Patent Description:
The compound represented by formula <NUM> has the compound name (E)-methyl <NUM>-((<NUM>,<NUM>,<NUM>,10R,<NUM>,<NUM>,17R)-<NUM>-(((<NUM>,6R)-<NUM>-acetoxy-<NUM>-(acetoxymethyl)-<NUM>,<NUM>-dihydro-<NUM>-pyran-<NUM>-yl)oxy)-<NUM>,<NUM>-dimethyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>-tetradecahydro-<NUM>-cyclopenta[a]phenanthrene-<NUM>-yl)hept-<NUM>-enoate, and is a compound disclosed in <CIT> under the code name SAC-<NUM>.

The compound inhibits the death of vascular endothelial cells, suppresses the formation of actin stress fibers induced by VEGF, increases the structure of cortical actin ring, and improves the stability of TJ (tight junction) between vascular cells, thereby inhibiting vascular leakage. The compound not only inhibits the permeability of blood vessels, but also has excellent activity to restore the integrity of damaged blood vessels. Therefore, it is known that the compound can be effectively used for preventing or treating various diseases caused by vascular leakage. The compound SA-<NUM> is also disclosed in <CIT>.

<CIT> discloses a new chemical preparation method capable of separating and mass-producing stereoisomers of the compound of formula <NUM>, and preparing the compound in high yield.

On the other hand, polymorphs refer to crystalline solids that have the same molecular structure, but whose crystal structure is changed by alterations in packing and molecular conformation of crystals.

The criterion for selecting a good crystalline form is due to the most important physicochemical properties required by drugs. The selection of the optimized crystalline form can vary depending on the purpose, such as choosing the thermodynamically most stable one, choosing the one optimized for the production of pharmaceutical raw materials and finished products, improving the solubility and dissolution rate of drugs, or changing pharmacokinetic properties.

Accordingly, the present inventors disclose the first crystalline form of (E)-methyl <NUM>-((<NUM>,<NUM>,<NUM>,10R,<NUM>,<NUM>,17R)-<NUM>-(((<NUM>,6R)-<NUM>-acetoxy-<NUM>-(acetoxymethyl)-<NUM>,<NUM>-dihydro-<NUM>-pyran-<NUM>-yl)oxy)-<NUM>,<NUM>-dimethyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>-tetradecahydro-<NUM>-cyclopenta[a]phenanthrene-<NUM>-yl)hept-<NUM>-enoate, the preparation method therefor, and the physicochemical properties of the novel crystalline form.

It is an object of the present invention to provide a novel crystalline form of the compound (E)-methyl <NUM>-((<NUM>,<NUM>,<NUM>,10R,<NUM>,<NUM>,17R)-<NUM>-(((<NUM>,6R)-<NUM>-acetoxy-<NUM>-(acetoxymethyl)-<NUM>,<NUM>-dihydro-<NUM>-pyran-<NUM>-yl)oxy)-<NUM>,<NUM>-dimethyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>-tetradecahydro-<NUM>-cyclopenta[a]phenanthrene-<NUM>-yl)hept-<NUM>-enoate.

It is another object of the present invention to provide a vascular leakage blocker comprising a novel crystalline form of the compound.

To achieve the above objects, in one aspect of the present invention, the present invention provides a crystalline solid of crystalline form I of (E)-methyl <NUM>-((<NUM>,<NUM>,<NUM>,10R,<NUM>,<NUM>,17R)-<NUM>-(((<NUM>,6R)-<NUM>-acetoxy-<NUM>-(acetoxymethyl)-<NUM>,<NUM>-dihydro-<NUM>-pyran-<NUM>-yl)oxy)-<NUM>,<NUM>-dimethyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>-tetradecahydro-<NUM>-cyclopenta[a]phenanthrene-<NUM>-yl)hept-<NUM>-enoate having peaks at the following 2Θ diffraction angles in the X-ray powder diffraction pattern:
<NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°.

In another aspect of the present invention, the present invention provides a crystalline solid of crystalline form II of (E)-methyl <NUM>-((<NUM>,<NUM>,<NUM>,10R,<NUM>,<NUM>,17R)-<NUM>-(((<NUM>,6R)-<NUM>-acetoxy-<NUM>-(acetoxymethyl)-<NUM>,<NUM>-dihydro-<NUM>-pyran-<NUM>-yl)oxy)-<NUM>,<NUM>-dimethyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>-tetradecahydro-<NUM>-cyclopenta[a]phenanthrene-<NUM>-yl)hept-<NUM>-enoate having peaks at the following 2Θ diffraction angles in the X-ray powder diffraction pattern:
<NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°.

In another aspect of the present invention, the present invention provides a crystalline solid of crystalline form III of (E)-methyl <NUM>-((<NUM>,<NUM>,<NUM>,10R,<NUM>,<NUM>,17R)-<NUM>-(((<NUM>,6R)-<NUM>-acetoxy-<NUM>-(acetoxymethyl)-<NUM>,<NUM>-dihydro-<NUM>-pyran-<NUM>-yl)oxy)-<NUM>,<NUM>-dimethyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>-tetradecahydro-<NUM>-cyclopenta[a]phenanthrene-<NUM>-yl)hept-<NUM>-enoate having peaks at the following 2Θ diffraction angles in the X-ray powder diffraction pattern:
<NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°.

In another aspect of the present invention, the present invention provides a crystalline solid of crystalline form IV of (E)-methyl <NUM>-((<NUM>,<NUM>,<NUM>,10R,<NUM>,<NUM>,17R)-<NUM>-(((<NUM>,6R)-<NUM>-acetoxy-<NUM>-(acetoxymethyl)-<NUM>,<NUM>-dihydro-<NUM>-pyran-<NUM>-yl)oxy)-<NUM>,<NUM>-dimethyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>-tetradecahydro-<NUM>-cyclopenta[a]phenanthrene-<NUM>-yl)hept-<NUM>-enoate having peaks at the following 2Θ diffraction angles in the X-ray powder diffraction pattern:
<NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°.

In another aspect of the present invention, the present invention provides a crystalline solid of crystalline form V of (E)-methyl <NUM>-((<NUM>,<NUM>,<NUM>,10R,<NUM>,<NUM>,17R)-<NUM>-(((<NUM>,6R)-<NUM>-acetoxy-<NUM>-(acetoxymethyl)-<NUM>,<NUM>-dihydro-<NUM>-pyran-<NUM>-yl)oxy)-<NUM>,<NUM>-dimethyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>-tetradecahydro-<NUM>-cyclopenta[a]phenanthrene-<NUM>-yl)hept-<NUM>-enoate having peaks at the following 2Θ diffraction angles in the X-ray powder diffraction pattern:
<NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°.

In another aspect of the present invention, the present invention provides a pharmaceutical composition for use in preventing or treating vascular leakage disease comprising any one of the crystalline solids of crystalline forms I to V of (E)-methyl <NUM>-((<NUM>,<NUM>,<NUM>,10R,<NUM>,<NUM>,17R)-<NUM>-(((<NUM>,6R)-<NUM>-acetoxy-<NUM>-(acetoxymethyl)-<NUM>,<NUM>-dihydro-<NUM>-pyran-<NUM>-yl)oxy)-<NUM>,<NUM>-dimethyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>-tetradecahydro-<NUM>-cyclopenta[a]phenanthrene-<NUM>-yl)hept-<NUM>-enoate.

The present invention provides a novel crystalline form of (E)-methyl <NUM>-((<NUM>,<NUM>,<NUM>,10R,<NUM>,<NUM>,17R)-<NUM>-(((<NUM>,6R)-<NUM>-acetoxy-<NUM>-(acetoxymethyl)-<NUM>,<NUM>-dihydro-<NUM>-pyran-<NUM>-yl)oxy)-<NUM>,<NUM>-dimethyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>-tetradecahydro-<NUM>-cyclopenta[a]phenanthrene-<NUM>-yl)hept-<NUM>-enoate, the compound represented by formula <NUM>, and a preparation method thereof. The novel crystalline form has high purity, excellent stability, excellent long-term storage and pharmaceutical stability, and can be used as a vascular leakage blocker, so it is very advantageous in producing high-quality drug substances.

The embodiments of this invention can be modified in various other forms, and the scope of the present invention is not limited to the embodiments described below. It is well understood by those in the art who has the average knowledge on this field that the embodiments of the present invention are given to explain the present invention more precisely. In addition, the "inclusion" of an element throughout the specification does not exclude other elements, but may include other elements, unless specifically stated otherwise.

At this time, among the two stereochemical structures of the compound of formula <NUM>, a structure showing a crystalline form is (E)-methyl <NUM>-((<NUM>,<NUM>,<NUM>,10R,<NUM>,<NUM>,17R)-<NUM>-(((<NUM>,<NUM>,6R)-<NUM>-acetoxy-<NUM>-(acetoxymethyl)-<NUM>,<NUM>-dihydro-<NUM>-pyran-<NUM>-yl)oxy)-<NUM>,<NUM>-dimethyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>-tetradecahydro-<NUM>-cyclopenta[a]phenanthrene-<NUM>-yl)hept-<NUM>-enoate.

The present document also describes a compound characterized in that the ratio of α-isomer of the compound represented by (E)-methyl <NUM>-((<NUM>,<NUM>,<NUM>,10R,<NUM>,<NUM>,17R)-<NUM>-(((<NUM>,6R)-<NUM>-acetoxy-<NUM>-(acetoxymethyl)-<NUM>,<NUM>-dihydro-<NUM>-pyran-<NUM>-yl)oxy)-<NUM>,<NUM>-dimethyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>-tetradecahydro-<NUM>-cyclopenta[a]phenanthrene-<NUM>-yl)hept-<NUM>-enoate is <NUM>% or more and is in a solid state.

At this time, the ratio of the α-isomer can be <NUM>% or more, <NUM>% or more, <NUM>% or more, <NUM>% or more, <NUM>% or more, <NUM>% or more, or <NUM>% or more.

The present document also describes a compound represented by (E)-methyl <NUM>-((<NUM>,<NUM>,<NUM>,10R,<NUM>,<NUM>,17R)-<NUM>-(((<NUM>,<NUM>,6R)-<NUM>-acetoxy-<NUM>-(acetoxymethyl)-<NUM>,<NUM>-dihydro-<NUM>-pyran-<NUM>-yl)oxy)-<NUM>,<NUM>-dimethyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>-tetradecahydro-<NUM>-cyclopenta[a]phenanthrene-<NUM>-yl)hept-<NUM>-enoate.

In one aspect of the present invention, the present invention provides a novel crystalline solid of crystalline form I of the compound represented by (E)-methyl <NUM>-((<NUM>,<NUM>,<NUM>,10R,<NUM>,<NUM>,17R)-<NUM>-(((<NUM>,SS,6R)-S-acetoxy-<NUM>-(acetoxymethyl)-<NUM>,<NUM>-dihydro-<NUM>-pyran-<NUM>-yl)oxy)-<NUM>,<NUM>-dimethyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>-tetradecahydro-<NUM>-cyclopenta[a]phenanthrene-<NUM>-yl)hept-<NUM>-enoate having the peaks with 2Θ diffraction angles of <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, and <NUM>°±<NUM>° in X-ray powder diffraction pattern (XRPD).

At this time, the crystalline form I can further include the peaks with 2Θ diffraction angles of <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, and <NUM>°±<NUM>°.

In addition, the crystalline form I can further include the peaks with 2Θ diffraction angles of <NUM>°±<NUM>°, <NUM>°±<NUM>°, and <NUM>°±<NUM>°.

Further, the crystalline form I can include the peaks with 2Θ diffraction angles of <NUM>°±<NUM>°, <NUM>°±<NUM>°, and <NUM>°±<NUM>°. Or, the crystalline form I can further include the peaks with 2Θ diffraction angles of <NUM>°±<NUM>°, <NUM>°±<NUM>°, and <NUM>°±<NUM>°.

For example, the crystalline form I can be a crystalline form having the characteristic peaks with 2θ diffraction angles of <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, and <NUM>°±<NUM>° having a relative intensity (I/I<NUM>) of <NUM>% or more.

In addition, the present document describes a novel crystalline form that exhibits an endothermic peak of <NUM>±<NUM> in differential scanning calorimetry (DSC).

In one aspect of the present invention, the present invention provides a novel crystalline solid of crystalline form II of the compound represented by (E)-methyl <NUM>-((<NUM>,<NUM>,<NUM>,10R,<NUM>,<NUM>,17R)-<NUM>-(((<NUM>,<NUM>,6R)-<NUM>-acetoxy-<NUM>-(acetoxymethyl)-<NUM>,<NUM>-dihydro-<NUM>-pyran-<NUM>-yl)oxy)-<NUM>,<NUM>-dimethyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>-tetradecahydro-<NUM>-cyclopenta[a]phenanthrene-<NUM>-yl)hept-<NUM>-enoate having the peaks with 2Θ diffraction angles of <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, and <NUM>°±<NUM>° in X-ray powder diffraction pattern (XRPD).

In one aspect of the present invention, the present invention provides a novel crystalline solid of crystalline form III of the compound represented by (E)-methyl <NUM>-((<NUM>,<NUM>,<NUM>,10R,<NUM>,<NUM>,17R)-<NUM>-(((<NUM>,<NUM>,6R)-<NUM>-acetoxy-<NUM>-(acetoxymethyl)-<NUM>,<NUM>-dihydro-<NUM>-pyran-<NUM>-yl)oxy)-<NUM>,<NUM>-dimethyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>-tetradecahydro-<NUM>-cyclopenta[a]phenanthrene-<NUM>-yl)hept-<NUM>-enoate having the peaks with 2Θ diffraction angles of <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, and <NUM>°±<NUM>° in X-ray powder diffraction pattern (XRPD).

At this time, the crystalline form III can further include the peaks with 2Θ diffraction angles of <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, and <NUM>°±<NUM>°.

For example, the crystalline form III can be a crystalline form having the characteristic peaks with 2θ diffraction angles of <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, and <NUM>°±<NUM>° having a relative intensity (I/I<NUM>) of <NUM>% or more.

In one aspect of the present invention, the present invention provides a novel crystalline solid of crystalline form IV of the compound represented by (E)-methyl <NUM>-((<NUM>,<NUM>,<NUM>,10R,<NUM>,<NUM>,17R)-<NUM>-(((<NUM>,<NUM>,6R)-<NUM>-acetoxy-<NUM>-(acetoxymethyl)-<NUM>,<NUM>-dihydro-<NUM>-pyran-<NUM>-yl)oxy)-<NUM>,<NUM>-dimethyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>-tetradecahydro-<NUM>-cyclopenta[a]phenanthrene-<NUM>-yl)hept-<NUM>-enoate having the peaks with 2Θ diffraction angles of <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, and <NUM>°±<NUM>° in X-ray powder diffraction pattern (XRPD).

At this time, the crystalline form IV can further include the peaks with 2Θ diffraction angles of <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, and <NUM>°±<NUM>°.

For example, the crystalline form IV can be a crystalline form having the characteristic peaks with 2θ diffraction angles of <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, and <NUM>°±<NUM>° having a relative intensity (I/I<NUM>) of <NUM>% or more.

In one aspect of the present invention, the present invention provides a novel crystalline solid of crystalline form V of the compound represented by (E)-methyl <NUM>-((<NUM>,<NUM>,<NUM>,10R,<NUM>,<NUM>,17R)-<NUM>-(((<NUM>,SS,6R)-S-acetoxy-<NUM>-(acetoxymethyl)-<NUM>,<NUM>-dihydro-<NUM>-pyran-<NUM>-yl)oxy)-<NUM>,<NUM>-dimethyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>-tetradecahydro-<NUM>-cyclopenta[a]phenanthrene-<NUM>-yl)hept-<NUM>-enoate having the peaks with 2Θ diffraction angles of <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, and <NUM>°±<NUM>° in X-ray powder diffraction pattern (XRPD).

At this time, the crystalline form V can further include the peaks with 2Θ diffraction angles of <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, and <NUM>°±<NUM>°.

For example, the crystalline form V can be a crystalline form having the characteristic peaks with 2θ diffraction angles of <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, and <NUM>°±<NUM>° having a relative intensity (I/I<NUM>) of <NUM>% or more.

The present document also describesa novel crystalline form VI of the compound represented by (E)-methyl <NUM>-((<NUM>,<NUM>,<NUM>,10R,<NUM>,<NUM>,17R)-<NUM>-(((<NUM>,<NUM>,6R)-<NUM>-acetoxy-<NUM>-(acetoxymethyl)-<NUM>,<NUM>-dihydro-<NUM>-pyran-<NUM>-yl)oxy)-<NUM>,<NUM>-dimethyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>-tetradecahydro-<NUM>-cyclopenta[a]phenanthrene-<NUM>-yl)hept-<NUM>-enoate having the peaks with 2Θ diffraction angles of <NUM>°±<NUM>°, <NUM>°±<NUM>°, and <NUM>°±<NUM>° in X-ray powder diffraction pattern (XRPD).

At this time, the crystalline form VI can further include the peaks with 2Θ diffraction angles of <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, and <NUM>°±<NUM>°.

For example, the crystalline form VI can be a crystalline form having the characteristic peaks with 2θ diffraction angles of <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, and <NUM>°±<NUM>° having a relative intensity (I/I<NUM>) of <NUM>% or more.

The present document also describes a novel crystalline form VII of the compound represented by (E)-methyl <NUM>-((<NUM>,<NUM>,<NUM>,10R,<NUM>,<NUM>,17R)-<NUM>-(((<NUM>,<NUM>,6R)-<NUM>-acetoxy-<NUM>-(acetoxymethyl)-<NUM>,<NUM>-dihydro-<NUM>-pyran-<NUM>-yl)oxy)-<NUM>,<NUM>-dimethyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>-tetradecahydro-<NUM>-cyclopenta[a]phenanthrene-<NUM>-yl)hept-<NUM>-enoate having the peaks with 2Θ diffraction angles of <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, and <NUM>°±<NUM>° in X-ray powder diffraction pattern (XRPD).

At this time, the crystalline form VII can further include the peaks with 2Θ diffraction angles of <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, and <NUM>°±<NUM>°.

For example, the crystalline form VII can be a crystalline form having the characteristic peaks with 2θ diffraction angles of <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, and <NUM>°±<NUM>° having a relative intensity (I/I<NUM>) of <NUM>% or more.

The present document also describes a novel crystalline form VIII of the compound represented by (E)-methyl <NUM>-((<NUM>,<NUM>,<NUM>,10R,<NUM>,<NUM>,17R)-<NUM>-(((<NUM>,<NUM>,6R)-<NUM>-acetoxy-<NUM>-(acetoxymethyl)-<NUM>,<NUM>-dihydro-<NUM>-pyran-<NUM>-yl)oxy)-<NUM>,<NUM>-dimethyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>-tetradecahydro-<NUM>-cyclopenta[a]phenanthrene-<NUM>-yl)hept-<NUM>-enoate having the peaks with 2Θ diffraction angles of <NUM>°±<NUM>° and <NUM>°±<NUM>° in X-ray powder diffraction pattern (XRPD).

At this time, the crystalline form VIII can further include the peaks with 2Θ diffraction angles of <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>, and <NUM>°±<NUM>.

For example, the crystalline form VIII can be a crystalline form having the characteristic peaks with 2θ diffraction angles of <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, and <NUM>°±<NUM>° having a relative intensity (I/I<NUM>) of <NUM>% or more.

The present document also describes a novel crystalline form IX of the compound represented by (E)-methyl <NUM>-((<NUM>,<NUM>,<NUM>,10R,<NUM>,<NUM>,17R)-<NUM>-(((<NUM>,<NUM>,6R)-<NUM>-acetoxy-<NUM>-(acetoxymethyl)-<NUM>,<NUM>-dihydro-<NUM>-pyran-<NUM>-yl)oxy)-<NUM>,<NUM>-dimethyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>-tetradecahydro-<NUM>-cyclopenta[a]phenanthrene-<NUM>-yl)hept-<NUM>-enoate having the peaks with 2Θ diffraction angles of <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, and <NUM>°±<NUM>° in X-ray powder diffraction pattern (XRPD).

At this time, the crystalline form IX can further include the peaks with 2Θ diffraction angles of <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, and <NUM>°±<NUM>°.

For example, the crystalline form IX can be a crystalline form having the characteristic peaks with 2θ diffraction angles of <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, and <NUM>°±<NUM>° having a relative intensity (I/I<NUM>) of <NUM>% or more.

The present document also describes a novel crystalline form X of the compound represented by (E)-methyl <NUM>-((<NUM>,<NUM>,<NUM>,10R,<NUM>,<NUM>,17R)-<NUM>-(((<NUM>,<NUM>,6R)-<NUM>-acetoxy-<NUM>-(acetoxymethyl)-<NUM>,<NUM>-dihydro-<NUM>-pyran-<NUM>-yl)oxy)-<NUM>,<NUM>-dimethyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>-tetradecahydro-<NUM>-cyclopenta[a]phenanthrene-<NUM>-yl)hept-<NUM>-enoate having the peaks with 2Θ diffraction angles of <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, and <NUM>°±<NUM>° in X-ray powder diffraction pattern (XRPD).

At this time, the crystalline form X can further include the peaks with 2Θ diffraction angles of <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, and <NUM>°±<NUM>°.

For example, the crystalline form X can be a crystalline form having the characteristic peaks with 2θ diffraction angles of <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, and <NUM>°±<NUM>° having a relative intensity (I/I<NUM>) of <NUM>% or more.

The present document also describes a novel crystalline form XI of the compound represented by (E)-methyl <NUM>-((<NUM>,<NUM>,<NUM>,10R,<NUM>,<NUM>,17R)-<NUM>-(((<NUM>,<NUM>,6R)-<NUM>-acetoxy-<NUM>-(acetoxymethyl)-<NUM>,<NUM>-dihydro-<NUM>-pyran-<NUM>-yl)oxy)-<NUM>,<NUM>-dimethyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>-tetradecahydro-<NUM>-cyclopenta[a]phenanthrene-<NUM>-yl)hept-<NUM>-enoate having the peaks with 2Θ diffraction angles of <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, and <NUM>°±<NUM>° in X-ray powder diffraction pattern (XRPD).

In another aspect of the present invention, the present invention provides a pharmaceutical composition for preventing or treating vascular leakage disease comprising any one of the compounds and the novel crystalline forms I to V of the compound. Or, the present invention provides a pharmaceutical composition for preventing or treating vascular leakage disease comprising any one of the crystalline forms I to X I of the compound.

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

Hereinafter, the present invention will be described in detail by the following examples and experimental examples.

However, the following examples and experimental examples are only for illustrating the present invention, and the contents of the present invention are not limited thereto.

The X-ray powder diffraction (XRPD) pattern was obtaine d on a Shimadzu XRD-<NUM> instrument.

Samples of compounds (~<NUM>) were tested in an aluminum pan pinhole under nitrogen purge.

Samples of compounds (<NUM>-<NUM>) were weighed into the pan, and heated under nitrogen purge.

Around <NUM> of samples were used to test its moisture sorption/desorption profiles.

Deliquescent: Sufficient water is absorbed to form a li quid.

Samples dispersed in silicone oil were observed using ocular lens: 10X and objective lens: <NUM>0X or 5X under crossed polarizers, and recorded by camera/computer system w ith magnification scale.

The compound <NUM> represented by the following formula <NUM> can be prepared by the preparation method described in <CIT> (unpublished). Particularly, the compound can be prepared by the method according to the following reaction formula <NUM> or <NUM>. <CHM>
<CHM>.

As shown in reaction formula <NUM>, the compound <NUM> represented by formula <NUM> can be prepared by the method comprising the following steps:.

At this time, R<NUM> in reaction formula <NUM> is straight or branched C<NUM>-<NUM> alkyl.

At this time, R<NUM> is straight or branched C<NUM>-<NUM> alkyl; and X<NUM> is halogen.

On the other hand, the compound <NUM> represented by formula <NUM> used in the following examples and experimental examples of the present invention was prepared by the method shown in reaction formula <NUM> below. <CHM>
<CHM>.

The specific preparation process is as follows.

Pregnenolone (<NUM>, <NUM> mol) was added to <NUM> of dichloromethane, which was placed in a <NUM> flask equipped with a thermometer, to which <NUM> (<NUM> mol) of <NUM>,<NUM>-dihydro-<NUM>-pyran was added. After the temperature was lowered to <NUM>-<NUM>, <NUM> (<NUM> mmol) of p-toluenesulphonic acid monohydrate was dissolved in <NUM> of tetrahydrofuran (THF), which was added thereto dropwise, followed by stirring at <NUM> for <NUM> hours. <NUM> of saturated sodium bicarbonate aqueous solution and <NUM> of triethylamine (TEA) were added to the reaction mixture at <NUM>, followed by stirring. After separating the layers, the organic layer was washed with <NUM> of brine, and the aqueous layers were extracted again with <NUM> of dichloromethane, combined with the organic layer, dried with <NUM> of anhydrous sodium sulfate, filtered, and distilled under reduced pressure. <NUM> of MeOH and <NUM> of TEA were added to the obtained residue, heated to completely dissolve, and the temperature was lowered, followed by stirring at -<NUM> for <NUM> hour. The resulting solid was filtered and washed with <NUM> of MeOH to give <NUM> (<NUM> mol) of the compound <NUM>-<NUM> (THP-Pregnenolone) as a pure white solid (yield: <NUM>%).

<NUM>H-NMR (<NUM>, CDCl<NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>).

After installing a condenser, heating mantle, and mechanical stirrer in a <NUM> reactor, it was heated to <NUM> (external temperature), and cooled to room temperature while flowing nitrogen for <NUM> minutes, to which <NUM> (<NUM> mol) of <NUM>-(carboxybutyl)triphenyl phosphonium bromide, <NUM> (<NUM> mol) of potassium t-butoxide, <NUM> of anhydrous toluene and <NUM> of anhydrous tetrahydrofuran were added, followed by stirring for about <NUM> hours while heating at <NUM> (external temperature, internal mild reflux).

The compound <NUM>-<NUM> (<NUM>, <NUM> mol) was dissolved in <NUM> of anhydrous toluene, which was added to the reaction solution, followed by reaction for about <NUM> hours.

Upon completion of the reaction, the reaction mixture was cooled to room temperature, to which <NUM> (<NUM> mol) of methyl iodide and <NUM> of acetone were added, followed by stirring at room temperature for <NUM> hours. The reaction mixture was distilled under reduced pressure to remove most of the organic solvent, to which <NUM> of ethyl acetate was added to dissolve, followed by washing with <NUM> of saturated ammonium chloride aqueous solution. The organic layer was washed with <NUM> of water twice and <NUM> of brine, dried over <NUM> of sodium sulfate, filtered with <NUM> of celite, and concentrated.

The obtained residue was dissolved in <NUM> of methanol, followed by stirring for <NUM> hours at <NUM> and <NUM> hour at <NUM>-<NUM>. The resulting solid was filtered, washed with <NUM> of methanol, and dried in vacuo to give <NUM> of the compound <NUM>-<NUM> as a white solid (yield: <NUM>%).

<NUM>H NMR(<NUM>, CDCl<NUM> ): δ <NUM> (t, J=<NUM>, <NUM>), <NUM>(t, J=<NUM>, <NUM>), <NUM>(m, <NUM>), <NUM>(m, <NUM>), <NUM>(s, <NUM>), <NUM>(m, <NUM>), <NUM>-<NUM>(m, <NUM>), <NUM>(s, <NUM>).

The compound <NUM>-<NUM> (<NUM>, <NUM> mol), <NUM> of methanol and <NUM> (<NUM> mol) of p-toluenesulphonic acid monohydrate were added to a <NUM> flask equipped with a thermometer, followed by stirring at <NUM> for <NUM> hours.

Upon completion of the reaction, the reaction solution was stirred at room temperature. When a solid was formed, the mixture was stirred at room temperature for <NUM> minutes and stirred at <NUM> for <NUM> hour. The reaction solution was filtered, washed with <NUM> of cooled methanol, and dried in vacuo to give <NUM> (<NUM> mol) of the compound <NUM>-<NUM> as a white solid (yield: <NUM>%).

<NUM>H-NMR (<NUM>, CDCl<NUM>) : δ <NUM>-<NUM>(m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>).

The compound <NUM>-<NUM> (<NUM>, <NUM> mol) and tri i-O-acetyl D-glucal (<NUM>, <NUM> mol) were dissolved in <NUM> of anhydrous toluene and <NUM> of acetonitrile, which were added to a <NUM> flask equipped with a thermometer and water bath. While maintaining the temperature at <NUM>-<NUM>, lithium nonafluoro-<NUM>-butylsulfonate (<NUM>, <NUM> mol) and (s)-camphor sulphonic acid (<NUM>, <NUM> mol) were added thereto, followed by stirring for <NUM> hours. Upon completion of the reaction, the reaction solution was quenched with <NUM> of saturated sodium bicarbonate aqueous solution, and extracted with <NUM> of heptane. The organic layer was washed with <NUM> of saturated sodium bicarbonate aqueous solution twice, and <NUM> of brine. The organic layer was stirred after adding <NUM> of anhydrous sodium sulfate and <NUM> of charcoal, filtered with <NUM> of celite, washed with <NUM> of methylene chloride, combined with the filtrate, concentrated and dried in vacuo.

<NUM>-NMR (<NUM>, CDCl3): δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>).

The compound <NUM> obtained through the reaction formula <NUM> is present as a mixture of α and β-isomers. At this time, the oily residue was heated and dissolved in <NUM> of ethanol at <NUM>-<NUM>, followed by stirring at <NUM>. When a solid was formed, the temperature was lowered to <NUM>, followed by stirring for <NUM> minutes. The solid was filtered under reduced pressure and dried in vacuo to separate the α-isomer as crystals, and the filtrate was subjected to column chromatography to separate the β-isomer. At this time, the α-isomer was obtained as a solid state, and the purity of the α-isomer was <NUM>%.

The results of NMR performed to confirm the structures of the α- and β-isomers are shown in <FIG>. As shown in <FIG>, it was confirmed that the prepared crude compound <NUM> has the α-isomer or β-isomer having different stereostructures.

On the other hand, the crude compound obtained by the preparation method disclosed in <CIT> was an oil phase in which α-isomer and β-isomer are mixed, whereas the compound prepared according to the preparation method disclosed in this application was a solid phase of α-isomer.

About <NUM> of the compound <NUM> prepared in Preparative Example <NUM> was dispersed in a solvent with relatively low solubility (water, methanol or ethanol), followed by stirring at room temperature (<NUM>) for <NUM> days. The resulting wet solid was separated by centrifugation. The solid was dried at room temperature for <NUM> hours under reduced pressure. In order to analyze the crystalline form characteristics of the dried solid, the following experiments were performed.

In order to analyze the characteristics of the crystalline form prepared in Example <NUM>, the crystalline form in the state of white powder was analyzed by solubility assay, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), dynamic vapor sorption (DVS), and polarization microscopy (PLM) according to the methods described in <Experimental Methods>. The results are shown in <FIG>, respectively.

Solubility assay was performed by visual observation and manual dilution at room temperature. Particularly, about <NUM> of the compound <NUM> prepared in Preparative Example <NUM> was weighed in a <NUM> glass vial, to which a solvent was sequentially added until no particles were observed with the naked eye (i.e., all dissolved) or the particles remained (i.e., not dissolved) even after adding <NUM> of the solvent (for example, total volume of <NUM>, <NUM>, <NUM>, <NUM>, or <NUM>µL). The total amount of the solvent was recorded to calculate the solubility for each solvent.

The peaks having a relative intensity (I/I<NUM>) of <NUM>% or more in XRPD spectrum of the crystalline form of <FIG> are shown in Table <NUM> below.

In general, the error range of the diffraction angle (2θ) in X-ray powder diffraction is within ±<NUM>°. Therefore, it should be understood that the values of the diffraction angles also include the values within the range of about ±<NUM>°. Accordingly, the present invention includes not only the crystals having the same diffraction angle and peak in X-ray powder diffraction, but also the crystals having the diffraction angle consistent with the value indicated by the error range of ±<NUM>°.

When the relative intensity (I/I<NUM>) of the peak was <NUM>% or more, the peak had the diffraction angles of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, and <NUM>° (2θ ± <NUM>°). The crystalline form of the compound <NUM> having such a crystalline form is called the crystalline form I.

The DVS graph analysis results of the crystalline form I are shown in Table <NUM> below.

From the XRPD results above, it was confirmed that the crystalline form I of the compound <NUM> prepared in Example <NUM> according to the present invention had excellent crystallinity. From the TGA results, it was confirmed that the crystalline form I of the compound <NUM> had a mass loss of <NUM>% while heating from room temperature to <NUM>. One endothermic peak (<NUM>) was confirmed through the DSC result graph, which corresponds to the melting point of the crystalline form I of the compound <NUM>. Through the DVS results, <NUM>% of water sorption was confirmed at <NUM>% RH, indicating that the crystalline form I of the compound <NUM> is non-hygroscopic.

About <NUM> of the compound <NUM> prepared in Preparative Example <NUM> was dispersed in isopropanol (<NUM>) in a <NUM> glass bottle, followed by stirring at high temperature (<NUM>) for <NUM> days. Then, the glass bottle was cooled in a <NUM> refrigerator for one day, and no solid precipitate was observed. The glass bottle was continuously stored in a - <NUM> refrigerator for <NUM> days, and the solid precipitate was separated by centrifugation (<NUM> rpm, <NUM> minutes). The precipitate was then dried at room temperature for <NUM> hours in a vacuum oven under reduced pressure. As a result, a thin plate-like lamellar solid or a flaked solid was obtained. In order to analyze the characteristics of the crystalline form of the prepared solid, XRPD was performed according to the method described in <Experimental Methods> <NUM>. X-ray Powder Diffractometer (XRPD). The results are shown in Table <NUM> and <FIG>.

When the relative intensity (I/I<NUM>) of the peak was <NUM>% or more, the peak had the diffraction angles of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, and <NUM>° (2θ ± <NUM>°). The crystalline form of the compound <NUM> having such a crystalline form is called the crystalline form II.

About <NUM> of the compound <NUM> prepared in Preparative Example <NUM> was completely dissolved in MEK or chloroform, a relatively good solvent, at room temperature, and then the reaction vessel was covered with an aluminum foil having a small hole. Then, it was allowed to evaporate naturally for <NUM> week at room temperature, and as a result, a little solid was precipitated. It was further dried at <NUM> for <NUM> hours under reduced pressure. In order to analyze the characteristics of the crystalline form of the prepared solid, XRPD was performed according to the method described in <Experimental Methods> <NUM>. X-ray Powder Diffractometer (XRPD). The results are shown in <FIG>. In addition, the crystalline form prepared under the same conditions, except that about <NUM> of MEK solvent was used, was analyzed by XRPD and the results are shown in <FIG>.

The peaks having a relative intensity (I/I<NUM>) of <NUM>% or more in XRPD spectrum (solvent: <NUM> of MEK) of the crystalline form of <FIG> are shown in Table <NUM> below.

When the relative intensity (I/I<NUM>) of the peak was <NUM>% or more, the peak had the diffraction angles of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, and <NUM>° (2θ ± <NUM>°). The crystalline form of the compound <NUM> having such a crystalline form is called the crystalline form III.

About <NUM> of the compound <NUM> prepared in Preparative Example <NUM> was completely dissolved in EtOH (<NUM>) at <NUM> to prepare a saturated solution, followed by mixing continuously for <NUM> minutes. Then, the solution was rapidly cooled to low temperature in a -<NUM> refrigerator, and stored for <NUM> days. After separating the prepared solid by centrifugation, it was dried in vacuo at <NUM> overnight. In order to analyze the characteristics of the crystalline form of the prepared solid, XRPD was performed according to the method described in <Experimental Methods> <NUM>. X-ray Powder Diffractometer (XRPD). The results are shown in Table <NUM> and <FIG>.

When the relative intensity (I/I<NUM>) of the peak was <NUM>% or more, the peak had the diffraction angles of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, and <NUM>° (2θ ± <NUM>°). The crystalline form of the compound <NUM> having such a crystalline form is called the crystalline form IV.

About <NUM> of the compound <NUM> prepared in Preparative Example <NUM> was completely dissolved in n-propanol (<NUM>) at <NUM> to prepare a saturated solution, followed by mixing continuously for <NUM> minutes. Then, the solution was rapidly cooled to low temperature in a -<NUM> refrigerator, and stored for <NUM> days. After separating the prepared solid by centrifugation, it was dried in vacuo at <NUM> overnight. In order to analyze the characteristics of the crystalline form of the prepared solid, XRPD was performed according to the method described in <Experimental Methods> <NUM>. X-ray Powder Diffractometer (XRPD). The results are shown in Table <NUM> and <FIG>.

When the relative intensity (I/I<NUM>) of the peak was <NUM>% or more, the peak had the diffraction angles of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, and <NUM>° (2θ ± <NUM>°). The crystalline form of the compound <NUM> having such a crystalline form is called the crystalline form V.

In order to observe whether the crystalline form IV of the compound <NUM> prepared in Example <NUM> changed after <NUM> months at room temperature, the characteristics of the crystalline form IV stored at room temperature for <NUM> months were analyzed. Particularly, XRPD was performed according to the method described in <Experimental Methods> <NUM>. X-ray Powder Diffractometer (XRPD). As a result, a novel crystalline form having the XRPD pattern different from that of the crystalline form IV was confirmed. The results are shown in Table <NUM> and <FIG>.

The peaks having a relative intensity (I/I<NUM>) of <NUM>% or more of the crystals after <NUM> months of the crystalline form IV in XRPD spectrum of the crystalline form of <FIG> are shown in Table <NUM> below.

When the relative intensity (I/I<NUM>) of the peak was <NUM>% or more, the peak had the diffraction angles of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, and <NUM>° (2θ ± <NUM>°). The crystalline form of the compound <NUM> having such a crystalline form is called the crystalline form VI.

The experiment was performed in the same manner as described in Example <NUM> except that the crystalline form IV of the compound <NUM> prepared in Example <NUM> was stored at room temperature for <NUM> months. As a result, a novel crystalline form having the XRPD pattern different from that of the crystalline form IV was confirmed. The results are shown in Table <NUM> and <FIG>.

When the relative intensity (I/I<NUM>) of the peak was <NUM>% or more, the peak had the diffraction angles of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, and <NUM>° (2θ ± <NUM>°). The crystalline form of the compound <NUM> having such a crystalline form is called the crystalline form VII.

In order to observe whether the crystalline form V of the compound <NUM> prepared in Example <NUM> changed after <NUM> months at room temperature, the characteristics of the crystalline form V stored at room temperature for <NUM> months were analyzed. Particularly, XRPD was performed according to the method described in <Experimental Methods> <NUM>. X-ray Powder Diffractometer (XRPD). As a result, a novel crystalline form having the XRPD pattern different from that of the crystalline form V was confirmed. The results are shown in Table <NUM> and <FIG>.

The peaks having a relative intensity (I/I<NUM>) of <NUM>% or more of the crystals after <NUM> months of the crystalline form V in XRPD spectrum of the crystalline form of <FIG> are shown in Table <NUM> below.

When the relative intensity (I/I<NUM>) of the peak was <NUM>% or more, the peak had the diffraction angles of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, and <NUM>° (2θ ± <NUM>°). The crystalline form of the compound <NUM> having such a crystalline form is called the crystalline form VIII.

The experiment was performed in the same manner as described in Example <NUM> except that the crystalline form V of the compound <NUM> prepared in Example <NUM> was stored at room temperature for <NUM> months. As a result, a novel crystalline form having the XRPD pattern different from that of the crystalline form V was confirmed. The results are shown in Table <NUM> and <FIG>.

When the relative intensity (I/I<NUM>) of the peak was <NUM>% or more, the peak had the diffraction angles of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, and <NUM>° (2θ ± <NUM>°). The crystalline form of the compound <NUM> having such a crystalline form is called the crystalline form IX.

The scale up of the crystalline form IV prepared in Example <NUM> was performed as follows. About <NUM> of the compound prepared in Preparative Example <NUM> was completely dissolved in EtOH (<NUM>) at <NUM> to prepare a saturated solution, followed by mixing continuously for <NUM> minutes. Then, the solution was rapidly cooled to low temperature in a -<NUM> refrigerator, and stored for <NUM> days. After separating the prepared solid by centrifugation, it was dried in vacuo at <NUM> overnight. In order to analyze the characteristics of the crystalline form of the prepared solid, XRPD was performed according to the method described in <Experimental Methods> <NUM>. X-ray Powder Diffractometer (XRPD). The results are shown in Table <NUM> and <FIG>.

When the relative intensity (I/I<NUM>) of the peak was <NUM>% or more, the peak had the diffraction angles of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, and <NUM>° (2θ ± <NUM>°). The crystalline form of the compound <NUM> having such a crystalline form is called the crystalline form X.

The scale up of the crystalline form V prepared in Example <NUM> was performed as follows. About <NUM> of the compound <NUM> prepared in Preparative Example <NUM> was completely dissolved in n-butanol (<NUM>) at <NUM> to prepare a saturated solution, followed by mixing continuously for <NUM> minutes. Then, the solution was rapidly cooled to low temperature in a -<NUM> refrigerator, and stored for <NUM> days. After separating the prepared solid by centrifugation, it was dried in vacuo at <NUM> overnight. In order to analyze the characteristics of the crystalline form of the prepared solid, XRPD was performed according to the method described in <Experimental Methods> <NUM>. X-ray Powder Diffractometer (XRPD). The results are shown in Table <NUM> and <FIG>.

When the relative intensity (I/I<NUM>) of the peak was <NUM>% or more, the peak had the diffraction angles of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, and <NUM>° (2θ ± <NUM>°). The crystalline form of the compound <NUM> having such a crystalline form is called the crystalline form XI.

About <NUM> of each of the crystalline forms prepared in Preparative Example <NUM> and Examples <NUM> to <NUM> was weighed in a <NUM> volumetric flask and analyzed according to the following purity analysis method. <NUM> of each crystalline form in a stable state was dissolved in <NUM> acetonitrile, and <NUM>µL of the mixture was injected into HPLC. HPLC conditions were the same as in <Experimental Methods> <NUM>. High performance liquid chromatography (HPLC). The results are shown in Table <NUM>.

Since a significant change is judged and the expiration date is set based on a described stability test method in order to determine the storage method and period of use of drugs, etc., the stability test is one of the important factors in securing appropriate stability and commercialization of drugs and the like.

In order to confirm the stability of the novel crystalline form according to the present invention, the stability of the crystalline form I prepared in Example <NUM> was evaluated using a liquid chromatography method under the analysis conditions of <Experimental Methods> <NUM>. High performance liquid chromatography (HPLC). The results of the accelerated stability test from <NUM> month to <NUM> months in the conditions of <NUM> & <NUM> RH are shown in Table <NUM> below.

As a result, it was confirmed that the crystalline form I of Example <NUM> according to the present invention was stably maintained for up to <NUM> months without affecting the purity.

As mentioned above, the present invention has been described in detail through the preferred preparative examples, examples and experimental examples, but the scope of the present invention is not limited to the specific examples, and should be interpreted by the appended claims. In addition, those of ordinary skill in the art should understand that many modifications and variations are possible without departing from the scope of the present invention.

Claim 1:
A crystalline solid of crystalline form I of (E)-methyl <NUM>-((<NUM>,<NUM>,<NUM>,10R,<NUM>,<NUM>,17R)-<NUM>-(((<NUM>,<NUM>,6R)-<NUM>-acetoxy-<NUM>-(acetoxymethyl)-<NUM>,<NUM>-dihydro-<NUM>-pyran-<NUM>-yl)oxy)-<NUM>,<NUM>-dimethyl-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>-tetradecahydro-<NUM>-cyclopenta[a]phenanthrene-<NUM>-yl)hept-<NUM>-enoate having peaks at the following 2Θ diffraction angles in the X-ray powder diffraction pattern:
<NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°.