and the dripping is completed in 3 h to obtain crystalline solid. The obtained crystalline solid is the crystal form CSVII of the present application, and the X-ray powder diffraction pattern thereof is shown in Figure 4 The X-ray powder diffraction data are shown in Table 3.

[0077] Table 3

[0078]

[0079]

[0080] Example 5: Preparation method of crystal form CSVII

[0081] Weigh 497.3 mg of Compound I dihydrobromide solid into a glass bottle, add 1 mL of formic acid to dissolve, and then filter. Add 3 mL of isopropyl acetate to the obtained filtrate, and then place it in a -20°C environment for suspension stirring for about 40 min to obtain crystalline solid. The obtained crystalline solid is the crystal form CSVII of the present application.

[0082] Example 6: Preparation method of crystal form CSVII

[0083] Weigh 499.4 mg of Compound I dihydrobromide solid into a glass bottle, add 4 mL of formic acid / 2-methyltetrahydrofuran (1:1, v / v) mixed solvent to dissolve, and then filter into a 5°C reaction kettle. Add 2 mL of 2-methyltetrahydrofuran, and then add 0.4 mL of a crystal seed suspension of formic acid / methyl tert-butyl ether (1:3, v / v), and the amount of crystal seed is about 2% (w / w) of the starting material. After aging for 15 min, add 6.75 mL of 2-methyltetrahydrofuran into the kettle at a constant speed, and the dripping is completed in 3 h to obtain crystalline solid. The obtained crystalline solid is the crystal form CSVII of the present application.

[0084] Example 7: Dynamic solubility of crystal form CSVII

[0085] When performing drug solubility tests to predict the in vivo performance of a drug, it is important to simulate in vivo conditions as much as possible. For oral drugs, FaSSGF (fasted state simulated gastric fluid), FaSSIF (fasted state simulated intestinal fluid), and FeSSIF (fed state simulated intestinal fluid) can be used to simulate in vivo conditions and predict the impact of feeding. The solubility tested in such media is closer to the solubility in the human body environment.

[0086] Take the appropriate amount of crystal form CSVII of the application and suspend it in 1.5 mL of FaSSGF, 1.5 mL of FaSSIF, 1.5 mL of FeSSIF and 1.5 mL of water to prepare a suspension. After equilibration for 1 hour, 4 hours and 24 hours, respectively, test the content of compound I in the solution (mg / mL) by high performance liquid chromatography.

[0087] Example 8: Intrinsic dissolution rate of crystal form CSVII

[0088] Take about 100 mg of crystal form CSVII of the application and pour it into an intrinsic dissolution mold. Under a pressure of 5 kN, continue for 1 min to prepare a flake with a surface area of 0.5 cm 2 Transfer the mold with the flake to a dissolution tester to test the intrinsic dissolution rate.

[0089] Example 9: Stability of crystal form CSVII

[0090] Take about 5 mg of crystal form CSVII prepared by the application and place it in 25℃ / 60%RH, 40℃ / 75%RH, 60℃ / 75%RH, 80℃ conditions, respectively. Test the purity and crystal form by HPLC and XRPD.

[0091] Example 10: Mechanical stability of crystal form CSVII

[0092] Take an appropriate amount of crystal form CSVII and select a suitable tabletting mold to press into shape under different pressures. Test by XRPD before and after tabletting.

[0093] Place crystal form CSVII in a mortar and manually grind for 5 minutes. Test by XRPD before and after grinding.

[0094] Example 11: Hygroscopicity of crystal form CSVII

[0095] Take about 10 mg of crystal form CSVII of the application and test its hygroscopicity by dynamic vapor sorption (DVS). Cycle once under 0-95%-0 relative humidity and record the mass change at each humidity.

[0096] Definition of hygroscopicity characteristics and hygroscopic weight gain (Guidelines for Drug Hygroscopicity Test, Chinese Pharmacopoeia 2020 Edition, General Test 9103, Experimental Conditions: 25℃±1℃, 80%±2% Relative Humidity):

[0097] Deliquescence: Absorbs sufficient moisture to form a liquid

[0098] Extremely hygroscopic: Hygroscopic weight gain is not less than 15.0%

[0099] Hygroscopic: Hygroscopic weight gain is less than 15.0% but not less than 2.0%

[0100] Slightly hygroscopic: hygroscopic weight gain less than 2.0% but not less than 0.2%

[0101] Non-hygroscopic or almost non-hygroscopic: hygroscopic weight gain less than 0.2%

[0102] (Definition of hygroscopicity in European Pharmacopoeia 10th edition 5.11 is similar to that in Chinese Pharmacopoeia)

[0103] Example 12: Purification effect of crystal form CSVII

[0104] The crystal form CSVII of the application and the prior art solid were prepared by the same starting material. The chemical purity of the starting material, the crystal form CSVII of the application and the prior art solid was determined by HPLC.

[0105] Example 13: Particle size distribution of crystal form CSVII

[0106] 10-30 mg of the prepared crystal form CSVII was taken, then about 5 mL of Isopar G (containing 0.2% lecithin) was added, the sample to be tested was mixed uniformly, then was added into Hydro MV dispersing device to reach a suitable range of light shielding, the experiment was started, the particle size distribution was tested after ultrasonic treatment for 30 seconds, and the particle size distribution was measured.

[0107] Example 14: Density of crystal form CSVII

[0108] About 500 mg of powder was gently loaded into a 5 mL graduated cylinder to measure the volume, then was tapped on a ZS-2E tap densimeter for 1250 times to make the powder in the tightest state, the volume after tapping was measured, and the bulk density and tapped density were calculated.

[0109] Example 15: Flowability of crystal form CSVII

[0110] During the preparation process, the compressibility index can be usually used to evaluate the flowability of powder or granules, the determination method is as follows: a certain amount of crystal form CSVII powder was gently loaded into a graduated cylinder to measure the volume before tapping; the powder was tapped to the tightest state, the volume after tapping was measured; the bulk density p0 and the tapped density p were calculated. f ; the compressibility index was calculated according to the formula c=(p f -p0) / p f

[0111] The definition standard of compressibility index for powder flowability refers to ICH Q4B Appendix 13, see Table 2.

[0112] Table 2

[0113] Compressibility factor (%) Flowability ≦10 Excellent 11-15 Good 16-20 Fair 21-25 Acceptable 26-31 Poor 32-37 Very poor >38 Extremely poor ​

[0114] Example 16: Adhesion of crystalline form CSV II

[0115] About 30 mg of crystalline form CSV II was added to a 8 mm round flat punch and tableted at 10 kN pressure. After tableting, the tablet was left to rest for about half a minute and the amount of powder adsorbed by the punch was weighed. After two consecutive tableting runs using this method, the final amount of adhesion accumulated by the punch, the maximum amount of adhesion during tableting and the average amount of adhesion were recorded.

[0116] Example 17: Compressibility of crystalline form CSV II

[0117] Tablets were prepared using a manual tablet press. To a Φ 6 mm round flat punch, 80 mg of crystalline form CSV II and prior art were added and tableted at 10 kN pressure. After 24 h at room temperature, the tablets were left to fully recover their elasticity and the diameter (D) and thickness (L) of the tablets were measured using a vernier caliper. The radial breaking force (hardness, H) was measured using a tablet hardness tester. The tensile strength of the powder was calculated using the formula T = 2H / πDL.

[0118] The above examples are only for illustrating the technical concept and characteristics of the present application, and the purpose is to enable those skilled in the art to understand the content of the present application and to implement it, and cannot limit the protection scope of the present application. Any equivalent changes or modifications made according to the spirit and essence of the present application shall be covered within the protection scope of the present application.

Claims

1. A crystalline form K1 of Compound I characterized by, Using Cu-Ka radiation, the X-ray powder diffraction pattern has characteristic peaks at at least one of the 2-theta values 4.3°±0.2°, 4.6°±0.2°, 5.4°±0.2°, 6.5°±0.2°, 7.3°±0.2°, 8.1°±0.2°, 8.9°±0.2°, 9.3°±0.2°, 11.9°±0.2°. Using Cu-Ka radiation, the X-ray powder diffraction pattern has characteristic peaks at at least one of the 2-theta values 4.9°±0.2°, 5.1°±0.2°, 6.1°±0.2°, 6.5°±0.2°, 8.6°±0.2°, 9.9°±0.2°, 17.4°±0.2°.

2. A crystalline form K3 of Compound I characterized by, The crystalline form CSVII is a formate solvate.

3. A crystalline form of Compound I dihydrobromide salt characterized by, Using Cu-Ka radiation, the X-ray powder diffraction pattern has characteristic peaks at at least one of the 2-theta values 9.2°±0.2°, 9.9°±0.2°, 25.3°±0.2°.

4. The crystalline form CSVII of Compound I dihydrobromide according to claim 3, characterized in that, Using Cu-Ka radiation, the X-ray powder diffraction pattern has characteristic peaks at at least one of the 2-theta values 4.3°±0.2°, 13.1°±0.2°, 20.9°±0.2°.

5. The crystalline form CSVII of Compound I dihydrobromide according to claim 3, characterized in that, Using Cu-Ka radiation, the X-ray powder diffraction pattern has characteristic peaks at at least one of the 2-theta values 7.8°±0.2°, 12.1°±0.2°, 15.6°±0.2°.

6. The crystalline form CSVII of Compound I dihydrobromide according to claim 3, characterized in that, Using Cu-Ka radiation, the X-ray powder diffraction pattern is substantially as shown in Figure 1.

7. The crystalline form CSVII of Compound I dihydrobromide according to claim 3, characterized in that, 8. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form CSVII of Compound I dihydrobromide of claim 3 and pharmaceutically acceptable excipients.

9. Use of the crystalline form CSVII of Compound I dihydrobromide as described in claim 3 for the manufacture of a gamma secretase inhibitor medicament or for the manufacture of a drug for the treatment of desmoid tumors. ​

Images