High-efficacy glucocorticoid polymorph, preparation method therefor, and use thereof

Abstract

NOT VISIBLE DUE TO STATUS OF PATENT

Description

High-potency glucocorticoid polymorphs and their preparation methods and uses Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to a high-potency glucocorticoid polymorph and its preparation and use. Background Art

[0002] Currently, inflammatory and autoimmune diseases such as asthma, arthritis, lupus, and Crohn's disease pose a serious threat to human health and reduce the quality of life. Glucocorticoids, such as prednisone, dexamethasone (DEX), and budesonide, are highly effective anti-inflammatory drugs that are widely used to treat inflammatory and autoimmune diseases. These drugs exert their physiological effects by binding to the glucocorticoid receptor (GR), a ligand-activated transcription factor of the nuclear receptor superfamily. In the absence of glucocorticoids, GR is present in the cytoplasm and binds to chaperone proteins such as hsp90 and hsp70. Hormone binding causes a conformational change in GR, leading to its translocation to the cell nucleus, where it exerts its transcriptional control activity, either activating (transcriptional activation) or inhibiting (transcriptional repression). In transcriptional activation, GR dimerizes, directly binds to specific glucocorticoid response elements, and then recruits coactivators to activate transcription. In transcriptional repression, the general model is as follows: GR binds to other transcription factors (e.g., NF-KB, AP-1) to indirectly tether their binding sites through protein-protein interactions. When tethered near target promoters, GR represses downstream gene expression. It is generally believed that transcriptional repression does not require GR dimerization.

[0003] Transcriptional inhibition is that glucocorticoid serves as the main mechanism of anti-inflammatory drugs. The tethering of GR and NF-KB / AP-1 promoter causes the transcriptional inhibition of major downstream proinflammatory factors, which include proinflammatory cytokines (for example, TNF-α, IL-113 and IL-6), chemokines (for example, CCL2, CCL19) and the ligands (for example, COX2, MMP13 and phosphatidylserine A2) relevant to inflammatory attacks. Due to its rapid action and sustainable effect, glucocorticoid remains the first choice for the treatment of inflammatory diseases. However, long-term use of glucocorticoid, especially high dose, has many adverse consequences, including diabetes / glucose intolerance, hypertension, obesity and osteoporosis. Major part in these consequences is due to the transcriptional activation of GR. For example, glucocorticoid induces the genes of the rate-limiting enzyme, glucose-6-phosphate and phosphoenolpyruvate carboxykinase of glucose production pathway in the coding liver, thereby increasing the de novo synthesis of glucose and ultimately causing weight gain or diabetes. Glucocorticoids also induce Dickkopf-1 (DKK1), a key regulatory gene for bone development, whose upregulation leads to osteoporosis and bone loss. Many of the side effects of glucocorticoids are often observed to be associated with high-dose use of glucocorticoids. For example, a "threshold pattern" has been observed with the use of prednisone: at 7.5 mg per day, it can cause glaucoma, depression, and hypertension. These side effects are caused by GR transcriptional activation and non-target activation of other receptors, such as the mineralocorticoid receptor (MR), whose activation can cause hypertension.

[0004] In addition, the development of insensitivity and resistance to glucocorticoid therapy is a major problem in the treatment of common inflammatory diseases such as chronic obstructive pulmonary disease, rheumatoid arthritis and inflammatory bowel disease. Glucocorticoid resistance is also an unsolved problem for white blood cell cancers, especially childhood acute leukemia. Several mechanisms of glucocorticoid resistance have been identified or proposed, including alterations in kinase pathways, changes in cofactors, and deletions or mutations in receptors. A common observation is that the affinity of the ligand for the receptor is reduced in glucocorticoid-resistant patients. Such patients have shown improvement with high-potency glucocorticoid treatment, but the effect gradually decreases.

[0005] Therefore, there is an urgent need in the art to develop more potent and selective glucocorticoids to reduce unwanted side effects and improve therapeutic effects. Summary of the Invention

[0006] The present invention aims to provide a glucocorticoid with higher potency and selectivity to reduce unwanted side effects and improve therapeutic efficacy, and specifically relates to a high-potency glucocorticoid polymorph, a preparation method and use thereof.

[0007] In the first aspect of the present invention, a polymorph of a compound represented by formula (I) is provided, wherein the crystalline form of the polymorph is selected from the group consisting of Form K, Form A, Form C, Form E, Form F, Form I, or Form L.

[0008] The polymorph is a crystalline form of (1R,2R,3aS,3bR,10aS,10bR,11S,12aS)-5,10b-difluoro-1-(((fluoromethyl)thio)carbonyl)-11-hydroxy-2,10a,12a-trimethyl-7-phenyl-1,2,3,3a,3b,7,10,10a,10b,11,12,12a-dodecylhydrocyclopenta[5,6]naphtho[1,2-F]indazol-1-ylfuran-2-carboxylate.

[0009] In another preferred embodiment, the XRPD pattern of the crystalline form K comprises 3 or more (such as 4, 5, or 6) diffraction peaks having 2θ selected from the group consisting of: 7.148 ± 0.20°, 9.336 ± 0.20°, 9.955 ± 0.20°, 11.239 ± 0.20°, 12,769 ± 0.20°, 13.826 ± 0.20°, 14.315 ± 0.20°, 15.581 ± 0.20°, 15.960 Soil 0.20°, 16.748 Soil 0.20°, 17.864 Soil 0.20°, 20.050 Soil 0.20°, 21.198 Soil 0.20°, 22,587 Soil 0.20°, 22.909 Soil 0.20°, 23.725 Soil 0.20°, 24.383 Soil 0.20°, 26.611 Soil 0.20°, 27.920 Soil 0.20°.

[0010] In another preferred embodiment, the XRPD pattern of the crystalline form K has a diffraction peak at 2θ selected from the group consisting of: 7.148 ± 0.20°, 9.336 ± 0.20°, 9.955 ± 0.20°, 11.239 ± 0.20°, 12.769 ± 0.20°, 13.826 ± 0.20°, 14.315 ± 0.20°, 15.581 ± 0.20°, 15. 960 Soil 0.20°, 16.748 Soil 0.20°, 17.864 Soil 0.20°, 20.050 Soil 0.20°, 21.198 Soil 0.20°, 22.587 Soil 0.20°, 22.909 Soil 0.20°, 23.725 Soil 0.20°, 24.383 Soil 0.20°, 26.611 Soil 0.20°, 27.920 Soil 0.20°.

[0011] In another preferred embodiment, the crystalline form K further has a diffraction peak of 2θ selected from the following group: 7.750 ± 0.20°, 11.639 ± 0.20°, 25.100 ± 0.20°, 29.369 ± 0.20°, 30.269 ± 0.20°, 36.306 ± 0.20°, and 36.978 ± 0.20°.

[0012] In another preferred embodiment, the crystal form K further has one or more characteristics selected from the following group:

[0013] 1) The XRPD pattern of Form K is substantially as shown in FIG5 ;

[0014] 2) The DSC spectrum of the crystal form K is substantially as shown in FIG6 ;

[0015] 3) The DSC spectrum of the crystal form K has an endothermic peak in the range of 286.4°C-290.4°C;

[0016] 4) The crystal form K is an anhydrate.

[0017] In another preferred embodiment, the preparation method of the crystal form K comprises: a) suspending the starting material in MeOH at room temperature and stirring; b) separating the solid by filtration to obtain the target crystal form K.

[0018] In another preferred embodiment, the XRPD pattern of the crystalline form A comprises 3 or more (such as 4, 5, or 6) diffraction peaks of 2θ selected from the following group: 5.636 ± 0.20°, 8.210 ± 0.20°, 11.248 ± 0.20°, 13.049 ± 0.20°, 16.898 ± 0.20°, and 17.722 ± 0.20°.

[0019] In another preferred embodiment, the XRPD pattern of the crystalline form A has a diffraction peak of 2θ selected from the following group: 5.636 ± 0.20°, 8.210 ± 0.20°, 11.248 ± 0.20°, 13.049 ± 0.20°, 16.898 ± 0.20°, and 17.722 ± 0.20°.

[0020] In another preferred embodiment, the XRPD pattern of the crystalline form A has a diffraction peak of 2θ selected from the following group: 8.684 ± 0.20°, 14.791 ± 0.20°, 15.592 ± 0.20°, 17.872 ± 0.20°, 18.721 ± 0.20°, 21.127 ± 0.20°, 22.543 ± 0.20°, 24.687 ± 0.20°, and 25.757 ± 0.20°.

[0021] In another preferred embodiment, the crystalline form A further has one or more characteristics selected from the following group:

[0022] 1) The XRPD pattern of Form A is substantially as shown in FIG1 ;

[0023] 2) The DSC spectrum of the crystalline form A is substantially as shown in FIG2 ;

[0024] 3) The DSC spectrum of the crystalline form A has endothermic peaks in the ranges of 211.5°C-215.5°C and 269.6°C-273.6°C.

[0025] In another preferred embodiment, the preparation method of the crystal form A comprises: a) suspending the starting material in MeOH at 5° C. and stirring; b) separating the solid by filtration to obtain the target crystal form A.

[0026] In another preferred embodiment, the XRPD pattern of the crystalline form C comprises 3 or more (such as 4, 5, or 6) diffraction peaks of 2θ selected from the following group: 6.463 ± 0.20°, 7.402 ± 0.20°, 8.988 ± 0.20°, 12.000 ± 0.20°, 12.898 ± 0.20°, 13.088 ± 0.20°, 13.611 ± 0.20°, 14.328 ± 0.20°, 16.233 ± 0.20°, 17.205 ± 0.20°, 19.794 ± 0.20°, and 21.032 ± 0.20°.

[0027] In another preferred embodiment, the XRPD pattern of the crystalline form C comprises a diffraction peak of 2θ selected from the group consisting of 6.463 ± 0.20°, 7.402 ± 0.20°, 8.988 ± 0.20°, 12.000 ± 0.20°, 12.898 ± 0.20°, 13.088 ± 0.20°, 13.611 ± 0.20°, 14.328 ± 0.20°, 16.233 ± 0.20°, 17.205 ± 0.20°, 19.794 ± 0.20°, and 21.032 ± 0.20°.

[0028] In another preferred embodiment, the XRPD pattern of the crystalline form C has a diffraction peak of 2θ selected from the following group: 10.812 ± 0.20°, 23.376 ± 0.20°, 24.173 ± 0.20°, 24.815 ± 0.20°, 26.038 ± 0.20°, and 29.921 ± 0.20°.

[0029] In another preferred embodiment, the crystalline form C further has one or more characteristics selected from the following group:

[0030] 1) The XRPD pattern of Form C is substantially as shown in FIG3 ;

[0031] 2) The DSC spectrum of the crystalline form C is substantially as shown in FIG4 ;

[0032] 3) The DSC spectrum of the crystalline form C has an endothermic peak in the range of 254.2°C-258.2°C.

[0033] In another preferred embodiment, the preparation method of the crystalline form C comprises: a) suspending the starting material in EtOAc / n-Heptane (1:3, v / v) and stirring at room temperature; b) separating the solid by filtration to obtain the target crystalline form C.

[0034] In another preferred embodiment, the XRPD pattern of the crystalline form E comprises 3 or more (such as 4, 5, or 6) diffraction peaks of 2θ selected from the following group: 4.773 ± 0.20°, 7.773 ± 0.20°, 13.086 ± 0.20°, and 21.528 ± 0.20°.

[0035] In another preferred embodiment, the crystalline form E comprises a diffraction peak of 2θ selected from the following group: 4.773 ± 0.20°, 7.773 ± 0.20°, 13.086 ± 0.20°, and 21.528 ± 0.20°.

[0036] In another preferred embodiment, the crystalline form E further comprises a diffraction peak of 2θ selected from the following group: 16.844 ± 0.20°, 18.108 ± 0.20°.

[0037] In another preferred embodiment, the crystalline form E further has one or more characteristics selected from the following group:

[0038] 1) The XRPD pattern of Form E is substantially as shown in FIG7 ;

[0039] 2) The DSC spectrum of the crystalline form E is substantially as shown in FIG8 ;

[0040] 3) The DSC spectrum of the crystalline form E has endothermic peaks in the ranges of 67.2°C-71.2°C, 114.5°C-118.5°C, 156.3°C-160.3°C and 259.5°C-263.5°C.

[0041] In another preferred embodiment, the preparation method of E comprises: a) suspending the starting material in IPA at 5° C. and stirring; b) separating the solid by filtration to obtain the target crystalline form E.

[0042] In another preferred embodiment, the XRPD pattern of the crystalline form F comprises 3 or more (such as 4, 5, or 6) diffraction peaks of 2θ selected from the following group: 12.132 ± 0.20°, 12.389 ± 0.20°, 12.809 ± 0.20°, 15.086 ± 0.20°, 17.853 ± 0.20°, 18.413 ± 0.20°, 18.627 ± 0.20°, 22.262 ± 0.20°, 24.325 ± 0.20°, and 25.191 ± 0.20°.

[0043] In another preferred embodiment, the crystalline form F comprises a 2θ diffraction peak selected from the following group: 12.132 soil 0.20°, 12.389 soil 0.20°, 12.809 soil 0.20°, 15.086 soil 0.20°, 17.853 soil 0.20°, 18.413 soil 0.20°, 18.627 soil 0.20°, 22.262 soil 0.20°, 24.325 soil 0.20°, and 25.191 soil 0.20°.

[0044] In another preferred embodiment, the XRPD pattern of the crystalline form F further comprises a 2θ diffraction peak selected from the group consisting of: 6.310 ± 0.20°, 13.849 ± 0.20°, 16.717 ± 0.20°, 17.088 ± 0.20°, 19.179 ± 0.20°, 19.493 ± 0.20°, 20.259 ± 0.20°, 23.851 ± 0.20°, 26.158 ± 0.20°, 28.159 ± 0.20°, 28.556 ± 0.20°, and 34.014 ± 0.20°.

[0045] In another preferred embodiment, the crystalline form F further has one or more characteristics selected from the following group:

[0046] 1) The XRPD pattern of Form F is substantially as shown in FIG9 ;

[0047] 2) The DSC spectrum of the crystalline form F is substantially as shown in FIG10 ;

[0048] 3) The DSC spectrum of the crystalline form F has endothermic peaks in the ranges of 103.3°C-107.3°C and 257.9°C-261.9°C.

[0049] In another preferred embodiment, the preparation method of F comprises: a) suspending the starting material in DMF / H2O (2:1, v / v) and stirring at room temperature; b) separating the solid by filtration to obtain the target crystalline form F.

[0050] In another preferred embodiment, the XRPD pattern of the crystalline form I comprises 3 or more (such as 4, 5, or 6) 2θ diffraction peaks selected from the following group: 5.120 ± 0.20°, 6.627 ± 0.20°, 12.714 ± 0.20°, 15.388 ± 0.20°, 18.439 ± 0.20°, 18.978 ± 0.20°, and 25.496 ± 0.20°.

[0051] In another preferred embodiment, the XRPD pattern of the crystalline form I further has a 2θ diffraction peak selected from the following group: 5.120 ± 0.20°, 6.627 ± 0.20°, 12.714 ± 0.20°, 15.388 ± 0.20°, 18.439 ± 0.20°, 18.978 ± 0.20°, and 25.496 ± 0.20°.

[0052] In another preferred embodiment, the polymorph is Form I, wherein the XRPD pattern of Form I comprises at least a 2θ diffraction peak selected from the following group: 5.120 ± 0.20°, 6.627 ± 0.20°, 12.714 ± 0.20°, 18.439 ± 0.20°, and 18.978 ± 0.20°.

[0053] In another preferred embodiment, the XRPD pattern of the crystalline form I further has a 2θ diffraction peak selected from the following group: 13.197 ± 0.20°, 14.183 ± 0.20°, 19.535 ± 0.20°, 22.701 ± 0.20°, and 34.482 ± 0.20°.

[0054] In another preferred embodiment, the crystalline form I further has one or more characteristics selected from the following group:

[0055] 1) The XRPD pattern of the Form I is substantially as shown in FIG11 ;

[0056] 2) The DSC spectrum of the Form I is substantially as shown in FIG12 ;

[0057] 3) The DSC spectrum of the crystalline form I has an endothermic peak in the range of 108.4°C-112.4°C.

[0058] In another preferred embodiment, the preparation method of I comprises: a) dissolving the starting material in DMF / 1-Butanol (1:1, v / v) and slowly cooling; b) separating the solid by filtration to obtain the target crystalline form I.

[0059] In another preferred embodiment, the XRPD pattern of the crystalline form L comprises 3 or more (such as 4, 5, or 6) 2θ diffraction peaks selected from the group consisting of 6.586 ± 0.20°, 8.336 ± 0.20°, 12.065 ± 0.20°, 12.568 ± 0.20°, 13.569 ± 0.20°, 14.503 ± 0.20°, 15.950 ± 0.20°, 17.259 ± 0.20°, 18.918 ± 0.20°, and 23.483 ± 0.20°.

[0060] In another preferred embodiment, the XRPD pattern of the crystalline form L comprises a 2θ diffraction peak selected from the group consisting of 6.586 ± 0.20°, 8.336 ± 0.20°, 12.065 ± 0.20°, 12.568 ± 0.20°, 13.569 ± 0.20°, 14.503 ± 0.20°, 15.950 ± 0.20°, 17.259 ± 0.20°, 18.918 ± 0.20°, and 23.483 ± 0.20°.

[0061] In another preferred embodiment, the XRPD pattern of the crystalline form L further has a 2θ diffraction peak selected from the following group: 5.867 ± 0.20°, 9.324 ± 0.20°, 10.609 ± 0.20°, 13.115 ± 0.20°, 17.783 ± 0.20°, 18.545 ± 0.20°, 19.713 ± 0.20°, 20.940 ± 0.20°, 21.336 ± 0.20°, 22.348 ± 0.20°, 28.165 ± 0.20°, and 31.875 ± 0.20°.

[0062] In another preferred embodiment, the crystalline form L further has one or more characteristics selected from the following group:

[0063] 1) The XRPD pattern of the crystalline form L is substantially as shown in FIG13 ;

[0064] 2) The DSC spectrum of the crystalline form L is substantially as shown in FIG14 ;

[0065] 3) The DSC spectrum of the crystalline form L has endothermic peaks in the ranges of 190.6°C-194.6°C and 276.8°C-280.8°C.

[0066] In another preferred embodiment, the preparation method of L comprises: a) stirring a mixed sample of starting material crystal forms A / C / K in EtOAc at room temperature; b) separating the solid by filtration to obtain the target crystal form L.

[0067] In a second aspect of the present invention, a pharmaceutical composition is provided, comprising the polymorph of formula (I) as described in the first aspect, and optionally, further comprising a pharmaceutically acceptable carrier.

[0068] In another preferred embodiment, the composition is suitable for oral administration, injection, nasal spray, oral inhalation of aerosol and external skin application.

[0069] In another preferred embodiment, the composition is suitable for nasal spray, oral inhalation of aerosol and external skin application.

[0070] In another preferred embodiment, the composition can be prepared into tablets, injections, injections, sprays, aerosols and creams.

[0071] In another preferred embodiment, the composition can be prepared into a spray, an aerosol and a cream.

[0072] In the third aspect of the present invention, there is provided a use of the polymorph as described in the first aspect for preparing a medicament for treating or preventing rhinitis, asthma or neurodermatitis.

[0073] In another preferred embodiment, the compound is used for preparing a drug for treating or preventing rhinitis, asthma or neurodermatitis.

[0074] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0075] FIG1 shows the XRPD pattern of Form A.

[0076] FIG2 shows the DSC graph of Form A.

[0077] FIG3 shows the XRPD pattern of Form C.

[0078] FIG4 shows the DSC graph of Form C.

[0079] FIG5 shows the XRPD pattern of Form K.

[0080] FIG6 shows the DSC graph of Form K.

[0081] FIG7 shows the XRPD pattern of Form E.

[0082] FIG8 shows the DSC graph of Form E.

[0083] FIG9 shows the XRPD pattern of Form F.

[0084] FIG10 shows the DSC graph of Form F.

[0085] FIG11 shows the XRPD pattern of Form I.

[0086] FIG12 shows the DSC graph of Form I.

[0087] FIG13 shows the XRPD pattern of Form L.

[0088] FIG14 shows the DSC graph of Form L.

[0089] Figure 15 shows the XRPD comparison charts of Forms A / C / K in the MeOH system at room temperature suspension competition.

[0090] FIG16 shows the XRPD comparison patterns of Forms A / C / K suspended in EtOAc system at room temperature.

[0091] FIG17 shows the DVS pattern of Form K.

[0092] FIG18 shows the XRPD comparison of Form K before and after DVS testing.

[0093] FIG19 shows the XRPD comparison diagrams of Form K before and after standing. DETAILED DESCRIPTION

[0094] The present inventors, after extensive and in-depth research and a large number of experimental screenings, unexpectedly developed for the first time a polymorph of a glucocorticoid drug (1R, 2R, 3aS, 3bR, 10aS, 10bR, 11S, 12aS)-5,10b-difluoro-1-(((fluoromethyl)thio)carbonyl)-11-hydroxy-2,10a, 12a-trimethyl-7-phenyl-1,2,3,3a,3b,7,10,10a, 10b, 11,12,12a-dodecylhydrocyclopenta[5,6]naphtho[1,2-F]indazol-1-ylfuran-2-carboxylate and a preparation method thereof. The crystalline form of the polymorph is selected from the following group: crystalline form A, crystalline form C, crystalline form K, crystalline form E, crystalline form F, crystalline form I, or crystalline form L. The polymorphs of the glucocorticoid of the present invention (especially Form K) have higher efficacy and selectivity, can reduce side effects during treatment and improve treatment effects. Based on this, the present invention was completed.

[0095] the term

[0096] High-efficacy glucocorticoid polymorph of the present invention

[0097] (1R,2R,3aS,3bR,10aS,10bR,11S,12aS)-5,10b-difluoro-1-(((fluoromethyl)thio)carbonyl)-11-hydroxy-2,10a,12a-trimethyl-7-phenyl-1,2,3,3a,3b,7,10,10a,10b,11,12,12a-dodecylhydrocyclopenta[5,6]naphtho[1,2-F]indazol-1-ylfuran-2-carboxylate (I). Has the following structure:

[0098] Effectiveness and efficacy are two key pharmacokinetic parameters of glucocorticoids. Although efficacy is the maximum activity that a given drug can achieve, usually at maximum concentration, efficacy is the given drug concentration (EC50) required to achieve half the maximum activity. For two glucocorticoids with the same efficacy, high-efficacy glucocorticoids will require lower dosages just to achieve the same therapeutic effect. Importantly, glucocorticoids may have different efficacy to transcriptional activation and transcriptional inhibition. For example, GR requires a glucocorticoid concentration 5 to 6 times higher than gene inhibition via the gene induction of DEX. This differential response provides the opportunity to develop the following high-efficacy glucocorticoid, which can be used in low doses to achieve complete inhibition of inflammatory signals with minimal transcriptional activation activity and side effects.

[0099] Currently, drug polymorphs have become an essential component of the drug research process and the quality control and testing of finished drugs. The study of drug polymorphs aids in the selection of bioactive compounds for new drug compounds, improves bioavailability, enhances clinical efficacy, facilitates the selection and design of drug administration routes, and determines drug formulation process parameters, thereby improving drug production quality. The bioavailability of different crystalline forms of the same drug can vary significantly. Certain crystalline forms of the same drug may exhibit higher bioactivity than others. Obtaining a crystalline form with increased bioactivity and better suitability for pharmaceutical applications is a long-awaited technical challenge in the pharmaceutical field.

[0100] The present invention provides a polymorph of (1R,2R,3aS,3bR,10aS,10bR,11S,12aS)-5,10b-difluoro-1-(((fluoromethyl)thio)carbonyl)-11-hydroxy-2,10a,12a-trimethyl-7-phenyl-1,2,3,3a,3b,7,10,10a,10b,11,12,12a-dodecylhydrocyclopenta[5,6]naphtho[1,2-F]indazol-1-ylfuran-2-carboxylate.

[0101] In the present invention, (1R,2R,3aS,3bR,10aS,10bR,11S,12aS)-5,10b-difluoro-1-(((fluoromethyl)thio)carbonyl)-11-hydroxy-2,10a,12a-trimethyl-7-phenyl-1,2,3,3a,3b,7,10,10a,10b,11,12,12a-dodecylhydrocyclopenta[5,6]naphtho[1,2-F]indazol-1-ylfuran-2-carboxylate is a novel, highly potent glucocorticoid. By determining the X-ray structure of the glucocorticoid receptor (GR) ligand-binding domain (LBD) bound to cortisol and mometasone furoate (MF), the inventors have developed a novel glucocorticoid with significantly enhanced potency based on structure-based design. High-potency glucocorticoids can minimize side effects and achieve the same therapeutic effect at a lower dose.

[0102] In another preferred embodiment, the polymorph is Form A, wherein the XRPD spectrum of Form A contains at least diffraction peaks of 2θ±0.20°: 5.636, 8.210, 11.248, 13.049, 16.898, and 17.722.

[0103] Preferably, the XRPD spectrum of the (1R, 2R, 3aS, 3bR, 10aS, 10bR, 11S, 12aS)-5,10b-difluoro-1-(((fluoromethyl)thio)carbonyl)-11-hydroxy-2,10a, 12a-trimethyl-7-phenyl-1,2,3,3a,3b,7,10,10a, 10b, 11,12,12a-dodecylhydrocyclopenta[5,6]naphtho[1,2-F]indazol-1-ylfuran-2-carboxylate crystalline form A comprises at least diffraction peaks at 2θ±0.20° of 5.636, 8.210, 8.684, 11.248, 13.049, 16.898, 17.722, 17.872, 21.127, and 24.687. More preferably, it further comprises diffraction peaks at 2θ±0.20° of 14.791, 15.592, 18.721, 22.543, and 25.757.

[0104] Particularly preferably, the crystalline form A has an XRPD pattern substantially as shown in FIG1 .

[0105] In another preferred embodiment, the polymorph is Form A. The differential thermal analysis results of Form A show that there are endothermic peaks at 198.4°C (starting temperature) and 271.6°C (peak temperature), and an exothermic peak at 243.6°C (peak temperature).

[0106] In another preferred embodiment, the polymorph is Form A, and Form A has a DSC spectrum substantially as shown in FIG2 .

[0107] In a specific embodiment of the present invention, a method for preparing Form A is also provided, comprising: a) suspending the starting material in MeOH at 5° C. and stirring; b) separating the solid by filtration to obtain the target Form A.

[0108] In another preferred embodiment, the polymorph is Form C, wherein the XRPD spectrum of Form C contains at least diffraction peaks of 2θ±0.20°: 8.988, 12.000, 12.898, 13.088, 13.611, 14.328, 16.233, 17.205, and 19.794.

[0109] Preferably, the (1R, 2R, 3aS, 3bR, 10aS, 10bR, 11S, 12aS)-5, 10b-difluoro-1-(((fluoromethyl)thio)carbonyl)-11-hydroxy-2, 10a, 12a-trimethyl-7-phenyl-1, 2, 3, 3a, 3b, 7, 10, 10a, 10b, 11, 12, 12a-dodecylhydrocyclopentyl[ The XRPD pattern of Form C of 5,6] naphtho[1,2-F]indazol-1-ylfuran-2-carboxylate contains at least diffraction peaks at 2θ±0.20° of 6.463, 7.402, 8.988, 12.000, 12.898, 13.088, 13.611, 14.328, 16.233, 17.205, 19.794, and 21.032. More preferably, the XRPD pattern further contains diffraction peaks at 2θ±0.20° of 10.812, 23.376, 24.173, 24.815, 26.038, and 29.921.

[0110] Particularly preferably, the crystalline form C has an XRPD pattern substantially as shown in FIG3 .

[0111] In another preferred embodiment, the polymorph is Form C, and the differential thermal analysis results of Form C show that a sharp endothermic melting peak appears at 256.2°C (peak temperature).

[0112] In another preferred embodiment, the polymorph is Form C, which has a DSC spectrum substantially as shown in FIG4 .

[0113] In one embodiment of the present invention, a method for preparing Form C is also provided, comprising: a) suspending the starting material in EtOAc / n-Heptane (1:3, v / v) and stirring at room temperature; b) separating the solid by filtration to obtain the target Form C.

[0114] In another preferred embodiment, the polymorph is Form K, wherein the XRPD spectrum of Form K comprises at least diffraction peaks of 2θ±0.20°: 9.336, 9.955, 12,769, 13.826, 14.315, 15.581, 15.960, 16.748, 17.864, 20.050, 21.198, 22,587, 22.909, 23.725, and 27.920.

[0115] Preferably, the (1R, 2R, 3aS, 3bR, 10aS, 10bR, 11S, 12aS)-5, 10b-difluoro-1-(((fluoromethyl)thio)carbonyl)-11-hydroxy-2, 10a, 12a-trimethyl-7-phenyl-1, 2, 3, 3a, 3b, 7, 10, 10a, 10b, 11, 12, 12a-dodecylhydrocyclopenta [5, 6] naphtho [1, 2-F] indazol-1-ylfuran-2-carboxylic The XRPD pattern of the acid ester crystalline form K comprises at least diffraction peaks at 2θ±0.20° of 7.148, 9.336, 9.955, 11.239, 12.769, 13.826, 14.315, 15.581, 15.960, 16.748, 17.864, 20.050, 21.198, 22.587, 22.909, 23.725, 24.383, 26.611, and 27.920. More preferably, the XRPD pattern further comprises diffraction peaks at 2θ±0.20° of 7.750, 11.639, 25.100, 29.369, 30.269, 36.306, and 36.978.

[0116] Particularly preferably, the crystalline form K has an XRPD pattern substantially as shown in FIG5 .

[0117] In another preferred embodiment, the polymorph is Form K. The differential thermal analysis results of Form K show that a sharp endothermic melting peak appears at 288.4°C (peak temperature).

[0118] In another preferred embodiment, the polymorph is Form K, which has a DSC spectrum substantially as shown in FIG6 .

[0119] In a specific embodiment of the present invention, a method for preparing Form K is also provided, comprising: a) suspending the starting material in MeOH at room temperature and stirring; b) separating the solid by filtration to obtain the target Form K.

[0120] In another preferred embodiment, the polymorph is Form E, wherein the XRPD spectrum of Form E at least comprises diffraction peaks at 2θ±0.20° of 4.773, 13.086, and 21.528.

[0121] Preferably, the XRPD pattern of the (1R,2R,3aS,3bR,10aS,10bR,11S,12aS)-5,10b-difluoro-1-(((fluoromethyl)thio)carbonyl)-11-hydroxy-2,10a,12a-trimethyl-7-phenyl-1,2,3,3a,3b,7,10,10a,10b,11,12,12a-dodecylhydrocyclopenta[5,6]naphtho[1,2-F]indazol-1-ylfuran-2-carboxylate Form E comprises at least diffraction peaks at 2θ±0.20° of 4.773, 7.773, 13.086, and 21.528. More preferably, it further comprises diffraction peaks at 2θ±0.20° of 16.844 and 18.108.

[0122] Particularly preferably, the crystalline form E has an XRPD pattern substantially as shown in FIG7 .

[0123] In another preferred embodiment, the polymorph is Form E. The differential thermal analysis results of Form E show that there are endothermic peaks at 69.2°C, 116.5°C, 158.3°C and 261.5°C (peak temperature), and an exothermic peak at 259.6°C (starting temperature).

[0124] In another preferred embodiment, the polymorph is Form E, and Form E has a DSC spectrum substantially as shown in FIG8 .

[0125] In a specific embodiment of the present invention, a method for preparing Form E is also provided, comprising: a) suspending the starting material in IPA at 5° C. and stirring; b) separating the solid by filtration to obtain the target Form E.

[0126] In another preferred embodiment, the polymorph is Form F, wherein the XRPD spectrum of Form F at least comprises diffraction peaks at 2θ±0.20° of 12.132, 12.389, 12.809, 18.627, 22.262, 24.325, and 25.191.

[0127] Preferably, the (1R, 2R, 3aS, 3bR, 10aS, 10bR, 11S, 12aS)-5,10b-difluoro-1-(((fluoromethyl)thio)carbonyl)-11-hydroxy-2,10a, 12a-trimethyl-7-phenyl-1,2,3,3a,3b,7,10,10a,10b,11,12,12a-dodecane The XRPD pattern of methylhydrocyclopenta[5,6]naphtho[1,2-F]indazol-1-ylfuran-2-carboxylate crystalline form F comprises at least diffraction peaks at 2θ±0.20° of 12.132, 12.389, 12.809, 15.086, 17.853, 18.413, 18.627, 22.262, 24.325, and 25.191. More preferably, the XRPD pattern further comprises diffraction peaks at 2θ±0.20° of 6.310, 13.849, 16.717, 17.088, 19.179, 19.493, 20.259, 23.851, 26.158, 28.159, 28.556, and 34.014.

[0128] Particularly preferably, the crystalline form F has an XRPD pattern substantially as shown in FIG9 .

[0129] In another preferred embodiment, the polymorph is Form F, and the differential thermal analysis results of Form F show that there are endothermic peaks at 105.3°C and 259.9°C (peak temperature).

[0130] In another preferred embodiment, the polymorph is Form F, which has a DSC spectrum substantially as shown in FIG10 .

[0131] In a specific embodiment of the present invention, a method for preparing Form F is also provided, comprising: a) suspending and stirring the starting material in DMF / H2O (2:1, v / v) at room temperature; b) separating the solid by filtration to obtain the target Form F.

[0132] In another preferred embodiment, the polymorph is Form I, wherein the XRPD spectrum of Form I at least comprises diffraction peaks at 2θ±0.20° of 5.120, 6.627, 12.714, 18.439, and 18.978.

[0133] Preferably, the XRPD spectrum of the (1R, 2R, 3aS, 3bR, 10aS, 10bR, 11S, 12aS)-5,10b-difluoro-1-(((fluoromethyl)thio)carbonyl)-11-hydroxy-2,10a, 12a-trimethyl-7-phenyl-1,2,3,3a,3b,7,10,10a, 10b, 11,12,12a-dodecylhydrocyclopenta[5,6]naphtho[1,2-F]indazol-1-ylfuran-2-carboxylate Form I contains at least diffraction peaks at 2θ±0.20° of 5.120, 6.627, 12.714, 15.388, 18.439, 18.978, and 25.496. More preferably, it further comprises diffraction peaks at 2θ±0.20° of 13.197, 14.183, 19.535, 22.701, and 34.482.

[0134] Particularly preferably, the crystalline form I has an XRPD pattern substantially as shown in FIG11 .

[0135] In another preferred embodiment, the polymorph is Form I, and the differential thermal analysis results of Form I show that there is an endothermic peak at 110.4°C (peak temperature).

[0136] In another preferred embodiment, the polymorph is Form I, and Form I has a DSC spectrum substantially as shown in FIG12 .

[0137] In a specific embodiment of the present invention, a method for preparing Form I is also provided, comprising: a) dissolving the starting material in DMF / 1-Butanol (1:1, v / v) and slowly cooling; b) separating the solid by filtration to obtain the target Form I.

[0138] In another preferred embodiment, the polymorph is Form L, wherein the XRPD spectrum of Form L contains at least diffraction peaks of 2θ±0.20°: 6.586, 8.336, 12.065, 12,568, 15.950, 17.259, 18.918, and 23.483.

[0139] Preferably, the XRPD pattern of the (1R, 2R, 3aS, 3bR, 10aS, 10bR, 11S, 12aS)-5,10b-difluoro-1-(((fluoromethyl)thio)carbonyl)-11-hydroxy-2,10a, 12a-trimethyl-7-phenyl-1,2,3,3a,3b,7,10,10a, 10b, 11,12,12a-dodecylhydrocyclopenta[5,6]naphtho[1,2-F]indazol-1-ylfuran-2-carboxylate crystalline form L contains at least diffraction peaks at 2θ±0.20° of 6.586, 8.336, 12.065, 12,568, 13.569, 14.503, 15.950, 17.259, 18.918, and 23.483. More preferably, it further comprises diffraction peaks of 2θ±0.20°: 5.867, 9.324, 10.609, 13.115, 17.783, 18.545, 19.713, 20.940, 21.336, 22.348, 28.165, and 31.875.

[0140] Particularly preferably, the crystalline form L has an XRPD pattern substantially as shown in FIG13 .

[0141] In another preferred embodiment, the polymorph is Form L. The differential thermal analysis results of Form L show that there are endothermic peaks at 192.6°C and 278.8°C (peak temperature), and an exothermic peak at 224.2°C (peak temperature).

[0142] In another preferred embodiment, the polymorph is Form L, and Form L has a DSC spectrum substantially as shown in FIG14 .

[0143] In one embodiment of the present invention, a method for preparing Form L is provided, comprising: a) mixing a mixed sample of starting materials Forms A / C / K in EtOAc at room temperature; and b) separating the solid by filtration to obtain the target Form L.

[0144] The present invention also provides a pharmaceutical composition comprising an effective amount of the crystal form. Optionally, the composition further comprises a pharmaceutically acceptable carrier.

[0145] The compositions of the present invention are suitable for oral administration, injection, nasal spray, oral inhalation of aerosol, and external skin application. Nasal spray, oral inhalation of aerosol, and external skin application are preferred. Dosage forms include tablets, injections, injections, sprays, aerosols, and creams, with sprays, aerosols, and creams being preferred.

[0146] The present invention also provides the use of the crystal form and a pharmaceutical composition containing the crystal form in the preparation of drugs for treating asthma, rhinitis or neurodermatitis.

[0147] Compared with the prior art, the present invention has the following beneficial effects:

[0148] The new polymorph of the present invention has the characteristics of significant efficacy, good stability, high yield, high purity, etc. The new polymorph of the present invention is helpful in the selection and design of drug administration routes and the determination of drug preparation process parameters, thereby improving the quality of drug production.

[0149] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0150] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention.

[0151] Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial channels.

[0152] Example 1: Preparation of Form A

[0153] 8.1 mg of the starting sample was weighed into a 1.5 mL vial, 0.3 mL of methanol was added, the sample was suspended and stirred at 5°C for 5 days, and the solid was separated by centrifugation to obtain Form A.

[0154] The obtained solid was subjected to an X-ray powder diffraction test, and its X-ray powder diffraction pattern was consistent with Figure 1, proving that the obtained was Form A. The powder diffraction data of Form A are shown in Table 1 below. The obtained solid was subjected to a DSC test, and the results are shown in Figure 2.

[0155] Table 1: Powder diffraction data of Form A

[0156] Example 2: Preparation of Form C

[0157] Weigh 200 mg of the starting sample into a 5 mL vial, add 2 mL of ethyl acetate / n-heptane (1:3, v / v), suspend and stir the sample at room temperature for 3 days, and filter and separate the solid to obtain Form C.

[0158] The obtained solid was subjected to an X-ray powder diffraction test, and its X-ray powder diffraction pattern was consistent with Figure 3, proving that the obtained was Form C. The powder diffraction data of Form C are shown in Table 2. The obtained solid was subjected to a DSC test, and the results are shown in Figure 4.

[0159] Table 2: Powder diffraction data of Form C

[0160] Example 3: Preparation of Form K

[0161] Weigh 300 mg of the starting sample into a 5 mL vial, add 3 mL of methanol, heat the sample to 50 °C and stir for 3 hours, turn off the heating, cool naturally to 20 °C, and filter the solid to obtain Form K.

[0162] The obtained solid was subjected to an X-ray powder diffraction test, and its X-ray powder diffraction pattern was consistent with FIG5 , proving that the obtained product was Form K. The obtained solid was subjected to a DSC test, and the results were shown in FIG6 .

[0163] Example 4: Preparation of Form K

[0164] Weigh 300 mg of the starting sample into a 5 mL vial, add 3 mL of ethanol, heat the sample to 50 °C and stir for 3 hours, turn off the heat, cool naturally to 20 °C, and filter the solid to obtain Form K.

[0165] The obtained solid was subjected to an X-ray powder diffraction test, and its X-ray powder diffraction pattern was consistent with Figure 5, proving that the obtained solid was Form K. The powder diffraction data of Form K are shown in Table 3.

[0166] Table 3: Powder diffraction data of Form K

[0167] Example 5: Preparation of Form E

[0168] 7.8 mg of the starting sample was weighed into a 1.5 mL vial, 0.1 mL of isopropanol was added, the sample was suspended and stirred at 5° C. for 7 days, and the solid was separated by centrifugation to obtain Form E.

[0169] The obtained solid was subjected to an X-ray powder diffraction test, and its X-ray powder diffraction pattern was consistent with Figure 7, proving that the obtained was Form E. The powder diffraction data of Form E are shown in Table 3. The obtained solid was subjected to a DSC test, and the results are shown in Figure 8.

[0170] Table 3: Powder diffraction data of Form E

[0171] Example 6: Preparation of Form F

[0172] 10 mg of the starting sample was weighed into a 1.5 mL vial, and 0.05 mL of N,N-dimethylformamide / water (2:1, v / v) was added. The sample was stirred at room temperature for 3 days, and the solid was separated by centrifugation to obtain Form F.

[0173] The obtained solid was subjected to an X-ray powder diffraction test, and its X-ray powder diffraction pattern was consistent with Figure 9, proving that the obtained was Form F. The powder diffraction data of Form F are shown in Table 5. The obtained solid was subjected to a DSC test, and the results are shown in Figure 10.

[0174] Table 5: Powder diffraction data of Form F

[0175] Example 7: Preparation of Form I

[0176] Weigh 12 mg of the starting sample into a 1.5 mL vial, add 0.2 mL of N,N-dimethylformamide / n-butanol (1:1, v / v), heat the sample to 50°C, stir to dissolve, turn off the heat, cool naturally to 20°C, continue stirring for 12 hours, and filter the solid to obtain Form I.

[0177] The obtained solid was subjected to an X-ray powder diffraction test, and its X-ray powder diffraction pattern was consistent with Figure 11, proving that the obtained was Form I. The powder diffraction data of Form I are shown in Table 6. The obtained solid was subjected to a DSC test, and the results are shown in Figure 12.

[0178] Table 6: Powder diffraction data of Form I

[0179] Example 8: Preparation of Form L

[0180] To 0.2 mL of ethyl acetate solution was added Form C until supersaturated, stirred at room temperature for 1 hour, and then filtered to obtain a saturated solution. To the resulting saturated solution was added 10 mg each of Forms A, C, and K, stirred at room temperature for 2 days, and the solid was filtered to obtain Form L.

[0181] The obtained solid was subjected to an X-ray powder diffraction test, and its X-ray powder diffraction pattern was consistent with Figure 13, proving that the obtained was Form L. The powder diffraction data of Form L are shown in Table 7. The obtained solid was subjected to a DSC test, and the results are shown in Figure 14.

[0182] Table 7: Powder diffraction data of Form L

[0183] Example 9: Study of Thermodynamic Stability Relationship

[0184] The thermodynamic stability relationship between Forms A, C, and K of the present invention was investigated at room temperature. Room-temperature suspension competition experiments were conducted in MeOH and EtOAc systems. Saturated solutions of Form C in MeOH and EtOAc were prepared, respectively. Equal mass ratios (approximately 10 mg each) of Forms A, C, and K were then added to 0.2 mL of the saturated solutions to form suspensions. After magnetic stirring (~600 rpm) at room temperature for two days, XRPD analysis was performed by centrifugation. The results, shown in Figures 15 and 16, indicate Form K in MeOH and Form L in EtOAc. Based on these data, Form K is the more thermodynamically stable anhydrous form at room temperature.

[0185] Example 10: DVS test

[0186] Dynamic moisture sorption (DVS) testing was performed on Form K of the present invention. The results (Error! Reference source not found) show that the sample absorbed 0.58% water at 25°C / 80% RH, indicating that Form K is slightly hygroscopic. The crystal form remained unchanged before and after the DVS test. A comparison of XRPD patterns of Form K before and after the DVS test is shown in Error! Reference source not found.

[0187] Example 11: Stability Study

[0188] Stability testing of Form K of the present invention demonstrated that Form K did not undergo crystal transformation during the stability test. XRPD comparisons before and after aging are shown in Figure 19. Form K also showed no chemical degradation and was stable at room temperature, meeting drug and formulation requirements. See Table 8 for details.

[0189] Table 8: Stability test

[0190] *: Relative purity = final purity / initial purity

[0191] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A polymorph of a compound represented by formula (I), characterized in that: The crystalline form of the polymorph is selected from the group consisting of crystalline form K, crystalline form A, crystalline form C, crystalline form E, crystalline form F, crystalline form I, or crystalline form L, The polymorph is a crystalline form of (1R,2R,3aS,3bR,10aS,10bR,11S,12aS)-5,10b-difluoro-1-(((fluoromethyl)thio)carbonyl)-11-hydroxy-2,10a,12a-trimethyl-7-phenyl-1,2,3,3a,3b,7,10,10a,10b,11,12,12a-dodecylhydrocyclopenta[5,6]naphtho[1,2-F]indazol-1-ylfuran-2-carboxylate.

2. The polymorph according to claim 1, characterized in that The XRPD spectrum of the crystalline form K comprises 3 or more (such as 4, 5, or 6) diffraction peaks having 2θ selected from the following group: 7.148 Soil 0.20°, 9.336 Soil 0.20°, 9.955 Soil 0.20°, 11.239 Soil 0.20°, 12,769 Soil 0.20°, 13.826 Soil 0.20°, 14.315 Soil 0.20°, 15.581 Soil 0.20°, 15.960 Soil 0.20°, 16.748 Soil 0.20°, 17.864 Soil 0.20°, 20.050 Soil 0.20°, 21.198 Soil 0.20°, 22,587 Soil 0.20°, 22.909 Soil 0.20°, 23.725 Soil 0.20°, 24.383 Soil 0.20°, 26.611 Soil 0.20°, 27.920 Soil 0.20°.

3. The polymorph according to claim 1, characterized in that The crystal form K also has a 2θ diffraction peak selected from the following group: 7.750 ± 0.20°, 11.639 ± 0.20°, 25.100 ± 0.20°, 29.369 ± 0.20°, 30.269 ± 0.20°, 36.306 ± 0.20°, 36.978 ± 0.20°.

4. The polymorph according to claim 1, characterized in that The crystal form K also has one or more characteristics selected from the following group: 1) The XRPD pattern of the crystal form K is substantially as shown in FIG5 ; 2) The DSC spectrum of the crystal form K is substantially as shown in FIG6 ; 3) The DSC spectrum of the crystal form K has an endothermic peak in the range of 286.4°C-290.4°C; 4) The crystal form K is an anhydrate.

5. The polymorph according to claim 1, characterized in that The XRPD spectrum of the crystalline form A comprises 3 or more (such as 4, 5, or 6) 2θ diffraction peaks selected from the following group: 5.636 ± 0.20°, 8.210 ± 0.20°, 11.248 ± 0.20°, 13.049 ± 0.20°, 16.898 ± 0.20°, 17.722 ± 0.20°.

6. The polymorph according to claim 1, wherein The XRPD spectrum of the crystalline form A has a 2θ diffraction peak selected from the following group: 8.684 ± 0.20°, 14.791 ± 0.20°, 15.592 ± 0.20°, 17.872 ± 0.20°, 18.721 ± 0.20°, 21.127 ± 0.20°, 22.543 ± 0.20°, 24.687 ± 0.20°, 25.757 ± 0.20°.

7. The polymorph according to claim 1, wherein The crystalline form A also has one or more characteristics selected from the following group: 1) The XRPD pattern of the crystalline form A is substantially as shown in FIG1 ; 2) The DSC spectrum of the crystalline form A is substantially as shown in FIG2 ; 3) The DSC spectrum of the crystalline form A has endothermic peaks in the ranges of 211.5°C-215.5°C and 269.6°C-273.6°C.

8. The polymorph according to claim 1, wherein The XRPD spectrum of the crystalline form C comprises 3 or more (such as 4, 5, or 6) 2θ diffraction peaks selected from the following group: 6.463 Soil 0.20°, 7.402 Soil 0.20°, 8.988 Soil 0.20°, 12.000 Soil 0.20°, 12.898 Soil 0.20°, 13.088 Soil 0.20°, 13.611 Soil 0.20°, 14.328 Soil 0.20°, 16.233 Soil 0.20°, 17.205 Soil 0.20°, 19.794 Soil 0.20°, 21.032 Soil 0.20°.

9. The polymorph according to claim 1, wherein The XRPD spectrum of the crystalline form C has a 2θ diffraction peak selected from the following group: 10.812 ± 0.20°, 23.376 ± 0.20°, 24.173 ± 0.20°, 24.815 ± 0.20°, 26.038 ± 0.20°, 29.921 ± 0.20°.

10. The polymorph according to claim 1, wherein The crystalline form C also has one or more characteristics selected from the following group: 1) The XRPD pattern of the crystalline form C is substantially as shown in FIG3 ; 2) The DSC spectrum of the crystalline form C is substantially as shown in FIG4 ; 3) The DSC spectrum of the crystalline form C has an endothermic peak in the range of 254.2°C-258.2°C.

11. The polymorph according to claim 1, wherein The XRPD spectrum of the crystalline form E comprises 3 or more (such as 4, 5, or 6) 2θ diffraction peaks selected from the following group: 4.773 ± 0.20°, 7.773 ± 0.20°, 13.086 ± 0.20°, 21.528 ± 0.20°.

12. The polymorph according to claim 1, wherein The crystalline form E further comprises a 2θ diffraction peak selected from the following group: 16.844 ± 0.20°, 18.108 ± 0.20°.

13. The polymorph according to claim 1, wherein The crystalline form E also has one or more characteristics selected from the following group: 1) The XRPD pattern of the crystalline form E is substantially as shown in FIG7 ; 2) The DSC spectrum of the crystalline form E is substantially as shown in FIG8 ; 3) The DSC spectrum of the crystalline form E has endothermic peaks in the ranges of 67.2°C-71.2°C, 114.5°C-118.5°C, 156.3°C-160.3°C and 259.5°C-263.5°C.

14. The polymorph according to claim 1, wherein The XRPD spectrum of the crystalline form F comprises 3 or more (such as 4, 5, or 6) 2θ diffraction peaks selected from the following group: 12.132 ± 0.20°, 12.389 ± 0.20°, 12.809 ± 0.20°, 15.086 ± 0.20°, 17.853 ± 0.20°, 18.413 ± 0.20°, 18.627 ± 0.20°, 22.262 ± 0.20°, 24.325 ± 0.20°, 25.191 ± 0.20°.

15. The polymorph according to claim 1, wherein The XRPD spectrum of the crystalline form F also includes a 2θ diffraction peak selected from the following group: 6.310 soil 0.20°, 13.849 soil 0.20°, 16.717 soil 0.20°, 17.088 soil 0.20°, 19.179 soil 0.20°, 19.493 soil 0.20°, 20.259 soil 0.20°, 23.851 soil 0.20°, 26.158 soil 0.20°, 28.159 soil 0.20°, 28.556 soil 0.20°, and 34.014 soil 0.20°.

16. The polymorph according to claim 1, wherein The crystalline form F also has one or more characteristics selected from the following group: 1) The XRPD pattern of the crystalline form F is substantially as shown in FIG9 ; 2) The DSC spectrum of the crystal form F is substantially as shown in FIG10 ; 3) The DSC spectrum of the crystalline form F has endothermic peaks in the ranges of 103.3°C-107.3°C and 257.9°C-261.9°C.

17. The polymorph according to claim 1, wherein The XRPD spectrum of the crystalline form I contains 3 or more (such as 4, 5, or 6) 2θ diffraction peaks selected from the following group: 5.120 ± 0.20°, 6.627 ± 0.20°, 12.714 ± 0.20°, 15.388 ± 0.20°, 18.439 ± 0.20°, 18.978 ± 0.20°, and 25.496 ± 0.20°.

18. The polymorph according to claim 1, wherein The XRPD spectrum of the crystalline form I also has a 2θ diffraction peak selected from the following group: 13.197 ± 0.20°, 14.183 ± 0.20°, 19.535 ± 0.20°, 22.701 ± 0.20°, and 34.482 ± 0.20°.

19. The crystalline form I according to claim 1, characterized in that: The crystalline form I also has one or more characteristics selected from the following group: 1) The XRPD pattern of the crystalline form I is substantially as shown in FIG11 ; 2) The DSC spectrum of the crystalline form I is substantially as shown in FIG12 ; 3) The DSC spectrum of the crystalline form I has an endothermic peak in the range of 108.4°C-112.4°C.

20. The polymorph according to claim 1, wherein The XRPD spectrum of the crystalline form L contains 3 or more (such as 4, 5, or 6) 2θ diffraction peaks selected from the group consisting of 6.586 ± 0.20°, 8.336 ± 0.20°, 12.065 ± 0.20°, 12.568 ± 0.20°, 13.569 ± 0.20°, 14.503 ± 0.20°, 15.950 ± 0.20°, 17.259 ± 0.20°, 18.918 ± 0.20°, and 23.483 ± 0.20°.

21. The polymorph according to claim 1, wherein The XRPD spectrum of the crystalline form L also has a 2θ diffraction peak selected from the following group: 5.867 soil 0.20°, 9.324 soil 0.20°, 10.609 soil 0.20°, 13.115 soil 0.20°, 17.783 soil 0.20°, 18.545 soil 0.20°, 19.713 soil 0.20°, 20.940 soil 0.20°, 21.336 soil 0.20°, 22.348 soil 0.20°, 28.165 soil 0.20°, and 31.875 soil 0.20°.

22. The polymorph according to claim 1, wherein The crystalline form L also has one or more characteristics selected from the following group: 1) The XRPD pattern of the crystalline form L is substantially as shown in FIG13 ; 2) The DSC spectrum of the crystal form L is basically represented by FIG14; 3) The DSC spectrum of the crystal form L has endothermic peaks in the ranges of 190.6°C-194.6°C and 276.8°C-280.8°C.

23. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the polymorph of formula (I) as described in any one of claims 1 to 22, and optionally, further comprises a pharmaceutically acceptable carrier.

24. The pharmaceutical composition according to claim 23, characterized in that The composition is suitable for oral administration, injection, nasal spray, oral inhalation of aerosol and external skin application.

25. The pharmaceutical composition according to claim 23, characterized in that The composition is suitable for administration via nasal spray, oral inhalation of aerosol and external skin application.

26. The pharmaceutical composition according to claim 23, characterized in that The composition can be prepared into tablets, injections, injections, sprays, aerosols and creams.

27. The pharmaceutical composition according to claim 23, characterized in that The composition can be prepared into sprays, aerosols and creams.

28. Use of the polymorph according to any one of claims 1 to 22, characterized in that Used for preparing medicines for treating or preventing rhinitis, asthma or neurodermatitis.

29. The use of the pharmaceutical composition according to any one of claims 23 to 27, characterized in that: Used for preparing medicines for treating or preventing rhinitis, asthma or neurodermatitis.