WO2019063002A1 - Crystal form of benvitimod, and use thereof and preparation method therefor - Google Patents

Abstract

The present application relates to a crystal form of Benvitimod (i.e., the compound represented by formula I), a pharmaceutical composition having the crystal form, and a use thereof and a preparation method therefor.

Description

Crystal form of phenenyl and its use and preparation method Technical field

The present application relates to a novel crystalline form of phenenimod, a process for preparing a new crystalline form, and a pharmaceutical composition containing the same, and also relates to the novel crystalline form and pharmaceutical composition thereof for treating autoimmune diseases or their concurrent The application of the disease.

Background technique

Benvitimod is a stilbene compound, a non-steroidal anti-inflammatory/immune and anti-cell spreading small molecule drug that significantly inhibits interleukin-2, interleukin-13, interleukin-17, and tumor necrosis. The expression of factors such as factors can also inhibit the activation and migration of T cells and can be used to treat a variety of major autoimmune, inflammatory and cell-dwelling diseases.

The examples that follow will illustrate these. There are many known compounds that have immunomodulatory activity. It has been reported in a large number of scientific literatures and patents. The commonly known and immunomodulatory compounds are known to be useful in the treatment of diseases related to animals and humans. . As is known in the literature, those compounds having immunomodulatory activity, as disclosed herein, are useful as active ingredients in pharmaceuticals for the treatment of various diseases, such as rejection of clinical transplants (including organs). Transplantation, acute transplantation, allogeneic transplantation and allogeneic transplantation, such as in the treatment of burns, to avoid ischemic or reperfusion injury, such as ischemic and multiple perfusion injuries caused by organ transplantation, can also treat urgency Infarction, stroke or other diseases; induction of transplant tolerance, treatment of arthritis (such as rheumatoid arthritis, psoriatic arthritis, osteoarthritis); multiple sclerosis, inflammatory bowel disease, including ulcerative colitis and Crohn's Disease; lupus (systemic lupus erythematosus); graft versus host disease; T cell hypersensitivity, including contact hypersensitivity, delayed hypersensitivity, gluten allergic bowel disease (gluten allergy), psoriasis, Contact dermatitis (including caused by poison ivy), Hashimoto's thyroiditis, Sjogren's syndrome, autoimmune hyperthyroidism, such as Grave's disease, Addison's disease, adrenal gland itself Immune disease, polygland autoimmune syndrome, immune alopecia, pernicious anemia, vitiligo, immune hypopituitarism, Guillain-Barre syndrome, and other immune diseases such as glomerulonephritis, serum Disease, urticaria, and allergic diseases such as respiratory allergic diseases (asthma, hay fever, allergic rhinitis) or skin allergies; scleracierma; mycosis fungoides; acute inflammatory reactions (such as acute respiratory distress syndrome and deficiency) Blood-reperfusion injury); dermatomyositis; alopecia areata; chronic actinic dermatitis, eczema, Behcet's disease, palmar impetigo, gangrenous pyoderma, Sezary's syndrome, ectopic Dermatitis, scleroderma. Skin disease is the change of the shape, structure and function of skin (including hair and nail) after internal and external factors, resulting in pathological processes, and correspondingly producing various clinical manifestations. It is a common disease that seriously affects people's health. One of the onset, such as leprosy, acne, fungal disease, psoriasis, skin bacterial infections. The incidence of skin diseases is very high, most of them are light, and often do not affect health (but a few are heavier or even life-threatening), but seriously affect the appearance of patients, which brings a heavy psychological burden to patients, which in turn affects patients' daily work. With life.

Among them, psoriasis, also known as "psoriasis", is a common immune-mediated chronic inflammatory skin disease. Its clinical manifestations are characterized by intractability and recurrence. The incidence rate is about 2% in the West and about 0.5% in Asia. But in recent years, it has grown rapidly. According to reports, the global market for psoriasis treatment drugs will reach $9.02 billion in 2019. Psoriasis has various forms of skin lesions, and is often classified into psoriasis vulgaris, erythrodermic psoriasis, pustular psoriasis, and arthritic psoriasis. Of these, the majority (>85%) were patients with vulgaris. Psoriasis can interfere with the patient's daily life and quality of life in addition to causing itching, bleeding and other discomforts in the lesion. Among them, erythrodermic psoriasis and pustular psoriasis can cause systemic metabolic disorders, complications such as cardiovascular and lung diseases, and infections, which are life-threatening.

Early studies suggest that the pathological mechanism of psoriasis is mainly the abnormality of epidermal hyperplasia and the activation of the immune system. The treatment of psoriasis is mainly based on the severity of the disease and the classification of psoriasis using external medicine, phototherapy and systemic administration. Nearly 90% of patients with psoriasis are mild to moderate; first-line treatments for mild to moderate psoriasis vulgaris are mostly topical drugs, usually including keratinolytic agents, vitamin D analogues, corticosteroids, and terpene , coal tar, external vitamin A acid. In 2008, the guidelines for the treatment of psoriasis in China included tazarotene (retinoic acid), intermediate-effect and potent glucocorticoids, and calcipotriol (VitD3 derivatives) as the recommended drugs for topical treatment. However, long-term use of corticosteroids can cause side effects such as skin atrophy, telangiectasia, folliculitis, hyperpigmentation or regression. Large-scale long-term application of potent glucocorticoid preparations can cause systemic reactions, and even induce pustular or erythrodermic psoriasis after stopping the drug. Vitamin A acid has skin mucous membrane irritation, especially in patients with allergies. The more common side effects of calcipotriol are pruritus, skin irritation, burning sensation, tingling, dry skin, erythema and rash, and have a certain effect on calcium metabolism. Therefore, although there are many methods to choose from, the drugs for treating psoriasis usually have limited efficacy, and long-term use has many toxicity and side effects, which cannot meet the needs of long-term effective treatment. For example, the occurrence and aggravation of erythrodermic psoriasis and pustular psoriasis, except for some unknown causes, is due to improper treatment.

Summary of the invention

The present application relates to a novel crystalline form of phenenimo (i.e., a compound of formula I), a pharmaceutical composition containing the novel crystalline form, a pharmaceutical use of the novel crystalline form and pharmaceutical composition, and a process for the preparation of a novel crystalline form.

In one aspect, the application provides Form I of phenenimod.

In some embodiments, the X-ray powder diffraction pattern of phenenyl Form I has characteristic peaks with diffraction angles 2θ of 15.0°, 19.0°, 20.1°, 21.4°, 22.3°, and 24.4°±0.2°.

In other embodiments, the X-ray powder diffraction pattern of phenenyl form I has diffraction angles 2θ of 15.0°, 17.8°, 19.0°, 20.1°, 21.4°, 22.3°, 24.4°, 26.2°, and Characteristic peak at 27.8 ° ± 0.2 °.

In other embodiments, the phenenyl form I has an X-ray powder diffraction pattern as shown in FIG.

In another aspect, the present application provides Form II of phenenimod.

In some embodiments, the X-ray powder diffraction pattern of phenenyl Form II has characteristic peaks with diffraction angles 2θ of 7.2°, 14.5°, 18.0°, 19.8°, 22.0°, and 23.5°±0.2°.

In other embodiments, the X-ray powder diffraction pattern of phenenyl form II has diffraction angles 2θ of 7.2°, 14.5°, 18.0°, 18.7°, 19.8°, 21.4°, 22.0°, 23.5°, and Characteristic peak of 27.6 ° ± 0.2 °.

In other embodiments, phenenyl Form II has an X-ray powder diffraction pattern as shown in FIG.

In another aspect, the present application provides Form III of phenenimod.

In some embodiments, the X-ray powder diffraction pattern of phenenyl Form III has characteristic peaks with diffraction angles 2θ of 5.8°, 11.5°, 12.5°, 14.1°, 16.0°, and 17.3°±0.2°.

In other embodiments, the X-ray powder diffraction pattern of phenenyl form III has diffraction angles 2θ of 5.8°, 11.5°, 12.5°, 14.1°, 16.0°, 16.8°, 17.3°, 19.1°, and Characteristic peak of 28.4 ° ± 0.2 °.

In other embodiments, phenenyl Form III has an X-ray powder diffraction pattern as shown in FIG.

In another aspect, the present application provides Form IV of phenenimod.

In some embodiments, the X-ray powder diffraction pattern of phenenyl Form IV has characteristic peaks with diffraction angles 2θ of 12.1°, 13.3°, 16.0°, 20.0°, 24.3°, and 27.1°±0.2°.

In other embodiments, the X-ray powder diffraction pattern of phenenyl Form IV has diffraction angles 2θ of 12.1°, 13.3°, 16.0°, 20.0°, 20.9°, 22.6°, 24.3°, 25.4°, and Characteristic peak of 27.1 ° ± 0.2 °.

In other embodiments, the phenenimomorph Form IV has an X-ray powder diffraction pattern as shown in FIG.

The present application further provides a pharmaceutical composition comprising a therapeutically effective amount of phenenyl Form I, II, III and/or IV and a pharmaceutically acceptable inactive ingredient.

In some embodiments, the purity of phenenyl Form I, II, III, and/or IV in the pharmaceutical composition is > 85% by mass.

In other embodiments, the purity of phenenyl Form I, II, III, and/or IV in the pharmaceutical composition is > 95% by mass.

In other embodiments, the purity of the phenenyl form I, II, III, and / or IV in the pharmaceutical composition is ≥ 99% by mass.

In other embodiments, the purity of phenenyl Form I, II, III, and/or IV in the pharmaceutical composition is > 99.5% by mass.

In some embodiments, the pharmaceutical composition comprises from 0.01% to 99% by mass of the crystalline form of the compound of Formula I. For example, the pharmaceutical composition comprises from 0.5% by mass to 90% by mass of a crystalline form of the compound of Formula I; the pharmaceutical composition comprising from 1.0% by mass to 80% by mass of a crystalline form of the compound of Formula I; The pharmaceutical composition comprises from 1.5% by mass to 70% by mass of a crystalline form of the compound of formula I; said pharmaceutical composition comprising from 3% by mass to 60% by mass of a crystalline form of the compound of formula I; the pharmaceutical composition comprising 4 masses % to 55% by mass of a crystalline form of the compound of formula I; the pharmaceutical composition comprising from 5% by mass to 50% by mass of a crystalline form of the compound of formula I; said pharmaceutical composition comprising from 7.5% by mass to 40% by mass a crystalline form of the compound of formula I; the pharmaceutical composition comprising 10% by mass to 30% by mass of the crystalline form of the compound of formula I.

In other embodiments, the pharmaceutical composition further comprises at least one other active ingredient.

In other embodiments, the pharmaceutical composition is suitable for topical administration (topical administration includes topical administration).

In other embodiments, the pharmaceutical composition is an ointment.

In other embodiments, the pharmaceutical composition is a cream.

In other embodiments, the pharmaceutical composition is a gel.

In other embodiments, the gelling agent is a clear gelling agent.

The present application also provides the use of the above phenenic mood crystal form or a pharmaceutical composition thereof for the preparation of a medicament for the treatment of an autoimmune disease, an inflammatory and a cell-diffusing disease.

As reported in the scientific literature and patents, compounds having immunomodulatory activity are related diseases that can be used to treat animals and humans. Compounds having immunomodulatory activity, such as the phenenable crystal form of the compound disclosed herein, can be used as an active ingredient in medicines to treat diseases associated with immunomodulatory activity, such as: rejection of clinical transplants (including organs) Transplantation, acute transplantation, allogeneic transplantation and allogeneic transplantation, such as in the treatment of burns, to avoid ischemic or reperfusion injury, such as ischemic and multiple perfusion injuries caused by organ transplantation, can also treat urgency Infarction, stroke or other diseases; induction of transplant tolerance, treatment of arthritis (such as rheumatoid arthritis, psoriatic arthritis, osteoarthritis); multiple sclerosis, inflammatory bowel disease, including ulcerative colitis and Crohn's Disease; lupus (systemic lupus erythematosus); graft versus host disease; T cell hypersensitivity, including contact hypersensitivity, delayed hypersensitivity, gluten allergic bowel disease (gluten allergy), psoriasis, Contact dermatitis (including caused by poison ivy), Hashimoto's thyroiditis, Sjogren's syndrome, autoimmune hyperthyroidism, such as Grave's disease, Addison's disease, adrenal gland Immune disease, polygland autoimmune syndrome, immune alopecia, pernicious anemia, vitiligo, immune hypopituitarism, Guillain-Barre syndrome, and other immune diseases such as glomerulonephritis, serum Disease, urticaria, and allergic diseases such as respiratory allergic diseases (asthma, hay fever, allergic rhinitis) or skin allergies; scleracierma; mycosis fungoides; acute inflammatory reactions (such as acute respiratory distress syndrome and deficiency) Blood-reperfusion injury); dermatomyositis; alopecia areata; chronic actinic dermatitis, eczema, Behcet's disease, palmar impetigo, gangrenous pyoderma, Sezary's syndrome, ectopic Dermatitis, scleroderma, acne and rosacea. In some embodiments, the autoimmune disease is a tissue hyperproliferative disease, colitis, or an allergic disease.

In other embodiments, the tissue hyperproliferative disorder is a skin disease or a skin tumor and a complication thereof; the colitis is hypersensitivity colitis.

In other embodiments, the skin condition comprises psoriasis, scleroderma, and/or eczema.

In other embodiments, the psoriasis is mild to moderate psoriasis or psoriasis vulgaris.

The present application further provides phenenic moore crystal form I, II, III and/or IV and the above pharmaceutical composition for inhibiting the overexpression of interleukin-2, interleukin-13, interleukin-17 and/or tumor necrosis factor, Or used to inhibit the activation and migration of T cells, or tumors associated with cell proliferation.

The present application still further provides a method of treating an autoimmune disease in a mammal comprising administering to a patient having an autoimmune disease a therapeutically effective amount of phenenyl Form I, II, III and/or IV or The above pharmaceutical composition. The present application still further provides a method of treating a tissue hyperproliferative disorder in a mammal comprising administering a therapeutically effective amount of phenenyl Form I, II, III and/or IV to a patient suffering from a tissue hyperproliferative disorder. Or the above pharmaceutical composition.

In some embodiments, the autoimmune disease comprises a tissue hyperproliferative disorder, colitis or an allergic disease. The colitis is allergic colitis.

In some embodiments, the tissue hyperproliferative disorder is a skin disease or a skin tumor and a complication thereof.

In other embodiments, the skin disorder is psoriasis, scleroderma, and/or eczema.

In other embodiments, the psoriasis is mild to moderate psoriasis or psoriasis vulgaris.

In other embodiments, the mammal is a human.

The application also provides a method of preparing phenenyl form I, the method comprising:

a) the compound of the formula I is dissolved in a positive solvent to prepare a saturated solution in the container A, and then 5 to 15 times the positive solvent volume of the anti-solvent is added to the other container B; after that, the container A is opened. The container B is allowed to stand at room temperature until the crystal is precipitated and the container B is sealed; wherein the positive solvent is ethanol, acetonitrile, ethyl acetate or methyl tert-butyl ether, and the anti-solvent is water or n-heptane. ;or

b) at room temperature, the compound of formula I is dissolved in a solvent or a mixed solvent to prepare a supersaturated solution, then heated to 30 to 70 ° C and stirred for 0.2-1 hours, filtered and cooled to 5 ° C or below. Crystallizing, wherein the solvent is a methanol/water mixture, especially a mixed solvent having a volume ratio of 1:1; or

c) at room temperature, the compound of formula I is dissolved in a solvent or a mixed solvent to prepare a supersaturated solution, then heated to 30 to 70 ° C and stirred for 0.2-1 hours, filtered and cooled to 5 ° C or below. And then, at room temperature, the solid is volatilized, wherein the solvent is a single solvent such as toluene or chloroform, or acetonitrile/water, isopropanol/n-hexane, ethyl acetate/n-heptane, 2-methyltetrahydrofuran/positive a mixture of heptane, or a mixture of 1,4 dioxane/n-heptane, especially a mixed solvent, having a volume ratio of 1:1;

d) the compound of the formula I is dissolved in a solvent or a mixed solvent to prepare a saturated solution, filtered into a new container to obtain a clear solution, and left to volatilize at room temperature, wherein the solvent is ethanol, isopropanol, Acetonitrile, ethyl acetate, or a mixed solvent of acetonitrile/water, 1,4 dioxane/water or isopropyl acetate/n-heptane, especially a mixed solvent having a volume ratio of 1:1;

e) the compound of the formula I is dissolved in a positive solvent to obtain a saturated solution, and the clear solution is filtered, and the anti-solvent is added until a solid precipitates; if the anti-solvent is added up to 25 times the volume, no solid precipitates, and the temperature is slowly set at room temperature. Volatilization and crystallization; when the positive solvent is methanol, ethanol or acetone, the anti-solvent is water, and when the positive solvent is toluene, chloroform, ethyl acetate or methyl tert-butyl ether, the anti-solvent is n-heptane;

f) a compound of the formula I is dissolved in a solvent/mixing solvent to prepare a saturated clear solution, and 10-30% of the mass of the compound of the formula I is added to the mixed polymer A, namely polyvinylpyrrolidone, polyethylene. Alcohol, polyvinyl chloride, polyvinyl acetate, a mixture of hydroxypropylmethylcellulose and methylcellulose, especially an equal mass mixture, or a blend of high polymer B, ie polycaprolactone, polyethylene glycol, Polymethyl methacrylate, a mixture of sodium alginate and hydroxyethyl cellulose, especially an equal mass mixture; or an aqueous solution of methyl cellulose or an aqueous solution of polyvinyl alcohol in a clear solution, which is volatilized at room temperature (test Be protected from light).

The method for preparing phenenyl form II provided by the present application includes:

a) the compound of the formula I or the form I is dissolved in the normal solvent tetrahydrofuran, or the toluene is prepared to obtain a saturated solution in the container A, and then 5 to 15 times the positive solvent volume of the anti-solvent n-heptane is added to the other Container B; then container A is placed in container B and allowed to stand at room temperature until crystals are precipitated and container B is sealed; or

b) at room temperature, the compound of Form I or Form I is dissolved in a mixed solvent to prepare a supersaturated solution, then heated to 30 to 70 ° C and stirred for 0.2-1 hours, filtered and cooled to 5 ° C or below. After standing and crystallization. The still clarified solution is slowly volatilized to precipitate a solid at room temperature, wherein the solvent is a mixture of tetrahydrofuran/water, especially a mixed solvent having a volume ratio of 1:1;

c) the compound of the formula I or the crystal form I is dissolved in a solvent or a mixed solvent to prepare a saturated solution, and filtered into a new container to obtain a clear solution, which is allowed to stand at room temperature for volatilization, wherein the solvent is methanol. Tetrahydrofuran, or a mixed solvent of dichloromethane/n-heptane, or methanol/water, especially a mixed solvent having a volume ratio of 1:1; or

d) a compound of the formula I or the form I is dissolved in a positive solvent to obtain a saturated solution, and a clear solution is obtained by filtration, and an anti-solvent is added until a solid precipitates; if an anti-solvent as high as 25 times by volume is added, no solid precipitates, Place slowly at room temperature to slowly crystallization, or first place the solution at 5 ° C or below, stir overnight, and then slowly devitrify and leave at room temperature; when the positive solvent is isopropanol, acetonitrile or tetrahydrofuran, the anti-solvent is water; When the positive solvent is isopropyl acetate, 1,4-dioxane, tetrahydrofuran or toluene, the anti-solvent is n-heptane;

e) a compound of the formula I or the form I is dissolved in tetrahydrofuran to prepare a saturated clear solution, and an amorphous liquid of the formula I or a 10-30% by mass of the crystalline form I [Bmim] PF6 (1) is added. -butyl-3-methylimidazolium hexafluorophosphate), which was crystallized at room temperature.

The method for preparing phenenyl form III of the present application includes:

a) the compound of the formula I or the crystal form I is dissolved in a mixed solvent to prepare a saturated solution, filtered into a new container to obtain a clear solution, and left to volatilize and crystallize at room temperature, wherein the mixed solvent is methyl unbranched Butyl ether/n-heptane, especially a mixed solvent having a volume ratio of 1:1; or

b) a compound of formula I or crystal form I is dissolved in methyl tert-butyl ether to prepare a clear solution, and then slowly crystallized at room temperature;

c) a compound of the formula I or the form I is dissolved in dimethyl sulfoxide (DMSO), filtered to obtain a clear solution, and the anti-solvent water is added to the transparent solution until a solid precipitates;

d) A compound of the formula I or the crystal form I is dissolved in methyl tert-butyl ether to prepare a clear solution, and the solution is placed at 5 ° C or below and stirred overnight, then left to slowly evaporate at room temperature, and then slowly at room temperature. Volatile crystals.

The method for preparing phenenyl form IV provided by the present application includes:

a) Form I is added to a mixed solvent of acetone/water to prepare a suspension of 20-30 mg/ml, and the suspension is heated to 40-60 ° C under stirring, especially about 50 ° C, 0.2 to 1 hour, and filtered. Preparing a clear solution in a new container, and after the solution is cooled to 5 ° C or below, the solution is allowed to stand at room temperature for volatilization; or

b) the compound of the formula I or the crystal form I is dissolved in chloroform or acetone, filtered to obtain a clear solution, and then the crystal is slowly evaporated at room temperature;

c) Form I is added to acetone / n-heptane, or a mixed solvent of acetonitrile / water, especially a volume ratio of 1:4, formulated into a 10-20mg / ml turbid liquid, the turbid liquid is stirred at room temperature (test Obtaining a light treatment after 1 to 3 days; or

d) The compound of the formula I or the crystalline form I is dissolved in chloroform, filtered to obtain a clear solution, and the anti-solvent n-heptane is added to the transparent solution until a solid precipitates.

The purity of phenenyl Form I, Form II, Form III or Form IV provided herein is ≥85%, ≥95%, or even ≥99% or 99.5%.

The crystalline forms disclosed herein may be crystallized from a suitable solvent system containing at least one solvent, by solvent evaporation, cooling, and/or by the addition of an anti-solvent (the solvent of the phenenimod solubility described herein is less soluble) ), achieving supersaturation in a solvent system.

As disclosed herein, crystals may or may not be seeded.

The crystallization of the unique crystalline form disclosed herein is related to the kinetics and equilibrium properties of the crystallization process under specific conditions. Thus, those skilled in the art will appreciate that the resulting crystalline form depends on the kinetics and thermodynamics of the crystallization process. Under certain conditions (eg, solvent, temperature, pressure, and concentration of the compound of the present application), one crystal form may be more stable (or indeed more stable than any other crystal form) than another crystal form. However, crystal forms with relatively low thermodynamic stability may be kinetically advantageous. Therefore, factors other than kinetics, such as time, impurity distribution, agitation, presence or absence of seed crystals, etc., may also affect the form of crystallization.

In another aspect, the application provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the above-described phenenyl crystal forms and at least one pharmaceutically acceptable inactive ingredient.

The term "therapeutically effective amount" refers to an amount of a compound which, when used in the treatment of a subject, is sufficient to affect such treatment of a disease, disorder or condition for the treatment of a disease, or at least one clinical condition of a disease or condition. A "therapeutically effective amount" can be a compound, a disease, a condition, and/or a symptom of a disease or condition, a disease, a condition, and/or a severity of a symptom of the disease or condition, the age of the patient being treated, and/or treated The patient's weight changes and so on. Wherever possible, a suitable dosage will be apparent to those skilled in the art and may be determined by routine experimentation. In the context of combination therapy, "therapeutically effective amount" refers to the total amount of a combination of subjects effective to treat a disease, disorder or condition.

The "pharmaceutically acceptable inactive ingredient" refers to a conventional pharmaceutically acceptable inactive ingredient suitable for the desired pharmaceutical preparation. For example: diluents such as water, various organic solvents, etc.; fillers such as starch, sucrose, etc.; binders such as cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone (PVP); humectants such as glycerin Disintegrants such as agar, calcium carbonate and sodium bicarbonate; such as quaternary ammonium compound absorption enhancers; surfactants such as cetyl alcohol; absorption carriers such as kaolin and soap clay; such as talc, calcium stearate , lubricants such as magnesium stearate and polyethylene glycol. In addition, other pharmaceutically acceptable inactive ingredients such as dispersing agents, stabilizers, thickeners, complexing agents, buffers, penetration enhancers, polymers, fragrances, sweeteners, and the like may also be added to the pharmaceutical compositions. dye. It is preferred to use an inactive ingredient suitable for the desired dosage form and the desired mode of administration.

The present application also provides a pharmaceutical composition comprising at least one compound of formula I capable of treating the above conditions in an effective amount and a pharmaceutically acceptable carrier or diluent. The compositions of the present application may contain other agents well known to those skilled in the art, possibly by the use of conventional solid or liquid carriers or diluents, and a class of pharmaceutical additives suitable for the desired mode of administration (e.g., shaping) Agents, binders, preservatives, stabilizers, flavoring agents, and the like) are formulated according to procedures well known in the art of pharmaceutical formulation.

The pharmaceutical compositions of the present application containing the active ingredient may be in a form suitable for systemic, oral, and/or topical use. For example, the pharmaceutical composition may be in the form of a sterile injectable aqueous solution or a oleaginous suspension. This suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are usually employed as a solvent or suspending medium. Any mild fixed oil may be used for this purpose, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

For the administration of the drug for rectal administration, the compound of the formula I can also be formulated in the form of a suppository. These compositions can be prepared by admixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and thus melts in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycol.

For oral administration, the preparation may be in the form of a tablet, a lozenge, a lozenge, an aqueous solution or an oily suspension, a dispersible powder or granule, an emulsion, a hard or soft capsule, or a syrup or elixir. Compositions for oral use can be prepared according to any method known in the art for preparing pharmaceutical compositions. The tablet contains a mixture of the active ingredient and a non-toxic pharmaceutically acceptable excipient suitable for the manufacture of tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gels Or gum arabic, as well as lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or may be coated for prolonged disintegration and absorption in the gastrointestinal tract by known techniques and thereby provide a relatively long duration of action. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.

The pharmaceutical compositions of the present application may also be in the form of an oil-in-water emulsifier. The oil phase can be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture of these. Suitable emulsifiers may be naturally occurring phospholipids, such as soy, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and the partial esters and ethylene oxide. Condensation products such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents. Syrups and elixirs can be prepared with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such preparations may also contain demulcents, preservatives, and flavoring and coloring agents.

For topical use, creams, ointments, gels, solutions or suspensions containing the compound of formula I, etc. may be used (for topical purposes, topical administration includes not only topical administration, but also mouthwash and gargle The mode of administration of the agent). The preparation of such topical formulations has been well described in pharmaceutical formulations in the art, for example in Remington's Pharmaceutical Science, 17th Edition, Mack Press, Easton, PA. For topical administration, these compounds may also be administered in the form of a powder or spray, especially in the form of an aerosol.

Dosage levels of from about 0.01 mg to about 140 mg per kilogram of body weight per day are effective for treating the conditions indicated above, or each patient can be administered from about 0.5 mg to about 7 grams per day. For example, administration of the present compound in an amount of from about 0.01 to 50 mg per kilogram of body weight per day, or from about 0.5 mg to about 3.5 g per patient per day, preferably from 2.5 mg to 1 gram per patient per day, can effectively treat inflammation. It will be understood, however, that a particular dosage level for a particular patient will depend on a number of factors, including age, weight, general state of health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and specific disease being treated. The severity of the situation.

The amount of active ingredient combined with the carrier materials to produce a single dosage form will vary depending upon the subject being treated and the particular mode of administration. For example, a human oral formulation may contain from 0.5 mg to 5 grams of active agent and is mixed with a suitable amount of carrier in an amount of from about 5 to about 95% of the total composition. The dosage unit form will generally contain from about 1 mg to about 500 mg of the active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

Diffusion In some embodiments, suitable pharmaceutically inactive ingredients are selected from the group consisting of water, various organic solvents, and various inert diluents or fillers. The pharmaceutical composition may contain one or more additives such as perfumes, binders and excipients, if desired. For oral administration, the tablet may comprise at least one inactive ingredient selected from, for example, citric acid; various decomposing agents such as starch, alginic acid and certain complex silicates; various such as sucrose, gelatin and gum arabic Adhesive. In addition, lubricants such as magnesium stearate and talc are commonly used in the manufacture of fillers for tablets. These ingredients can also be filled in soft and hard gelatin capsules. When used orally and in the case of an aqueous suspension, the active compound may be mixed with at least one ingredient selected from the group consisting of various sweeteners or flavoring agents, pigments or dyes. Various emulsifiers or suspending agents can be used if desired; diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof can also be used.

In some embodiments, the pharmaceutical composition further comprises at least one other active ingredient.

A pharmaceutical composition comprising a crystalline form of the present application can be administered to a patient in need of treatment by transdermal administration or topical administration. When administered transdermally, the pharmaceutical composition can be formulated into a dosage form such as a cream or a gel.

In some embodiments, the pharmaceutical composition can be administered in the form of a topical application such as a cream, cream or ointment.

In some embodiments, the pharmaceutical compositions of the present application can be prepared by conventional methods in the pharmaceutical arts. For example, the active ingredient is combined with one or more inactive ingredients which are then brought into the preparations required.

The main characteristic peaks of the above crystal forms are reproducible and within the margin of error (i.e., the value is ± 0.2°).

In the present application, "having an X-ray powder diffraction pattern as shown in FIG. 1" means that the main peak shown by the X-ray powder diffraction pattern is as shown in FIG. 1, wherein the main peak is the highest in FIG. The peaks, whose relative intensities are set at 100%, have a relative intensity of more than 10%, preferably more than 30%. Similarly, in the present application, there is an X-ray powder diffraction pattern as shown in FIG. 2, FIG. 3 or FIG. 4, which respectively means that the main peaks shown by the X-ray diffraction pattern are as shown in FIG. 2, FIG. 3 and FIG. The main peaks are those in which the relative intensity exceeds 10%, preferably exceeds 30%, as compared with the highest peaks in Figures 2, 3 and 4 (the relative intensity is set at 100%).

DRAWINGS

Figure 1: X-ray powder diffraction pattern of Form I of the compound of Formula I;

Figure 2: X-ray powder diffraction pattern of Form II of the compound of Formula I;

Figure 3: X-ray powder diffraction pattern of Form III of the compound of Formula I;

Figure 4: X-ray powder diffraction pattern of Form IV of the compound of Formula I;

Detailed ways

This application is further illustrated by, but not limited to, the following examples. The techniques or methods used in these examples, unless otherwise indicated, are conventional techniques or methods in the art.

The XRPD reflection pattern was acquired on a PANalytacal Empyrean (CPE-026) and X'Pert3 (CPE-135) X-ray powder diffraction analyzer, and the transmission parameters were collected on a PANalytacal Empyrean (CPE-026) X-ray powder diffraction analyzer. As shown in Table 1.

Table 1

Example 1. Preparation of Form I

Preparation method of crystal form I

About 15 mg of the amorphous form of the compound of formula I (abbreviated as the starting material) was dissolved in the corresponding positive solvent in Table 1-1 to prepare a saturated solution, and filtered into a 3 ml vial to prepare a clear liquid. Add 4.0 ml of anti-solvent to the 20 ml vial (as shown in Table 1-1), place the 3 ml vial containing the clear solution in a 20 ml vial, seal the 20 ml vial and let stand at room temperature. (The test is protected from light and charged with N ₂ protection). All observed solids were separated and analyzed by XRPD and confirmed to be all Form I. The clear liquid in which no solid was precipitated was slowly devitrified and crystallized at room temperature, and the obtained solid was analyzed by XRPD to confirm that it was all in Form I. In particular, Form I with "*" is produced by slow volatilization under a greenhouse.

Table 1-1

Preparation method 2 of crystal form I

About 25 mg of the compound of the formula I (abbreviated as raw material) in a 3 ml vial at room temperature was added to 1.0 ml of the corresponding solvent or mixed solvent in Table 1-2 to prepare a supersaturated suspension. After the suspension was heated to 50 ° C and stirred for 0.5 hours, it was filtered into a new vial to obtain a clear solution. After the temperature was lowered to 5 ° C, the solution was placed in a biological incubator at a constant temperature of 5 ° C (tested to be protected from light). Crystallization was carried out to separate all precipitated solids. The clear liquid which still had no solid precipitation was slowly volatilized to precipitate a solid at room temperature and the resulting solid was separated. It was confirmed by XRPD analysis that it was all Form I. In particular, Form I with "*" is produced by slow volatilization under a greenhouse.

Table 1-2

Preparation method 3 of crystal form I

About 15 mg of the compound of the formula I (abbreviated as raw material) into a 3 ml vial, dissolved in 1.0 to 1.5 mL of the solvent or mixed solvent in Tables 1-3 to prepare a saturated solution, and filtered to a new vial. A clear solution was prepared, and the vial containing the clear solution was sealed with a sealing film and 5 to 6 small holes were placed thereon, and then slowly volatilized at room temperature (tested to be protected from light). The obtained solids were separately collected, and confirmed to be crystal form I by XRPD analysis.

Table 1-3

Raw material quality (mg)	Solvent, V: V	Solvent volume (ml)	Crystal form
15.0	Ethanol	1.0	Crystal form I
15.0	Isopropanol	1.0	Crystal form I
14.8	Acetonitrile/water, 1:1	1.5	Crystal form I
14.8	1,4 dioxane / water, 1:1	1.0	Crystal form I
15.1	Isopropyl acetate / n-heptane, 1:1	1.0	Crystal form I

Preparation method 4 of crystal form I

About 15 mg of the compound of the formula I (abbreviated as raw material) into a 3 ml vial, dissolved in 1.0 mL of the solvent in Table 1-4 to prepare a solution, filtered into a new vial to prepare a clear solution, and placed open. Volatile at room temperature (tested as protected from light). The obtained solids were separated and analyzed by XRPD to confirm that they were all crystal form I.

Table 1-4

Raw material quality (mg)	Solvent	Solvent volume (ml)	Crystal form
14.9	Acetonitrile	1.0	Crystal form I
14.9	Ethyl acetate	1.0	Crystal form I

Preparation method of crystal form I

About 20 mg of the amorphous form of the compound of formula I (abbreviated as raw material) was placed in a 3 ml vial, dissolved in a suitable amount of the positive solvent in Tables 1-5 and filtered to a 20 ml vial, and then added to the clear solution. The solvent was stirred while dropping until a solid precipitated, and the precipitated solid was separated and confirmed by XRPD analysis. If no solid precipitated after adding 10.0 ml of the anti-solvent, the clear liquid was allowed to stand at room temperature and slowly volatilized (tested to be protected from light). The obtained solids were separately collected, and confirmed to be crystal form I by XRPD analysis. In particular, Form I with "*" is produced by slow volatilization under a greenhouse.

Table 1-5

Preparation method of crystal form I

15 mg of the amorphous form of the compound of formula I (abbreviated as the starting material) is dissolved in the corresponding solvent/mixing solvent of Table 1-6 to prepare a clear solution, and about 2.0 mg of the mixed polymer A (polyvinylpyrrolidone, polyvinyl alcohol) is added. , polyvinyl chloride, polyvinyl acetate, hydroxypropyl methylcellulose and methyl cellulose, etc., mixed with high polymer B (polycaprolactone, polyethylene glycol, polymethyl methacrylate) , a mixture of sodium alginate and hydroxyethyl cellulose, or 0.5 ml of water-soluble polymer 1 (methylcellulose aqueous solution, 5 mg/ml), water-soluble polymer 2 (98% hydrolyzed polyethylene) An aqueous alcohol solution (5 mg/ml) was added to the clear solution, and the vial was sealed with a parafilm and 5 to 6 small holes were placed thereon, and volatilized at room temperature (tested to be protected from light). The obtained solids were separately collected and analyzed by XRPD to confirm that they were all crystal form I.

Table 1-6

Preparation method of crystal form I

At room temperature, about 15 mg of the amorphous form of the compound of formula I (abbreviated as raw material) into a 3 ml vial, dissolved in the corresponding positive solvent in Table 1-7, and the resulting clear solution was added in one portion to the corresponding antisolvent containing 4.0 ml. The 20 ml vial was stirred for 5 minutes and the resulting solid was isolated. If no solids are precipitated, the clear liquid is slowly volatilized at room temperature (tested to be protected from light). The obtained solids were separately collected and analyzed by XRPD to confirm that they were all in Form I. In particular, Form I with "*" is produced by slow volatilization under a greenhouse.

Table 1-7

Example 2. Preparation of Form II

Method 1 for preparing Form II

Two 14.9 mg of Form I were dissolved in 0.4 ml of tetrahydrofuran and 1 ml of toluene, respectively, and the supernatant was separately filtered, and transferred to a 3 ml vial. Take two 20 ml vials, add 4.0 ml of n-heptane, place the two 3 ml vials containing the supernatant in two 20 ml vials, seal the 20 ml vial and incubate at room temperature. Let it sit still (protected from light and charged with N ₂ ) for one day. The clear liquid was then transferred to room temperature and slowly volatilized. The obtained solid was collected and analyzed by XRPD to confirm that it was all crystal form II.

Preparation method 2 of crystal form II

Weigh 25.1 mg of Form I in a 3 ml vial, add 1.0 ml of a mixed solvent (tetrahydrofuran / water, v / v = 1:1), stir at 50 ° C for about 0.5 hours, then filter the supernatant, The obtained supernatant was slowly volatilized and crystallized at room temperature, and the obtained solid was analyzed by XRPD to confirm that it was all crystal form II.

Preparation method 3 of crystal form II

About 15 mg of Form I is dissolved in 1.0 to 1.5 mL of the solvent or mixed solvent listed in Table 2-1, filtered to obtain a clear liquid, and the vial containing the clear solution is sealed and 5 small holes are placed in the seal. Place at room temperature and slowly evaporate (test as a light-proof treatment). The obtained solids were separately collected and analyzed by XRPD to confirm that they were all crystal form II.

table 2-1

Form I sample quality (mg)	Solvent, v:v	Solvent volume (ml)	Crystal form
15.1	Methanol	1.0	Form II
15.3	Tetrahydrofuran	1.0	Form II
15.0	Dichloromethane/n-heptane, 1:1	1.5	Form II

Method 4 for preparing Form II

About 15 mg of Form I was dissolved in 1 ml of the solvent or mixed solvent listed in Table 2-2, and filtered to obtain a clear liquid. The open place was quickly volatilized at room temperature (tested to be protected from light). The obtained solids were separately collected and analyzed by XRPD to confirm that they were all crystal form II.

Table 2-2

Preparation method of crystal form II

At room temperature, about 20 mg of Form I was dissolved in 0.4 ml of the solvent listed in Table 2-3 and filtered into a 20 ml vial. After adding the anti-solvent, the mixture was stirred while stirring until solid precipitation or anti-solvent. The volume was 10.0 ml. If no solid precipitated, the clear liquid was stirred at 5 ° C overnight. If no solid precipitated, the clear liquid was allowed to stand at room temperature and slowly volatilized (tested to be protected from light). The obtained solids were separately collected and analyzed by XRPD to confirm that they were all crystal form II. In particular, Form II with "*" in it is obtained by slowly volatilizing and crystallizing at room temperature.

Table 2-3

Form I sample quality (mg)	Solvent	Antisolvent	Antisolvent volume (ml)	Crystal form
20.2	Isopropanol	water	1.8	Form II
20.0	Acetonitrile	water	1.0	Form II
19.9	Tetrahydrofuran	water	0.8	Form II
20.3	Isopropyl acetate	Positive alkane	10.0	Crystal II*
19.9	1,4-dioxane	Positive alkane	10.0	Crystal II*

Method 6 for preparing Form II

15.2 mg of Form I was dissolved in 1.0 ml of tetrahydrofuran to prepare a clear solution in a 3-mL glass vial. Then, 0.5 ml of an aqueous solution of polyethylene oxide (5.0 mg/ml) was added to the clear solution and allowed to stand at room temperature. Volatilize (protected from light). The obtained solid was collected and analyzed by XRPD to confirm crystal form II.

Preparation method of crystal form II

15.2 mg of Form I was dissolved in 1 mL of tetrahydrofuran to prepare a clear solution in a 3-mL glass vial, and 2.5 mg of ionic liquid [Bmim]PF6 (1-butyl-3-methylimidazolium hexafluorophosphate) was added to seal The vial was immersed in 5 to 6 small holes on the parafilm, and volatilized at room temperature (tested as a light-proof treatment), and the obtained solid was collected, and confirmed to be Form II by XRPD analysis.

Preparation method of crystal form II

At room temperature, 15.1 mg of Form I was dissolved in 0.4 mL of tetrahydrofuran to prepare a clear solution in a 3-mL glass vial. The resulting clear solution was added in one portion to a 20 ml vial containing 4.0 ml of water (anti-solvent) and stirred for about 5 minutes. If no solid precipitated, the clear liquid was stirred at 5 ° C overnight, and then the clear solution was slowly evaporated at room temperature ( The obtained solid was collected and protected by XRPD and identified as Form II.

Example 3 Preparation of Form III

Preparation method of crystal form III

200.6 mg of Form I was dissolved in 4.0 ml of methyl tert-butyl ether/n-heptane (v/v, 1:1), filtered into a vial to obtain a clear solution, the vial of the vial was sealed and sealed on the seal. Five small holes were then slowly evaporated at room temperature (tested as protected from light). The obtained solid was collected and confirmed to be crystal form III by XRPD analysis.

Preparation method 2 of crystal form III

15.1 mg of Form I was dissolved in 1.0 ml of mixed solvent methyl tert-butyl ether/n-heptane (v/v, 1:1), filtered into a 3-mL glass vial to obtain a clear solution, and the vial was sealed. Mouth, and after 5 small holes, slowly volatilize at room temperature (protected from light). The obtained solid was collected and confirmed to be crystal form III by XRPD analysis.

Preparation method 3 of crystal form III

Weigh 14.9 mg of Form I sample in a 3 ml glass vial, add 4.0 ml of methyl tert-butyl ether to a 20 ml vial, and place the 3 ml vial in a 20 ml vial. Vial seal (tested to protect from light and protected by N2). After standing at room temperature for 7 days, the clear liquid was slowly volatilized at room temperature, and the obtained solid was collected and analyzed by XRPD to confirm crystal form III.

Preparation method 4 of crystal form III

At room temperature, 20.2 mg of Form I was dissolved in 0.4 ml of dimethyl sulfoxide (DMSO), and filtered to a 20 ml vial to prepare a clear solution. Water (anti-solvent) was added to the clear solution, and the side was added dropwise. The mixture was stirred until a solid precipitated (water volume: 0.4 ml), and the obtained solid was separated and analyzed by XRPD to confirm crystal form III.

Preparation method of crystal form III

A clear solution was prepared by dissolving 15.2 mg of Form I in 0.4 ml of methyl tert-butyl ether at room temperature. The clear solution was added to a 20 ml vial containing 4 ml of n-heptane (antisolvent) and stirred for about 5 minutes. The clear liquid was cooled to 5 ° C and stirred at 5 ° C overnight. The clear liquid was then slowly volatilized (protected from light) at room temperature, and the obtained solid was collected and analyzed by XRPD to confirm crystal form III.

Example 4. Preparation of Form IV

Method 1 for preparing Form IV

A suspension was prepared by adding 25.2 mg of Form I to 1.0 ml of a mixed solvent acetone/water (v/v, 1:1) at room temperature. The suspension was heated to 50 ° C and stirred for 0.5 hours, then filtered. The new vial produced a clear solution. The resulting clear solution was slowly cooled from 50 ° C to 5 ° C, and then slowly volatilized at room temperature, and the collected solid was analyzed by XRPD to confirm crystal form IV.

Method 2 for preparing Form IV

Two portions of 15.0 mg of Form I were dissolved in 1.0 mL of chloroform and acetone, respectively, and the resulting solution was separately filtered, and the vials containing the clear solution were separately sealed and 5 small holes were placed on the seal, and then slowly evaporated at room temperature. (The test is done in the dark). The obtained solids were separately collected, and analyzed by XRPD to confirm that they were all crystalline form IV.

Method 3 for preparing Form IV

About 20 mg of a crystal form I to 1.5 ml glass vial, 0.3 ml of the solvent listed in Table 4-1 was added, and the obtained turbid liquid was stirred at room temperature for 2 days (the test was protected from light and protected by N ₂ ), and the solid was separated. According to XRPD analysis, it was confirmed that all were Form IV.

Table 4-1

Form I quality (mg)	Solvent, V: V	Solvent volume (ml)	Crystal form
20.5	Acetonitrile / water, 1:4	0.3	Form IV
20.1	Acetone / n-heptane, 1:4	0.3	Form IV

Method 4 for preparing Form IV

19.8 mg of Form I was dissolved in 1.0 ml of chloroform and filtered into a 20 ml vial. Then, n-heptane (antisolvent) was added, and the mixture was stirred until a solid precipitated (a total of 4.6 mL of n-heptane) was separated and precipitated. The solid was confirmed to be Form IV by XRPD analysis.

Preparation method of crystal form IV

15.1 mg of the Form I sample was dissolved in 1.0 ml of acetone to obtain a clear solution, and 0.5 ml of an aqueous solution of hydroxyethylcellulose (5.0 mg/ml) was added, and the vial was sealed with a parafilm and 5 to 6 small pieces were placed thereon. The wells were volatilized at room temperature (tested to be protected from light). The obtained solid was separated and analyzed by XRPD to confirm crystal form IV.

Example 5. Solid state stability of phenenic moore crystal forms I, II, III and IV

An appropriate amount of the sample was weighed and left open for one week at 25 ° C / 60% RH and 40 ° C / 75% RH, while another set of samples was sealed at 80 ° C for 24 hours. The placed sample was characterized by XRPD and HPLC to detect changes in crystal form and purity. The test results are summarized in Table 2.

Table 2

H: hour; W: week, week; relative purity: the ratio of the purity of the crystal form to the purity of the original crystal form after the experiment X100.

*: HPLC results showed that new impurity peaks appeared at RRT = 0.41 (0.01%) and 1.33 (0.05%).

The results show that Form I has good physical and chemical stability under the selected test conditions.

Example 6. Equilibrium Solubility of Phenylene Mod Forms I, II, III and IV

About 10 mg of Form I and 2.0 ml of deionized water were added to a 4 ml centrifuge tube to prepare a suspension, and the resulting suspension was placed on a rotary incubator for mixing (25 rpm) and passed through a biochemical incubator. The control temperature is 25 °C. 0.8 ml of the suspension was weighed at 24 hours and 48 hours, and the solid was centrifuged (6000 rpm, 3 minutes), and the supernatant was taken to an HPLC vial for solubility test, and the solid was measured for XRPD. The test results are summarized in Table 3.

table 3

--: After the balance was observed for 24 hours, the crystal was observed, so no relevant data was collected;

N/A: No relevant data collected

The equilibrium solubility test results show that crystal forms II, III and IV have been crystallized at 24 hours. On the other hand, Form I showed no crystal transformation for 48 hours, and the dissolution values at 24 hours and 48 hours were similar, indicating that the equilibrium solubility of Form I in water at 25 ° C was about 0.019 mg / ml.

The above embodiments are merely illustrative of the specific embodiments of the present application, and the scope of the present application is subject to the claims, and is not limited to the specific embodiments described above. All equivalent substitutions or alterations made by those skilled in the art without departing from the scope of the present invention are also within the scope of the present application. Therefore, the gist and scope of the present application is not limited to the specific description herein.

All of the content disclosed in this application, including the abstract and the drawings, and all steps in any method or process disclosed, can be arbitrarily combined unless certain features and/or steps are mutually exclusive combinations. Each of the features disclosed in the present application, including the abstract and the drawings, may be replaced by alternative features that may achieve the same, equivalent or similar purpose, unless explicitly stated otherwise. Therefore, unless expressly stated otherwise, each feature disclosed herein is a specific example of a generic series having equivalent or similar features. Various modifications to the present application based on the description herein may be apparent to those skilled in the art. Such modifications are also intended to fall within the scope of the appended claims.

Each of the references cited herein is hereby incorporated by reference in its entirety.

Claims (18)

1. a crystalline form of the compound of formula I,

   
2. The crystalline form of the compound of formula I according to claim 1, wherein the crystalline form is crystalline form I, and the X-ray powder diffraction pattern has diffraction angles 2θ of 15.0°, 19.0°, 20.1°, Characteristic peaks of 21.4°, 22.3° and 24.4°±0.2°.
3. The crystalline form of the compound of formula I according to claim 1, wherein the crystalline form is crystalline form II, and the X-ray powder diffraction pattern has diffraction angles 2θ of 7.2°, 14.5°, 18.0°, Characteristic peaks of 19.8°, 22.0°, and 23.5° ± 0.2°.
4. The crystalline form of the compound of formula I according to claim 1, wherein the crystalline form is crystalline form III, and the X-ray powder diffraction pattern has a diffraction angle 2θ of 5.8°, 11.5°, 12.5°, Characteristic peaks of 14.1°, 16.0°, and 17.3° ± 0.2°.
5. The crystalline form of the compound of formula I according to claim 1, wherein the crystalline form is crystalline form IV, and the X-ray powder diffraction pattern has diffraction angles 2θ of 12.1°, 13.3°, 16.0°, Characteristic peaks of 20.0°, 24.3° and 27.1° ± 0.2°.
6. A pharmaceutical composition comprising a therapeutically effective amount of Form I, II, III and/or IV of a compound of Formula I and a pharmaceutically acceptable inactive ingredient.
7. The pharmaceutical composition according to claim 6, wherein the crystalline form of the compound of formula I has a purity of ≥ 85% by mass.
8. The pharmaceutical composition according to any one of claims 6 to 7, wherein the pharmaceutical composition comprises 0.01% by mass to 99% by mass of a crystalline form of the compound of the formula I.
9. The pharmaceutical composition according to any one of claims 6-8, wherein the pharmaceutical composition further comprises at least one active ingredient other than phenenable.
10. The pharmaceutical composition according to any one of claims 6 to 9, wherein the pharmaceutical composition is for transdermal administration, oral administration, parenteral administration and/or topical administration.
11. The pharmaceutical composition according to any one of claims 6 to 10, wherein the pharmaceutical composition is selected from the group consisting of an ointment, a cream or a gel.
12. Use of the crystalline form according to any one of claims 1 to 5 or the pharmaceutical composition according to any one of claims 6 to 11 for the preparation of a medicament for the treatment of an autoimmune disease and a complication thereof.
13. The use according to claim 12, characterized in that the autoimmune disease is a tissue hyperproliferative disease, colitis or an allergic disease.
14. The use according to claim 13, wherein the tissue hyperproliferative diseases are skin diseases or skin tumors and their complications; the colitis is allergic colitis.
15. The use according to claim 14, characterized in that the skin condition is selected from the group consisting of psoriasis, scleroderma and/or eczema.
16. The use according to claim 12, wherein the disease is selected from the group consisting of rheumatoid arthritis, allergic rhinitis, type II diabetes, ulcerative colitis, lupus erythematosus or pulmonary fibrosis.
17. The crystalline form according to any one of claims 1 to 5 or the pharmaceutical composition according to any one of claims 6 to 11 for use in the preparation of an inhibitor of interleukin-2, interleukin-13, interleukin-17 and/or tumor necrosis factor Over-expression of agents, or applications in drugs that inhibit the activation and migration of T cells.
18. A method of preparing Form I of a compound of Formula I, characterized in that the method comprises:

    a) the compound of the formula I is dissolved in a positive solvent to prepare a saturated solution in the container A, and then 5 to 15 times the positive solvent volume of the anti-solvent is added to the other container B; after that, the container A is opened. The container B is allowed to stand at room temperature until the crystal is precipitated and the container B is sealed; wherein the positive solvent is ethanol, acetonitrile, ethyl acetate or methyl tert-butyl ether, and the anti-solvent is water or n-heptane. ;or

    b) at room temperature, the compound of formula I is dissolved in a solvent or a mixed solvent to prepare a supersaturated solution, then heated to 30 to 70 ° C and stirred for 0.2-1 hours, filtered and cooled to 5 ° C or below. Crystallizing, wherein the solvent is a methanol/water mixture, especially a mixed solvent having a volume ratio of 1:1; or

    c) at room temperature, the compound of formula I is dissolved in a solvent or a mixed solvent to prepare a supersaturated solution, then heated to 30 to 70 ° C and stirred for 0.2-1 hours, filtered and cooled to 5 ° C or below. And then, at room temperature, the solid is volatilized, wherein the solvent is a single solvent of toluene or chloroform, or acetonitrile / water, isopropanol / n-hexane, ethyl acetate / n-heptane, 2-methyltetrahydrofuran / n-glycol a mixture of alkane or 1,4 dioxane/n-heptane, especially a mixed solvent, having a volume ratio of 1:1; or

    d) the compound of the formula I is dissolved in a solvent or a mixed solvent to prepare a saturated solution, filtered into a new container to obtain a clear solution, and volatilized at room temperature (tested as a light-proof treatment), wherein the solvent Is a mixed solvent of ethanol, isopropanol, acetonitrile, ethyl acetate, or a mixed solvent of acetonitrile / water, 1,4 dioxane / water or isopropyl acetate / n-heptane, especially a volume ratio of 1:1; or

    e) the compound of the formula I is dissolved in a positive solvent to obtain a saturated solution, and the clear solution is filtered, and the anti-solvent is added until a solid precipitates; if the anti-solvent is added up to 25 times the volume, no solid precipitates, and the temperature is slowly set at room temperature. Volatilization and crystallization; when the positive solvent is methanol, ethanol or acetone, the anti-solvent is water; when the positive solvent is toluene, chloroform, ethyl acetate or methyl tert-butyl ether, the anti-solvent is n-heptane;

    f) a compound of the formula I is dissolved in a solvent or a mixed solvent to prepare a saturated clear solution, and 10-30% of the mass of the compound of the formula I is added to the mixed polymer A, namely polyvinylpyrrolidone, polyethylene. a mixture of alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropylmethylcellulose and methylcellulose, especially a mixture of equal masses, or a mixture of high polymers B, ie polycaprolactone, polyethylene Mixture of alcohol, polymethyl methacrylate, sodium alginate and hydroxyethyl cellulose, especially in equal mass, or aqueous methylcellulose or aqueous polyvinyl alcohol in a clear solution of the compound of formula I, at room temperature The crystals are volatilized.

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