BMS-986165 CRYSTAL FORM, PREPARATION METHOD THEREFOR AND USE THEREOF

Abstract

A crystal form of a compound I and a preparation method therefor, a pharmaceutical composition containing the crystal form, and a use of the crystal form in the preparation of a TYK2 inhibitor drug and a drug for treating psoriasis, systemic lupus erythematosus, and Crohn's disease. The crystallization of the compound I has one or more improved properties compared to the existing technology, and has an important value to the future optimization and development of the drug.

##STR00001##

Claims

1. A crystalline form CSI of Compound I, wherein the X-ray powder diffraction pattern comprises characteristic peaks at 2theta values of 3.2°±0.2°, 5.6°±0.2° and 8.6°±0.2° using CuKα radiation, ##STR00003##

2. The crystalline form CSI of Compound I according to claim 1, wherein the X-ray powder diffraction pattern comprises one or two or three characteristic peaks at 2theta values of 11.8°±0.2°, 14.2°±0.2° and 15.0°±0.2° using CuKα radiation.

3. The crystalline form CSI of Compound I according to claim 1, wherein the X-ray powder diffraction pattern comprises one or two characteristic peaks at 2theta values of 17.3°±0.2° and 18.2°±0.2° using CuKα radiation.

4. The crystalline form CSI of Compound I according to claim 1, wherein, the X-ray powder diffraction pattern of form CSI is substantially as depicted in FIG. 1.

5. A process for preparing crystalline form CSI of Compound I according to claim 1, wherein the process comprises: adding Compound I solid in a solvent, stirring, separating and drying to obtain crystalline form CSI; wherein the solvent is selected from water, a mixture of water and an alcohol, a mixture of water and a ketone, a mixture of water and a nitrile, or a mixture of water and an ether.

6. The process according to claim 5, wherein said alcohol is a C1-C8 alcohol, said ketone is a C3-C6 ketone, said nitrile is a C2-C4 nitrile, said ether is a C2-C7 ether.

7. The process according to claim 5, wherein said alcohol is ethanol, said ketone is acetone, said nitrile is acetonitrile, said ether is 1,4-dioxane.

8-10. (canceled)

11. A pharmaceutical composition, said pharmaceutical composition comprises a therapeutically effective amount of the crystalline form CSI of Compound I according to claim 1 and pharmaceutically acceptable excipients.

12. A method of inhibiting TYK2 receptor, comprising administering to a subject in need thereof a therapeutically effective amount of the crystalline form CSI of Compound I according to claim 1.

13. A method for treating psoriasis, systemic lupus erythematosus, and Crohn's disease, comprising administering to a subject in need thereof a therapeutically effective amount of the crystalline form CSI of Compound I according to claim 1.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0065] FIG. 1 shows an XRPD pattern of Form CSI in Example 1.

[0066] FIG. 2 shows an XRPD pattern of Form CSI in Example 2.

[0067] FIG. 3 shows a TGA curve of Form CSI in Example 3.

[0068] FIG. 4 shows a DSC curve of Form CSI in Example 3.

[0069] FIG. 5 shows an XRPD pattern of Form CSII in Example 4.

[0070] FIG. 6 shows a TGA curve of Form CSII in Example 4.

[0071] FIG. 7 shows a DSC curve of Form CSII in Example 4.

[0072] FIG. 8 shows an XRPD pattern of Form CSII in Example 5.

[0073] FIG. 9 shows an XRPD pattern overlay of Form CSI and Form A before and after stirring at a solvent mixture of water and acetonitrile (v/v, 1:9) (from top to bottom: initial Form A, initial Form CSI, stirring for 5 minutes, stirring for 6 days).

[0074] FIG. 10 shows an XRPD pattern overlay of Form CSI before and after storage under different conditions for 6 months (from top to bottom: initial, 25° C./60% RH (sealed), 25° C./60% RH (open), 40° C./75% RH (sealed), 40° C./75% RH (open)).

[0075] FIG. 11 shows an XRPD pattern overlay of Form CSI before and after tableting under different pressures (from top to bottom: initial, tableting under 3 kN, tableting under 7 kN, tableting under 14 kN).

[0076] FIG. 12 shows an XRPD pattern overlay of Form CSII before and after storage under different conditions for 6 months (from top to bottom: initial, 25° C./60% RH (sealed), 25° C./60% RH (open), 40° C./75% RH (sealed), 40° C./75% RH (open)).

[0077] FIG. 13 shows an XRPD pattern overlay of Form CSII before and after tableting under different pressures (from top to bottom: initial, tableting under 5 kN, tableting under 10 kN, tableting under 20 kN).

[0078] FIG. 14 shows an XRPD pattern overlay of Form CSII before and after grinding (top: after grinding, bottom: before grinding).

DETAILED DESCRIPTION

[0079] The present disclosure is further illustrated by the following examples which describe the preparation and use of the crystalline forms of the present disclosure in detail. It is obvious to those skilled in the art that many changes in the materials and methods can be accomplished without departing from the scope of the present disclosure.

[0080] The abbreviations used in the present disclosure are explained as follows:

[0081] XRPD: X-ray Powder Diffraction

[0082] DSC: Differential Scanning calorimetry

[0083] TGA: Thermo Gravimetric Analysis

[0084] .sup.1H NMR: Proton Nuclear Magnetic Resonance

[0085] HPLC: High Performance Liquid Chromatography

[0086] Instruments and Methods Used for Data Collection:

[0087] X-ray powder diffraction patterns in the present disclosure examples 1-5 were acquired by a Bruker D2 PHASER X-ray powder diffractometer. The parameters of the X-ray powder diffraction method of the present disclosure are as follows:

X-ray source: Cu, Kα

Kα1 (Å): 1.54060; Kα2 (Å): 1.54439

[0088] Kα2/Kα1 intensity ratio: 0.50

Voltage: 30 (kV)

Current: 10 (mA)

[0089] Scan range: from 3.0 degree to 40.0 degree

[0090] X-ray powder diffraction patterns in the present disclosure examples 6-8 and 11-12 were acquired by Bruker D8 DISCOVER X-ray powder diffractometer. The parameters of the X-ray powder diffraction method of the present disclosure are as follows:

X-ray source: Cu, Kα

Kα1 (Å): 1.54060; Kα2 (Å): 1.54439

[0091] Kα2/Kα1 intensity ratio: 0.50

Voltage: 40 (kV)

Current: 40 (mA)

[0092] Scan range: from 4.0 degree to 40.0 degree

[0093] Differential scanning calorimetry (DSC) data in the present disclosure were acquired by a TA Q2000. The parameters of the DSC method of the present disclosure are as follows:

Heating rate: 10° C./min
Purge gas: nitrogen

[0094] Thermo gravimetric analysis (TGA) data in the present disclosure were acquired by a TA Q500. The parameters of the TGA method of the present disclosure are as follows:

Heating rate: 10° C./min
Purge gas: nitrogen

[0095] Proton nuclear magnetic resonance spectrum data (.sup.1H NMR) were collected from a Bruker Avance II DMX 400M Hz NMR spectrometer. 1-5 mg of sample was weighed and dissolved in 0.5 mL of deuterated chloroform to obtain a solution with a concentration of 2-10 mg/mL.

[0096] The parameters for related substance detection in the present disclosure are shown in Table 1.

TABLE-US-00001 TABLE 1 HPLC Waters ACQUITY H-class UPLC with PDA detector Column Waters ACQUITY UPLC BEH C18, 2.1 × 50 mm, 1.7 μm Mobile Phase A: 0.1% Trifluoroacetic acid (TFA) in H.sub.2O (v/v) B: 0.1% TFA in Acetonitrile (v/v) Gradient Time (min) % B 0.0 10 0.5 10 7.0 80 8.0 80 8.1 10 10.0 10 Running time 10.0 min Stop time 0 min Speed 0.5 mL/min Injection Volume 1 μL Detection wavelength UV, 240 nm Column Temperature 40° C. Sample Temperature Room Temperature Diluent Acetonitrile: H.sub.2O = 50:50 (v/v)

[0097] Unless otherwise specified, the following examples were conducted at room temperature. Said “room temperature” is not a specific temperature, but a temperature range of 10-30° C.

[0098] According to the present disclosure, Compound I used as a raw material includes but not limited to solid (crystalline or amorphous), oil, liquid and solution. Preferably, Compound I and/or its salts used as the raw material is a solid.

[0099] Compound I used in the following examples can be prepared by known methods in the prior arts, for example, the method disclosed in WO2018183656A1.

EXAMPLES

Example 1 Preparation of Form CSI

[0100] 86.1 mg of Compound I solid was weighed into a glass vial, and then 0.8 mL of water was added. The system was stirred at room temperature for 8 days. A solid was obtained by separating and drying.

[0101] The solid was confirmed to be Form CSI. The XRPD pattern of Form CSI is shown in FIG. 1, and the XRPD data are listed in Table 2.

TABLE-US-00002 TABLE 2 Diffraction angle 2θ d spacing Intensity % 3.20 27.64 100.00 5.62 15.73 57.58 6.44 13.71 8.70 8.59 10.30 98.62 9.75 9.07 3.76 11.75 7.53 21.95 14.23 6.22 18.21 14.98 5.91 16.16 16.28 5.44 2.58 17.25 5.14 7.63 18.17 4.88 10.16 19.84 4.48 4.54 21.47 4.14 4.27 23.60 3.77 12.17 26.08 3.42 5.11

Example 2 Preparation of Form CSI

[0102] 230.8 mg of Compound I solid was weighed and dissolved into 13 mL of chloroform to obtain a clear solution. The solution was filtered, and the filtrate was rotary evaporated at 40° C. to obtain a dry solid. A certain amount of the dried solid was weighed into a vial, and then a certain volume of solvent was added according to Table 3. The system was stirred at room temperature for a certain period, filtered and dried to obtain a solid. Samples 1˜4 were confirmed to be Form CSI. The XRPD pattern of Sample 2 is shown in FIG. 2, and the XRPD data are listed in Table 4.

TABLE-US-00003 TABLE 3 Weight of Vol- Stirring Crystal- Num- the dried ume time line ber solid (mg) Solvent (v:v) (mL) (day) form 1 12.0 water 0.30 1 CSI 2 20.7 water/ethanol 0.35 4 CSI (6:4) 3 17.8 water/acetone 0.35 4 CSI (4:6) 4 17.9 water/1,4- 0.30 4 CSI dioxane (1:1)

TABLE-US-00004 TABLE 4 Diffraction angle 2θ d spacing Intensity % 3.26 27.11 100.00 5.69 15.54 45.27 6.53 13.54 7.53 8.59 10.30 74.67 9.84 8.99 2.91 11.75 7.53 17.73 14.21 6.23 15.79 15.00 5.91 15.17 16.38 5.41 1.97 17.29 5.13 7.05 18.24 4.86 7.58 19.91 4.46 3.77 21.46 4.14 3.81 23.64 3.76 9.46 24.69 3.61 3.95 26.19 3.40 4.96

Example 3 Preparation of Form CSI

[0103] 306.6 mg of Compound I solid was weighed into a glass vial, and 15 mL of water was added. The system was stirred at room temperature for 10 days and filtered to obtain a solid. The obtained solid was dried under vacuum at room temperature for 9 hours. The solid was confirmed to be Form CSI.

[0104] The TGA curve of Form CSI is substantially as depicted in FIG. 3, which shows about 7.6% weight loss when heated to 200° C.

[0105] The DSC curve of Form CSI is substantially as depicted in FIG. 4. The DSC curve shows the first endothermic peak at around 108° C. (onset temperature) corresponding to dehydration, an exothermic peak at around 137° C. (onset temperature), and the second endothermic peak at around 263° C. (onset temperature).

[0106] The .sup.1H NMR data of Form CSI are: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.97 (s, 1H), 9.44 (s, 1H), 8.20 (s, 1H), 8.10 (s, 1H), 8.05 (s, 1H), 7.79 (dd, J=7.9, 1.6 Hz, 1H), 7.50 (dd, J=8.0, 1.5 Hz, 1H), 7.25 (t, J=7.9 Hz, 1H), 4.00 (s, 3H), 3.80 (s, 3H), 1.84-1.75 (m, 1H), 1.14-1.05 (m, 2H), 0.93-0.84 (m, 2H).

Example 4 Preparation of Form CSII

[0107] A certain amount of Compound I solid was weighed and dissolved into a certain volume of solvent according to Table 5 to form a solution. The solution was evaporated at room temperature for one day to obtain a solid. The solid was dried under vacuum at 35° C. for two days, and then dried under vacuum at 80° C. for 3.5 hours. Samples 1-5 were confirmed to be Form CSII. The XRPD pattern of Sample 3 is shown in FIG. 5, and the XRPD data are listed in Table 6.

[0108] The TGA curve of Form CSII is substantially as depicted in FIG. 6, which shows about 0.3% weight loss when heated to 200° C.

[0109] The DSC curve of Form CSII is substantially as depicted in FIG. 7, which shows the first endothermic peak at 259.5° C. (onset temperature), which is the melting endotherm peak.

TABLE-US-00005 TABLE 5 Weight of Crystal- Num- Compound Volume line ber I (mg) Solvent (v:v:v) (mL) form 1 9.5 water/ 1 CSII tetrahydrofuran/ acetone (1:20:1) 2 9.8 water/ 1 CSII tetrahydrofuran/ acetone (1:15:1) 3 9.9 water/ 1 CSII tetrahydrofuran/ acetone (1:15:5) 4 9.3 water/ 1 CSII tetrahydrofuran/ ethanol (1:20:1) 5 10.4 water/ 1 CSII tetrahydrofuran/ ethanol (1:15:1)

TABLE-US-00006 TABLE 6 Diffraction angle 2θ d spacing Intensity % 3.98 22.18 48.40 7.43 11.89 50.29 8.08 10.94 100.00 8.74 10.11 66.90 11.40 7.77 98.70 11.96 7.40 25.38 13.50 6.56 80.28 14.88 5.96 30.47 15.97 5.55 47.52 16.23 5.46 39.04 17.54 5.06 28.54 19.44 4.57 4.25 20.00 4.44 13.46 20.85 4.26 23.07 22.39 3.97 12.84 23.10 3.85 16.93 24.05 3.70 23.81 24.48 3.64 6.28 25.85 3.45 7.80 26.19 3.40 4.55 27.20 3.28 6.97 28.84 3.10 7.95 31.47 2.84 3.88 32.46 2.76 3.70 36.95 2.43 3.90 37.89 2.37 7.12 38.16 2.36 4.29

Example 5 Preparation of Form CSII

[0110] Form CSII was exposed to a high relative humidity condition for a certain time, the XRPD pattern of Form CSII is substantially as depicted in FIG. 8, and the XRPD data are listed in Table 7.

[0111] The .sup.1H NMR data of Form CSII are: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.98 (s, 1H), 9.98 (s, 1H), 8.24 (s, 1H), 8.11 (s, 1H), 8.04 (s, 1H), 7.80 (dd, J=7.8, 1.2 Hz, 1H), 7.52 (dd, J=7.9, 1.0 Hz, 1H), 7.26 (t, J=7.9 Hz, 1H), 4.00 (s, 3H), 3.81 (s, 3H), 1.92-1.84 (m, 1H), 1.13-1.07 (m, 2H), 0.92-0.85 (m, 2H).

TABLE-US-00007 TABLE 7 Diffraction angle 2θ d spacing Intensity % 3.77 23.42 40.82 7.68 11.51 73.93 9.38 9.43 24.87 11.38 7.78 14.64 12.08 7.33 100.00 15.20 5.83 40.02 15.45 5.74 14.78 16.26 5.45 7.25 18.22 4.87 3.81 18.86 4.71 35.48 22.31 3.99 6.02 22.90 3.88 26.07 23.27 3.82 8.13 24.29 3.66 5.59 25.70 3.47 10.75 26.78 3.33 6.27 27.61 3.23 5.59 31.06 2.88 1.34 32.43 2.76 1.09 37.96 2.37 1.55

Example 6 Thermodynamic Stability of Form CSI

[0112] A certain amount of Form A was weighed into glass vail and 0.3 mL of solvent mixtures of water and acetonitrile, water and methanol, or water and acetone according to table 8 were added to form suspensions. Approximately 6 mg of Form CSI of the present disclosure was added in the suspension. After mixing at 5° C. for 5 minutes, a portion of the solid was taken out and tested by XRPD. After the suspension was stirred at 5° C. for 6 days, a portion of the solid was taken out and tested by XRPD again. The results are shown in Table 8. The XRPD overlay of Sample 1 before and after stirring in water/acetonitrile is shown in FIG. 9.

TABLE-US-00008 TABLE 8 Sam- Weight of Stirring time ple Form A (mg) Solvent (v/v) 5 minutes 6 days 1 5.0 water/acetonitrile Form A + Form 2 4.6 water/acetonitrile Form CSI 3 6.4 water/methanol (5:5) CSI 4 5.9 water/methanol (7:3) 5 6.5 water/acetone (2:8) 6 6.4 water/acetone (3:7) 7 5.4 water/acetone (7:3)

[0113] The results show that Form CSI has better stability than Form A in the solvent systems of water/acetonitrile, water/methanol or water/acetone with a certain volume ratio under 5° C. condition.

Example 7 Stability of Form CSI

[0114] Approximately 5 mg of Form CSI in the present disclosure was stored under different conditions of 25° C./60% RH and 40° C./75% RH. Crystalline form and chemical purity were checked by XRPD and HPLC, respectively. The results are shown in Table 9, and the XRPD overlay is shown in FIG. 10.

TABLE-US-00009 TABLE 9 Crystal- Initial line form Conditions Time form Purity Form Initial — Form 98.13% CSI 25.sup.o C./60% RH (open) 6 months CSI 98.76% 25.sup.o C./60% RH (sealed) 6 months 98.79% 40.sup.o C./75% RH (open) 6 months 98.74% 40.sup.o C./75% RH (sealed) 6 months 98.73%

[0115] The results show that Form CSI is stable for at least 6 months at 25° C./60% RH and 40° C./75% RH. Form CSI has good stability under long-term and accelerated conditions.

Example 8 Physical Stability of Form CSI Under Pressure

[0116] A certain amount of Form CSI was compressed into tablets under 3 kN, 7 kN and 14 kN with suitable tableting die. Crystalline forms before and after tableting were checked by XRPD. The test results show that crystalline state of Form CSI does not change under different pressures. The XRPD overlay is shown in FIG. 11.

Example 9 Compressibility of Form CSI

[0117] ENERPAC manual tablet press was used for compression. 80 mg of Form CSI and Form A were weighed and added into the dies of a φ6 mm round tooling, compressed at 10 KN manually, then stored at room temperature for 24 h until complete elastic recovery. Hardness (H) was tested with an intelligent tablet hardness tester. Diameter (D) and thickness (L) were tested with caliper. Tensile strength of the powder was calculated with the following formula: T=2H/πDL*9.8. Under a certain force, the greater the tensile strength, the better the compressibility. The results are presented in Table 10. The results indicate that Form A is splintering during the tablet pressing process, Form CSI has better compressibility compared with Form A.

TABLE-US-00010 TABLE 10 Thickness Diameter Hardness Tensile Form (mm) (mm) (kgf) strength (MPa) Form A N/A N/A N/A N/A Form CSI 2.39 6.06 7.87 3.39

Example 10 Adhesiveness of Form CSI

[0118] Approximately 30 mg of Form CSI and Form A were weighed and added into the dies of φ8 mm round tooling, compressed at 10 kN and held for 30 s. The material sticking to the punch was recorded. The compression was repeated twice and the cumulative amount, maximum amount and average amount of material sticking to the punch during the compression process were recorded. The results are shown in Table 11. The results indicate that the adhesiveness of Form CSI is superior to that of Form A.

TABLE-US-00011 TABLE 11 Maximum Average Form amount (mg) amount (mg) Form A 0.260 0.190 Form CSI 0.130 0.105

Example 11 Stability of Form CSII

[0119] Approximately 5 mg of Form CSII in the present disclosure was stored under different conditions of 25° C./60% RH and 40° C./75% RH. Crystalline form and chemical purity were checked by XRPD and HPLC, respectively. The results are shown in Table 12, and the XRPD overlay is shown in FIG. 12.

TABLE-US-00012 TABLE 12 Initial Crystalline form Conditions Time form Form Initial — Form CSII CSII 25.sup.o C./60% RH (open) 6 months 25.sup.o C./60% RH (closed) 6 months 40.sup.o C./75% RH (open) 6 months 40.sup.o C./75% RH (closed) 6 months

[0120] The results show that Form CSII is stable for at least 6 months at 25° C./60% RH and 40° C./75% RH. Form CSII has good stability under long-term and accelerated conditions.

Example 12 Physical Stability of Form CSII Under Pressure

[0121] A certain amount of Form CSII was compressed into tablets under 5 kN, 10 kN and 20 kN with suitable tableting die. Crystalline forms before and after tableting were checked by XRPD. The test results show that crystalline state of Form CSII does not change under different pressures. The XRPD overlay is shown in FIG. 13.

[0122] Form CSII was grounded manually for 5 minutes in a mortar. Crystalline form before and after grinding were checked by XRPD. The test results show that crystalline state of Form CSII does not change after grinding. The XRPD overlay of the solid before and after grinding is shown in FIG. 14.

Example 13 Compressibility of Form CSII

[0123] ENERPAC manual tablet press was used for compression. 80 mg of Form CSII and Form A were weighed and added into the dies of a φ6 mm round tooling, compressed at 10 KN manually, then stored at room temperature for 24 h until complete elastic recovery. Hardness (H) was tested with an intelligent tablet hardness tester. Diameter (D) and thickness (L) were tested with caliper. Tensile strength of the powder was calculated with the following formula: T=2H/πDL*9.8. Under a certain force, the greater the tensile strength, the better the compressibility. The results are shown in Table 13. The results indicate that Form A is splintering during the tablet pressing process, Form CSII has better compressibility compared with Form A.

TABLE-US-00013 TABLE 13 Tensile Thickness Diameter Hardness strength Form (mm) (mm) (kgf) (MPa) Form A N/A N/A N/A N/A Form CSII 2.30 6.08 4.24 1.89

Example 14 Adhesiveness of Form CSII

[0124] Approximately 30 mg of Form CSII and Form A were weighed and then added into the dies of φ8 mm round tooling, compressed at 10 kN and held for 30 s. The material sticking to the punch was recorded. The compression was repeated twice and the cumulative amount, maximum amount and average amount of material sticking to the punch during the compression were recorded. The results are shown in Table 14. The results indicate that the adhesion quantity of Form A is 3.2 times that of Form CSII and the adhesiveness of Form CSII is superior to that of Form A.

TABLE-US-00014 TABLE 14 Maximum Average Form amount (mg) amount (mg) Form A 0.260 0.190 Form CSII 0.06 0.06

[0125] The examples described above are only for illustrating the technical concepts and features of the present disclosure and intended to make those skilled in the art being able to understand the present disclosure and thereby implement it and should not be concluded to limit the protective scope of this disclosure. Any equivalent variations or modifications according to the spirit of the present disclosure should be covered by the protective scope of the present disclosure.