New crystal form of vascular leakage blocker compound

Abstract

The present application relates to a crystalline form of (E)-methyl 6-((3S,8S,9S,10R,13S,14S,17R)-3-(((5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)hept-5-enoate, and a vascular leakage blocker comprising the crystalline form. The new crystalline form has high purity, excellent stability, excellent long-term storage and drug stability, and can be used as a vascular leakage blocker, so it is very advantageous in producing high-quality drugs.

Description

Technical Field

[0001] The invention relates to a new crystal form of a vascular leakage blocker compound. Background Art

[0002] The compound represented by the general formula 1 is named (E)-methyl 6-((3S,8S,9S,10R,13S,14S,17R)-3-(((5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)hept-5-enoate, which is a compound disclosed in Korean Patent Publication No. 10-2011-0047170 and is code-named SAC-1004.

[0003] [General formula 1]

[0004]

[0005] The compound inhibits the death of vascular endothelial cells, inhibits the formation of VEGF-induced actin stress fibers, increases the structure of cortical actin rings, and improves the stability of TJ (tight junctions) between vascular cells, thereby inhibiting vascular leakage. The compound not only inhibits the permeability of blood vessels, but also has excellent activity in restoring the integrity of damaged blood vessels. Therefore, it is known that the compound can be effectively used to prevent or treat various diseases caused by vascular leakage.

[0006] Korean patent application number 10-2019-0166864 discloses a new chemical preparation method that can separate and mass-produce stereoisomers of a compound of formula 1 and prepare the compound in high yield.

[0007] On the other hand, polymorph refers to a crystalline solid having the same molecular structure, but its crystal structure is altered due to the packing of crystals and changes in the molecular conformation.

[0008] The criteria for selecting a good crystal form should be attributed to the most important physicochemical properties required by the drug. The purpose is different, and the choice of optimized crystal form is different. For example, the most thermodynamically stable crystal form can be selected, the crystal form that can optimize the production of drug raw materials and finished products, the crystal form that can improve the solubility and dissolution of the drug, or the crystal form that changes the pharmacokinetic properties can be selected.

[0009] Therefore, the inventors of the present application disclosed the first crystalline form of (E)-methyl 6-((3S,8S,9S,10R,13S,14S,17R)-3-(((5s,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)hept-5-enoate, as well as its preparation method and the physicochemical properties of the new crystalline form. Summary of the invention

[0010] Technical issues

[0011] An object of the present invention is to provide a new crystalline form of the compound (E)-methyl 6-((3S,8S,9S,10R,13S,14S,17R)-3-(((5s,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)hept-5-enoate.

[0012] Another object of the present invention is to provide a vascular leakage blocking agent, which comprises a new crystal form of the compound.

[0013] Technical Solution

[0014] To achieve the above-mentioned purpose, in one aspect of the present invention, the present invention provides a compound, characterized in that the proportion of the α-isomer of the compound represented by the formula (E)-methyl 6-((3S,8S,9S,10R,13S,14S,17R)-3-(((5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)hept-5-enoate is 85% or more and is in a solid state.

[0015] In another aspect of the present invention, the present invention provides a compound represented by the formula (E)-methyl 6-((3S,8S,9S,10R,13S,14S,17R)-3-(((2S,5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)hept-5-enoate.

[0016] In another aspect of the present invention, the present invention provides a crystalline form I of formula (E)-methyl 6-((3S,8S,9S,10R,13S,14S,17R)-3-(((5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)hept-5-enoate, which has a peak at the following 2θ diffraction angle in the X-ray powder diffraction pattern:

[0017] 16.0°±0.2°, 19.5°±0.2°, 18.3°±0.2°, 15.1°±0.2°, 21.9°±0.2°.

[0018] In another aspect of the present invention, the present invention provides a crystalline form II of (E)-methyl 6-((3S,8S,9S,10R,13S,14S,17R)-3-(((5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)hept-5-enoate, which has a peak at the following 2θ diffraction angle in an X-ray powder diffraction pattern:

[0019] 17.3°±0.2°, 11.4°±0.2°, 35.2°±0.2°, 19.0°±0.2°, 15.3°±0.2°, 5.7°±0.2°.

[0020] In another aspect of the present invention, the present invention provides a crystalline form III of (E)-methyl 6-((3S,8S,9S,10R,13S,14S,17R)-3-(((5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)hept-5-enoate, which has a peak at the following 2θ diffraction angle in an X-ray powder diffraction pattern:

[0021] 15.6°±0.2°, 18.2°±0.2°, 14.4°±0.2°, 24.6°±0.2°, 16.9°±0.2°, 17.2°±0.2°.

[0022] In another aspect of the present invention, the present invention provides a crystalline form IV of (E)-methyl 6-((3S,8S,9S,10R,13S,14S,17R)-3-(((5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)hept-5-enoate, which has a peak at the following 2θ diffraction angle in an X-ray powder diffraction pattern:

[0023] 15.3°±0.2°, 22.4°±0.2°, 17.2°±0.2°, 36.5°±0.2°, 24.8°±0.2°, 22.7°±0.2°, 11.7°±0.2°, 18.5°±0.2°, 21.8°±0.2°, 23.8°±0.2°, 16.3°±0.2°, 17.6°±0.2°.

[0024] In another aspect of the present invention, the present invention provides a crystalline form V of (E)-methyl 6-((3S,8S,9S,10R,13S,14S,17R)-3-(((5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)hept-5-enoate, which has a peak at the following 2θ diffraction angle in an X-ray powder diffraction pattern:

[0025] 23.8°±0.2°, 16.2°±0.2°, 17.4°±0.2°, 35.3°±0.2°, 26.0°±0.2°, 36.6°±0.2°, 22.2°±0.2°, 20.7°±0.2°.

[0026] In another aspect of the present invention, the present invention provides a pharmaceutical composition for preventing or treating vascular leakage diseases, comprising a (E)-methyl 6-((3S,8S,9S,10R,13S,14S,17R)-3-(((5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopentadien[a]phenanthrene-17-yl)hept-5-enoate compound and any one of new crystal forms I to V.

[0027] Technical Effects

[0028] The present invention provides a new crystal form of (E)-methyl 6-((3S,8S,9S,10R,13S,14S,17R)-3-(((5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)hept-5-enoate, a compound represented by general formula I and a preparation method thereof. The new crystal form has high purity, excellent stability, excellent long-term storage and drug stability, and can be used as a vascular leakage blocker, and is therefore very advantageous in producing high-quality drugs.

[0029] BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 A diagram showing the results of nuclear magnetic resonance analysis to confirm the structures of the α-isomer and β-isomer of Compound 1 prepared in Preparation Example 1, and the stereochemical structures of the α-isomer and β-isomer.

[0031] Figure 2 The X-ray powder diffraction (XRPD) result of Form I of Example 1 is shown.

[0032] Figure 3 The differential scanning calorimetry (DSC) result graph of Form I of Example 1 is shown.

[0033] Figure 4 The thermogravimetric analysis (TGA) result graph of Form I of Example 1 is shown.

[0034] Figure 5 The dynamic vapor sorption (DVS) result diagram of Form I of Example 1 is shown.

[0035] Figure 6 A photograph of Form I of Example 1 taken with a polarizing microscope (PLM) is shown.

[0036] Figure 7 The X-ray powder diffraction (XRPD) result diagram of the crystal form II of Example 2 is shown.

[0037] Figure 8 The X-ray powder diffraction (XRPD) results of Form III of Example 3 prepared in MEK (30 mg, 50 mg) or chloroform (50 mg) solvent are shown.

[0038] Fig. 9 The X-ray powder diffraction (XRPD) comparison result of Form IV and Form I of Example 4 is shown.

[0039] Fig.10 The X-ray powder diffraction (XRPD) comparison results of Form V and Form I of Example 5 are shown.

[0040] Fig.11 The X-ray powder diffraction (XRPD) comparison results of Form VI and Form VII of Examples 6 and 7 and Forms I and IV are shown.

[0041] Fig.12 The X-ray powder diffraction (XRPD) comparison results of Form VIII and Form IX of Examples 8 and 9 and Forms I and V are shown.

[0042] Fig.13 The X-ray powder diffraction (XRPD) comparison results of Form X of Example 10 and Forms I and VI are shown.

[0043] Fig.14 The X-ray powder diffraction (XRPD) comparison results of Form XI of Example 11 and Forms I and V are shown. DETAILED DESCRIPTION

[0044] Hereinafter, the present invention will be described in detail.

[0045] The embodiments of the present invention can be modified into a variety of other forms, and the scope of the present invention is not limited to the embodiments described below. It will be appreciated by those skilled in the art that the embodiments provided by the present invention are intended to more accurately explain the present invention. In addition, "comprising" an element throughout the specification does not exclude other elements, but may include other elements, unless otherwise specifically stated.

[0046] [General formula 1]

[0047]

[0048] (E)-methyl 6-((3S,8S,9S,10R,13S,14S,17R)-3-(((5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)hept-5-enoate.

[0049] At this time, in the two stereochemical structures of the compound of general formula 1, the structure of the crystalline form is shown to be (E)-methyl 6-((3S,8S,9S,10R,13S,14S,17R)-3-(((2S,5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)hept-5-enoate.

[0050] In one aspect of the present invention, the present invention provides a compound characterized in that the proportion of the α-isomer of the compound represented by the formula (E)-methyl 6-((3S,8S,9S,10R,13S,14S,17R)-3-(((5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)hept-5-enoate is 85% or more and is in a solid state.

[0051] At this time, the ratio of the α-isomer may be 87% or more, 89% or more, 90% or more, 92% or more, 95% or more, 98% or more, or 99% or more.

[0052] In another aspect of the present invention, the present invention provides a compound represented by the general formula (E)-methyl 6-((3S,8S,9S,10R,13S,14S,17R)-3-(((2S,5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)hept-5-enoate.

[0053] In another aspect of the present invention, the present invention provides a compound of the general formula (E)-methyl 6-((3S,8S,9S,10R,13S,14S,17R)-3-(((2S,5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12, The new crystalline form I of the compound represented by 13,14,15,16,17-tetradecahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)hept-5-enoate has peaks at the following 2θ diffraction angles in the X-ray powder diffraction pattern (XRPD): 16.0°±0.2°, 19.5°±0.2°, 18.3°±0.2°, 15.1°±0.2°, and 21.9°±0.2°.

[0054] At this time, Form I may further include peaks at the following 2θ diffraction angles: 10.7°±0.2°, 8.9°±0.2°, 17.8°±0.2°, 21.3°±0.2° and 17.2°±0.2°.

[0055] In addition, Form I further includes peaks at the following 2θ diffraction angles: 14.1°±0.2°, 20.5°±0.2° and 11.7°±0.2°.

[0056] In addition, Form I may include peaks at the following 2θ diffraction angles: 24.0°±0.2°, 24.6°±0.2°, and 26.1°±0.2°. Alternatively, Form I may further include peaks at the following 2θ diffraction angles: 24.0°±0.2°, 24.6°±0.2°, and 26.1°±0.2°.

[0057] For example, Form I may be a form having characteristic peaks at the following 2θ diffraction angles: 8.9°±0.2°, 10.7°±0.2°, 11.7°±0.2°, 14.1°±0.2°, 15.1°±0.2°, 16.0°±0.2°, 17.2°±0.2°, 17.8°±0.2°, 18.3°±0.2°, 19.5°±0.2°, 20.5°±0.2°, 21.3°±0.2°, 21.9°, ±2.2°°±0.2°, 24.0°±0.2°, 24.6°±0.2°, 26.1°±0.2°, and a relative intensity (I / I0) of 10% or more.

[0058] In addition, the present invention provides a new crystal form, which has an endothermic peak at 100.96°C±3°C as shown in differential scanning calorimetry (DSC).

[0059] In one aspect of the present invention, the present invention provides a novel crystalline form II of a compound represented by (E)-methyl 6-((3S,8S,9S,10R,13S,14S,17R)-3-(((2S,5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)hept-5-enoate, which has a peak at the following 2θ diffraction angle in an X-ray powder diffraction pattern (XRPD):

[0060] 17.3°±0.2°, 11.4°±0.2°, 35.2°±0.2°, 19.0°±0.2°, 15.3°±0.2° and 5.7°±0.2°.

[0061] In one aspect of the present invention, the present invention provides a novel crystalline form III of a compound represented by (E)-methyl 6-((3S,8S,9S,10R,13S,14S,17R)-3-(((2S,5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)hept-5-enoate, which has a peak at the following 2θ diffraction angle in an X-ray powder diffraction pattern (XRPD):

[0062] 15.6°±0.2°, 18.2°±0.2°, 14.4°±0.2°, 24.6°±0.2°, 16.9°±0.2° and 17.2°±0.2°.

[0063] At this time, Form III further has peaks at the following 2θ diffraction angles: 8.5°±0.2°, 24.3°±0.2°, 15.0°±0.2°, 3.5°±0.2°, 9.3°±0.2°, 20.6°±0.2°, 9.0°±0.2°, 24.0°±0.2°, 20.9°±0.2° and 20.7°±0.2°.

[0064] For example, the crystal form III may be a crystal form having a characteristic peak at the following 2θ diffraction angle:

[0065] 3.5°±0.2°, 8.5°±0.2°, 9.0°±0.2°, 9.3°±0.2°, 14.4°±0.2°, 15.0°±0.2°, 15.6°±0.2°, 16.9°±0.2°, 17.2°±0.2°, 18.2°±0.2°, 20.6°±0.2°, 20.7°±0.2°, 20.9°±2, 24.0°±0.2°, 24.3°±0.2°, 24.6°±0.2°, the relative intensity (I / I0) is 10% or more.

[0066] In one aspect of the present invention, the present invention provides (E)-methyl 6-((3S,8S,9S,10R,13S,14S,17R)-3-(((2S,5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopentadien[a]phenanthrene-17-yl)heptyl-5- The present invention relates to a new crystalline form IV of the compound represented by the enoate ester, which has peaks at the following 2θ diffraction angles in the X-ray powder diffraction pattern (XRPD): 15.3°±0.2°, 22.4°±0.2°, 17.2°±0.2°, 36.5°±0.2°, 24.8°±0.2°, 22.7°±0.2°, 11.7°±0.2°, 18.5°±0.2°, 21.8°±0.2°, 23.8°±0.2°, 16.3°±0.2° and 17.6°±0.2°.

[0067] At this time, Form IV further has peaks at the following 2θ diffraction angles: 26.5°±0.2°, 19.6°±0.2°, 19.1°±0.2°, 16.6°±0.2°, 23.4°±0.2°, 11.5°±0.2°, 18.8°±0.2°, 35.2°±0.2°, 15.6°±0.2°, 18.0°±0.2°, 20.1°±0.2°, 34.7°±0.2°, 47.1°±0.2°, 10.8°±0.2°, 5.9°±0.2° and 14.3°±0.2°.

[0068] For example, Form IV may be a form having characteristic peaks at the following 2θ diffraction angles: 5.9°±0.2°, 10.8°±0.2°, 11.5°±0.2°, 11.7°±0.2°, 14.3°±0.2°, 15.3°±0.2°, 15.6°±0.2°, 16.3°±0.2°, 16.6°±0.2°, 17.2°±0.2°, 17.6°±0.2°, 18.0°±0.2°, 18.5°±0.2°, 18.2°±0.2°, 18.8°±0.2°. 0.2°, 19.1°±0.2°, 19.6°±0.2°, 20.1°±0.2°, 21.8°±0.2°, 22.4°±0.2°, 22.7°±0.2°, 23.4°±0.2°, 23.8°±0.2°, 24.8°±0.2°, 26.5°±0.2°, 34.7°±0.2°, 35.2°±0.2°, 36.5°±0.2° and 47.1°±0.2°, with a relative intensity (I / I0) of 10% or more.

[0069] In one aspect of the present invention, the present invention provides (E)-methyl 6-((3S,8S,9S,10R,13S,14S,17R)-3-(((2S,5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro -1H-cyclopentadienyl[a]phenanthrene-17-yl) hept-5-enoate represented by a new crystalline form V, which has peaks at the following 2θ diffraction angles in the X-ray powder diffraction pattern (XRPD): 23.8°±0.2°, 16.2°±0.2°, 17.4°±0.2°, 35.3°±0.2°, 26.0°±0.2°, 36.6°±0.2°, 22.2°±0.2° and 20.7°±0.2°.

[0070] At this time, Form V may further include peaks at the following 2θ diffraction angles: 17.7°±0.2°, 18.6°±0.2°, 11.5°±0.2°, 15.1°±0.2°, 15.4°±0.2°, 19.0°±0.2°, 19.4°±0.2°, 21.8°±0.2°, 21.6°±0.2°, 22.9°±0.2°, 36.0°±0.2°, 30.1°±0.2°, 18.4°±0.2°, 23.3°°, 37.5°±0.2° and 11.8°±0.2°.

[0071] For example, Form V may be a form having the following 2θ diffraction angle characteristic peaks: 11.5°±0.2°, 11.8°±0.2°, 15.1°±0.2°, 15.4°±0.2°, 16.2°±0.2°, 17.4°±0.2°, 17.7°±0.2°, 18.4°±0.2°, 18.6°±0.2°, 19.0°±0.2°, 19.4°±0.2°, 20.7°±0.2° .2°, 21.6°±0.2°, 21.8°±0.2°, 22.2°±0.2°, 22.9°±0.2°, 23.3°±0.2°, 23.8°±0.2°, 26.0°±0.2°, 30.1°±0.2°, 35.3°±0.2°, 36.0°±0.2°, 36.6°±0.2° and 37.5°±0.2°, with a relative intensity (I / I0) of 10% or more.

[0072] On the one hand, the present invention provides a new crystalline form VI of a compound represented by (E)-methyl 6-((3S,8S,9S,10R,13S,14S,17R)-3-(((2S,5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopentadien[a]phenanthrene-17-yl)hept-5-enoate, which has peaks at the following 2θ diffraction angles in its X-ray powder diffraction pattern (XRPD): 17.3°±0.2°, 15.2°±0.2° and 11.5°±0.2°.

[0073] At this time, Form VI may further include peaks having the following 2θ diffraction angles: 16.2°±0.2°, 21.6°±0.2°, 36.1°±0.2°, 23.2°±0.2°, 19.6°±0.2°, 22.0°±0.2°, 17.6°±0.2° and 18.5°±0.2°.

[0074] For example, Form VI may be a form having the following characteristic peaks at 2θ diffraction angles: 11.5°±0.2°, 15.2°±0.2°, 16.2°±0.2°, 17.3°±0.2°, 17.6°±0.2°, 18.5°±0.2°, 19.6°±0.2°, 21.6°±0.2°, 22.0°±0.2°, 23.2°±0.2° and 36.1°±0.2°, and a relative intensity (I / I0) of 10% or more.

[0075] In one aspect, the present invention provides a novel crystalline form VII of a compound represented by (E)-methyl 6-((3S,8S,9S,10R,13S,14S,17R)-3-(((2S,5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)hept-5-enoate, which has a peak at the following 2θ diffraction angles in an X-ray powder diffraction pattern (XRPD):

[0076] 15.2°±0.2°, 19.6°±0.2°, 18.5°±0.2°, 18.3°±0.2°, 17.2°±0.2°, 10.8°±0.2°, 21.8°±0.2°, 11.7°±0.2°, 18.1°±0.2°, 19.0°±0.2° and 16.0°±0.2°.

[0077] At this time, the crystalline form VII may further include peaks having the following 2θ diffraction angles: 26.0°±0.2°, 28.5°±0.2°, 21.3°±0.2°, 24.6°±0.2°, 30.3°±0.2°, 23.0°±0.2°, 31.4°±0.2°, 20.4°±0.2°, 14.3°±0.2°, 33.4°±0.2°, 23 .3°±0.2°, 9.0°±0.2°, 25.8°±0.2°, 32.3°±0°, 11.4°±0.2°, 8.7°±0.2°, 40.7°±0.2°, 36.4°±0.2°, 12.6°±0.2°, 49.1°±0.2°, 34.6°±0.2°, 37.6°±0.2° and 24.2°±0.2°.

[0078] For example, the crystalline form VII may be a crystalline form having the following characteristic peaks of 2θ diffraction angles: 8.7°±0.2°, 9.0°±0.2°, 10.8°±0.2°, 11.4°±0.2°, 11.7°±0.2°, 12.6°±0.2°, 14.3°±0.2°, 15.2°±0.2°, 16.0°±0.2°, 17.2°±0.2°, 18.1°±0.2°, 18.3°±0.2°, 18.5°±0.2°, 19.2°±0.2°, 19.6°±0.2°, 20.4°±0.2°, 21.3°±0.2°. .2°, 21.8°±0.2°, 23.0°±0.2°, 23.3°±0.2°, 24.2°±0.2°, 24.6°±0.2°, 25.8°±0.2°, 26.0°±0.2°, 28.5°±0.2°, 30.3°±0.2°, 31.4°±0.2°, 32.3°±0.2°, 33.4°±0.2°, 34.6°±0.2°, 36.4°±0.2°, 37.6°±0.2°, 40.7°±0.2° and 49.1°±0.2°, and the relative intensity (I / I0) is 10% or more.

[0079] In one aspect, the present invention provides a novel crystalline form VIII of a compound represented by (E)-methyl 6-((3S,8S,9S,10R,13S,14S,17R)-3-(((2S,5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)hept-5-enoate, which has a peak at the following 2θ diffraction angles in an X-ray powder diffraction pattern (XRPD):

[0080] 22.4°±0.2° and 20.5°±0.2°.

[0081] At this time, Form VIII may further include the following peaks at 2θ diffraction angles: 16.3°±0.2°, 18.0°±0.2°, 18.9°±0.2°, 19.6°±0.2°, 21.6°±0.2° and 36.1°±0.2°.

[0082] For example, the crystalline form VIII can be a crystalline form having the following characteristic peaks of 2θ diffraction angles: 16.3°±0.2°, 18.0°±0.2°, 18.9°±0.2°, 19.6°±0.2°, 20.5°±0.2°, 21.6°±0.2°, 22.4°±0.2° and 36.1°±0.2°, and the relative intensity (I / I0) is 10% or more.

[0083] In one aspect, the present invention provides a novel crystalline form IX of a compound represented by (E)-methyl 6-((3S,8S,9S,10R,13S,14S,17R)-3-(((2S,5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)hept-5-enoate, which has a peak at the following 2θ diffraction angles in an X-ray powder diffraction pattern (XRPD):

[0084] 18.2°±0.2°, 17.3°±0.2°, 11.5°±0.2°, 18.8°±0.2°, 26.0°±0.2°, 19.5°±0.2° and 16.0°±0.2°.

[0085] At this time, Form IX may further include the following peaks at 2θ diffraction angles: 35.2°±0.2°, 34.1°±0.2°, 20.1°±0.2°, 24.6°±0.2°, 21.8°±0.2°, 23.2°±0.2°, 14.9°±0.2°, 11.7°±0.2°, 34.5°±0.2°, 31.3°±0.2°, 37.0°±0.2°, 27.8°±0.2°, 28.6°±0.2°, 14.2°, 33.1°±0.2°, 5.5°±0.2°, 37.5°±0.2°, 8.9°±0.2° and 12.4°±0.2°.

[0086] For example, Form IX may be a form having the following 2θ diffraction angle characteristic peaks: 5.5°±0.2°, 8.9°±0.2°, 11.5°±0.2°, 11.7°±0.2°, 12.4°±0.2°, 14.2°±0.2°, 14.9°±0.2°, 16.0°±0.2°, 17.3°±0.2°, 18.2°±0.2°, 18.8°±0.2°, 19.5°±0.2°, 20.1°±0.2°, 21.3°±0.2°, 23.1°±0.2°, 24.7°±0.2°, 25.9°±0.2°, 26.8°±0.2°, 27.9°±0.2°, 28. 21.2°±0.2°, 23.2°±0.2°, 24.6°±0.2°, 26.0°±0.2°, 27.8°±0.2°, 28.6°±0.2°, 31.3°±0.2°, 33.1°±0.2°, 34.1°±0.2°, 34.5°±0.2°, 35.2°±0.2°, 37.0°±0.2° and 37.5°±0.2°, with a relative intensity (I / I0) of 10% or more.

[0087] In one aspect, the present invention provides a novel crystalline form X of a compound represented by (E)-methyl 6-((3S,8S,9S,10R,13S,14S,17R)-3-(((2S,5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)hept-5-enoate, which has a peak at the following 2θ diffraction angle in an X-ray powder diffraction pattern (XRPD):

[0088] 18.6°±0.2°, 21.9°±0.2°, 19.8°±0.2°, 17.2°±0.2°, 17.4°±0.2°, 19.1°±0.2°, 15.4°±0.2° and 28.9°±0.2°.

[0089] At this time, the crystal form X may further include the following peaks of 2θ diffraction angles: 11.5°±0.2°, 36.1°±0.2°, 17.8°±0.2°, 24.8°±0.2° and 31.6°±0.2°.

[0090] For example, the crystal form X can be a crystal form having the following characteristic peaks of 2θ diffraction angles: 11.5°±0.2°, 15.4°±0.2°, 17.2°±0.2°, 17.4°±0.2°, 17.8°±0.2°, 18.6°±0.2°, 19.1°±0.2°, 19.8°±0.2°, 21.9°±0.2°, 24.8°±0.2°, 28.9°±0.2°, 31.6°±0.2°, 36.1°±0.2°, and the relative intensity (I / I0) is 10% or more.

[0091] In one aspect, the present invention provides a novel crystalline form XI of a compound represented by (E)-methyl 6-((3S,8S,9S,10R,13S,14S,17R)-3-(((2S,5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)hept-5-enoate, which has a peak at the following 2θ diffraction angles in an X-ray powder diffraction pattern (XRPD):

[0092] 15.0°±0.2°, 19.3°±0.2°, 21.8°±0.2°, 18.2°±0.2°, 17.3°±0.2° and 35.0°±0.2°.

[0093] On the other hand, the present invention provides a pharmaceutical composition for preventing or treating vascular leakage disease, comprising any one of the above-mentioned compound and its new crystal forms I to V. Alternatively, the present invention provides a pharmaceutical composition for preventing or treating vascular leakage disease, comprising any one of crystal forms I to VI.

[0094] At this time, the vascular leakage disease can be diabetes, inflammation, retinopathy, diabetic retinopathy, macular degeneration, glaucoma, stenosis, restenosis, arteriosclerosis, atherosclerosis, cerebral edema, arthritis, arthropathy, uveitis, inflammatory bowel disease, macular edema, cancer, immune anticancer adjuvant, hereditary angioedema (HAE), hyperlipidemia, ischemic disease, diabetic foot ulcer, pulmonary hypertension, acute lung injury, myocardial ischemia, heart failure, acute lower limb ischemia, myocardial infarction, stroke, local ischemia or reperfusion injury, VLS (vascular leakage syndrome), edema, transplant rejection, burns, acute or adult respiratory distress syndrome (ARDS), sepsis or autoimmune disease. DETAILED DESCRIPTION

[0096] Hereinafter, the present invention will be described in detail through the following Examples and Experimental Examples.

[0097] However, the following embodiments and experimental examples are only used to illustrate the present invention, and the contents of the present invention are not limited thereto.

[0098] Experimental methods

[0099] 1. X-ray powder diffractometer (XRPD)

[0100] X-ray powder diffraction patterns (XRPD) were obtained on a Shimadzu XRD-6000 instrument.

[0101] -set up

[0102] Tube:Cu:

[0103] Generator: Voltage: 40kV; Current: 30mA

[0104] Scanning range: 3-50 degrees. Scanning speed: 5 degrees / minute

[0105] 2. Differential Scanning Calorimetry (DSC)

[0106] Compound samples (about 1 mg) were tested in the pinholes of aluminum pans under a nitrogen purge.

[0107] -set up

[0108] Heating rate: 20℃ / min in the range of 30℃-300℃

[0109] Nitrogen purge: 50mL / min

[0110] Sample: about 1 mg

[0111] 3. Thermogravimetric analysis (TGA)

[0112] Compound samples (4-6 mg) were weighed into a pan and heated under a nitrogen purge.

[0113] -set up

[0114] Heating rate: 20℃ / min in the range of 30℃-300℃

[0115] Nitrogen purge: 50mL / min

[0116] Sample: about 5 mg

[0117] 4. Dynamic Vapor Sorption (DVS)

[0118] About 10 mg of sample was used to test its moisture absorption / desorption curve.

[0119] -set up

[0120] Temperature: 25℃

[0121] Balance: dm / dt: 0.01% / min

[0122] Relative humidity (RH) measurement step range: 0%-95%-0% RH

[0123] Relative humidity (RH) measurement step: 5% RH

[0124] Sample: 10-20mg

[0125] - Hygroscopicity classification

[0126] Hygroscopicity: Water absorption standard*

[0127] Deliquescent: Absorbs enough water to form a liquid.

[0128] High moisture absorption: W% ≥ 15%

[0129] Moisture absorption: W% ≥ 2%

[0130] Slightly hygroscopic: W% ≥ 0.2%

[0131] No moisture absorption: W%<0.2%

[0132] *25±1℃, 80±2%RH

[0133] 5. Polarized Light Microscopy (PLM)

[0134] The samples dispersed in silicone oil were observed under crossed polarizers using an eyepiece (10X) and an objective lens (10X or 5X) and recorded by a camera / computer system with magnification.

[0135] 6. High Performance Liquid Chromatography (HPLC)

[0136] Chromatographic column: Agilent Zorbax Rx C8, 4.6mm×250mm, 5.0μm

[0137] Mobile phase: 85% acetonitrile

[0138] Flow rate: 1.0mL / min

[0139] Wavelength: 205nm

[0140] Injection volume: 10 μL

[0141] Column temperature: 30°C

[0142] Diluent: 100% acetonitrile

[0143] Preparation Example 1 Preparation of Compound 1

[0144] The compound 1 represented by the following general formula 1 can be prepared according to the method described in Korean Patent Application No. 10-2019-0166864 (unpublished). Specifically, the compound can be prepared by the method of the following reaction formula 1 or 2.

[0145] [General formula 1]

[0146]

[0147] [Reaction 1]

[0148]

[0149] As shown in Reaction Scheme 1, the compound 1 shown in Formula 1 can be prepared by a method comprising the following steps:

[0150] Pregnenolone is reacted with the compound of Formula 8 to prepare the compound of Formula 6 (Step 1);

[0151] The compound represented by the general formula 6 obtained in the above step 1 is reacted with the compound represented by the general formula 7, and then treated under acidic conditions to prepare the compound represented by the general formula 4 (step 2);

[0152] The compound represented by the general formula 4 obtained in the above step 2 is reacted with the compound represented by the general formula 5 to prepare the compound represented by the general formula 2 (step 3); and

[0153] The compound represented by the general formula 2 obtained in the above step 3 is reacted with the compound represented by the general formula 3 in the presence of a catalyst to prepare the compound represented by the general formula 1 (step 4).

[0154] At this time, R in reaction formula 1 1 C is a straight chain or branched chain 1-10 alkyl.

[0155] [Reaction 2]

[0156]

[0157] As shown in Reaction Scheme 2, the compound 1 shown in Formula 1 can be prepared by a method comprising the following steps:

[0158] Pregnenolone is reacted with the compound of Formula 8 to prepare the compound of Formula 6 (Step 1);

[0159] Reacting the compound represented by Formula 6, the compound represented by Formula 7 and the compound represented by Formula 9 to prepare the compound represented by Formula 10 (Step 2);

[0160] reacting the compound represented by the general formula 10 obtained in the above step 2 with an acidic substance to prepare a compound represented by the general formula 2 (step 3); and

[0161] The compound represented by the general formula 2 obtained in the above step 3 is reacted with the compound represented by the general formula 3 in the presence of a catalyst to prepare the compound represented by the general formula 1 (step 4).

[0162] At this time, R 1 Straight or branched chain C 1-10 Alkyl; X 1 It is a halogen.

[0163] On the other hand, the compound 1 represented by the general formula 1 used in the following examples and experimental examples of the present invention is prepared by the method represented by the following reaction formula 3.

[0164] [Reaction 3]

[0165]

[0166] The specific preparation process is as follows.

[0167] Step 1: Preparation of compound 6-1

[0168]

[0169] Pregnenolone (200 g, 0.632 mol) was added to 2000 mL of dichloromethane, which was placed in a 5L flask equipped with a thermometer, and 173 mL (1.896 mol) of 3,4-dihydro-2H-pyran was added thereto. After cooling to 0-5°C, 3.0 g (15.8 mmol) of p-toluenesulfonic acid monohydrate was dissolved in 50 mL of tetrahydrofuran (THF), which was added dropwise, and then stirred at 0°C for 1.5 hours. 800 mL of saturated sodium bicarbonate aqueous solution and 10 mL of triethylamine (TEA) were added to the reaction mixture at 0°C, and then stirred. After separation, the organic layer was washed with 800 mL of brine, and the aqueous layer was extracted with 200 mL of dichloromethane, the organic layers were combined, dried over 200 g of anhydrous sodium sulfate, filtered, and distilled under reduced pressure. To the obtained residue, 1000 mL of MeOH and 5 mL of TEA were added, heated until completely dissolved, cooled, and stirred at -5°C for 1 hour. The obtained solid was filtered and washed with 200 mL of MeOH to obtain 232.0 g (0.579 mol) of compound 6-1 (THP-pregnenolone) in the form of a pure white solid (yield: 91.6%).

[0170] 1 H-NMR (400MHz, CDCl3): δ5.33-5.36(m,1H),4.71-4.72(m,1H),3.85-3.94(m,1H),3.46-3.56(m,2H),1.00-2.55(m,32H),0.62(s,3H).

[0171] Step 2: Preparation of compound 4-2

[0172]

[0173] After installing a condenser, a heating jacket and a mechanical stirrer in a 5L reactor, it was heated to 119°C (external temperature) and cooled to room temperature for 5 minutes under a nitrogen stream, 332.5g (0.75mol) of 4-(carboxybutyl)triphenylphosphonium bromide, 168.1g (1.50mol) of potassium tert-butoxide, 2000mL of anhydrous toluene and 750mL of anhydrous tetrahydrofuran were added thereto, and then stirred for about 2 hours while heating at 119°C (external temperature, internal mild reflux).

[0174] Compound 6-1 (100.0 g, 0.250 mol) was dissolved in 500 mL of anhydrous toluene, added to the reaction solution, and reacted for about 20 hours.

[0175] After reaction finished, reaction mixture was cooled to room temperature, 320mL (5.14mol) methyl iodide and 1000mL acetone were added thereto, and then stirred at room temperature for 15 hours. Reaction mixture was distilled under reduced pressure to remove most of organic solvent, 1500mL ethyl acetate was added thereto to dissolve, and then 1000mL saturated aqueous ammonium chloride solution was washed. Organic layer was washed twice with 1000mL water and 1000mL salt water, dried over 100g sodium sulfate, filtered and concentrated with 80g diatomite.

[0176] The obtained residue was dissolved in 2000 mL of methanol and then stirred at 10° C. for 13 hours and at 4-5° C. for 1 hour. The obtained solid was filtered, washed with 200 mL of methanol and dried in vacuo to obtain 66.2 g of compound 4-2 in the form of a white solid (yield: 53.2%).

[0177] 1 H NMR (400MHz, CDCl3): δ5.36(t,J=5.80Hz,1H),5.16(t,J=7.00Hz,1H),4.71(m ,1H),3.93(m,1H),3.66(s,3H),3.56(m,2H),2.37-0.88(m,38H),0.54(s,3H).

[0178] Step 3: Preparation of compound 2-1

[0179]

[0180] Compound 4-2 (100 g, 0.200 mol), 1000 mL of methanol and 3.82 g (0.020 mol) of p-toluenesulfonic acid monohydrate were added to a 2 L flask equipped with a thermometer and stirred at 60° C. for 3 hours.

[0181] After the reaction was completed, the reaction solution was stirred at room temperature. When a solid was formed, the mixture was stirred at room temperature for 30 minutes and at 10°C for 1 hour. The reaction solution was filtered, washed with 100 mL of cooled methanol, and vacuum dried to obtain 61.2 g (0.150 mol) of compound 2-1 as a white solid (yield 75.0%).

[0182] 1 H-NMR (400MHz, CDCl3): δ5.33-5.35(m,1H),5.12-5.16(m,1H),3.66(s,3H),3.50-3.52(m,1H),0.98-2.32(m,33H),0.53(s,3H).

[0183] Step 4: Preparation of Compound 1

[0184]

[0185] Compound 2-1 (42.0 g, 0.101 mol) and tri-O-acetyl D-glucan (34.5 g, 0.126 mol) were dissolved in 126 mL of anhydrous toluene and 252 mL of acetonitrile and added to a 1 L flask equipped with a thermometer and a water bath. While maintaining the temperature at 30-35 ° C, lithium nonafluoro-1-butanesulfonate (3.87 g, 0.0130 mol) and (s)-camphorsulfonic acid (0.117 g, 0.0005 mol) were added thereto and then stirred for 2 hours. After the reaction was completed, the reaction solution was quenched with 504 mL of saturated sodium bicarbonate aqueous solution and extracted with 630 mL of heptane. The organic layer was washed twice with 504 mL of saturated sodium bicarbonate aqueous solution and 504 mL of brine. After adding 42 g of anhydrous sodium sulfate and 34 g of charcoal, the organic layer was stirred, filtered through 34 g of celite, washed with 210 mL of dichloromethane, and the filtrates were combined, concentrated and dried in vacuo.

[0186] 1 H-NMR (400MHz, CDCl3): δ5.79-5.88(m,2H),5.35-5.36(m,1H),5.27-5.29(m,1H),5.12-5.16 (m,2H),4.15-4.24(m,3H),3.66(s,3H),3.54-3.57(m,1H),0.91-2.32(m,38H),0.54(s,3H).

[0187] Stereochemical analysis of compound 1

[0188] The compound 1 obtained by reaction formula 3 exists as a mixture of α-isomer and β-isomer. At this time, the oily residue is heated and dissolved in 336 mL of ethanol at 50-55°C, and then stirred at 30°C. When a solid is formed, the temperature is lowered to 0°C and stirred for 30 minutes. The solid is filtered under reduced pressure, vacuum dried, and the crystallized α-isomer is separated. The filtrate is subjected to column chromatography to separate the β-isomer. At this time, a solid α-isomer is obtained, and the purity of the α-isomer is 93.0%.

[0189] The results of NMR performed to confirm the structures of α- and β-isomers are shown in Figure 1 shown. Figure 1 It was confirmed that the prepared crude compound 1 had α-isomers or β-isomers with different stereostructures.

[0190] On the other hand, the crude compound obtained by the preparation method of Korean Patent Application Publication No. 10-2011-0047170 is an oil phase in which α-isomer and β-isomer are mixed, while the compound prepared by the method disclosed in the present application is a solid phase α-isomer.

[0191] Example 1 Preparation of Compound 1 Crystalline Form I

[0192] About 50 mg of compound 1 prepared in Preparation Example 1 was dispersed in a solvent (water, methanol or ethanol) with low solubility, and then stirred at room temperature (25° C.) for 3 days. A wet solid was obtained by centrifugation. The solid was dried under reduced pressure at room temperature for 24 hours. In order to analyze the crystalline characteristics of the dried solid, the following experiment was performed.

[0193] Characteristic analysis

[0194] In order to analyze the characteristics of the crystal form prepared in Example 1, the crystal form in the white powder state was analyzed by solubility measurement, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS) and polarizing microscopy (PLM) according to the method described in <Experimental Methods>, and the results are shown in Figures 2 to 6 middle.

[0195] Solubility determination

[0196] Solubility determination was performed by visual observation and manual dilution at room temperature. Specifically, about 4.0 mg of compound 1 prepared in Preparation Example 1 was weighed in a 4.0 mL glass vial, and solvent was added thereto successively until particles were not observed by the naked eye (i.e., all dissolved) or particles were still present (i.e., undissolved) even after adding 4 mL of solvent (e.g., a total volume of 200, 500, 1000, 2000 or 4000 μL). The total amount of solvent was recorded to calculate the solubility for each solvent. The results are shown in Table 1 below.

[0197] Table 1

[0198] Solvents Solubility (mg / mL) <![CDATA[Water (H2O)]]> <1 Methanol (MeOH) 6.9～8.2 Ethanol (EtOH) 5.1～6.4 Isopropyl alcohol (IPA) 5.1～6.8 Acetonitrile (ACN) >82.6 acetone >100 Methyl Ethyl Ketone (MEK) >100 Ethyl acetate (EtOAc) >100 Isopropyl acetate (iPrOAc) >100 Methyl tert-butyl ether (MTBE) >85.4 n-Butanol 26～52 n-Propanol 26.1～52.1 n-Butyl acetate >88.6 Tetrahydrofuran (THF) >76 Toluene >83 n-Heptane 6.3～8.8 Dichloromethane (DCM) >100 Dimethyl sulfoxide (DMSO) 30～45 Dimethylformamide (DMF) >100 Cyclohexane 26～40 1,4-Dioxane >100 Isopropyl ether 65.2～130.4 2-Methyl-tetrahydrofuran >93.2 Chloroform >100 Anisole >100 Petroleum ether 11.5～15.3

[0199] X-ray powder diffraction (XRPD)

[0200] exist Figure 2 In the XRPD spectrum of the crystalline form, peaks with a relative intensity (I / I0) of 10% or more are shown in Table 2 below.

[0201] Table 2

[0202]

[0203]

[0204] 2θ: diffraction angle, d: crystal plane distance, I / I0(%): relative intensity (I: peak intensity; I0: highest peak intensity)

[0205] Generally speaking, the error range of the diffraction angle (2θ) in X-ray powder diffraction is within ±0.2°. Therefore, it should be understood that the value of the diffraction angle also includes values ​​within the range of about ±0.2°. Therefore, the present invention includes not only crystals having the same diffraction angle and peak in X-ray powder diffraction, but also crystals having a diffraction angle consistent with the value represented by the error range of ±0.2°.

[0206] When the relative intensity (I / I0) of the peak is 10% or more, the diffraction angles of the peaks are 8.9°, 10.7°, 11.7°, 14.1°, 15.1°, 16.0°, 17.2°, 17.8°, 18.3°, 19.5°, 20.5°, 21.3°, 21.9°, 24.0°, 24.6° and 26.1° (2θ±0.2°), respectively. The crystal form of compound 1 having this crystal form is called crystal form I.

[0207] Dynamic Vapor Sorption (DVS)

[0208] The DVS analysis results of Form I are shown in Table 3 below.

[0209] Table 3

[0210]

[0211]

[0212] According to the above XRPD results, it is confirmed that the crystalline form I of compound 1 prepared in Example 1 of the present invention has excellent crystallinity. It is confirmed by the TGA results that the weight loss of the crystalline form I of compound 1 is 0.078% when heated from room temperature to 120°C. An endothermic peak (100.96°C) corresponding to the melting point of the crystalline form I of compound 1 is confirmed by the DSC result graph. By the DVS results, a water absorption rate of 0.11% is confirmed at 80% RH, indicating that the crystalline form I of compound 1 is non-hygroscopic.

[0213] Example 2 Preparation of Compound 1 Crystalline Form II

[0214] About 50 mg of compound 1 prepared in Preparation Example 1 was dispersed in isopropanol (1 mL) in a 4 mL glass bottle and stirred at high temperature (50°C) for 3 days. The glass bottle was then cooled in a 4°C refrigerator for 1 day, and no solid precipitation was observed. The glass bottle was kept in a -20°C refrigerator for 7 consecutive days, and the solid precipitate was separated by centrifugation (12,000 rpm, 5 minutes). The precipitate was then dried under reduced pressure in a vacuum oven at room temperature for 24 hours. As a result, a thin plate-like layered solid or a flaky solid was obtained. In order to analyze the crystalline characteristics of the prepared solid, XRPD was performed according to the method described in <Experimental Method> 1. X-ray powder diffractometer (XRPD). The results are shown in Tables 4 and Figure 7 shown.

[0215] exist Figure 7 In the XRPD spectrum of the crystalline form, peaks having a relative intensity (I / I0) of 10% or more are shown in the following Table 4.

[0216] Table 4

[0217] serial number 2θ(±0.2°) d value (A) <![CDATA[I / I0(%)]]> 1 5.7 15.4 10.7 2 11.4 7.6 78.9 3 15.3 5.7 13.8 4 17.3 5.1 100.0 5 19.0 4.6 14.7 6 35.2 2.5 16.8

[0218] 2θ: diffraction angle, d: crystal plane distance, I / I0(%): relative intensity (I: peak intensity; I0: highest peak intensity)

[0219] When the relative intensity of the peak (I / I0) is 10% or more, the diffraction angles of the peaks are 5.7°, 11.4°, 15.3°, 17.3°, 19.0°, 35.2° (2θ±0.2°), respectively. The crystal form of Compound 1 having this crystal form is called Crystal Form II.

[0220] Example 3 Preparation of Compound 1 Crystalline Form III

[0221] About 50 mg of compound 1 prepared in Preparation Example 1 was completely dissolved in a preferred solvent such as MEK or chloroform at room temperature, and then the reaction vessel was covered with aluminum foil with small holes. Then, it was naturally evaporated at room temperature for 1 week, and a small amount of solid precipitated. It was further dried under reduced pressure at 40°C for 24 hours. In order to analyze the crystalline characteristics of the prepared solid, XRPD was performed according to the method described in <Experimental Method> 1. X-ray Powder Diffractometer (XRPD). The results are as follows Figure 8 In addition, except for using about 30 mg of MEK solvent, the crystalline form was prepared under the same conditions and analyzed by XRPD. The results are as follows Figure 8 shown.

[0222] exist Figure 8 In the XRPD spectrum of the crystalline form (solvent: 50 mg MEK), peaks having a relative intensity (I / I0) of 10% or more are shown in the following Table 5.

[0223] Table 5

[0224] serial number 2θ(±0.2°) d value (A) <![CDATA[I / I0(%) <!-- 16 -->]]> 1 3.5 25.0 20.2 2 8.5 10.3 26.5 3 9.0 9.7 12.5 4 9.3 9.4 14.4 5 14.4 6.1 63.9 6 15.0 5.8 24.9 7 15.6 5.6 100.0 8 16.9 5.2 33.6 9 17.2 5.1 30.9 10 18.2 4.8 99.3 11 20.6 4.2 12.8 12 20.7 4.2 11.4 13 20.9 4.2 11.5 14 24.0 3.6 12.1 15 24.3 3.6 25.9 16 24.6 3.6 40.6

[0225] 2θ: diffraction angle, d: crystal plane distance, I / I0(%): relative intensity (I: peak intensity; I0: highest peak intensity)

[0226] When the relative intensity (I / I0) of the peak is 10% or more, the diffraction angles of the peaks are 3.5°, 8.5°, 9.0°, 9.3°, 14.4°, 15.0°, 15.6°, 16.9°, 17.2°, 18.2°, 20.6°, 20.7°, 20.9°, 24.0°, 24.3° and 24.6° (2θ±0.2°), respectively. The crystalline form of compound 1 having this crystalline form is called crystalline form III.

[0227] Example 4 Preparation of Compound 1 Crystalline Form IV

[0228] About 50 mg of compound 1 prepared in Preparation Example 1 was completely dissolved in ethanol (0.8 mL) at 55°C to prepare a saturated solution, and mixing was continued for 30 minutes. The solution was then rapidly cooled to a low temperature in a -20°C refrigerator and stored for 3 days. After the solid was obtained by centrifugation, it was vacuum dried at 40°C overnight. In order to analyze the crystalline characteristics of the prepared solid, XRPD was performed according to the method described in <Experimental Methods> 1. X-ray Powder Diffractometer (XRPD). The results are shown in Tables 6 and Fig. 9 shown.

[0229] exist Fig. 9 In the XRPD spectrum of the crystalline form, peaks having a relative intensity (I / I0) of 10% or more are shown in the following Table 6.

[0230] Table 6

[0231]

[0232]

[0233] 2θ: diffraction angle, d: crystal plane distance, I / I0(%): relative intensity (I: peak intensity; I0: highest peak intensity)

[0234] When the relative intensity (I / I0) of the peak is 10% or more, the diffraction angles of the peaks are 5.9°, 10.8°, 11.5°, 11.7°, 14.3°, 15.3°, 15.6°, 16.3°, 16.6°, 17.2°, 17.6°, 18.0°, 18.5°, 18.8°, 19.1°, 19.6°, 20.1°, 21.8°, 22.4°, 22.7°, 23.4°, 23.8°, 23.8°, 24.6°35.2°, 36.5° and 47.1° (2θ±0.2°), respectively. The crystalline form of Compound 1 having this crystalline form is called crystalline form IV.

[0235] Example 5 Preparation of Compound 1 Crystalline Form V

[0236] About 50 mg of compound 1 prepared in Preparation Example 1 was completely dissolved in n-propanol (0.8 mL) at 55°C to prepare a saturated solution, and mixing was continued for 30 minutes. The solution was then rapidly cooled to a low temperature in a -20°C refrigerator and stored for 3 days. After the solid was obtained by centrifugation, it was vacuum dried at 40°C overnight. In order to analyze the crystalline characteristics of the prepared solid, XRPD was performed according to the method described in <Experimental Methods> 1. X-ray Powder Diffractometer (XRPD). The results are shown in Tables 7 and Fig.10 shown.

[0237] exist Fig.10 In the XRPD spectrum of the crystalline form, peaks having a relative intensity (I / I0) of 10% or more are shown in the following Table 7.

[0238] Table 7

[0239]

[0240]

[0241] 2θ: diffraction angle, d: crystal plane distance, I / I0(%): relative intensity (I: peak intensity; I0: highest peak intensity)

[0242] When the relative intensity (I / I0) of the peak is 10% or more, the diffraction angles of the peaks are 11.5°, 11.8°, 15.1°, 15.4°, 16.2°, 17.4°, 17.7°, 18.4°, 18.6°, 19.0°, 19.4°, 20.7°, 21.6°, 21.8°, 22.2°, 22.9°, 23.3°, 23.8°, 26.0°, 30.1°, 35.3°, 36.0°, 36.6° and 37.5° (2θ±0.2°), respectively. The crystalline form of Compound 1 having this crystalline form is called crystalline form V.

[0243] Example 6 Preparation of Form VI of Compound 1

[0244] In order to observe whether the crystal form IV of compound 1 prepared in Example 4 changes after 2 months at room temperature, the characteristics of the crystal form IV stored at room temperature for 2 months were analyzed. Specifically, XRPD was performed according to the method described in <Experimental Method> 1. X-ray Powder Diffractometer (XRPD). As a result, a new crystal form having an XRPD pattern different from that of the crystal form IV was confirmed. The results are shown in Tables 8 and Fig.11 shown.

[0245] exist Fig.11 In the XRPD spectrum of the crystalline form IV after 2 months, the peaks with a relative intensity (I / I0) of 10% or more are shown in the following Table 8.

[0246] Table 8

[0247]

[0248]

[0249] 2θ: diffraction angle, d: crystal plane distance, I / I0(%): relative intensity (I: peak intensity; I0: highest peak intensity)

[0250] When the relative intensity (I / I0) of the peak is 10% or more, the diffraction angles of the peaks are 11.5°, 15.2°, 16.2°, 17.3°, 17.6°, 18.5°, 19.6°, 21.6°, 22.0°, 23.2° and 36.1° (2θ±0.2°), respectively. The crystal form of Compound 1 having this crystal form is called Crystal Form VI.

[0251] Example 7 Preparation of Form VII of Compound 1

[0252] The experiment was conducted in the same manner as described in Example 6, except that the crystalline form IV of compound 1 prepared in Example 4 was stored at room temperature for 3 months. As a result, a new crystalline form having an XRPD pattern different from that of the crystalline form IV was confirmed. The results are shown in Tables 9 and Fig.11 shown.

[0253] exist Fig.11 In the XRPD spectrum of the crystalline form IV after 3 months, the peaks with a relative intensity (I / I0) of 10% or more are shown in the following Table 9.

[0254] Table 9

[0255]

[0256]

[0257] 2θ: diffraction angle, d: crystal plane distance, I / I0(%): relative intensity (I: peak intensity; I0: highest peak intensity)

[0258] When the relative intensity (I / I0) of the peak is 10% or higher, the diffraction angles of the peak are 8.7°, 9.0°, 10.8°, 11.4°, 11.7°, 12.6°, 14.3°, 15.2°, 16.0°, 17.2°, 18.1°, 18.3°, 18.5°, 19.0°, 19.6°, 20.4°, 21.3°, 21.8°, 23.0°, 23.3°, 24.2°, 24.6°, 25.8°, 26.0°, 28.5°, 30.3°, 31.4°, 32.3°, 33.4°, 34.6°, 36.4°, 37.6°, 40.7° and 49.1° (2θ±0.2°), respectively. The crystalline form of Compound 1 having this crystalline form is referred to as Form VII.

[0259] Example 8 Preparation of Compound 1 Crystalline Form VIII

[0260] In order to observe whether the crystalline form V of compound 1 prepared in Example 5 changes after being placed at room temperature for 2 months, the characteristics of the crystalline form V stored at room temperature for 2 months were analyzed. Specifically, XRPD was performed according to the method described in <Experimental Method> 1. X-ray Powder Diffractometer (XRPD). As a result, a new crystalline form having a new XRPD pattern different from that of the crystalline form V was confirmed. The results are shown in Tables 10 and Fig.12 shown.

[0261] exist Fig.12 In the XRPD spectrum of the crystalline form V after 2 months, the peaks with a relative intensity (I / I0) of 10% or more are shown in the following Table 10.

[0262] Table 10

[0263] serial number 2θ(±0.2°) d value (A) <![CDATA[I / I0(%)]]> 1 16.3 5.4 13.6 2 18.0 4.9 18.1 3 18.9 4.9 28.3 4 19.6 4.5 16.3 5 20.5 4.3 38.7 6 21.6 4.0 13.9 7 22.4 3.9 100.0 8 36.1 2.4 26.0

[0264] 2θ: diffraction angle, d: crystal plane distance, I / I0(%): relative intensity (I: peak intensity; I0: highest peak intensity)

[0265] When the relative intensity (I / I0) of the peak is 10% or higher, the diffraction angles of the peaks are 16.3°, 18.0°, 18.9°, 19.6°, 20.5°, 21.6°, 22.4°, and 36.1° (2θ±0.2°), respectively. The crystal form of Compound 1 having this crystal form is called Crystal Form VIII.

[0266] Example 9 Preparation of Form IX of Compound 1

[0267] The experiment was conducted in the same manner as described in Example 8, except that the Form V of Compound 1 prepared in Example 5 was stored at room temperature for 3 months. As a result, a new form having an XRPD pattern different from that of Form V was confirmed. The results are shown in Tables 11 and Fig.12 shown.

[0268] exist Fig.12 In the XRPD spectrum of the crystalline form V after 3 months, the peaks with a relative intensity (I / I0) of 10% or more are shown in the following Table 11.

[0269] Table 11

[0270] serial number 2θ(±0.2°) d value (A) <![CDATA[I / I0(%)]]> 1 5.5 15.7 11.4 2 8.9 9.8 10.7 3 11.5 7.6 69.0 4 11.7 7.5 14.9 5 12.4 7.0 10.0 6 14.2 6.2 12.4 7 14.9 5.9 15.9 8 16.0 5.5 30.3 9 17.3 5.1 80.0 10 18.2 4.8 100.0 11 18.8 4.7 56.4 12 19.5 4.5 34.7 13 20.1 4.3 26.3 14 21.8 4.0 20.0 15 23.2 3.8 17.5 16 24.6 3.6 21.0 17 26.0 3.4 55.5 18 27.8 3.2 13.5 19 28.6 3.2 13.5 20 31.3 2.8 14.2 21 33.1 2.7 11.7 22 34.1 2.6 26.6 23 34.5 2.5 14.5 24 35.2 2.5 28.4 25 37.0 2.4 13.8 26 37.5 2.3 11.2

[0271] 2θ: diffraction angle, d: crystal plane distance, I / I0(%): relative intensity (I: peak intensity; I0: highest peak intensity)

[0272] When the relative intensity (I / I0) of the peak is 10% or more, the diffraction angles of the peaks are 5.5°, 8.9°, 11.5°, 11.7°, 12.4°, 14.2°, 14.9°, 16.0°, 17.3°, 18.2°, 18.8°, 19.5°, 20.1°, 21.8°, 23.2°, 24.6°, 26.0°, 27.8°, 28.6°, 31.3°, 33.1°, 34.1°, 33.7°, 33.7° and 37.5° (2θ±0.2°), respectively. The crystalline form of Compound 1 having this crystalline form is called crystalline form IX.

[0273] Example 10 Upward expansion of Form IV and preparation of Form X

[0274] The upward expansion of the crystalline form IV prepared in Example 4 was carried out as follows. About 100 mg of the compound prepared in Preparation Example 1 was completely dissolved in ethanol (1.6 mL) at 55°C to prepare a saturated solution, and mixing was continued for 30 minutes. The solution was then quickly cooled to a low temperature in a -20°C refrigerator and stored for 3 days. After the solid was obtained by centrifugation, it was vacuum dried at 40°C overnight. In order to analyze the crystalline characteristics of the prepared solid, XRPD was performed according to the method described in <Experimental Method> 1. X-ray Powder Diffractometer (XRPD). The results are shown in Tables 12 and Fig.13 shown.

[0275] exist Fig.13 In the XRPD spectrum of the crystalline form, peaks having a relative intensity (I / I0) of 10% or more are shown in the following Table 12.

[0276] Table 12

[0277] serial number 2θ(±0.2°) d value (A) <![CDATA[I / I0(%)]]> 1 11.5 7.6 23.6 2 15.4 5.7 40.2 3 17.2 5.1 43.1 4 17.4 5.0 41.0 5 17.8 4.9 11.8 6 18.6 4.7 100.0 7 19.1 4.6 40.4 8 19.8 4.4 59.3 9 21.9 4.0 66.0 10 24.8 3.5 10.3 11 28.9 3.0 38.0 12 31.6 2.8 10.0 13 36.1 2.4 12.6

[0278] 2θ: diffraction angle, d: crystal plane distance, I / I0(%): relative intensity (I: peak intensity; I0: highest peak intensity)

[0279] When the relative intensity (I / I0) of the peak is 10% or more, the diffraction angles of the peaks are 11.5°, 15.4°, 17.2°, 17.4°, 17.8°, 18.6°, 19.1°, 19.8°, 21.9°, 24.8°, 28.9°, 31.6° and 36.1° (2θ±0.2°), respectively. The crystal form of Compound 1 having this crystal form is called Crystal Form X.

[0280] Example 11 Upward expansion of Form V and preparation of Form XI

[0281] The upward expansion of Form V prepared in Example 5 was carried out as follows. About 100 mg of Compound 1 prepared in Preparation Example 1 was completely dissolved in n-butanol (1.6 mL) at 55°C to prepare a saturated solution, and mixed continuously for 30 minutes. The solution was then quickly cooled to a low temperature in a -20°C refrigerator and stored for 3 days. After the solid was obtained by centrifugation, it was vacuum dried at 40°C overnight. In order to analyze the crystalline characteristics of the prepared solid, XRPD was performed according to the method described in <Experimental Method> 1. X-ray Powder Diffractometer (XRPD). The results are shown in Tables 13 and Fig.14 shown.

[0282] exist Fig.14 In the XRPD spectrum of the crystalline form, peaks having a relative intensity (I / I0) of 10% or more are shown in the following Table 13.

[0283] Table 13

[0284] serial number 2θ(±0.2°) d value (A) <![CDATA[I / I0(%)]]> 1 15.0 5.8 100.0 2 17.3 5.1 22.6 3 18.2 4.8 38.0 4 19.3 4.5 43.7 5 21.8 4.0 38.5 6 35.0 2.5 11.7

[0285] 2θ: diffraction angle, d: crystal plane distance, I / I0(%): relative intensity (I: peak intensity; I0: highest peak intensity)

[0286] When the relative intensity (I / I0) of the peak is 10% or higher, the diffraction angles of the peaks are 15.0°, 17.3°, 18.2°, 19.3°, 21.8°, 35.0° (2θ±0.2°), respectively. The crystal form of Compound 1 having this crystal form is called Crystal Form XI.

[0287] Experimental Example 1: Purity Measurement Based on Crystalline Form

[0288] About 5 mg of each crystalline form prepared in Preparation Example 1 and Examples 1-5 was weighed in a 10 mL volumetric flask and analyzed according to the following purity analysis method. 5 mg of each crystalline form in a stable state was dissolved in 10 mL of acetonitrile, and 10 μL of the mixture was injected into HPLC. HPLC conditions were the same as <Experimental Method> 6. High Performance Liquid Chromatography (HPLC). The results are shown in Table 14.

[0289] Table 14

[0290] Crystalline form purity(%) Total related substances (%) Preparation Example 1 99.55 0.45 Example 1 Crystal Form I 99.85 0.15 Example 2 Crystalline Form II 99.69 0.31 Example 3 Crystalline Form III 99.63 3.37 Example 4 Crystalline Form IV 99.55 0.45 Example 5 Crystalline Form V 99.74 0.26

[0291] Experimental Example 2 Accelerated stability test

[0292] Since significant changes are judged and the expiration date is set according to the stability test method described in order to determine the storage method and shelf life of the drug, etc., the stability test is one of the important factors to ensure proper stability and commercialization of the drug.

[0293] In order to confirm the stability of the new crystal form of the present invention, the stability of the crystal form I prepared in Example 1 was evaluated by liquid chromatography under the conditions of <Experimental Method> 6. High Performance Liquid Chromatography (HPLC) analysis. The results of the accelerated stability test from 1 month to 6 months at 40±2°C and 75±5RH are shown in Table 15 below.

[0294] Table 15

[0295]

[0296] The results confirmed that the crystal form I of Example 1 of the present invention could be stably maintained for up to 6 months without affecting the purity.

[0297] As mentioned above, the present invention has been described in detail by preferred preparation examples, embodiments and experimental examples, but the scope of the present invention is not limited to specific embodiments, but should be interpreted by the appended claims. In addition, it should be understood by those of ordinary skill in the art that various modifications and changes can be made without departing from the scope of the present invention.

[0298] Industrial Applicability

[0299] The present invention relates to (E)-methyl 6-((3S,8S,9S,10R,13S,14S,17R)-3-(((5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)hept-5-enoate and a vascular leakage blocker containing the same. The new crystal form has high purity, good stability, good long-term storage and drug stability, can be used as a vascular leakage blocker, and is very advantageous in producing high-quality raw materials.

Claims

1. A crystal of Form I of (E)-methyl 6-((3S,8S,9S,10R,13S,14S,17R)-3-(((2S,5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)hept-5-enoate, which has a peak at the following 2θ diffraction angle in an X-ray powder diffraction pattern: 16.0°±0.2°、19.5°±0.2°、18.3°±0.2°、15.1°±0.2°、21.9°±0.2°。 2. The crystal according to claim 1, characterized in that The crystalline form further has peaks at the following 2θ diffraction angles: 10.7°±0.2°、8.9°±0.2°、17.8°±0.2°、21.3°±0.2°、17.2°±0.2°。 3. The crystal according to claim 2, characterized in that The crystalline form further has peaks at the following 2θ diffraction angles: 14.1°±0.2°,20.5°±0.2°,11.7°±0.2°。 4. The crystal according to claim 3, characterized in that The crystalline form further has peaks at the following 2θ diffraction angles: 24.0°±0.2°、24.6°±0.2°、26.1°±0.2°。 5. A crystal of form II of (E)-methyl 6-((3S,8S,9S,10R,13S,14S,17R)-3-(((2S,5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)hept-5-enoate, which has a peak at the following 2θ diffraction angle in an X-ray powder diffraction pattern: 17.3°±0.2°、11.4°±0.2°、35.2°±0.2°、19.0°±0.2°、15.3°±0.2°、5.7°±0.2°。 6. A crystal of Form III of (E)-methyl 6-((3S,8S,9S,10R,13S,14S,17R)-3-(((2S,5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)hept-5-enoate, which has a peak at the following 2θ diffraction angle in an X-ray powder diffraction pattern: 15.6°±0.2°、18.2°±0.2°、14.4°±0.2°、24.6°±0.2°、16.9°±0.2°、17.2°±0.2°。 7. A crystal of Form IV of (E)-methyl 6-((3S,8S,9S,10R,13S,14S,17R)-3-(((2S,5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)hept-5-enoate, which has a peak at the following 2θ diffraction angle in an X-ray powder diffraction pattern: 15.3°±0.2°、22.4°±0.2°、17.2°±0.2°、36.5°±0.2°、24.8°±0.2°、22.7°±0.2°、11.7°±0.2°、18.5°±0.2°、21.8°±0.2°、23.8°±0.2°、16.3°±0.2°、17.6°±0.2°。 8. A crystal of Form V of (E)-methyl 6-((3S,8S,9S,10R,13S,14S,17R)-3-(((2S,5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)hept-5-enoate, which has a peak at the following 2θ diffraction angle in an X-ray powder diffraction pattern: 23.8°±0.2°、16.2°±0.2°、17.4°±0.2°、35.3°±0.2°、26.0°±0.2°、36.6°±0.2°、22.2°±0.2°、20.7°±0.2°。 9. Use of the crystal according to any one of claims 1 to 8 in the preparation of a medicament for preventing or treating vascular leakage diseases.

10. The use according to claim 9, characterized in that The vascular leakage disease is diabetes, inflammation, retinopathy, macular degeneration, glaucoma, stenosis, restenosis, arteriosclerosis, arthritis, cancer, hyperlipidemia, ischemic disease, diabetic foot ulcer, pulmonary hypertension, acute lung injury, heart failure, myocardial infarction, stroke, VLS (vascular leakage syndrome), edema, transplant rejection, burns, acute or adult respiratory distress syndrome (ARDS), sepsis or autoimmune disease.

11. The use according to claim 10, characterized in that The retinopathy is diabetic retinopathy.

12. The use according to claim 10, characterized in that The arteriosclerosis is atherosclerosis.

13. The use according to claim 10, characterized in that The inflammation is arthritis, uveitis or inflammatory bowel disease.

14. The use according to claim 10, characterized in that The ischemic disease is myocardial ischemia, acute lower limb ischemia or local ischemia or reperfusion injury.

15. The use according to claim 10, characterized in that The edema is cerebral edema, macular edema or hereditary angioedema (HAE).

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