CN111148729A

CN111148729A - Crystal form of benvitimod, application and preparation method thereof

Info

Publication number: CN111148729A
Application number: CN201880063583.9A
Authority: CN
Inventors: 陈庚辉; 李建雄
Original assignee: Welichem Biotech Inc
Current assignee: Welichem Biotech Inc
Priority date: 2017-09-30
Filing date: 2018-09-30
Publication date: 2020-05-12
Also published as: WO2019063002A1

Abstract

The application relates to a crystal form of benvitimod (namely a compound shown in a formula I), a pharmaceutical composition containing the crystal form, and application and a preparation method of the crystalline form.

Description

Crystal form of benvitimod, application and preparation method thereof

Technical Field

The application relates to a novel crystal form of benvitimod, a preparation method of the novel crystal form, a pharmaceutical composition containing the novel crystal form, and application of the novel crystal form and the pharmaceutical composition in treating autoimmune diseases or complications thereof.

Background

The Benvitimod is a stilbene compound, is a non-steroidal anti-inflammatory/immune and anti-cell-diffusion small molecule drug, can remarkably inhibit the expression of factors such as interleukin-2, interleukin-13, interleukin-17, tumor necrosis factor and the like, can also inhibit the activation and migration of T cells, and can be used for treating various serious autoimmune, inflammatory and cell-spreading diseases.

The examples that follow will illustrate this. Immunomodulatory compounds are well known and reported in a number of scientific and technical literature and patents, and generally known and accepted immunomodulatory compounds are useful in the treatment of animal and human related diseases. Compounds with immunomodulatory activity, as disclosed herein, are known in the literature as useful as active ingredients in pharmaceuticals for the treatment of various diseases, such as: clinical transplant rejection (including organ transplantation, acute transplantation, allograft and autograft, as used in the treatment of burns), prevention of ischemic or reperfusion injury, such as that caused by organ transplantation, and multiple perfusion injury, and treatment of myocardial infarction, stroke or other diseases; inducing transplant tolerance, and treating arthritis (such as rheumatic arthritis, psoriatic arthritis, and 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 type hypersensitivity, gluten irritable bowel disease (gluten allergy), psoriasis, contact dermatitis (including that caused by poison ivy), hashimoto's thyroiditis, sjogren's syndrome, autoimmune hyperthyroidism such as Grave's disease, addison's disease, adrenal autoimmune disease, polyglandular autoimmune syndrome, immune alopecia, pernicious anemia, vitiligo, immune hypopituitarism, guillain-barre syndrome, and other immune diseases such as: glomerulonephritis, seropathy, urticaria, and furthermore allergic diseases such as respiratory allergic diseases (asthma, hay fever, allergic rhinitis) or skin allergy; scleroracierma; mycosis fungoides; acute inflammatory responses (such as acute respiratory distress syndrome and ischemia-reperfusion injury); dermatomyositis; alopecia areata; chronic actinic dermatitis, eczema, Behcet's disease, pustulosis palmaris et pedis, pyoderma gangrenosum, Sezary's syndrome, atopic dermatitis, and scleroderma. The skin disease is a pathological process caused by the change of the form, structure and function of the skin (including hair and nails) under the influence of internal and external factors, and correspondingly generates various clinical manifestations, and is one of common diseases and frequently encountered diseases which seriously affect the health of people, such as leprosy, scabies, mycosis, psoriasis, skin bacterial infection and the like. The incidence of skin diseases is high, most of the skin diseases are mild, the health is not affected frequently (but a few of the skin diseases are severe and even can endanger life), but the appearance of the patient is seriously affected, heavy psychological burden is brought to the patient, and the daily work and life of the patient are further affected.

The psoriasis is also called as psoriasis, is a common immune-mediated chronic inflammatory skin disease, has the characteristics of intractable and recurrent clinical manifestations, has the incidence rate of about 2% in the western world and is about 0.5% in asia, but the incidence rate is rapidly increased in recent years. The worldwide psoriasis treatment drug market in 2019 is reported to be $ 90.2 billion. Psoriasis has various skin lesions, and is often classified into psoriasis vulgaris, erythrodermic psoriasis, pustular psoriasis, and arthropathic psoriasis. Of these, the majority (> 85%) are the usual patients. Psoriasis can interfere with the daily life and quality of life of the patient in addition to causing discomfort such as itching, bleeding, etc. at the site of the skin lesion. Among them, erythrodermic psoriasis and pustular psoriasis can cause metabolic disorders of the whole body, and complications and infections of multiple organs such as cardiovascular and lung are caused, thus threatening life.

Early studies thought that the pathological mechanisms of psoriasis were mainly abnormalities in epidermal hyperplastic differentiation and activation of the immune system. The psoriasis is treated by adopting external medicines, phototherapy, systemic drug delivery and the like mainly according to the severity of the disease and the type of the psoriasis. Approximately 90% of psoriasis patients are mild and moderate; the first-line treatment medicines for treating the mild and moderate psoriasis vulgaris are mostly external medicines, and generally comprise keratolytic agents, vitamin D analogues, corticosteroids, dithranol, coal tar, external tretinoin and the like. In the Chinese psoriasis treatment guideline of 2008, tazarotene (tretinoin), intermediate and potent glucocorticoids and calcipotriol (VitD3 derivative) are used as recommended drugs for local treatment. However, long-term use of corticosteroids can cause side effects such as skin atrophy, telangiectasia, folliculitis, pigmentation or hypopsia. The large-area long-term application of the potent glucocorticoid preparation can cause systemic reaction, even induce pustular or erythrodermic psoriasis after the withdrawal of the drug. Tretinoin has skin mucosa irritation symptom, and is easy to occur to patients with allergic constitution. The more common side effects of calcipotriol are itching, skin irritation, burning sensation, stinging sensation, dry skin, erythema and rash, and have a certain effect on calcium metabolism. Therefore, despite numerous alternatives, drugs for treating psoriasis are generally limited in efficacy, often have toxic and side effects over long-term use, and do not meet the need for long-term effective treatment. For example, psoriasis erythroderma and psoriasis pustulosa occur and aggravate, and except for some patients with unknown etiology, a considerable part of the psoriasis is caused by improper treatment.

Disclosure of Invention

The application relates to a novel crystal form of benvitimod (namely a compound shown as a formula I), a pharmaceutical composition containing the novel crystal form, medical application of the novel crystal form and the pharmaceutical composition, and a preparation method of the novel crystal form.

In one aspect, this application provides crystalline form I of benvitimod.

In some embodiments, the crystalline form I of phendanimod has an X-ray powder diffraction pattern having characteristic peaks at diffraction angles 2 Θ of 15.0 °, 19.0 °, 20.1 °, 21.4 °, 22.3 °, and 24.4 ° ± 0.2 °.

In other embodiments, the crystalline form I of phendanimod has an X-ray powder diffraction pattern having characteristic peaks at diffraction angles 2 Θ of 15.0 °, 17.8 °, 19.0 °, 20.1 °, 21.4 °, 22.3 °, 24.4 °, 26.2 °, and 27.8 ° ± 0.2 °.

In other embodiments, crystalline form I of phendanimod has an X-ray powder diffraction pattern as shown in figure 1.

In another aspect, this application provides crystalline form II of benvitimod.

In some embodiments, the crystalline form II of phendanimod has an X-ray powder diffraction pattern having characteristic peaks at diffraction angles 2 Θ of 7.2 °, 14.5 °, 18.0 °, 19.8 °, 22.0 °, and 23.5 ° ± 0.2 °.

In other embodiments, the crystalline form II of phendanimod has an X-ray powder diffraction pattern having characteristic peaks at diffraction angles 2 Θ of 7.2 °, 14.5 °, 18.0 °, 18.7 °, 19.8 °, 21.4 °, 22.0 °, 23.5 °, and 27.6 ° ± 0.2 °.

In other embodiments, crystalline form II of phendanimod has an X-ray powder diffraction pattern as shown in figure 2.

In another aspect, this application provides crystalline form III of benvitimod.

In some embodiments, the crystalline form III of phendanimod has an X-ray powder diffraction pattern having characteristic peaks at diffraction angles 2 Θ 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 crystalline form III of phendanimod has characteristic peaks at diffraction angles 2 Θ of 5.8 °, 11.5 °, 12.5 °, 14.1 °, 16.0 °, 16.8 °, 17.3 °, 19.1 °, and 28.4 ° ± 0.2 °.

In other embodiments, crystalline form III of phendanimod has an X-ray powder diffraction pattern as shown in figure 3.

In another aspect, this application provides crystalline form IV of benvitimod.

In some embodiments, the crystalline form IV of phendanimod has an X-ray powder diffraction pattern having characteristic peaks at diffraction angles 2 Θ of 12.1 °, 13.3 °, 16.0 °, 20.0 °, 24.3 °, and 27.1 ° ± 0.2 °.

In other embodiments, the crystalline form IV of phendanimod has an X-ray powder diffraction pattern having characteristic peaks at diffraction angles 2 Θ of 12.1 °, 13.3 °, 16.0 °, 20.0 °, 20.9 °, 22.6 °, 24.3 °, 25.4 °, and 27.1 ° ± 0.2 °.

In other embodiments, crystalline form IV of phendanimod has an X-ray powder diffraction pattern as shown in figure 4.

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

In some embodiments, the purity of crystalline form I, II, III, and/or IV of benvitimod in the pharmaceutical composition is 85% by mass or more.

In other embodiments, the purity of crystalline form I, II, III, and/or IV of benvitimod in the pharmaceutical composition is 95% by mass or more.

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

In other embodiments, the purity of crystalline form I, II, III, and/or IV of benvitimod in the pharmaceutical composition is not less than 99.5 mass%.

In some embodiments, the pharmaceutical composition comprises 0.01% to 99% by mass of the crystalline form of the compound of formula I. For example, the pharmaceutical composition comprises 0.5% to 90% by mass of the crystalline form of the compound of formula I; the pharmaceutical composition comprises 1.0-80% by mass of a crystalline form of a compound of formula I; the pharmaceutical composition comprises 1.5-70% by mass of a crystalline form of a compound of formula I; the pharmaceutical composition comprises 3-60% by mass of a crystalline form of a compound of formula I; the pharmaceutical composition comprises 4-55% by mass of the crystalline form of the compound of formula I; the pharmaceutical composition comprises 5-50% by mass of a crystal form of a compound represented by formula I; the pharmaceutical composition comprises 7.5-40% by mass of a crystal form of a compound shown in formula I; the pharmaceutical composition comprises 10-30% by mass of the crystal form of the compound shown in the formula I.

In other embodiments, the pharmaceutical composition further comprises at least one additional 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 application also provides application of the crystalline form of the benvitimod or the pharmaceutical composition thereof in preparing medicines for treating autoimmune diseases, inflammatory diseases and cell diffusion diseases.

As reported in the scientific literature and patents, compounds with immunomodulatory activity are useful in the treatment of diseases related to animals and humans. Compounds having immunomodulatory activity, such as the crystalline form of the compound benvitimod as disclosed herein, are useful as active ingredients in medicaments for the treatment of diseases associated with immunomodulatory activity, such as: clinical transplant rejection (including organ transplantation, acute transplantation, allograft and autograft, as used in the treatment of burns), prevention of ischemic or reperfusion injury, such as that caused by organ transplantation, and multiple perfusion injury, and treatment of myocardial infarction, stroke or other diseases; inducing transplant tolerance, and treating arthritis (such as rheumatic arthritis, psoriatic arthritis, and 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 type hypersensitivity, gluten irritable bowel disease (gluten allergy), psoriasis, contact dermatitis (including that caused by poison ivy), hashimoto's thyroiditis, sjogren's syndrome, autoimmune hyperthyroidism such as Grave's disease, addison's disease, adrenal autoimmune disease, polyglandular autoimmune syndrome, immune alopecia, pernicious anemia, vitiligo, immune hypopituitarism, guillain-barre syndrome, and other immune diseases such as: glomerulonephritis, seropathy, urticaria, and furthermore allergic diseases such as respiratory allergic diseases (asthma, hay fever, allergic rhinitis) or skin allergy; scleroracierma; mycosis fungoides; acute inflammatory responses (such as acute respiratory distress syndrome and ischemia-reperfusion injury); dermatomyositis; alopecia areata; chronic actinic dermatitis, eczema, behcet's disease, palmar digital impetigo, pyoderma gangrenosum, Sezary's syndrome, atopic dermatitis, scleroderma, acne, and rosacea (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 skin tumor and complications thereof; the colitis is allergic colitis.

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

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

This application still further provides crystalline forms I, II, III and/or IV of phenyimod and the above pharmaceutical compositions for use in inhibiting the overexpression of interleukin-2, interleukin-13, interleukin-17 and/or tumor necrosis factor, or for use in inhibiting the activation and migration of T cells, or tumors associated with cell spread.

This application still further provides a method of treating an autoimmune disease in a mammal comprising administering to a patient suffering from an autoimmune disease a therapeutically effective amount of crystalline form I, II, III, and/or IV of benvitimod or a pharmaceutical composition as described above. This application still further provides a method of treating a tissue hyperproliferative disorder in a mammal comprising administering to a patient suffering from a tissue hyperproliferative disorder a therapeutically effective amount of crystalline form I, II, III and/or IV of benvitimod or a pharmaceutical composition as described above.

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

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

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

In other embodiments, the mammal is a human.

This application also provides a method of preparing crystalline form I of phenformimod, comprising:

a) dissolving the compound shown in the amorphous formula I in a normal solvent to prepare a saturated solution, storing the saturated solution in a container A, and adding an anti-solvent with the volume of 5-15 times that of the normal solvent into another container B; then placing the container A in a container B in an open way, standing at room temperature until crystals are separated out, and sealing the container B; wherein the normal solvent is ethanol, acetonitrile, ethyl acetate or methyl tert-butyl ether, and the anti-solvent is water or n-heptane; or

b) Dissolving an amorphous compound shown as a formula I in a solvent or a mixed solvent at room temperature to prepare a supersaturated solution, heating to 30-70 ℃, stirring for 0.2-1 hour, filtering, cooling to 5 ℃ or below, standing and crystallizing, wherein the solvent is a methanol/water mixture, and particularly the volume ratio of the mixed solvent is 1: 1; or

c) Dissolving an amorphous compound shown as a formula I in a solvent or a mixed solvent at room temperature to prepare a supersaturated solution, heating to 30-70 ℃, stirring for 0.2-1 hour, filtering, cooling to 5 ℃ or below, standing, and then placing at room temperature to volatilize and separate out a solid, wherein the solvent is a single solvent such as toluene, chloroform and the like, or a mixture of acetonitrile/water, isopropanol/n-kanane, ethyl acetate/n-heptane, 2-methyltetrahydrofuran/n-heptane or 1,4 dioxane/n-heptane, and particularly the volume ratio of the mixed solvent is 1: 1; or

d) Dissolving the compound shown in the amorphous formula I in a solvent or a mixed solvent to prepare a saturated solution, filtering the saturated solution into a new container to prepare a clear solution, standing the clear solution at room temperature for volatilization and crystallization, wherein the solvent is ethanol, isopropanol, acetonitrile and ethyl acetate, or the mixed solvent is acetonitrile/water, 1,4 dioxane/water or isopropyl acetate/n-heptane, and particularly the mixed solvent with the volume ratio of 1: 1; or

e) Dissolving the compound shown in the amorphous formula I in a normal solvent to prepare a saturated solution, filtering to obtain a clear solution, and adding an anti-solvent until a solid is separated out; if the added antisolvent with volume as high as 25 times that of the mixture still has no solid precipitation, the mixture is placed at room temperature to slowly volatilize and crystallize; when the normal solvent is methanol, ethanol or acetone, the anti-solvent is water, and when the normal solvent is toluene, chloroform, ethyl acetate or methyl tert-butyl ether, the anti-solvent is n-heptane;

f) dissolving the compound shown in the amorphous formula I in a solvent/mixed solvent to prepare a saturated clear solution, adding a mixed high polymer A which accounts for 10-30% of the mass of the compound shown in the amorphous formula I, namely a mixture of polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropyl methyl cellulose and methyl cellulose, especially an equal-mass mixture, or a mixed high polymer B which accounts for a mixture of polycaprolactone, polyethylene glycol, polymethyl methacrylate, sodium alginate and hydroxyethyl cellulose, especially an equal-mass mixture; or the methyl cellulose aqueous solution or the polyvinyl alcohol aqueous solution is put into the clear solution and is put at room temperature to volatilize and separate out crystals (the test is carried out by light-shielding treatment).

The method for preparing crystalline form II of phenformimod provided by the present application comprises:

a) dissolving an amorphous compound or crystal form I shown in the formula I in tetrahydrofuran serving as an n-solvent or toluene to prepare a saturated solution, storing the saturated solution in a container A, and adding n-heptane serving as an anti-solvent with the volume 5-15 times that of the n-solvent into another container B; then placing the container A in a container B in an open way, standing at room temperature until crystals are separated out, and sealing the container B; or

b) At room temperature, dissolving the amorphous compound or crystal form I shown in the formula I in a mixed solvent to prepare a supersaturated solution, then heating to 30-70 ℃, stirring for 0.2-1 hour, filtering, cooling to 5 ℃ or below, and standing for crystallization. Slowly volatilizing the still clear solution at room temperature to separate out a solid, wherein the solvent is a tetrahydrofuran/water mixture, and particularly the volume ratio of the mixed solvent is 1: 1; or

c) Dissolving an amorphous compound or crystal form I shown in the formula I in a solvent or a mixed solvent to prepare a saturated solution, filtering the saturated solution into a new container to prepare a clear solution, standing the clear solution at room temperature, and volatilizing and crystallizing the clear solution, wherein the solvent is methanol, tetrahydrofuran, or a mixed solvent of dichloromethane/n-heptane or methanol/water, and particularly the mixed solvent with the volume ratio of 1: 1; or

d) Dissolving the amorphous compound or crystal form I shown in the formula I in a normal solvent to prepare a saturated solution, filtering to obtain a clear solution, and adding an anti-solvent until a solid is separated out; if the added antisolvent with volume up to 25 times is still free from solid precipitation, the solution is placed at room temperature for slow volatilization and crystallization, or the solution is placed at 5 ℃ or below and stirred overnight, and then the solution is placed at room temperature for slow volatilization and crystallization; when the normal solvent is isopropanol, acetonitrile or tetrahydrofuran, the anti-solvent is water; when the normal solvent is isopropyl acetate, 1, 4-dioxane, tetrahydrofuran or toluene, the anti-solvent is n-heptane;

e) dissolving the compound or crystal form I shown in the amorphous formula I in tetrahydrofuran to prepare a saturated clear solution, adding ionic liquid [ Bmim ] PF6 (1-butyl-3-methylimidazolium hexafluorophosphate) accounting for 10-30% of the mass of the compound or crystal form I shown in the amorphous formula I, and volatilizing and crystallizing at room temperature.

The method for preparing crystalline form III of phenformimod provided by the present application comprises:

a) dissolving an amorphous compound or crystal form I shown in the formula I in a mixed solvent to prepare a saturated solution, filtering the saturated solution into a new container to prepare a clear solution, standing the clear solution at room temperature, volatilizing and crystallizing the clear solution, wherein the mixed solvent is methyl tert-butyl ether/n-heptane, and particularly the mixed solvent with the volume ratio of 1: 1; or

b) Dissolving the amorphous compound or crystal form I shown in the formula I in methyl tert-butyl ether to prepare a clear solution, standing, and slowly volatilizing at room temperature to separate out crystals;

c) dissolving the compound or crystal form I shown in the amorphous formula I in dimethyl sulfoxide (DMSO), filtering to obtain a clear solution, and adding anti-solvent water into the clear solution until a solid is separated out;

d) dissolving the amorphous compound or crystal form I shown in the formula I in methyl tert-butyl ether to prepare a clear solution, placing the solution at 5 ℃ or below, stirring overnight, then placing the solution at room temperature, slowly volatilizing at room temperature to crystallize, and then slowly volatilizing at room temperature to crystallize.

The method for preparing crystalline form IV of benvitimod provided by the application comprises the following steps:

a) adding the crystal form I into a mixed solvent of acetone/water to prepare a suspension of 20-30mg/ml, heating the suspension to 40-60 ℃, particularly about 50 ℃ under stirring for 0.2-1 hour, filtering the suspension into a new container to prepare a clear solution, cooling the solution to 5 ℃ or below, and standing the clear solution at room temperature for volatilization and crystallization; or

b) Dissolving the amorphous compound or crystal form I shown in the formula I in chloroform or acetone, filtering to obtain a clear solution, and slowly volatilizing at room temperature to separate out crystals;

c) addition of form I to acetone/n-heptane, or acetonitrile/water mixed solvents, especially 1:4, preparing a turbid solution of 10-20mg/ml according to the volume ratio, and stirring the turbid solution at room temperature (for test, light-proof treatment) for 1-3 days to obtain crystals; or

d) Dissolving the amorphous compound shown in the formula I or the crystal form I in chloroform, filtering to obtain a clear solution, and adding an anti-solvent n-heptane into the clear solution until a solid is separated out.

The purity of the benvitimod crystal form I, the crystal form II, the crystal form III or the crystal form IV provided by the application is more than or equal to 85 percent, more than or equal to 95 percent, or even more than or equal to 99 percent or 99.5 percent.

The crystalline forms disclosed herein may be crystallized from a suitable solvent system containing at least one solvent, which may be achieved by solvent evaporation, cooling and/or by addition of an anti-solvent (the less soluble solvent described herein for benvitimod), to achieve supersaturation in the solvent system.

Crystallization may or may not use seed crystals, as disclosed herein.

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

In another aspect, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the aforementioned crystalline forms of phendanimod and at least one pharmaceutically acceptable inactive ingredient.

The term "therapeutically effective amount" refers to an amount of a compound that, when used to treat a subject, is sufficient to effect such treatment of a disease, disorder or condition, for the treatment of a disease, or at least one clinical symptom of a disease or condition. The "therapeutically effective amount" may vary with the compound, the disease, disorder, and/or symptoms of the disease or disorder, the severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the patient being treated, and/or the weight of the patient being treated, etc. An appropriate dosage, where possible, will be readily apparent to those skilled in the art and may be determined by routine experimentation. In the case of combination therapy, "therapeutically effective amount" refers to the total amount of the combination subject that is effective to treat the disease, disorder, or condition.

The "pharmaceutically acceptable inactive ingredient" refers to a conventional pharmaceutically inactive ingredient suitable for a desired pharmaceutical preparation. For example: diluents such as water, various organic solvents, and the like; fillers such as starch, sucrose, and the like; binders such as cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone (PVP); humectants such as glycerin; disintegrating agents such as agar, calcium carbonate and sodium bicarbonate; such as quaternary ammonium compound absorption promoters; surfactants such as cetyl alcohol; absorptive carriers such as kaolin and bentonite clay; lubricants such as talc, calcium stearate, magnesium stearate, and polyethylene glycol. Other pharmaceutically acceptable inactive ingredients such as dispersing agents, stabilizers, thickening agents, complexing agents, buffering agents, permeation enhancers, polymers, flavoring agents, sweeteners, and dyes may also be added to the pharmaceutical composition. Preferably, inactive ingredients suitable for the desired dosage form and the desired mode of administration are used.

The present application also provides pharmaceutical compositions comprising at least one compound of formula I capable of treating the above-mentioned conditions in an effective amount and a pharmaceutically acceptable carrier or diluent. The compositions of the present application may contain other agents known to those skilled in the art, perhaps formulated according to procedures well known in the art of pharmaceutical formulation, by using conventional solid or liquid carriers or diluents, as well as a variety of pharmaceutical additives (e.g., excipients, binders, preservatives, stabilizers, flavoring agents, etc.) appropriate for the desired mode of administration.

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 compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. The suspension may be formulated according to the known art 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, for example 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 conventionally employed as a solvent or suspending medium. Any bland fixed oil may be employed for this purpose including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

For rectal administration the compounds of formula I may also be formulated in the form of suppositories. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

For oral administration, the formulations may be in the form of tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions for oral use may be prepared according to any method known in the art for the preparation of pharmaceutical compositions. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are 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; binding agents, such as starch, gelatin or acacia, and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract 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 oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil such as liquid paraffin or mixtures of these. Suitable emulsifiers may be naturally occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitol monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents.

For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compounds of formula I may be used (for this purpose, topical application includes not only topical administration, but also administration in the form of mouthwashes and gargles). The preparation of such topical formulations is well described in the art of Pharmaceutical formulation, for example, in Remington's Pharmaceutical Science, 17 th edition, Mack press, Easton, PA. For topical application, the compounds may also be administered as a powder or spray, particularly 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 the treatment of the conditions indicated above, or each patient may be dosed from about 0.5 mg to about 7 g per day. For example, administration of the present compounds at about 0.01 to 50 mg per kg of body weight per day, or about 0.5 mg to about 3.5 g per patient per day, preferably 2.5 mg to 1 g per patient per day, is effective in treating inflammation. It will be understood, however, that the specific dose level for a particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

The amount of active ingredient that is combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, an oral formulation for humans may contain 0.5 milligrams to 5 grams of active agent mixed with an appropriate amount of carrier to about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain from about 1 mg to about 500 mg of an 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 water, various organic solvents, and various inert diluents or fillers. If desired, the pharmaceutical composition may contain one or more additives such as flavors, binders, and excipients. For oral administration, the tablet may comprise at least one inactive ingredient selected from, for example, citric acid; various disintegrating agents such as starch, alginic acid and certain complex silicates; various binders such as sucrose, gelatin and acacia. Additionally, lubricants such as magnesium stearate and talc are commonly used as fillers in the manufacture of tablets. These ingredients may also be filled into soft and hard gelatin capsules. When intended for oral administration and, where desired, as an aqueous suspension, the active compound therein may be mixed with at least one ingredient selected from various sweetening or flavoring agents, pigments or dye combinations. Various emulsifying or suspending agents may be used if desired; diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof may also be used.

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

Pharmaceutical compositions comprising the crystalline forms of the present application may be administered to a patient in need of treatment by transdermal administration or topical administration. For transdermal administration, the pharmaceutical composition may be formulated into dosage forms such as cream, gel, etc

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

In some embodiments, the pharmaceutical compositions of the present application can be prepared by methods conventional in the pharmaceutical arts. For example, the active ingredient is mixed with one or more inactive ingredients and then formulated into the desired dosage form.

The major characteristic peaks of the above crystalline forms are reproducible and within the margin of error (i.e., the values ± 0.2 °).

In the present application, "having an X-ray powder diffraction pattern as shown in FIG. 1" means that the X-ray powder diffraction pattern shows major peaks as shown in FIG. 1, wherein the major peaks mean those having a relative intensity of more than 10%, preferably more than 30%, as compared with the highest peak in FIG. 1 (the relative intensity thereof is defined as 100%). Similarly, in the present application, the X-ray powder diffraction pattern shown in fig. 2, 3 or 4 indicates the main peaks shown in the X-ray diffraction pattern shown in fig. 2, 3 and 4, respectively, wherein the main peaks indicate those peaks having a relative intensity of more than 10%, preferably more than 30%, as compared with the highest peak (the relative intensity of which is 100%) in fig. 2, 3 and 4.

Drawings

FIG. 1: an X-ray powder diffraction pattern of a crystal form I of the compound shown as the formula I;

FIG. 2: an X-ray powder diffraction pattern of a compound crystal form II shown in a formula I;

FIG. 3: an X-ray powder diffraction pattern of a compound crystal form III shown in a formula I;

FIG. 4: an X-ray powder diffraction pattern of a compound crystal form IV shown in a formula I;

Detailed Description

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

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

TABLE 1

Example 1 preparation of form I

Preparation method I of crystal form I

Approximately 15 mg of the amorphous compound of formula I (starting material) was dissolved in the corresponding n-solvent of Table 1-1 to give a saturated solution, which was filtered into a 3 ml vial to give a clear solution. After 4.0 ml of the anti-solvent (shown in Table 1-1) was added to the 20 ml vial, the 3 ml vial containing the supernatant was opened to the 20 ml vial, and the 20 ml vial was sealed and allowed to stand at room temperature (test was conducted in the dark and filled with N)₂Protection processing). All observed solids were isolated and confirmed to be form I by XRPD analysis. And (4) standing the clear liquid without the precipitated solid at room temperature for slow volatilization and crystallization, and analyzing the obtained solid by XRPD to confirm that the solid is the crystal form I. In particular, form I with "") was prepared by slow volatilization in the greenhouse.

TABLE 1-1

Preparation method II of crystal form I

At room temperature, about 25 mg of an amorphous compound of formula I (referred to as starting material) was placed in a 3 ml vial, and 1.0ml of the corresponding solvent or mixed solvent shown in Table 1-2 was added to the vial to obtain a supersaturated suspension. The suspension was heated to 50 ℃ and stirred for 0.5 hour, then filtered into a new vial to obtain a clear solution, which was cooled to 5 ℃ and then placed in a biological incubator (test for light-shielding treatment) at a constant temperature of 5 ℃ for crystallization, and all precipitated solids were separated respectively. The clear liquid without solid precipitation is placed at room temperature to slowly volatilize the precipitated solid and isolate the resulting solid. XRPD analysis confirmed that all are form I. In particular, form I with "") was prepared by slow volatilization in the greenhouse.

Tables 1 to 2

Preparation method III of crystal form I

Dissolving about 15 mg of amorphous compound (raw material for short) shown in formula I in 1.0-1.5 mL of solvent or mixed solvent shown in tables 1-3 in a 3 mL small bottle to prepare saturated solution, filtering the saturated solution to a new small bottle to prepare clear solution, sealing the small bottle filled with the clear solution by using a sealing film, pricking 5-6 small holes on the small bottle, and standing the small bottle at room temperature for slow volatilization (test for light-shielding treatment). The resulting solids were collected separately and confirmed to be form I by XRPD analysis.

Tables 1 to 3

Raw material quality (mg)	Solvent, V: V	Volume of solvent (ml)	The obtained crystal form
15.0	Ethanol	1.0	Crystal form I
15.0	Isopropanol (I-propanol)	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 of crystal form I

About 15 mg of the amorphous compound of formula I (starting material for short) was dissolved in 1.0mL of each of the solvents listed in tables 1 to 4 in a 3 mL vial to prepare a solution, which was filtered into a new vial to prepare a clear solution, which was left open to evaporate at room temperature (test performed with light-shielding treatment). The resulting solids were isolated separately and analyzed by XRPD to confirm that all were crystalline form I.

Tables 1 to 4

Raw material quality (mg)	Solvent(s)	Volume of solvent (ml)	The obtained crystal form
14.9	Acetonitrile	1.0	Crystal form I
14.9	Ethyl acetate	1.0	Crystal form I

Preparation method five of crystal form I

After about 20mg of the amorphous compound of formula I (abbreviated as starting material) was placed in a 3 ml vial, dissolved in an appropriate amount of the n-solvent of tables 1-5 and filtered to a 20 ml vial, the anti-solvent was added to the clear solution while stirring dropwise until a solid precipitated, and the precipitated solid was isolated and confirmed by XRPD analysis. If no solid is precipitated after 10.0 ml of anti-solvent is added, the clear solution is left at room temperature to slowly volatilize and crystallize (test is carried out in a dark treatment). The resulting solids were collected separately and confirmed to be form I by XRPD analysis. In particular, form I with "") was prepared by slow volatilization in the greenhouse.

Tables 1 to 5

Preparation method VI of crystal form I

Dissolving 15 mg of amorphous compound of formula I (raw material for short) in the corresponding solvent/mixed solvent shown in tables 1-6 to obtain clear solution, adding about 2.0 mg of mixed high polymer A (mixed mass of polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropyl methylcellulose and methylcellulose), mixed high polymer B (mixed mass of polycaprolactone, polyethylene glycol, polymethyl methacrylate, sodium alginate and hydroxyethyl cellulose) or 0.5 ml of water-soluble high polymer 1 (methyl cellulose aqueous solution, 5 mg/ml), water-soluble high polymer 2 (98% hydrolyzed polyvinyl alcohol aqueous solution, 5 mg/ml) in the clear solution, the vial was sealed with a sealing film and punctured with 5-6 small holes, and left to volatilize at room temperature (test for dark treatment). The resulting solids were collected separately and confirmed to be form I by XRPD analysis.

Tables 1 to 6

Preparation method seven of crystal form I

At room temperature, about 15 mg of the amorphous compound of formula I (starting material for short) was dissolved in a 3 ml vial using the corresponding n-solvent of tables 1-7, and the resulting clear solution was added in one portion to a 20 ml vial containing 4.0 ml of the corresponding anti-solvent and stirred for 5 minutes, and the resulting solid was isolated. If no solid is precipitated, the clear liquid is slowly volatilized at room temperature (the test is protected from light). The resulting solids were collected separately and analyzed by XRPD, respectively, confirming that all were crystalline form I. In particular, form I with "") was prepared by slow volatilization in the greenhouse.

Tables 1 to 7

Example 2 preparation of form II

Preparation method I of crystal form II

Two portions of 14.9 mg of form I were dissolved in 0.4 ml of tetrahydrofuran and 1ml of toluene, and the resulting solution was filtered to obtain supernatants, which were transferred to 3 ml vials. Another 20 ml vial was taken, 4.0 ml of N-heptane was added to each vial, and the two 3 ml vials containing the supernatant were placed in the two 20 ml vials in an open state, respectively, and then the 20 ml vials were sealed and allowed to stand at room temperature (protected from light and filled with N)₂Protection) for one day. The clear liquid was then transferred to room temperature for slow evaporative crystallization. The resulting solid was collected and confirmed to be form II by XRPD analysis.

Preparation method II of crystal form II

Weighing 25.1 mg of the crystal form I in a 3 ml vial, adding 1.0ml of a mixed solvent (tetrahydrofuran/water, v/v ═ 1:1), stirring at 50 ℃ for about 0.5 hour, filtering to obtain a supernatant, slowly volatilizing the obtained supernatant at room temperature for crystallization, and analyzing the obtained solid by XRPD to confirm that the solid is the crystal form II.

Preparation method III of crystal form II

About 15 mg of form I was dissolved in 1.0 to 1.5mL of the solvent or mixed solvent listed in table 2-1, filtered to obtain a clear solution, the vial containing the clear solution was sealed and sealed with 5 small holes, and then left to slowly evaporate at room temperature (test for light-shielding treatment). The resulting solids were collected separately and confirmed to be form II by XRPD analysis.

TABLE 2-1

Crystal form I sample quality (milligrams)	Solvent, v: v	Volume of solvent (ml)	The obtained crystal form
15.1	Methanol	1.0	Crystal form II
15.3	Tetrahydrofuran (THF)	1.0	Crystal form II
15.0	Dichloromethane/n-heptane, 1:1	1.5	Crystal form II

Preparation method of crystal form II

About 15 mg of form I was dissolved in 1ml of the solvent or solvent mixture listed in table 2-2, filtered separately to give a clear solution, which was left open to the atmosphere to evaporate rapidly at room temperature (test performed with dark treatment). The resulting solids were collected separately and confirmed to be form II by XRPD analysis.

Tables 2 to 2

Preparation method five of crystal form II

At room temperature, about 20mg of the crystal form I is dissolved in 0.4 ml of the solvent listed in tables 2-3 and filtered to a 20 ml vial, then the anti-solvent is added, and the mixture is stirred while dropwise adding until solid is separated out or until the volume of the anti-solvent is 10.0 ml, if no solid is separated out, the clear liquid is stirred at 5 ℃ overnight, and if no solid is separated out, the clear liquid is placed at room temperature for slow volatilization and crystallization (test is carried out for light-shielding treatment). The resulting solids were collected separately and confirmed to be form II by XRPD analysis. In particular, form II with "-" therein was obtained by slow evaporation crystallization at room temperature.

Tables 2 to 3

Crystal form I sample quality (milligrams)	Solvent(s)	Anti-solvent	Volume of anti-solvent (ml)	The obtained crystal form
20.2	Isopropanol (I-propanol)	Water (W)	1.8	Crystal form II
20.0	Acetonitrile	Water (W)	1.0	Crystal form II
19.9	Tetrahydrofuran (THF)	Water (W)	0.8	Crystal form II
20.3	Acetic acid isopropyl ester	Ortho-kan alkane	10.0	Form II
19.9	1, 4-dioxane	Ortho-kan alkane	10.0	Form II

Preparation method six of crystal form II

15.2 mg of form I are dissolved in 1.0mL of tetrahydrofuran to obtain a clear solution, the clear solution is placed in a 3-mL glass bottle, then 0.5 mL of polyethylene oxide aqueous solution (5.0 mg/mL) is added into the clear solution, and the mixture is volatilized (protected from light) at room temperature. The resulting solid was collected and analyzed by XRPD to confirm form II.

Preparation method of crystal form II

Dissolving 15.2 mg of the crystal form I in 1mL of tetrahydrofuran to prepare a clear solution, adding 2.5 mg of ionic liquid [ Bmim ] PF6 (1-butyl-3-methylimidazolium hexafluorophosphate) into a 3-mL glass bottle, sealing the bottle, pricking 5-6 small holes on a sealing film, volatilizing at room temperature (test for light-shielding treatment), collecting the obtained solid, and analyzing by XRPD to confirm the solid to be the crystal form II.

Preparation method eight of crystal form II

At room temperature, 15.1 mg of form I was dissolved in 0.4 mL of tetrahydrofuran to make a clear solution in a 3-mL glass bottle. 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 ℃ overnight, then the clear solution was left to slowly evaporate at room temperature (protected from light), the resulting solid was collected and analyzed by XRPD to confirm crystalline form II.

EXAMPLE 3 preparation of form III

Preparation method I of crystal form III

200.6 mg of form I are dissolved in 4.0 ml of methyl tert-butyl ether/n-heptane (v/v,1:1), filtered into a vial to give a clear solution, the vial is closed at its mouth and 5 wells are sealed, and then left to evaporate slowly at room temperature (test for protection from light). The resulting solid was collected and analyzed by XRPD to confirm form III.

Preparation method II of crystal form III

15.1 mg of form I are dissolved in 1.0mL of a mixed solvent of methyl tert-butyl ether/n-heptane (v/v,1:1), filtered into a 3-mL glass bottle to obtain a clear solution, the mouth of the bottle is sealed, 5 small holes are punched, and then the clear solution is slowly volatilized at room temperature (protected from light). The resulting solid was collected and analyzed by XRPD to confirm form III.

Preparation method III of crystal form III

14.9 mg of form I sample was weighed into a 3 ml glass vial, 4.0 ml of methyl tert-butyl ether was added to a 20 ml vial, and after the 3 ml vial was opened into the 20 ml vial, the 20 ml vial was sealed (test protected from light and protected by N2). After standing at room temperature for 7 days, the clear solution was left at room temperature to slowly volatilize and crystallize, and the resulting solid was collected and analyzed by XRPD to confirm crystalline form III.

Preparation method IV 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 into a 20 ml vial to obtain a clear solution, to which water (anti-solvent) was added dropwise with stirring until a solid precipitated (volume of water 0.4 ml), which was isolated and analyzed by XRPD to confirm form III.

Preparation method five 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. After the clear solution was added to a 20 ml vial containing 4 ml of n-heptane (anti-solvent) and stirred for about 5 minutes, the clear liquid was cooled to 5 ℃ and stirred at 5 ℃ overnight. The clear liquid was then left to evaporate slowly (away from light) at room temperature, and the resulting solid was collected and analyzed by XRPD to confirm form III.

Example 4 preparation of form IV

Preparation method I of crystal form IV

25.2 mg of form I was added to 1.0ml of a mixed solvent of acetone/water (v/v,1:1) at room temperature to form a suspension, which was heated to 50 ℃ and stirred for 0.5 hour, and then filtered into a new vial to form a clear solution. The clear solution was slowly cooled from 50 ℃ to 5 ℃ and then slowly evaporated at room temperature, and the solid collected was analyzed by XRPD and confirmed to be form IV.

Preparation method II of crystal form IV

Two 15.0mg portions of form I were dissolved in 1.0mL portions of chloroform and acetone, respectively, and the resulting solutions were filtered, the vials containing the clear solutions were sealed, and after 5 small holes were punched in the seals, the solutions were allowed to evaporate slowly at room temperature (test performed with dark treatment). The resulting solids were collected separately and confirmed to be form IV by XRPD analysis.

Preparation method III of crystal form IV

About 20mg of form I to 1.5ml glass vial, 0.3 ml of the solvent listed in Table 4-1 was added, and the resulting turbid solution was stirred at room temperature for 2 days (test protected from light and filled with N)₂Protected), the solid was isolated and confirmed to be form IV by XRPD analysis.

TABLE 4-1

Crystal form I mass (milligrams)	Solvent, V: V	Volume of solvent (ml)	The obtained crystal form
20.5	acetonitrile/Water, 1:4	0.3	Crystal form IV
20.1	Acetone/n-heptane, 1:4	0.3	Crystal form IV

Preparation method IV of crystal form IV

19.8 mg of form I was dissolved in 1.0mL of chloroform and filtered into a 20 mL vial, and then n-heptane (anti-solvent) was added thereto, and the mixture was stirred while dropping until a solid precipitated (4.6 mL in total of n-heptane), and the precipitated solid was separated and analyzed by XRPD to confirm that it was form IV.

Preparation method five of crystal form IV

15.1 mg of the crystal form I sample is dissolved in 1.0ml of acetone to obtain a clear solution, 0.5 ml of hydroxyethyl cellulose aqueous solution (5.0 mg/ml) is added, a small bottle is sealed by using a sealing film and is pricked with 5-6 small holes, and the mixture is placed at room temperature for volatilization (the test is carried out in a dark treatment). The resulting solid was isolated and analyzed by XRPD to confirm form IV.

Example 5 solid State stability of crystalline forms I, II, III and IV of Benzimod

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

TABLE 2

H, H is hour; w is week and week; relative purity, the ratio X100 of the purity of the crystal form after the experiment to the purity of the original crystal form.

*: HPLC results showed new impurity peaks 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 crystalline forms I, II, III and IV of benvitimod

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, which was then mixed (25 rpm) in a rotary incubator and passed through a biochemical incubator at a controlled temperature of 25 ℃. 0.8 ml of suspension was measured at 24 hours and 48 hours, the solid was centrifuged (6000 rpm, 3 minutes), the supernatant was taken to an HPLC vial for solubility testing and the solid was measured for XRPD. The test results are summarized in Table 3.

TABLE 3

- -: after 24 hours of equilibration, crystal transformation was observed, so no relevant data was collected;

N/A: no relevant data was collected

The equilibrium solubility test result shows that: crystal transformation of forms II, III and IV occurred already at 24 hours. And the crystal transformation phenomenon does not occur in 48 hours of the crystal form I, and the dissolution values at 24 hours and 48 hours are similar, which shows that the equilibrium solubility of the crystal form I in water at 25 ℃ is about 0.019 mg/ml.

The above-mentioned embodiments are merely specific examples for fully illustrating the present application, and the scope of the present application is defined by the claims and not limited to the above-mentioned embodiments. Equivalent substitutions or changes which may be made by those skilled in the art based on the present application without departing from the spirit of the present application are also within the scope of the present application. Therefore, the spirit and scope of the present application is not limited to the specific description herein.

All matter disclosed in this application, including the abstract and drawings, and all steps in any method or process disclosed, may be combined in any combination, except combinations where certain features and/or steps are mutually exclusive. Each feature disclosed in this application, including the abstract and drawings, may be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed in this application is one specific example only of a generic series of equivalent or similar features. Various modifications of the present application, in addition to those described herein, may be apparent to those of ordinary skill in the art based on the description herein. Such modifications are intended to fall within the scope of the appended claims.

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

Claims

A crystalline form of a compound of formula I,
a crystalline form of the compound of formula I according to claim 1, characterized in that it is crystalline form I having an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2 Θ of 15.0 °, 19.0 °, 20.1 °, 21.4 °, 22.3 ° and 24.4 ° ± 0.2 °.
A crystalline form of the compound of formula I according to claim 1, characterized in that it is crystalline form II having an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2 Θ of 7.2 °, 14.5 °, 18.0 °, 19.8 °, 22.0 ° and 23.5 ° ± 0.2 °.
A crystalline form of the compound of formula I according to claim 1, characterized in that it is crystalline form III having an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2 Θ of 5.8 °, 11.5 °, 12.5 °, 14.1 °, 16.0 ° and 17.3 ° ± 0.2 °.
A crystalline form of the compound of formula I according to claim 1, characterized in that it is form IV having an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2 Θ of 12.1 °, 13.3 °, 16.0 °, 20.0 °, 24.3 ° and 27.1 ° ± 0.2 °.
A pharmaceutical composition comprising a therapeutically effective amount of crystalline form I, II, III and/or IV of a compound of formula I and a pharmaceutically acceptable inactive ingredient.
The pharmaceutical composition according to claim 6, wherein the purity of the crystalline form of the compound of formula I is not less than 85% by mass.
The pharmaceutical composition according to any one of claims 6 to 7, wherein the pharmaceutical composition comprises 0.01% to 99% by mass of the crystalline form of the compound of formula I.
Pharmaceutical composition according to any one of claims 6 to 8, characterized in that it further comprises at least one active ingredient other than benvitimod.
Pharmaceutical composition according to any of claims 6 to 9, wherein the pharmaceutical composition is for transdermal, oral, parenteral and/or topical administration.
Pharmaceutical composition according to any one of claims 6 to 10, characterized in that it is selected from the group consisting of ointments, creams or gels.
Use of the crystalline form of any one of claims 1-5 or the pharmaceutical composition of any one of claims 6-11 for the manufacture of a medicament for the treatment of autoimmune diseases and complications thereof.
Use according to claim 12, wherein the autoimmune disease is a tissue hyperproliferative disease, colitis or an allergic disease.
The use according to claim 13, wherein the tissue hyperproliferative disorder is a skin disease or a skin tumor and their complications; the colitis is allergic colitis.
Use according to claim 14, characterized in that the skin diseases are selected from psoriasis, scleroderma and/or eczema.
Use according to claim 12, wherein the disease is selected from rheumatoid arthritis, allergic rhinitis, type II diabetes, ulcerative colitis, lupus erythematosus or pulmonary fibrosis.
Use of the crystalline form of any one of claims 1-5 or the pharmaceutical composition of any one of claims 6-11 in the manufacture of a medicament for inhibiting the overexpression of interleukin-2, interleukin-13, interleukin-17, and/or a tumor necrosis factor agent, or for inhibiting the activation and migration of T cells.
A process for preparing crystalline form I of the compound of formula I, characterized in that said process comprises:

a) dissolving the compound shown in the amorphous formula I in a normal solvent to prepare a saturated solution, storing the saturated solution in a container A, and adding an anti-solvent with the volume of 5-15 times that of the normal solvent into another container B; then placing the container A in a container B in an open way, standing at room temperature until crystals are separated out, and sealing the container B; wherein the normal solvent is ethanol, acetonitrile, ethyl acetate or methyl tert-butyl ether, and the anti-solvent is water or n-heptane; or

b) Dissolving an amorphous compound shown as a formula I in a solvent or a mixed solvent at room temperature to prepare a supersaturated solution, heating to 30-70 ℃, stirring for 0.2-1 hour, filtering, cooling to 5 ℃ or below, standing and crystallizing, wherein the solvent is a methanol/water mixture, and particularly the volume ratio of the mixed solvent is 1: 1; or

c) Dissolving an amorphous compound shown as a formula I in a solvent or a mixed solvent at room temperature to prepare a supersaturated solution, heating to 30-70 ℃, stirring for 0.2-1 hour, filtering, cooling to 5 ℃ or below, standing, and then placing at room temperature to volatilize and separate out a solid, wherein the solvent is a single solvent of toluene or chloroform, or a mixed solvent of acetonitrile/water, isopropanol/n-kanane, ethyl acetate/n-heptane, 2-methyltetrahydrofuran/n-heptane or 1,4 dioxane/n-heptane, and particularly the volume ratio of the mixed solvent is 1: 1; or

d) Dissolving the compound shown in the amorphous formula I in a solvent or a mixed solvent to prepare a saturated solution, filtering the saturated solution into a new container to prepare a clear solution, standing and volatilizing the clear solution at room temperature (performing a test for light-shielding treatment) for crystallization, wherein the solvent is ethanol, isopropanol, acetonitrile and ethyl acetate, or a mixed solvent of acetonitrile/water, 1,4 dioxane/water or isopropyl acetate/n-heptane, and particularly the mixed solvent with the volume ratio of 1: 1; or

e) Dissolving the compound shown in the amorphous formula I in a normal solvent to prepare a saturated solution, filtering to obtain a clear solution, and adding an anti-solvent until a solid is separated out; if the added antisolvent with volume as high as 25 times that of the mixture still has no solid precipitation, the mixture is placed at room temperature to slowly volatilize and crystallize; when the positive solvent is methanol, ethanol or acetone, the anti-solvent is water; when the normal solvent is toluene, chloroform, ethyl acetate or methyl tert-butyl ether, the anti-solvent is normal heptane;

f) dissolving the amorphous compound shown in the formula I in a solvent or a mixed solvent to prepare a saturated clear solution, adding a mixed high polymer A which accounts for 10-30% of the mass of the amorphous compound shown in the formula I, namely a mixture of polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropyl methyl cellulose and methyl cellulose, especially an equal-mass mixture, or mixing a mixed high polymer B which is a mixture of polycaprolactone, polyethylene glycol, polymethyl methacrylate, sodium alginate and hydroxyethyl cellulose, especially an equal-mass mixture, or adding a methyl cellulose aqueous solution or a polyvinyl alcohol aqueous solution in the clear solution of the compound shown in the formula I, and standing at room temperature for crystallization.