CN112876490A - Crystal forms of nitrogen-containing tricyclic compounds and uses thereof - Google Patents

Abstract

The present invention relates to crystalline forms of a nitrogen-containing tricyclic compound and uses thereof. The invention also relates to a pharmaceutical composition comprising the crystalline form and the use of the crystalline form or the pharmaceutical composition for the manufacture of a medicament for preventing, treating or alleviating FXR mediated diseases in a patient.

Description

Crystal forms of nitrogen-containing tricyclic compounds and uses thereof

Technical Field

The invention belongs to the field of medicines, relates to a crystal form of a nitrogenous tricyclic compound and application thereof, and particularly relates to a crystal form of 2- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazole-4-yl) methoxy) -10H-spiro [ benzo [6,7] oxepin [3,2-b ] pyridine-11, 1' -cyclopropane ] -7-formic acid (a compound shown in a formula (I)) and application thereof, and further relates to a pharmaceutical composition containing the crystal form. The crystalline form or the pharmaceutical composition is for use in preventing, treating or alleviating a disease mediated by FXR in a patient.

Background

Farnesoid X Receptor (FXR) is a member of the nuclear hormone receptor superfamily and is expressed mainly in the liver, kidney and intestine (Seol et al, mol. Endocrinol (1995),9: 72-85; Forman et al, Cell (1995),81: 687-. It functions as a heterodimer with the Retinoid X Receptor (RXR) and binds to response elements in the promoter of target genes to regulate gene transcription. The FXR-RXR heterodimer binds with highest affinity to the inverted repeat-1 (IR-1) response element, where the hexamers that bind to the consensus receptor (consensus receptor) are separated by one nucleotide. FXR can be activated by bile acids (end products of cholesterol metabolism) (Makishima et al Science (1999),284: 1362-.

FXR is a key regulator of cholesterol homeostasis, triglyceride synthesis, and adipogenesis (Crawley, Expert Opinion. patents (2010),20: 1047-. Besides being used as targets for treating dyslipidemia, obesity, vitamin D-related diseases, intestinal diseases, drug-induced side effects and hepatitis (Crawley, Expert Opinion patients patents (2010),20: 1047-.

Patent applications WO 2018024224 and CN 107686486 disclose nitrogen-containing tricyclic compounds useful as FXR activity modulators, and methods for preparing and using the same, wherein compound 7, i.e., compound 2- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -10H-spiro [ benzo [6,7] oxepin [3,2-b ] pyridine-11, 1' -cyclopropane ] -7-carboxylic acid (compound represented by formula (I)), is specifically disclosed. However, the patent application does not disclose the specific microstructure of the compound, i.e. does not disclose any crystal structure thereof.

It is well known in the art that drug polymorphism is a common phenomenon in drug development and is an important factor affecting drug quality. Different crystal forms of the same drug may be significantly different in appearance, solubility, melting point, dissolution rate, bioavailability and the like, and also have different influences on the stability, bioavailability, curative effect and the like of the drug. Therefore, in drug development, the problem of polymorphism of drugs should be considered comprehensively.

Disclosure of Invention

The invention provides a crystal form of a compound shown in a formula (I) and a pharmaceutical composition thereof, wherein the crystal form or the pharmaceutical composition has better pharmacological properties (such as good pharmacokinetic properties) and obviously improved properties such as stability and the like, so that the crystal form or the pharmaceutical composition has better pharmaceutical properties.

In particular, the invention relates to a crystal form of a compound shown as a formula (I) and a pharmaceutical composition thereof, and application of the crystal form or the pharmaceutical composition in preparing a medicament for preventing, treating or relieving FXR-mediated diseases of a patient. The crystalline forms of the present invention may also be in the form of solvates, for example hydrates.

In one aspect, the invention provides a crystalline form of a compound of formula (I),

in some embodiments, the crystalline form of the compound of formula (I) of the present invention is form B, wherein form B has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 18.88 ° ± 0.2 °,21.87 ° ± 0.2 °,22.06 ° ± 0.2 °,25.29 ° ± 0.2 °,25.45 ° ± 0.2 °.

In some embodiments, the crystalline form of the compound of formula (I) of the present invention is form B, wherein form B has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 12.54 ° ± 0.2 °,16.20 ° ± 0.2 °,18.20 ° ± 0.2 °,18.75 ° ± 0.2 °,18.88 ° ± 0.2 °,21.87 ° ± 0.2 °,22.06 ° ± 0.2 °,24.58 ° ± 0.2 °,25.29 ° ± 0.2 °,25.45 ° ± 0.2 °,26.75 ° ± 0.2 °,30.49 ° ± 0.2 °,31.74 ° ± 0.2 °.

In some embodiments, the crystalline form of the compound of formula (I) of the present invention is form B, wherein form B has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.24 ° ± 0.2 °,8.11 ° ± 0.2 °,10.82 ° ± 0.2 °,11.13 ° ± 0.2 °,11.84 ° ± 0.2 °,12.21 ° ± 0.2 °,12.54 ° ± 0.2 °,13.67 ° ± 0.2 °,14.02 ° ± 0.2 °,14.50 ° ± 0.2 °,14.81 ° ± 0.2 °,15.40 ° ± 0.2 °,15.67 ° ± 0.2 °,16.20 ° ± 0.2 °,17.27 ° ± 0.2 °,17.56 ° ± 0.2 °,18.20 ° ± 0.2 °,18.75 ° ± 0.88 ° ± 0.2 °,19.19 ° ± 0.2 °,19.65 ° ± 0.2 °,20.34 ° ± 0.2 °,20.83 ° ± 0.2.2.2 ° ± 0.2 °,2 ± 0.26 °, 2.26 ° ± 0.26 °, 2.26 ° ± 0.0.26 °,2 ° ± 0.26 °, 2.0.26 ° ± 0.26 °, 2.2.2 °,2 °, 2.0.0.0.2 ° ± 0.0.26 ° ± 0.2 °,2 °, 2.0.0.26 ° ± 0.2.2 ° ± 0.2 °,2 °, 2.2 °,2 °, 2.2.2 °, 2.0.9 ° ± 0.2 °, 2.2.2 °,2 °, 2.0.0.2.2.2 °, 2.2.9 ° ±,30.49 ° ± 0.2 °,31.74 ° ± 0.2 °,32.70 ° ± 0.2 °,33.49 ° ± 0.2 °,34.17 ° ± 0.2 °,34.57 ° ± 0.2 °,34.98 ° ± 0.2 °,35.45 ° ± 0.2 °,36.54 ° ± 0.2 °,37.67 ° ± 0.2 °,38.30 ° ± 0.2 °,38.75 ° ± 0.2 °,39.50 ° ± 0.2 °,40.91 ° ± 0.2 °,42.81 ° ± 0.2 °,44.32 ° ± 0.2 °,45.39 ° ± 0.2 °,45.99 ° ± 0.2 °,48.44 ° ± 0.2 °,50.29 ° ± 0.2 °,52.52 ° ± 0.2 °,56.49 ° ± 0.2 °,58.25 ° ± 0.2 °.

In some embodiments, the crystalline form of the compound of formula (I) of the present invention is form B, wherein form B has an X-ray powder diffraction pattern substantially as shown in figure 1.

In some embodiments, the crystalline form of the compound of formula (I) of the present invention is form C, wherein the crystalline form C has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 13.66 ° ± 0.2 °,17.45 ° ± 0.2 °,20.88 ° ± 0.2 °,22.48 ° ± 0.2 °,25.70 ° ± 0.2 °.

In some embodiments, the crystalline form of the compound of formula (I) of the present invention is form C, wherein the crystalline form C has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 11.69 ° ± 0.2 °,13.66 ° ± 0.2 °,15.19 ° ± 0.2 °,16.42 ° ± 0.2 °,17.45 ° ± 0.2 °,19.22 ° ± 0.2 °,20.88 ° ± 0.2 °,22.48 ° ± 0.2 °,22.81 ° ± 0.2 °,24.27 ° ± 0.2 °,25.70 ° ± 0.2 °,27.01 ° ± 0.2 °,31.06 ° ± 0.2 °.

In some embodiments, the crystalline form of the compound of formula (I) of the present invention is form C, wherein the crystalline form C has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 7.43 ° ± 0.2 °,8.10 ° ± 0.2 °,10.24 ° ± 0.2 °,10.97 ° ± 0.2 °,11.69 ° ± 0.2 °,12.15 ° ± 0.2 °,13.14 ° ± 0.2 °,13.66 ° ± 0.2 °,15.19 ° ± 0.2 °,15.46 ° ± 0.2 °,16.42 ° ± 0.2 °,17.45 ° ± 0.2 °,18.06 ° ± 0.2 °,18.58 ° ± 0.2 °,19.22 ° ± 0.2 °,19.66 ° ± 0.2 °,20.88 ° ± 0.2 °,21.33 ° ± 0.2 °,22.01 ° ± 0.2 °,22.48 ° ± 0.2 °,22.81 ° ± 0.2 °,24.27 ° ± 0.2 °,24.99 ° ± 0.25.45 ° ± 0.2 °, 0.2 ° ± 0.2 °, 22.2.2 ° ± 0.2 °,22.2 °,2 ° ± 0.2.2 °, 2.2.2 °,2 ° ± 0.9 ° ± 0.2 °,2 °, 2.9 ° ± 0.9 ° ± 0.2 °, 2.9 ° ± 0.2.2.2.2.2 °,2 °, 2.9 ° ± 0.2 °,2 °, 2.2.2 °,2 °, 2.2 °, 2.9 ° ± 0.9 ° ± 0.2.2.2 °,2 °, 2.9 ° ± 0.9, 46.63 ° ± 0.2 °,47.69 ° ± 0.2 °,59.99 ° ± 0.2 °.

In some embodiments, the crystalline form of the compound of formula (I) of the present invention is form C, wherein form C has an X-ray powder diffraction pattern substantially as shown in figure 2.

In some embodiments, the crystalline form of the compound of formula (I) of the present invention is form E, wherein the form E has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.23 degrees +/-0.2 degrees, 18.15 degrees +/-0.2 degrees, 18.81 degrees +/-0.2 degrees, 20.88 degrees +/-0.2 degrees and 30.37 degrees +/-0.2 degrees.

In some embodiments, the crystalline form of the compound of formula (I) of the present invention is form E, wherein the form E has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.23 ° ± 0.2 °,12.50 ° ± 0.2 °,14.23 ° ± 0.2 °,18.15 ° ± 0.2 °,18.81 ° ± 0.2 °,20.88 ° ± 0.2 °,21.77 ° ± 0.2 °,22.49 ° ± 0.2 °,25.20 ° ± 0.2 °,25.39 ° ± 0.2 °,28.8 ° ± 0.2 °,30.37 ° ± 0.2 °,31.65 ° ± 0.2 °.

In some embodiments, the crystalline form of the compound of formula (I) of the present invention is form E, wherein the form E has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.23 ° ± 0.2 °,7.08 ° ± 0.2 °,8.12 ° ± 0.2 °,10.97 ° ± 0.2 °,12.50 ° ± 0.2 °,13.88 ° ± 0.2 °,14.23 ° ± 0.2 °,15.77 ° ± 0.2 °,16.18 ° ± 0.2 °,17.20 ° ± 0.2 °,18.15 ° ± 0.2 °,18.65 ° ± 0.2 °,18.81 ° ± 0.2 °,20.31 ° ± 0.2 °,20.88 ° ± 0.2 °,21.49 ° ± 0.2 °,21.77 ° ± 0.2 °,22.05 ° ± 0.2 °,22.21 ° ± 0.2 °,22.49 ° ± 0.2 °,22.74 ° ± 0.2 °,23.19 ° ± 0.24.16 ° ± 0.24.24 ° ± 0.2 °,22.21 ° ± 0.2 °,22.2 ° ± 0.2 °, 22.2.2.2 ° ± 0.19 ° ± 0.2 °,22 ° ± 0.2 °, 22.2.2 °, 22.2.2.2 ° ± 0.2 °,22 ° ± 0.2.2.2.2 °, 2.2.2 ° ± 0.2 ° ± 0.2.2 °,2 ° ± 0.2 °, 2.2 °,2 °, 2.2.2 °,30 ° ± 0.2.2.2.2 ° ± 0.2 °,30 ° ± 0.2.2.2 °,30 ° ±,47.69 ° ± 0.2 °,50.06 ° ± 0.2 °,54.56 ° ± 0.2 °,56.25 ° ± 0.2 °.

In some embodiments, the crystalline form of the compound of formula (I) of the present invention is form E, wherein form E has an X-ray powder diffraction pattern substantially as shown in figure 3.

In some embodiments, the crystalline form of the compound of formula (I) of the present invention is form F, wherein the crystalline form F has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 15.51 ° ± 0.2 °,18.43 ° ± 0.2 °,22.35 ° ± 0.2 °,25.27 ° ± 0.2 °.

In some embodiments, the crystalline form of the compound of formula (I) of the present invention is form F, wherein the crystalline form F has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.10 ° ± 0.2 °,12.12 ° ± 0.2 °,14.31 ° ± 0.2 °,15.51 ° ± 0.2 °,18.25 ° ± 0.2 °,18.43 ° ± 0.2 °,19.29 ° ± 0.2 °,20.59 ° ± 0.2 °,22.35 ° ± 0.2 °,22.52 ° ± 0.2 °,24.77 ° ± 0.2 °,25.27 ° ± 0.2 °,30.20 ° ± 0.2 °.

In some embodiments, the crystalline form of the compound of formula (I) of the present invention is form F, wherein the crystalline form F has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.10 ° ± 0.2 °,8.31 ° ± 0.2 °,10.39 ° ± 0.2 °,11.11 ° ± 0.2 °,12.12 ° ± 0.2 °,12.78 ° ± 0.2 °,12.91 ° ± 0.2 °,13.57 ° ± 0.2 °,14.12 ° ± 0.2 °,14.31 ° ± 0.2 °,15.51 ° ± 0.2 °,16.16 ° ± 0.2 °,16.69 ° ± 0.2 °,17.39 ° ± 0.2 °,17.62 ° ± 0.2 °,18.25 ° ± 0.2 °,18.43 ° ± 0.2 °,18.71 ° ± 0.19 ° ± 0.2 °,19.68 ° ± 0.2 °,20.59 ° ± 0.76 ° ± 0.2.24 ° ± 0.53 ° ± 0.2 °,2 ° ± 0.2 °, 2.2 ° ± 0.2 °,2 ° ± 0.2 °, 2.2 °,2 °, 2.2.2 ° ± 0.2 °, 2.2 °, 2.2.2 ° ± 0.2 °,2 ° ± 0.2 °, 2.2.2.2.2 ° ± 0.2 °,2 °, 2.2.2 ° ± 0.2.2 ° ± 0.2 °,2 °, 2.2.2 °,2 °, 2.2 °, 2.2.2.2.2.2 ° ± 0.2.2 °,2 °, 2.2 °, 2.2.2 ° ± 0.2.2 °,30.98 ° ± 0.2 °,31.34 ° ± 0.2 °,31.68 ° ± 0.2 °,32.23 ° ± 0.2 °,32.94 ° ± 0.2 °,33.40 ° ± 0.2 °,34.00 ° ± 0.2 °,34.45 ° ± 0.2 °,34.83 ° ± 0.2 °,35.37 ° ± 0.2 °,35.90 ° ± 0.2 °,37.39 ° ± 0.2 °,38.66 ° ± 0.2 °,39.38 ° ± 0.2 °,40.92 ° ± 0.2 °,42.21 ° ± 0.2 °,43.56 ° ± 0.2 °,44.34 ° ± 0.2 °,45.63 ° ± 0.2 °,46.33 ° ± 0.2 °,47.75 ° ± 0.2 °,48.75 ° ± 0.2 °,51.15 ° ± 0.2 °,53.95 ° ± 0.2 °,56.18 ° ± 0.18 °.

In some embodiments, the crystalline form of the compound of formula (I) of the present invention is form F, wherein form F has an X-ray powder diffraction pattern substantially as shown in figure 4.

In some embodiments, the crystalline form of the compound of formula (I) of the present invention is form G, wherein form G has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 13.63 ° ± 0.2 °,19.50 ° ± 0.2 °,21.08 ° ± 0.2 °,22.59 ° ± 0.2 °.

In some embodiments, the crystalline form of the compound of formula (I) of the present invention is form G, wherein form G has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 11.65 ° ± 0.2 °,13.63 ° ± 0.2 °,15.11 ° ± 0.2 °,17.50 ° ± 0.2 °,19.50 ° ± 0.2 °,20.64 ° ± 0.2 °,21.08 ° ± 0.2 °,21.40 ° ± 0.2 °,22.59 ° ± 0.2 °,24.43 ° ± 0.2 °,25.17 ° ± 0.2 °,25.74 ° ± 0.2 °,25.97 ° ± 0.2 °.

In some embodiments, the crystalline form of the compound of formula (I) of the present invention is form G, wherein form G has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 7.53 ° ± 0.2 °,8.14 ° ± 0.2 °,8.62 ° ± 0.2 °,10.31 ° ± 0.2 °,10.93 ° ± 0.2 °,11.65 ° ± 0.2 °,12.06 ° ± 0.2 °,13.35 ° ± 0.2 °,13.63 ° ± 0.2 °,15.11 ° ± 0.2 °,15.51 ° ± 0.2 °,16.32 ° ± 0.2 °,16.41 ° ± 0.2 °,17.50 ° ± 0.2 °,17.84 ° ± 0.2 °,18.29 ° ± 0.2 °,18.94 ° ± 0.2 °,19.50 ° ± 0.20.64 ° ± 0.2 °,21.08 ° ± 0.2 °,21.40 ° ± 0.2 °,21.50 ° ± 0.21.21.95 ° ± 0.2.2.2 ° ± 0.2 °,19.2 ± 0.2.2 ° ± 0.2 ° ± 0.2.2 °,19 ° ± 0.2.2 °, 0.2 ° ± 0.2 °,3 ° ± 0.2 °, 2.2 °,2 °, 2.2.2 °, 2.2.2.2 °,21.2 °,2 ° ± 0.2 °,2 ° ± 0.2.2.2.2 °,2 °, 2.2 °, 2.2.2 ° ± 0.2.2 °,2 ° ± 0.2 °,2 °, 2.2.2 °,2 °, 2.2 °, 2.2.2.2.2.2.2 °,3 ° ± 0.2 °,2 °, 2.2.2 ° ± 0.2, 34.41 ° ± 0.2 °,34.59 ° ± 0.2 °,35.58 ° ± 0.2 °,36.50 ° ± 0.2 °,37.65 ° ± 0.2 °,38.30 ° ± 0.2 °,39.98 ° ± 0.2 °,40.54 ° ± 0.2 °,42.15 ° ± 0.2 °,43.03 ° ± 0.2 °,44.51 ° ± 0.2 °,46.21 ° ± 0.2 °,47.29 ° ± 0.2 °,49.47 ° ± 0.2 °,50.80 ° ± 0.2 °.

In some embodiments, the crystalline form of the compound of formula (I) of the present invention is form G, wherein form G has an X-ray powder diffraction pattern substantially as shown in figure 5.

In some embodiments, the crystalline form of the compound of formula (I) of the present invention is form B, wherein the differential scanning calorimetry trace of form B comprises an endothermic peak at 130.48 ℃ ± 3 ℃.

In some embodiments, the crystalline form of the compound of formula (I) of the present invention is form B, wherein form B has a differential scanning calorimetry trace substantially as shown in figure 6.

In some embodiments, the crystalline form of the compound of formula (I) of the present invention is form C, wherein the differential scanning calorimetry trace of form C comprises an endothermic peak at 155.16 ℃ ± 3 ℃.

In some embodiments, the crystalline form of the compound of formula (I) of the present invention is form C, wherein form C has a differential scanning calorimetry trace substantially as shown in figure 7.

In some embodiments, the crystalline form of the compound of formula (I) of the present invention is form E, wherein a differential scanning calorimetry trace of form E comprises endothermic peaks at 56.31 ℃ ± 3 ℃ and 195.41 ℃ ± 3 ℃.

In some embodiments, the crystalline form of the compound of formula (I) of the present invention is form E, wherein form E has a differential scanning calorimetry trace substantially as shown in figure 8.

In some embodiments, the crystalline form of the compound of formula (I) of the present invention is form F, wherein the differential scanning calorimetry trace of form F comprises an endothermic peak at 104.45 ℃ ± 3 ℃.

In some embodiments, the crystalline form of the compound of formula (I) of the present invention is form F, wherein form F has a differential scanning calorimetry trace substantially as shown in figure 9.

In some embodiments, the crystalline form of the compound of formula (I) of the present invention is form G, wherein the differential scanning calorimetry trace of form G comprises an endothermic peak at 169.28 ℃ ± 3 ℃.

In some embodiments, the crystalline form of the compound of formula (I) of the present invention is form G, wherein form G has a differential scanning calorimetry trace substantially as shown in figure 10.

In one aspect, the present invention also provides a pharmaceutical composition comprising any one of the crystalline forms described herein or a combination thereof, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.

In another aspect, the invention also relates to the use of a crystalline form of the compound of formula (I) or the pharmaceutical composition for the manufacture of a medicament for the prevention, treatment or alleviation of a disease or a condition mediated by FXR in a patient; further, the use comprises administering a therapeutically effective amount of the crystalline form of the invention or the pharmaceutical composition to a human or animal.

In some embodiments, the FXR-mediated disease described herein is a cardiovascular disease, a dyslipidemia-related disease, a metabolic syndrome, a hyperproliferative disease, fibrosis, an inflammatory disease, or a hepatobiliary-related disease.

In other embodiments, the cardiovascular and cerebrovascular diseases according to the invention are atherosclerosis, acute myocardial infarction, venous occlusive disease, portal hypertension, pulmonary hypertension, heart failure, peripheral arterial occlusive disease, sexual dysfunction, stroke, or thrombosis.

In other embodiments, the metabolic syndrome described herein is insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol in the blood, hyperlipidemia, obesity, hypertriglyceridemia, hypercholesterolemia, syndrome X, diabetic complications, atherosclerosis, hypertension, acute anemia, neutropenia, dyslipidemia, type II diabetes, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, dyslipidemia, or a combination of diabetes and abnormally high body mass index.

In other embodiments, the hyperproliferative diseases described herein are hepatocellular carcinoma, colon adenoma, polyposis, colon adenocarcinoma, breast cancer, membranous adenocarcinoma, Bart's esophageal carcinoma, and other forms of gastrointestinal or hepatic neoplastic disease.

In other embodiments, the fibrosis, inflammatory disease or hepatobiliary related disease described herein is non-alcoholic fatty liver, non-alcoholic steatohepatitis, cholestasis, liver fibrosis, primary biliary cirrhosis, primary sclerosing cholangitis, progressive familial cholestasis, cystic fibrosis, drug-induced bile duct injury, gallstones, cirrhosis, hepatitis b, steatosis, alcohol-induced cirrhosis, biliary tract obstruction, cholelithiasis, colitis, neonatal jaundice, riboflavin, or intestinal bacterial overgrowth.

In one aspect, the invention relates to a method for preventing, treating or alleviating FXR mediated diseases in a patient, comprising administering to the patient an effective amount of the crystalline form or the pharmaceutical composition of the invention that is pharmaceutically acceptable.

In another aspect, the invention relates to the use of said crystalline form of the compound of formula (I) or said pharmaceutical composition for the prevention, treatment or alleviation of FXR mediated diseases in a patient.

In another aspect, the invention also relates to a preparation method of the crystal form of the compound shown in the formula (I).

The solvent used in the method for producing the crystalline form of the present invention is not particularly limited, and any solvent that can dissolve the starting materials to an extent that does not affect the properties thereof is included in the present invention. Further, many equivalents, substitutions, or equivalents in the art to which this invention pertains, as well as different proportions of solvents, solvent combinations, and solvent combinations described herein, are deemed to be encompassed by the present invention. The invention provides a preferable solvent used in each reaction step.

The experiments for the preparation of the crystalline forms of the invention are described in detail in the examples section. Meanwhile, the invention provides activity test experiments of the crystal form, such as pharmacokinetic experiments, stability experiments, hygroscopicity experiments and the like. According to experimental results, the crystal form of the compound shown in the formula (I) has good biological activity and high stability, and is suitable for pharmaceutical application. In particular, the crystalline forms of the present invention have superior pharmacokinetic properties, e.g., have higher exposure.

Wherein, the description of the hygroscopicity characteristics and the definition of the hygroscopicity increase (the guideline of the hygroscopicity test of the medicine of appendix 9103 in the 2015 edition of Chinese pharmacopoeia, the experimental conditions are 25 ℃ plus or minus 1 ℃ and 80 percent plus or minus 2 percent relative humidity) are shown in the following table:

characterization of hygroscopicity and definition of hygroscopicity increase

The crystal form is not easy to deliquesce under the influence of high humidity, and is convenient for long-term storage and placement of the medicine.

Definitions and general terms

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are described herein.

"crystalline form" or "crystalline form" refers to a solid having a highly regular chemical structure, including, but not limited to, single or multicomponent crystals, and/or polymorphs, solvates, hydrates, clathrates, co-crystals, salts, solvates of salts, hydrates of salts of compounds. Crystalline forms of the substance can be obtained by a number of methods known in the art. Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a defined space, e.g., in a nanopore or capillary, on a surface or template, e.g., on a polymer, in the presence of an additive such as a co-crystallizing counter molecule, desolventization, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, anti-solvent addition, milling, and solvent drop milling, among others.

"solvent" refers to a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid). Solvents useful in the practice of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, methylene chloride, dimethyl sulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, butanol, t-butanol, N-dimethylacetamide, N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like.

By "anti-solvent" is meant a fluid that facilitates precipitation of the product (or product precursor) from the solvent. The anti-solvent may comprise a cold gas, or a fluid that promotes precipitation by a chemical reaction, or a fluid that reduces the solubility of the product in the solvent; it may be the same liquid as the solvent but at a different temperature, or it may be a different liquid than the solvent.

"solvate" refers to a compound having a solvent on a surface, in a crystal lattice, or on and in a crystal lattice, which may be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, methylene chloride, dimethyl sulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, butanol, t-butanol, N-dimethylacetamide, N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like. A specific example of a solvate is a hydrate, wherein the solvent on the surface, in the crystal lattice or on the surface and in the crystal lattice is water. The hydrates may or may not have other solvents than water on the surface of the substance, in the crystal lattice or both.

Crystalline forms can be identified by a variety of techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point methods, Differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance methods, raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, Scanning Electron Microscopy (SEM), quantitative analysis, solubility, and dissolution rate, and the like.

Information such as change, crystallinity, crystal structure state and the like of the crystal form can be detected by X-ray powder diffraction (XRPD), and the method is a common means for identifying the crystal form. In some embodiments, the crystalline form of the present invention is characterized by an XRPD pattern having certain peak positions, substantially as shown in the XRPD patterns provided in the figures of the present invention. Also, the 2 θ measurement of the XRPD pattern may have experimental error, and the 2 θ measurement of the XRPD pattern may be slightly different from instrument to instrument and from sample to sample, so the 2 θ value cannot be considered absolute. The diffraction peaks have a tolerance of ± 0.2 ° according to the conditions of the instrument used in the test.

Differential Scanning Calorimetry (DSC) is to measure the temperature of a sample and an inert reference substance (usually alpha-Al) by continuously heating or cooling under the control of a program₂O₃) The energy difference therebetween varies with temperature. In some embodiments, the crystalline form of the present invention is characterized by a DSC profile with characteristic peak positions substantially as shown in the DSC profiles provided in the figures of the present invention. Meanwhile, the DSC profile may have experimental errors, and the peak position and peak value of the DSC profile may slightly differ between different instruments and different samples, so the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute. The endothermic peaks have a tolerance of ± 3 ° depending on the condition of the instrument used in the test.

In the context of the present invention, the 2 θ values in the X-ray powder diffraction pattern are all in degrees (°).

The term "substantially as shown" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in an X-ray powder diffraction pattern or DSC diagram are shown in the figure.

When referring to a spectrogram or/and data appearing in a graph, "peak" refers to a feature that one skilled in the art would recognize as not being attributable to background noise.

The invention relates to various novel crystal forms of the 2- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -10H-spiro [ benzo [6,7] oxepin [3,2-b ] pyridine-11, 1' -cyclopropane ] -7-carboxylic acid (compound shown in a formula (I)), which exist in a basically pure crystal form.

By "substantially pure" is meant that a crystalline form is substantially free of one or more additional crystalline forms, i.e., the crystalline form is at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9% pure, or the crystalline form contains additional crystalline forms, the percentage of which in the total volume or weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.

By "substantially free" is meant that the percentage of one or more other crystalline forms in the total volume or weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.

"relative intensity" (or "relative peak height") in an XRPD pattern refers to the ratio of the intensity of the first strong peak to the intensity of the other peaks when the intensity of the first strong peak is 100% of all the diffraction peaks in an X-ray powder diffraction pattern (XRPD).

In the context of the present invention, the word "about" or "approximately" when used or whether used, means within 10%, suitably within 5%, and especially within 1% of a given value or range. Alternatively, the term "about" or "approximately" means within an acceptable standard error of the mean, for one of ordinary skill in the art. Whenever a number is disclosed with a value of N, any number within the values of N +/-1%, N +/-2%, N +/-3%, N +/-5%, N +/-7%, N +/-8% or N +/-10% is explicitly disclosed, wherein "+/-" means plus or minus.

"room temperature" in the present invention means a temperature of from about 10 ℃ to about 40 ℃. In some embodiments, "room temperature" refers to a temperature of from about 20 ℃ to about 30 ℃; in other embodiments, "room temperature" refers to 20 ℃,22.5 ℃,25 ℃,27.5 ℃, and the like.

Pharmaceutical compositions, formulations, administration and uses of the crystalline forms of the invention

The pharmaceutical composition of the invention is characterized by comprising any crystal form of the compound shown in the formula (I) or any combination thereof and a pharmaceutically acceptable carrier, adjuvant or excipient. The amount of the crystalline form of the compound in the pharmaceutical composition of the invention is effective to detectably treat or ameliorate an FXR-mediated condition in a patient.

As described herein, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or excipient, as used herein, including any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickening agent, emulsifier, preservative, solid binder or lubricant, and the like, as appropriate for the particular target dosage form. As described in the following documents: in Remington, The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988. Annu 1999, Marcel Dekker, New York, taken together with The disclosure of this document, indicates that different carriers can be used In The preparation of pharmaceutically acceptable compositions and their well known methods of preparation. Except insofar as any conventional carrier vehicle is incompatible with the compounds or crystalline forms thereof, e.g., any adverse biological effects that result or interaction in a deleterious manner with any other component of a pharmaceutically acceptable composition, their use is contemplated by the present invention.

The crystalline forms of the invention can be incorporated homogeneously in mixtures as active ingredients together with pharmaceutical carriers according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). When preparing compositions for oral dosage form, any conventional pharmaceutical media may be used, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the preparation of oral liquid preparations such as suspensions, elixirs and solutions; or in the preparation of oral solid preparations such as powders, hard capsules, soft capsules and tablets using, for example, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like, wherein solid oral preparations are more preferable than liquid preparations.

Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, the tablets may be coated using standard aqueous or non-aqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active ingredient. Of course, the percentage of active ingredient in these compositions may vary, and may conveniently vary from about 2% to about 60% of the weight of the unit. The active ingredient may be administered intranasally, for example, in the form of droplets or a spray.

The tablets, pills, capsules, etc. may also comprise: binders (such as gum tragacanth, acacia, corn starch or gelatin); excipients (such as dicalcium phosphate); disintegrating agents (such as corn starch, potato starch, alginic acid); lubricants (such as magnesium stearate); and a sweetening agent (such as sucrose, lactose or saccharin). When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

A wide variety of other materials may be present as coatings or to modify the shape of the dosage unit. For example, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl or propylparabens as preservatives, a dye and flavoring (e.g., cherry or orange flavor).

Also included within the scope of the present invention are ophthalmic formulations, ophthalmic ointments, powders, solutions, and the like.

The crystalline forms of the invention may also be administered parenterally. Solutions or suspensions of these actives can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersants may also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof, and in oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the drug form must be sterile and must be a fluid in a form that is easily injectable. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example: water, ethanol, polyols (such as glycerol, propylene glycol and liquid polyethylene glycols), suitable mixtures thereof and vegetable oils.

Any suitable method of administration may be used to provide an effective dose of the crystalline forms of the invention to a mammal, particularly a human. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like methods of administration may be used. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, emulsions, ointments, aerosols, and the like. Preferably, the crystalline forms of the invention are administered orally.

The therapeutically effective dose of the crystalline form, the pharmaceutical composition or the combination thereof of the present invention depends on the species, the weight, the age and the individual condition of the individual, the disorder or disease to be treated or the severity thereof. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient required to prevent, treat or inhibit the progression of the disorder or disease.

When the compound of the present invention or a crystalline form thereof is used for the treatment or prevention of the condition mediated by FXR according to the present invention, a substantially satisfactory effect is obtained when the compound of the present invention or a crystalline form thereof is administered at a daily dose of about 0.1 mg to about 100 mg per kg of animal body weight, preferably at a single daily dose, or at divided doses of 2 to 6 times per day, or in a continuous release form. For most large mammals, the total daily dosage is from about 1.0 mg to about 1000 mg, preferably from about 1mg to about 50 mg. For a 70 kg adult, the total daily dose is typically from 7mg to about 350 mg. This dosage regimen can be adjusted to provide the best therapeutic effect.

The crystalline form or the pharmaceutical composition thereof according to the present invention is useful for preventing, treating or alleviating FXR mediated diseases in a patient, in particular for treating non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), obesity, hypertriglyceridemia, atherosclerosis, chronic intrahepatic cholestasis, Primary Biliary Cirrhosis (PBC), Primary Sclerosing Cholangitis (PSC), progressive familial cholestasis (PFIC), drug-induced bile duct damage, gallstones, cirrhosis, hepatitis b, steatosis, alcohol-induced cirrhosis, cystic fibrosis, biliary tract obstruction, cholelithiasis, liver fibrosis, dyslipidemia, atherosclerosis, type II diabetes, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, peripheral tissue arterial obstructive disease (PAOD), Colitis, neonatal jaundice, kerithromosis, venous occlusive disease, portal hypertension, metabolic syndrome, acute myocardial infarction, acute stroke, thrombosis, hypercholesterolemia, intestinal bacterial overgrowth, erectile dysfunction, gastrointestinal neoplastic disease, hepatic neoplastic disease, and the like.

Drawings

FIG. 1 is an X-ray powder diffraction (XRPD) pattern of form B of the compound of formula (I) prepared according to example 1 of the present invention.

Figure 2 is an X-ray powder diffraction (XRPD) pattern of form C of the compound of formula (I) prepared according to the method of example 2 of the present invention.

FIG. 3 is an X-ray powder diffraction (XRPD) pattern of form E of the compound of formula (I) prepared according to example 3 of the present invention.

FIG. 4 is an X-ray powder diffraction (XRPD) pattern of crystalline form F of the compound of formula (I) prepared according to example 4 of the present invention.

FIG. 5 is an X-ray powder diffraction (XRPD) pattern of form G of the compound of formula (I) prepared according to example 5 of the present invention.

FIG. 6 is a Differential Scanning Calorimetry (DSC) profile of form B of the compound of formula (I) prepared according to example 1 of the present invention.

FIG. 7 is a Differential Scanning Calorimetry (DSC) profile of form C of the compound of formula (I) prepared according to example 2 of the present invention.

FIG. 8 is a Differential Scanning Calorimetry (DSC) profile of form E of the compound of formula (I) prepared according to example 3 of the present invention.

FIG. 9 is a Differential Scanning Calorimetry (DSC) profile of crystalline form F of the compound of formula (I) prepared according to example 4 of the present invention.

FIG. 10 is a Differential Scanning Calorimetry (DSC) profile of form G of the compound of formula (I) prepared according to example 5 of the present invention.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.

The X-ray powder diffraction analysis method used by the invention comprises the following steps: an Empyrean diffractometer, using Cu-Ka radiation (45KV,40mA) to obtain an X-ray powder diffraction pattern. The powdered sample was prepared as a thin layer on a single crystal silicon sample holder, placed on a rotating sample stage and analyzed in 0.0167 ° steps over a range of 3 ° -60 °. Data Collector software was used to collect Data, High Score Plus software was used to process Data, and Data Viewer software was used to read Data.

The Differential Scanning Calorimetry (DSC) analysis method used in the invention comprises the following steps: differential scanning calorimetry was performed using a TA Q2000 module with a thermoanalytical controller. Data were collected and analyzed using TA Instruments Thermal Solutions software. About 1-5mg of the sample was accurately weighed into a specially made aluminum crucible with a lid and the sample analysis was performed from room temperature to about 300 c using a 10 c/min linear heating device. During use, the DSC cell was purged with dry nitrogen.

Detailed description of the invention

A specific synthesis method of 2- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -10H-spiro [ benzo [6,7] oxepin [3,2-b ] pyridine-11, 1' -cyclopropane ] -7-carboxylic acid, a compound represented by formula (I), is referred to example 9 in patent application CN 107686486.

Examples

EXAMPLE 1 crystalline form B of the Compound of formula (I)

1. Preparation of form B

The compound 2- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -10H-spiro [ benzo [6,7] oxepin [3,2-b ] pyridine-11, 1' -cyclopropane ] -7-carboxylic acid (223.6mg) was added to a single vial at room temperature, suspended in a mixed solvent of dimethyl sulfoxide (1.1mL) and ethyl acetate (1.1mL) at room temperature, stirred for 12 hours, then cooled to 6 ℃, isopropanol (3.0mL) was added, stirred at 6 ℃ for 48 hours, suction filtered, the cake was washed with isopropanol (1.0mL), and vacuum-dried at 80 ℃ for 6 hours to give a white solid (182.1mg, 81.4%).

2. Identification of form B

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 6.24 °,8.11 °,10.82 °,11.13 °,11.84 °,12.21 °,12.54 °,13.67 °,14.02 °,14.50 °,14.81 °,15.40 °,15.67 °,16.20 °,17.27 °,17.56 °,18.20 °,18.75 °,18.88 °,19.19 °,19.65 °,20.34 °,20.83 °,21.87 °,22.06 °,22.73 °,23.08 °,23.39 °,23.74 °,24.19 °,24.58 °,25.29 °,25.45 °,25.76 °,26.26 °,26.75 °,27.53 °,28.10 °,28.26 °,28.50 °,28.74 °,29.00 °,29.41 °,30.49 °,31.74 °,32.70 °,33.49 °,34.17 °,34.98 °, 3945 °, 36.54.67 °, 37.75 °, 38.30.41 °, 30.75 °, 31.75 °, 31.74.74 °, 32.75 °, 3.75 °, 3.45 °, 3.75 °, 3.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained an endotherm peak at 130.48 ℃, with a margin of error of ± 3 ℃.

EXAMPLE 2 crystalline form C of the Compound of formula (I)

1. Preparation of form C

Dissolving a compound 2- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -10H-spiro [ benzo [6,7] oxepin [3,2-b ] pyridine-11, 1' -cyclopropane ] -7-carboxylic acid (101.3mg) in N, N-dimethylacetamide (0.5mL) at room temperature, dropping the solution into water (1.0mL) while stirring, and continuing to stir at room temperature for crystallization for 12 hours after dropping; suction filtration and vacuum drying of the filter cake at 60 ℃ for 12 h gave a white solid (76.8mg, 75.8%).

2. Identification of form C

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 7.43 °,8.10 °,10.24 °,10.97 °,11.69 °,12.15 °,13.14 °,13.66 °,15.19 °,15.46 °,16.42 °,17.45 °,18.06 °,18.58 °,19.22 °,19.66 °,20.88 °,21.33 °,22.01 °,22.48 °,22.81 °,24.27 °,24.99 °,25.45 °,25.70 °,26.55 °,27.01 °,27.80 °,28.17 °,29.33 °,30.22 °,31.06 °,31.40 °,32.68 °,33.28 °,34.00 °,34.80 °,36.62 °,38.39 °,39.41 °,40.36 °,41.93 °,42.96 °,46.63 °,47.69 °, and 59.99 °, there is a tolerance of ± 0.2 °.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained an endotherm peak at 155.16 ℃, with a margin of error of ± 3 ℃.

EXAMPLE 3 crystalline form E of the Compound of formula (I)

1. Preparation of form E

The compound 2- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -10H-spiro [ benzo [6,7] oxepin [3,2-b ] pyridine-11, 1' -cyclopropane ] -7-carboxylic acid (199.6mg) was added to a single vial at room temperature, dissolved in acetone (3.0mL) at room temperature, cooled to-10 ℃ and stirred for 12 hours of crystallization; suction filtered and the filter cake was dried under vacuum at room temperature for 4 hours to give a white solid (96.2mg, 48.2%).

2. Identification of form E

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 6.23 °,7.08 °,8.12 °,10.97 °,12.50 °,13.88 °,14.23 °,15.77 °,16.18 °,17.20 °,18.15 °,18.65 °,18.81 °,20.31 °,20.88 °,21.49 °,21.77 °,22.05 °,22.21 °,22.49 °,22.74 °,23.19 °,24.16 °,24.48 °,24.7 °,25.20 °,25.39 °,25.98 °,26.19 °,26.67 °,27.50 °,28.20 °,28.80 °,29.31 °,30.37 °,31.65 °,32.66 °,34.36 °,35.39 °,36.26 °,38.21 °,38.66 °,45.17 °,47.69 °,50.06 °,54.56 ° and 56.25 °, with a tolerance of ± 0.2 °.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained endothermic peaks at 56.31 ℃ and 195.41 ℃, with a margin of error of ± 3 ℃.

EXAMPLE 4 crystalline form F of the Compound of formula (I)

1. Preparation of form F

Adding a compound 2- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -10H-spiro [ benzo [6,7] oxepin [3,2-b ] pyridine-11, 1' -cyclopropane ] -7-carboxylic acid (203.2mg) into a single-necked bottle at room temperature, suspending the mixture in a mixed solvent of pyridine (2.0mL) and water (3.0mL) at room temperature, heating and refluxing, dissolving the solid, and then naturally cooling to room temperature; water (5.0mL) was added to precipitate a solid, which was further crystallized under stirring at room temperature for 12 hours, filtered with suction, and the filter cake was dried under vacuum at room temperature for 6 hours to give a white solid (148.7mg, 73.2%).

2. Identification of form F

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 6.10 °,8.31 °,10.39 °,11.11 °,12.12 °,12.78 °,12.91 °,13.57 °,14.12 °,14.31 °,15.51 °,16.16 °,16.69 °,17.39 °,17.62 °,18.25 °,18.43 °,18.71 °,19.29 °,19.68 °,20.59 °,20.76 °,21.24 °,21.53 °,21.82 °,22.35 °,22.52 °,23.36 °,23.84 °,24.13 °,24.38 °,24.77 °,24.96 °,25.27 °,25.69 °,25.92 °,26.34 °,26.53 °,27.13 °,27.37 °,28.39 °,28.79 °,30.20 °,30.98 °,31.34 °,31.68, 32.23 °,32.94 °,33.40 °,34.00 °,34.83 °, 34.32 °,35.90 °, 28.36.36 °, 30.36.36 °,30.98 °,31.34 °,31.68 °, 31.32.23 °,32.23 °,32 °, 32.43.42 °, 18.45 °, 56.45 °,56 °,18.75 °, 18.45 °, and 2.43.45 ° 19.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained an endotherm peak at 104.45 ℃, with a margin of error of ± 3 ℃.

EXAMPLE 5 crystalline form G of the Compound of formula (I)

1. Preparation of form G

The compound 2- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -10H-spiro [ benzo [6,7] oxepin [3,2-b ] pyridine-11, 1' -cyclopropane ] -7-carboxylic acid (199.6mg) was added to a single vial at room temperature, dissolved in N-methylpyrrolidone (2.5mL) at room temperature, then water (1.4mL) was slowly added dropwise, and crystallization was continued with stirring for 3 hours; suction filtration and drying of the filter cake under vacuum at room temperature for 4h gave a white solid (110.0mg, 55.1%).

2. Identification of form G

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: tolerance errors of 7.53 °,8.14 °,8.62 °,10.31 °,10.93 °,11.65 °,12.06 °,13.35 °,13.63 °,15.11 °,15.51 °,16.32 °,16.41 °,17.50 °,17.84 °,18.29 °,18.94 °,19.50 °,20.64 °,21.08 °,21.40 °,21.50 °,21.95 °,22.59 °,23.98 °,24.43 °,25.17 °,25.74 °,25.97 °,26.93 °,27.42 °,28.02 °,28.39 °,28.99 °,29.51 °,29.80 °,30.14 °,31.02 °,31.61 °,32.34 °,33.16 °,33.56 °,34.18 °,34.41 °,34.59 °,35.58 °,36.50 °, 64 °,38.30 °,39.98 °,40.54 °, 6742.15 °,43.03 °, 46.21.51 °, 47.29.27 °,49.47 ° and 3647.78 °.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained an endotherm peak at 169.28 ℃, with a margin of error of ± 3 ℃.

Example 6 pharmacokinetic experiments of the crystalline forms of the invention

Various crystal forms of the compound shown in the formula (I) (compound 2- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -10H-spiro [ benzo [6,7] oxepin [3,2-b ] pyridine-11, 1' -cyclopropane ] -7-formic acid) are filled into capsules and used for oral administration.

Male Beagle dogs, 8-12KG, were given orally 5mg/KG test samples with 3 animals per group. Blood was collected at time points 0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24h after dosing. A standard curve of the appropriate range is established based on the sample concentration, and the concentration of the test sample in the plasma sample is determined in MRM mode using LC-MS/MS model AB SCIEX API4000 and subjected to quantitative analysis. Pharmacokinetic parameters were calculated according to the drug concentration-time curve using a WinNonLin 6.3 software non-compartmental model.

And (4) experimental conclusion: the crystal form provided by the invention has better pharmacokinetic properties in beagle dogs.

Example 7 stability experiments of the crystalline forms of the invention

(1)High temperature experiment: taking a proper amount of a batch of samples to be tested, putting the samples into a flat weighing bottle, spreading the samples into a thin layer with the thickness of less than or equal to 5mm, standing the thin layer at the temperature of 60 ℃ for 30 days, sampling the samples at the 5 th, 10 th and 30 th days, observing the color change of the samples, and detecting the purity of the samples by HPLC.

(2)High humidity experiment: taking a proper amount of a batch of test samples, putting the test samples into a flat weighing bottle, spreading the test samples into a thin layer with the thickness of less than or equal to 5mm, standing the test samples for 30 days at 25 ℃ under the condition of RH 90% +/-5%, sampling the test samples for 5 days, 10 days and 30 days, observing the color change of the samples, and detecting the purity of the samples by HPLC.

(3)Illumination experiment: taking a proper amount of a batch of samples, placing into a flat weighing bottle, spreading into a thin layer with thickness of less than or equal to 5mm, placing in a light box (with ultraviolet) with an opening at the illumination of 4500 + -500 lx and the ultraviolet light of more than or equal to 0.7w/m²Standing for 30 days under the condition, sampling at 5, 13 and 30 days, observing the color change of the sample, and detecting the purity of the sample by HPLC.

And (4) experimental conclusion:

under the conditions of high temperature, high humidity and illumination, the crystal form has no obvious change in appearance and purity, has good stability effect and is suitable for pharmaceutical application.

Example 8 hygroscopicity test of the crystalline form of the invention

Taking a proper amount of a sample, and testing the hygroscopicity of the sample by using a dynamic moisture adsorption instrument. Experimental results prove that the crystal form is not easy to deliquesce under the influence of high humidity.

The above description is only a basic description of the present invention, and any equivalent changes made according to the technical solution of the present invention should fall within the protection scope of the present invention.

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.

Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims (10)

1. A crystal form of a compound shown in a formula (I),

wherein the crystal form is a crystal form B, and is characterized in that an X-ray powder diffraction pattern of the crystal form B has diffraction peaks at the following 2 theta angles: 18.88 ° ± 0.2 °,21.87 ° ± 0.2 °,22.06 ° ± 0.2 °,25.29 ° ± 0.2 °,25.45 ° ± 0.2 °; or

The crystal form is a crystal form C, and is characterized in that an X-ray powder diffraction pattern of the crystal form C has diffraction peaks at the following 2 theta angles: 13.66 ° ± 0.2 °,17.45 ° ± 0.2 °,20.88 ° ± 0.2 °,22.48 ° ± 0.2 °,25.70 ° ± 0.2 °; or

The crystal form is a crystal form E, and is characterized in that an X-ray powder diffraction pattern of the crystal form E has diffraction peaks at the following 2 theta angles: 6.23 +/-0.2 degrees, 18.15 +/-0.2 degrees, 18.81 +/-0.2 degrees, 20.88 +/-0.2 degrees and 30.37 +/-0.2 degrees; or

The crystal form is a crystal form F, and is characterized in that an X-ray powder diffraction pattern of the crystal form F has diffraction peaks at the following 2 theta angles: 15.51 ° ± 0.2 °,18.43 ° ± 0.2 °,22.35 ° ± 0.2 °,25.27 ° ± 0.2 °; or

The crystal form is a crystal form G, and is characterized in that an X-ray powder diffraction pattern of the crystal form G has diffraction peaks at the following 2 theta angles: 13.63 ° ± 0.2 °,19.50 ° ± 0.2 °,21.08 ° ± 0.2 °,22.59 ° ± 0.2 °.

2. The crystalline form of claim 1, wherein the crystalline form is form B, characterized by an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 12.54 ° ± 0.2 °,16.20 ° ± 0.2 °,18.20 ° ± 0.2 °,18.75 ° ± 0.2 °,18.88 ° ± 0.2 °,21.87 ° ± 0.2 °,22.06 ° ± 0.2 °,24.58 ° ± 0.2 °,25.29 ° ± 0.2 °,25.45 ° ± 0.2 °,26.75 ° ± 0.2 °,30.49 ° ± 0.2 °,31.74 ° ± 0.2 °; or

The crystal form is a crystal form C, and is characterized in that an X-ray powder diffraction pattern of the crystal form C has diffraction peaks at the following 2 theta angles: 11.69 ° ± 0.2 °,13.66 ° ± 0.2 °,15.19 ° ± 0.2 °,16.42 ° ± 0.2 °,17.45 ° ± 0.2 °,19.22 ° ± 0.2 °,20.88 ° ± 0.2 °,22.48 ° ± 0.2 °,22.81 ° ± 0.2 °,24.27 ° ± 0.2 °,25.70 ° ± 0.2 °,27.01 ° ± 0.2 °,31.06 ° ± 0.2 °; or

The crystal form is a crystal form E, and is characterized in that an X-ray powder diffraction pattern of the crystal form E has diffraction peaks at the following 2 theta angles: 6.23 ° ± 0.2 °,12.50 ° ± 0.2 °,14.23 ° ± 0.2 °,18.15 ° ± 0.2 °,18.81 ° ± 0.2 °,20.88 ° ± 0.2 °,21.77 ° ± 0.2 °,22.49 ° ± 0.2 °,25.20 ° ± 0.2 °,25.39 ° ± 0.2 °,28.8 ° ± 0.2 °,30.37 ° ± 0.2 °,31.65 ° ± 0.2 °; or

The crystal form is a crystal form F, and is characterized in that an X-ray powder diffraction pattern of the crystal form F has diffraction peaks at the following 2 theta angles: 6.10 ° ± 0.2 °,12.12 ° ± 0.2 °,14.31 ° ± 0.2 °,15.51 ° ± 0.2 °,18.25 ° ± 0.2 °,18.43 ° ± 0.2 °,19.29 ° ± 0.2 °,20.59 ° ± 0.2 °,22.35 ° ± 0.2 °,22.52 ° ± 0.2 °,24.77 ° ± 0.2 °,25.27 ° ± 0.2 °,30.20 ° ± 0.2 °; or

The crystal form is a crystal form G, and is characterized in that an X-ray powder diffraction pattern of the crystal form G has diffraction peaks at the following 2 theta angles: 11.65 ° ± 0.2 °,13.63 ° ± 0.2 °,15.11 ° ± 0.2 °,17.50 ° ± 0.2 °,19.50 ° ± 0.2 °,20.64 ° ± 0.2 °,21.08 ° ± 0.2 °,21.40 ° ± 0.2 °,22.59 ° ± 0.2 °,24.43 ° ± 0.2 °,25.17 ° ± 0.2 °,25.74 ° ± 0.2 °,25.97 ° ± 0.2 °.

3. The crystalline form of claim 1 or 2, wherein the crystalline form is form B, characterized in that the form B has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.24 ° ± 0.2 °,8.11 ° ± 0.2 °,10.82 ° ± 0.2 °,11.13 ° ± 0.2 °,11.84 ° ± 0.2 °,12.21 ° ± 0.2 °,12.54 ° ± 0.2 °,13.67 ° ± 0.2 °,14.02 ° ± 0.2 °,14.50 ° ± 0.2 °,14.81 ° ± 0.2 °,15.40 ° ± 0.2 °,15.67 ° ± 0.2 °,16.20 ° ± 0.2 °,17.27 ° ± 0.2 °,17.56 ° ± 0.2 °,18.20 ° ± 0.2 °,18.75 ° ± 0.88 ° ± 0.2 °,19.19 ° ± 0.2 °,19.65 ° ± 0.2 °,20.34 ° ± 0.2 °,20.83 ° ± 0.2.2.2 ° ± 0.2 °,2 ± 0.26 °, 2.26 ° ± 0.26 °, 2.26 ° ± 0.0.26 °,2 ° ± 0.26 °, 2.0.26 ° ± 0.26 °, 2.2.2 °,2 °, 2.0.0.0.2 ° ± 0.0.26 ° ± 0.2 °,2 °, 2.0.0.26 ° ± 0.2.2 ° ± 0.2 °,2 °, 2.2 °,2 °, 2.2.2 °, 2.0.9 ° ± 0.2 °, 2.2.2 °,2 °, 2.0.0.2.2.2 °, 2.2.9 ° ±,30.49 ° ± 0.2 °,31.74 ° ± 0.2 °,32.70 ° ± 0.2 °,33.49 ° ± 0.2 °,34.17 ° ± 0.2 °,34.57 ° ± 0.2 °,34.98 ° ± 0.2 °,35.45 ° ± 0.2 °,36.54 ° ± 0.2 °,37.67 ° ± 0.2 °,38.30 ° ± 0.2 °,38.75 ° ± 0.2 °,39.50 ° ± 0.2 °,40.91 ° ± 0.2 °,42.81 ° ± 0.2 °,44.32 ° ± 0.2 °,45.39 ° ± 0.2 °,45.99 ° ± 0.2 °,48.44 ° ± 0.2 °,50.29 ° ± 0.2 °,52.52 ° ± 0.2 °,56.49 ° ± 0.2 °,58.25 ° ± 0.2 ° ±; or

The crystal form is a crystal form C, and is characterized in that an X-ray powder diffraction pattern of the crystal form C has diffraction peaks at the following 2 theta angles: 7.43 ° ± 0.2 °,8.10 ° ± 0.2 °,10.24 ° ± 0.2 °,10.97 ° ± 0.2 °,11.69 ° ± 0.2 °,12.15 ° ± 0.2 °,13.14 ° ± 0.2 °,13.66 ° ± 0.2 °,15.19 ° ± 0.2 °,15.46 ° ± 0.2 °,16.42 ° ± 0.2 °,17.45 ° ± 0.2 °,18.06 ° ± 0.2 °,18.58 ° ± 0.2 °,19.22 ° ± 0.2 °,19.66 ° ± 0.2 °,20.88 ° ± 0.2 °,21.33 ° ± 0.2 °,22.01 ° ± 0.2 °,22.48 ° ± 0.2 °,22.81 ° ± 0.2 °,24.27 ° ± 0.2 °,24.99 ° ± 0.25.45 ° ± 0.2 °, 0.2 ° ± 0.2 °, 22.2.2 ° ± 0.2 °,22.2 °,2 ° ± 0.2.2 °, 2.2.2 °,2 ° ± 0.9 ° ± 0.2 °,2 °, 2.9 ° ± 0.9 ° ± 0.2 °, 2.9 ° ± 0.2.2.2.2.2 °,2 °, 2.9 ° ± 0.2 °,2 °, 2.2.2 °,2 °, 2.2 °, 2.9 ° ± 0.9 ° ± 0.2.2.2 °,2 °, 2.9 ° ± 0.9, 46.63 ° ± 0.2 °,47.69 ° ± 0.2 °,59.99 ° ± 0.2 °; or

The crystal form is a crystal form E, and is characterized in that an X-ray powder diffraction pattern of the crystal form E has diffraction peaks at the following 2 theta angles: 6.23 ° ± 0.2 °,7.08 ° ± 0.2 °,8.12 ° ± 0.2 °,10.97 ° ± 0.2 °,12.50 ° ± 0.2 °,13.88 ° ± 0.2 °,14.23 ° ± 0.2 °,15.77 ° ± 0.2 °,16.18 ° ± 0.2 °,17.20 ° ± 0.2 °,18.15 ° ± 0.2 °,18.65 ° ± 0.2 °,18.81 ° ± 0.2 °,20.31 ° ± 0.2 °,20.88 ° ± 0.2 °,21.49 ° ± 0.2 °,21.77 ° ± 0.2 °,22.05 ° ± 0.2 °,22.21 ° ± 0.2 °,22.49 ° ± 0.2 °,22.74 ° ± 0.2 °,23.19 ° ± 0.2 °,24.16 ° ± 0.24.48 ° ± 0.2 °, 0.2 ° ± 0.2 °,22.2 ° ± 0.2 °, 2.2 ° ± 0.2 °,22.2 °, 2.2.2 ° ± 0.19 ° ± 0.2 °, 2.2.2 °,2 ° ± 0.2 °, 2.30 ° ± 0.30 ° ± 0.2 °,2 °, 2.30 ° ± 0.2.2.2.2 °,2 °, 2.2.30 ° ± 0.2 °, 2.2 ° ± 0.2 ° ± 0.2.2 °,2 °, 2.2.2 °, 2.2.2.2 ° ± 0.2 °, 2.2 °,30 ° ± 0.2 °, 2.2.2 °, 2.2, 47.69 ° ± 0.2 °,50.06 ° ± 0.2 °,54.56 ° ± 0.2 °,56.25 ° ± 0.2 °; or

The crystal form is a crystal form F, and is characterized in that an X-ray powder diffraction pattern of the crystal form F has diffraction peaks at the following 2 theta angles: 6.10 ° ± 0.2 °,8.31 ° ± 0.2 °,10.39 ° ± 0.2 °,11.11 ° ± 0.2 °,12.12 ° ± 0.2 °,12.78 ° ± 0.2 °,12.91 ° ± 0.2 °,13.57 ° ± 0.2 °,14.12 ° ± 0.2 °,14.31 ° ± 0.2 °,15.51 ° ± 0.2 °,16.16 ° ± 0.2 °,16.69 ° ± 0.2 °,17.39 ° ± 0.2 °,17.62 ° ± 0.2 °,18.25 ° ± 0.2 °,18.43 ° ± 0.2 °,18.71 ° ± 0.19 ° ± 0.2 °,19.68 ° ± 0.2 °,20.59 ° ± 0.76 ° ± 0.2.24 ° ± 0.53 ° ± 0.2 °,2 ° ± 0.2 °, 2.2 ° ± 0.2 °,2 ° ± 0.2 °, 2.2 °,2 °, 2.2.2 ° ± 0.2 °, 2.2 °, 2.2.2 ° ± 0.2 °,2 ° ± 0.2 °, 2.2.2.2.2 ° ± 0.2 °,2 °, 2.2.2 ° ± 0.2.2 ° ± 0.2 °,2 °, 2.2.2 °,2 °, 2.2 °, 2.2.2.2.2.2 ° ± 0.2.2 °,2 °, 2.2 °, 2.2.2 ° ± 0.2.2 °,30.98 ° ± 0.2 °,31.34 ° ± 0.2 °,31.68 ° ± 0.2 °,32.23 ° ± 0.2 °,32.94 ° ± 0.2 °,33.40 ° ± 0.2 °,34.00 ° ± 0.2 °,34.45 ° ± 0.2 °,34.83 ° ± 0.2 °,35.37 ° ± 0.2 °,35.90 ° ± 0.2 °,37.39 ° ± 0.2 °,38.66 ° ± 0.2 °,39.38 ° ± 0.2 °,40.92 ° ± 0.2 °,42.21 ° ± 0.2 °,43.56 ° ± 0.2 °,44.34 ° ± 0.2 °,45.63 ° ± 0.2 °,46.33 ° ± 0.2 °,47.75 ° ± 0.2 °,48.75 ° ± 0.2 °,51.15 ° ± 0.2 °,53.95 ° ± 0.2 °,56.18 ° ± 0.18 ° ± 0.2 °; or

The crystal form is a crystal form G, and is characterized in that an X-ray powder diffraction pattern of the crystal form G has diffraction peaks at the following 2 theta angles: 7.53 ° ± 0.2 °,8.14 ° ± 0.2 °,8.62 ° ± 0.2 °,10.31 ° ± 0.2 °,10.93 ° ± 0.2 °,11.65 ° ± 0.2 °,12.06 ° ± 0.2 °,13.35 ° ± 0.2 °,13.63 ° ± 0.2 °,15.11 ° ± 0.2 °,15.51 ° ± 0.2 °,16.32 ° ± 0.2 °,16.41 ° ± 0.2 °,17.50 ° ± 0.2 °,17.84 ° ± 0.2 °,18.29 ° ± 0.2 °,18.94 ° ± 0.2 °,19.50 ° ± 0.20.64 ° ± 0.2 °,21.08 ° ± 0.2 °,21.40 ° ± 0.2 °,21.50 ° ± 0.21.21.95 ° ± 0.2.2.2 ° ± 0.2 °,19.2 ± 0.2.2 ° ± 0.2 ° ± 0.2.2 °,19 ° ± 0.2.2 °, 0.2 ° ± 0.2 °,3 ° ± 0.2 °, 2.2 °,2 °, 2.2.2 °, 2.2.2.2 °,21.2 °,2 ° ± 0.2 °,2 ° ± 0.2.2.2.2 °,2 °, 2.2 °, 2.2.2 ° ± 0.2.2 °,2 ° ± 0.2 °,2 °, 2.2.2 °,2 °, 2.2 °, 2.2.2.2.2.2.2 °,3 ° ± 0.2 °,2 °, 2.2.2 ° ± 0.2, 34.41 ° ± 0.2 °,34.59 ° ± 0.2 °,35.58 ° ± 0.2 °,36.50 ° ± 0.2 °,37.65 ° ± 0.2 °,38.30 ° ± 0.2 °,39.98 ° ± 0.2 °,40.54 ° ± 0.2 °,42.15 ° ± 0.2 °,43.03 ° ± 0.2 °,44.51 ° ± 0.2 °,46.21 ° ± 0.2 °,47.29 ° ± 0.2 °,49.47 ° ± 0.2 °,50.80 ° ± 0.2 °.

4. The crystalline form of any one of claims 1-3, wherein the crystalline form is form B, characterized in that the form B has an X-ray powder diffraction pattern substantially as shown in figure 1; or

The crystalline form is form C, characterized in that the crystalline form C has an X-ray powder diffraction pattern substantially as shown in figure 2; or

The crystalline form is form E, characterized in that form E has an X-ray powder diffraction pattern substantially as shown in figure 3; or

The crystalline form is crystalline form F, characterized in that the crystalline form F has an X-ray powder diffraction pattern substantially as shown in figure 4; or

The crystalline form is form G, characterized in that the crystalline form G has an X-ray powder diffraction pattern substantially as shown in figure 5.

5. A crystal form of a compound shown in a formula (I),

wherein the crystalline form is form B, characterized in that the differential scanning calorimetry trace of form B comprises an endothermic peak at 130.48 ℃ ± 3 ℃; or

The crystalline form is crystalline form C, characterized in that the differential scanning calorimetry trace of crystalline form C comprises an endothermic peak at 155.16 ℃ ± 3 ℃; or

The crystalline form is crystalline form E, characterized in that a differential scanning calorimetry trace of the crystalline form E comprises endothermic peaks at 56.31 ℃ ± 3 ℃ and 195.41 ℃ ± 3 ℃; or

The crystalline form is crystalline form F, characterized in that the differential scanning calorimetry trace of crystalline form F comprises an endothermic peak at 104.45 ℃ ± 3 ℃; or

The crystalline form is crystalline form G, characterized in that a differential scanning calorimetry trace of the crystalline form G comprises an endothermic peak at 169.28 ℃ ± 3 ℃.

6. The crystalline form of claim 5, wherein the crystalline form is form B, characterized in that the form B has a differential scanning calorimetry trace substantially as shown in figure 6; or

The crystalline form is form C, characterized in that the form C has a differential scanning calorimetry trace substantially as shown in figure 7; or

Said crystalline form is form E, characterized in that said form E has a differential scanning calorimetry trace substantially as shown in figure 8; or

Said crystalline form is form F, characterized in that said form F has a differential scanning calorimetry trace substantially as shown in figure 9; or

The crystalline form is form G, characterized in that the form G has a differential scanning calorimetry pattern substantially as shown in figure 10.

7. A pharmaceutical composition comprising the crystalline form of any one of claims 1-6, or a combination thereof, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.

8. Use of the crystalline form of any one of claims 1 to 6 or a combination thereof or the pharmaceutical composition of claim 7 for the manufacture of a medicament for preventing, treating or ameliorating a disease mediated by FXR in a patient.

9. The use according to claim 8, wherein the FXR mediated disease is a cardiovascular and cerebrovascular disease, a dyslipidemia-related disease, a metabolic syndrome, a hyperproliferative disease, fibrosis, an inflammatory disease or a hepatobiliary-related disease.

10. The use according to claim 9, wherein the cardiovascular and cerebrovascular disease is atherosclerosis, acute myocardial infarction, venous occlusive disease, portal hypertension, pulmonary hypertension, heart failure, peripheral tissue arterial occlusive disease, sexual dysfunction, stroke, or thrombosis;

the metabolic syndrome is insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol in the blood, hyperlipidemia, obesity, hypertriglyceridemia, hypercholesterolemia, syndrome X, diabetic complications, atherosclerosis, hypertension, acute anemia, neutropenia, dyslipidemia, type II diabetes, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, dyslipidemia, or a combination of diabetes and abnormally high body mass index;

the hyperproliferative diseases are hepatocellular carcinoma, colon adenoma, polyposis, colon adenocarcinoma, breast cancer, membrane adenocarcinoma, Bart's esophagus cancer and other forms of gastrointestinal or hepatic neoplastic diseases;

the fibrosis, inflammatory disease or hepatobiliary related disease is non-alcoholic fatty liver, non-alcoholic steatohepatitis, cholestasis, liver fibrosis, primary biliary cirrhosis, primary sclerosing cholangitis, progressive familial cholestasis, cystic fibrosis, drug-induced bile duct injury, gallstone, cirrhosis, hepatitis b, steatosis, alcohol-induced cirrhosis, biliary tract obstruction, cholelithiasis, colitis, neonatal jaundice, riboflavin disease, or intestinal bacterial overgrowth.

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