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

Crystal form of benvitimod, and use thereof and preparation method therefor Download PDF

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WO2019063002A1
WO2019063002A1 PCT/CN2018/108990 CN2018108990W WO2019063002A1 WO 2019063002 A1 WO2019063002 A1 WO 2019063002A1 CN 2018108990 W CN2018108990 W CN 2018108990W WO 2019063002 A1 WO2019063002 A1 WO 2019063002A1
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solvent
compound
formula
crystalline form
pharmaceutical composition
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PCT/CN2018/108990
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French (fr)
Chinese (zh)
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陈庚辉
李建雄
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北京文丰天济医药科技有限公司
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Priority to CN201880063583.9A priority Critical patent/CN111148729A/en
Publication of WO2019063002A1 publication Critical patent/WO2019063002A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/68—Purification; separation; Use of additives, e.g. for stabilisation
    • C07C37/70—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment
    • C07C37/84—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment by crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/205—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings
    • C07C39/21—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings with at least one hydroxy group on a non-condensed ring

Definitions

  • 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.
  • 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.
  • 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
  • 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.
  • psoriasis also known as "psoriasis”
  • 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.
  • erythrodermic psoriasis and pustular psoriasis can cause systemic metabolic disorders, complications such as cardiovascular and lung diseases, and infections, which are life-threatening.
  • 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.
  • tazarotene retinoic acid
  • intermediate-effect and potent glucocorticoids calcipotriol
  • calcipotriol VitD3 derivatives
  • corticosteroids can cause side effects such as skin atrophy, telangiectasia, folliculitis, hyperpigmentation or regression.
  • 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.
  • calcipotriol 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.
  • 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.
  • the application provides Form I of phenenimod.
  • the X-ray powder diffraction pattern of phenenyl Form I has characteristic peaks with diffraction angles 2 ⁇ of 15.0°, 19.0°, 20.1°, 21.4°, 22.3°, and 24.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of phenenyl form I has diffraction angles 2 ⁇ 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 °.
  • the phenenyl form I has an X-ray powder diffraction pattern as shown in FIG.
  • the present application provides Form II of phenenimod.
  • the X-ray powder diffraction pattern of phenenyl Form II has characteristic peaks with diffraction angles 2 ⁇ of 7.2°, 14.5°, 18.0°, 19.8°, 22.0°, and 23.5° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of phenenyl form II has diffraction angles 2 ⁇ 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 °.
  • phenenyl Form II has an X-ray powder diffraction pattern as shown in FIG.
  • the present application provides Form III of phenenimod.
  • the X-ray powder diffraction pattern of phenenyl Form III has characteristic peaks with diffraction angles 2 ⁇ of 5.8°, 11.5°, 12.5°, 14.1°, 16.0°, and 17.3° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of phenenyl form III has diffraction angles 2 ⁇ 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 °.
  • phenenyl Form III has an X-ray powder diffraction pattern as shown in FIG.
  • the present application provides Form IV of phenenimod.
  • the X-ray powder diffraction pattern of phenenyl Form IV has characteristic peaks with diffraction angles 2 ⁇ of 12.1°, 13.3°, 16.0°, 20.0°, 24.3°, and 27.1° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of phenenyl Form IV has diffraction angles 2 ⁇ 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 °.
  • 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.
  • the purity of phenenyl Form I, II, III, and/or IV in the pharmaceutical composition is > 85% by mass.
  • the purity of phenenyl Form I, II, III, and/or IV in the pharmaceutical composition is > 95% by mass.
  • the purity of the phenenyl form I, II, III, and / or IV in the pharmaceutical composition is ⁇ 99% by mass.
  • the purity of phenenyl Form I, II, III, and/or IV in the pharmaceutical composition is > 99.5% by mass.
  • the pharmaceutical composition comprises from 0.01% to 99% by mass of the crystalline form of the compound of Formula I.
  • 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.
  • the pharmaceutical composition further comprises at least one other active ingredient.
  • the pharmaceutical composition is suitable for topical administration (topical administration includes topical administration).
  • the pharmaceutical composition is an ointment.
  • the pharmaceutical composition is a cream.
  • the pharmaceutical composition is a gel.
  • 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.
  • compounds having immunomodulatory activity are related diseases that can be used to treat animals and humans.
  • Compounds having immunomodulatory activity 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,
  • the tissue hyperproliferative disorder is a skin disease or a skin tumor and a complication thereof; the colitis is hypersensitivity colitis.
  • the skin condition comprises psoriasis, scleroderma, and/or eczema.
  • 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.
  • the autoimmune disease comprises a tissue hyperproliferative disorder, colitis or an allergic disease.
  • the colitis is allergic colitis.
  • the tissue hyperproliferative disorder is a skin disease or a skin tumor and a complication thereof.
  • the skin disorder is psoriasis, scleroderma, and/or eczema.
  • the psoriasis is mild to moderate psoriasis or psoriasis vulgaris.
  • the mammal is a human.
  • the application also provides a method of preparing phenenyl form I, the method comprising:
  • 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
  • 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
  • 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.
  • 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;
  • 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;
  • 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;
  • 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;
  • 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:
  • 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;
  • 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.
  • 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.
  • 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;
  • the method for preparing phenenyl form III of the present application includes:
  • 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
  • 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;
  • DMSO dimethyl sulfoxide
  • 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
  • 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
  • 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.
  • 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.
  • the resulting crystalline form depends on the kinetics and thermodynamics of the crystallization process.
  • one crystal form may be more stable (or indeed more stable than any other crystal form) than another crystal form.
  • 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.
  • 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.
  • terapéuticaally 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.
  • therapeuticically 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.
  • 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
  • talc calcium stearate
  • lubricants such as magnesium stearate and polyethylene glycol.
  • 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.
  • compositions of the present application also provides a pharmaceutical composition
  • 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.
  • compositions of the present application containing the active ingredient may be in a form suitable for systemic, oral, and/or topical use.
  • 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.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • 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.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • topical administration includes not only topical administration, but also mouthwash and gargle The mode of administration of the agent).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the active compound 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.
  • 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.
  • the pharmaceutical composition can be formulated into a dosage form such as a cream or a gel.
  • the pharmaceutical composition can be administered in the form of a topical application such as a cream, cream or ointment.
  • the pharmaceutical compositions of the present application can be prepared by conventional methods in the pharmaceutical arts.
  • the active ingredient is combined with one or more inactive ingredients which are then brought into the preparations required.
  • “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%.
  • 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%).
  • 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;
  • 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.
  • 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.
  • the mixed polymer A polyvinylpyrrolidone, polyvinyl alcohol
  • 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.
  • 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.
  • 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.
  • 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.
  • 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*
  • Form I 15.2 mg 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.
  • Form I 15.2 mg 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.
  • 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.
  • Form I 200.6 mg 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.
  • Form I 15.1 mg 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.
  • 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.
  • 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.
  • 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.
  • 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
  • Form I 19.8 mg 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.
  • Form I sample 15.1 mg 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.

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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

苯烯莫德的晶型及其用途与制备方法Crystal form of phenenyl and its use and preparation method 技术领域Technical field
本申请涉及苯烯莫德的新晶型、新晶型的制备方法及含有该新晶型的药物组合物，同时也涉及所述新晶型及其药物组合物在治疗自身免疫性病或其并发症中的应用。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.
背景技术Background technique
苯烯莫德(Benvitimod)为二苯乙烯类化合物，是一只非甾体抗炎/免疫和抗细胞扩散小分子药物，能显著抑制如白介素-2、白介素-13、白介素-17以及肿瘤坏死因子等因子的表达，还能抑制T细胞的活化与迁移，可用于治疗多种重大自身免疫性，炎症性和细胞扩散性疾病。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.
随后的例子将说明这些。人们对有免疫调控活性的化合物了解很多，在大量的科技文献和专利中有报道，通常为人们所知道、为人们所接受的有免疫调控活性的化合物是可以用于治疗动物和人的相关疾病。在文献中为人们所知的，那些有免疫调控活性的化合物，正如本申请在此公开的化合物是可以用作药物中的有效成分来治疗各种疾病，如：临床移植的排异(包括器官移植、急性移植、异体移植和同体移植，如利用在烧伤的处理中)，避免缺血性或再灌注损伤，如在器官移植中引起的缺血性和多次灌注的损伤，还可以治疗心急梗死、中风或其它疾病；诱导移植耐受、治疗关节炎(如风湿性关节炎、牛皮癣型关节炎、骨关节炎)；多种硬化症、炎症性肠道疾病，包括溃疡性结肠炎和Crohn’s疾病；狼疮(***性红斑狼疮)；移植物抗宿主病；T细胞超敏反应，包括接触性超敏反应，延迟型超敏反应，麸质过敏性肠病(麸质过敏症)、牛皮癣、接触性皮炎(包括由毒葛导致的)、桥本甲状腺炎、干燥综合症、自体免疫性甲状腺功能亢进，如Grave病、阿狄森病、肾上腺自身免疫性疾病、多腺体自身免疫综合症、免疫性脱发、恶性贫血、白癜风、免疫性垂体机能减退、格林—巴利综合症，还有其他的免疫性疾病，如：肾小球肾炎、血清病、荨麻疹，再有过敏性疾病如呼吸***过敏性疾病(哮喘、花粉热、过敏性鼻炎)或者皮肤过敏；scleracierma；蕈样肉芽肿；急性炎性反应(如急性呼吸窘迫综合症和缺血-再灌注损伤)；皮肌炎；斑秃；慢性光化性皮炎、湿疹、***、掌趾脓疱病、坏疽性脓皮病、塞泽瑞综合症(Sezary’s syndrome)、异位性皮炎、硬皮病。皮肤病是皮肤(包括毛发和甲)受到内外因素的影响 后，其形态、结构和功能均发生变化，产生病理过程，并相应的产生各种临床表现，是严重影响人们健康的常见病、多发病之一，如麻风、疥疮、真菌病、银屑病、皮肤细菌感染等。皮肤病的发病率很高，多数较轻，常不影响健康(但少数较重甚至可以危及生命)，但严重影响患者外观相貌，给患者带来了沉重的心理负担，进而影响患者的日常工作与生活。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.
其中，银屑病又称“牛皮癣”，是一种常见的免疫介导的慢性炎症性皮肤病，临床表现具有顽固性和复发性的特点，发病率在西方约为2％，亚洲大概0.5％，但近年来增长迅速。据报道，2019年全球银屑病治疗药物市场将达90.2亿美元。银屑病的皮肤损害形式多种多样，常分为寻常型银屑病、红皮病型银屑病、脓疱型银屑病、关节病型银屑病。其中，大部分(＞85％)为寻常型患者。银屑病除引起皮损部位瘙痒、出血等不适外还可干扰患者的日常生活和生活质量。其中，红皮病型银屑病和脓疱型银屑病可引起全身的代谢紊乱，出现心血管和肺等多脏器的并发症以及感染等，威胁生命。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.
早期研究认为，银屑病的病理机制主要为表皮增生分化的异常和免疫***的激活。银屑病的治疗主要依据病情的轻重和银屑病的分型而采用外用药物、光疗和全身***给药等治疗方法。接近90％的银屑病患者为轻、中度；轻、中度寻常型银屑病的一线治疗药物多为外用药物，通常包括角质松解剂、维生素D类似物、皮质类固醇、地蒽酚、煤焦油、外用维A酸等。2008年中国银屑病治疗指南将他扎罗汀(维A酸类)、中效与强效的糖皮质激素、卡泊三醇(VitD3衍生物)做为局部治疗的推荐药物。然而皮质类固醇激素长期使用可引起皮肤萎缩、毛细血管扩张、毛囊炎、色素沉着或减退等副反应。大面积长期应用强效糖皮质激素制剂可引起全身反应，停药后甚至诱发脓疱型或红皮病型银屑病。维A酸类存在皮肤黏膜刺激症状，尤其过敏体质患者容易发生。卡泊三醇较常见的副作用为瘙痒症、皮肤刺激、灼烧感、刺痛感、皮肤干燥、红斑和皮疹，并对钙代谢有一定的影响。因此，虽然有众多方法可供选择，但治疗银屑病的药物通常情况下疗效有限、长期使用多有毒性和副作用，不能满足长期有效治疗的需要。如红皮病型银屑病和脓疱型银屑病的发生和加重，除一部分病因不明者外，相当一部分是治疗不当所致。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.
发明内容Summary of the invention
本申请涉及苯烯莫德(即式Ⅰ所示的化合物)的新晶型、含有该新晶型的药物组合物、该新晶型和药物组合物的医药用途及新晶型的制备方法。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.
Figure PCTCN2018108990-appb-000001
Figure PCTCN2018108990-appb-000001
一方面，本申请提供了苯烯莫德的晶型I。In one aspect, the application provides Form I of phenenimod.
在一些实施方式中，苯烯莫德晶型I的X射线粉末衍射谱图具有衍射角2θ为15.0°、19.0°、20.1°、21.4°、22.3°和24.4°±0.2°的特征峰。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°.
在另一些实施方式中，苯烯莫德晶型I的X射线粉末衍射谱图具有衍射角2θ为15.0°、17.8°、19.0°、20.1°、21.4°、22.3°、24.4°、26.2°和27.8°±0.2°的特征峰。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 °.
在另一些实施方式中，苯烯莫德晶型I具有如图1所示的X-射线粉末衍射图。In other embodiments, the phenenyl form I has an X-ray powder diffraction pattern as shown in FIG.
另一方面，本申请提供了苯烯莫德的晶型II。In another aspect, the present application provides Form II of phenenimod.
在一些实施方式中，苯烯莫德晶型II的X射线粉末衍射谱图具有衍射角2θ为7.2°、14.5°、18.0°、19.8°、22.0°和23.5°±0.2°的特征峰。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°.
在另一些实施方式中，苯烯莫德晶型II的X射线粉末衍射谱图具有衍射角2θ为7.2°、14.5°、18.0°、18.7°、19.8°、21.4°、22.0°、23.5°和27.6°±0.2°的特征峰。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 °.
在另一些实施方式中，苯烯莫德晶型II具有如图2所示的X-射线粉末衍射图。In other embodiments, phenenyl Form II has an X-ray powder diffraction pattern as shown in FIG.
另一方面，本申请提供了苯烯莫德的晶型III。In another aspect, the present application provides Form III of phenenimod.
在一些实施方式中，苯烯莫德晶型III的X射线粉末衍射谱图具有衍射角2θ为5.8°、11.5°、12.5°、14.1°、16.0°和17.3°±0.2°的特征峰。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°.
在另一些实施方式中，苯烯莫德晶型III的X射线粉末衍射谱图具有衍射角2θ为5.8°、11.5°、12.5°、14.1°、16.0°、16.8°、17.3°、19.1°和28.4°±0.2°的特征峰。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 °.
在另一些实施方式中，苯烯莫德晶型III具有如图3所示的X-射线粉末衍射图。In other embodiments, phenenyl Form III has an X-ray powder diffraction pattern as shown in FIG.
另一方面，本申请提供了苯烯莫德的晶型IV。In another aspect, the present application provides Form IV of phenenimod.
在一些实施方式中，苯烯莫德晶型IV的X射线粉末衍射谱图具有衍射角2θ为12.1°、13.3°、16.0°、20.0°、24.3°和27.1°±0.2°的特征峰。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°.
在另一些实施方式中，苯烯莫德晶型IV的X射线粉末衍射谱图具有衍射角2θ为12.1°、13.3°、16.0°、20.0°、20.9°、22.6°、24.3°、25.4°和27.1°±0.2°的特征峰。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 °.
在另一些实施方式中，苯烯莫德晶型IV具有如图4所示的X-射线粉末衍射图。In other embodiments, the phenenimomorph Form IV has an X-ray powder diffraction pattern as shown in FIG.
本申请进一步提供了一种药物组合物，该药物组合物含有治疗有效量的苯烯莫德晶型I、II、III和/或IV和药学上可接受的非活性成分。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.
在一些实施方式中，所述药物组合物中苯烯莫德晶型I、II、III和/或IV的纯度为≥85质量％。In some embodiments, the purity of phenenyl Form I, II, III, and/or IV in the pharmaceutical composition is > 85% by mass.
在另一些实施方式中，所述药物组合物中苯烯莫德晶型I、II、III和/或IV的纯度为≥95质量％。In other embodiments, the purity of phenenyl Form I, II, III, and/or IV in the pharmaceutical composition is > 95% by mass.
在另一些实施方式中，所述药物组合物中苯烯莫德晶型I、II、III和/或IV的纯度为≥99质量％.In other embodiments, the purity of the phenenyl form I, II, III, and / or IV in the pharmaceutical composition is ≥ 99% by mass.
在另一些实施方式中，所述药物组合物中苯烯莫德晶型I、II、III和/或IV的纯度为≥99.5质量％。In other embodiments, the purity of phenenyl Form I, II, III, and/or IV in the pharmaceutical composition is > 99.5% by mass.
在一些实施方式中，所述药物组合物包含0.01质量％-99质量％的式I所示化合物的晶型。例如，所述药物组合物包含0.5质量％-90质量％的式I所示化合物的晶型；所述药物组合物包含1.0质量％-80质量％的式I所示化合物的晶型；所述药物组合物包含1.5质量％-70质量％的式I所示化合物的晶型；所述药物组合物包含3质量％-60质量％的式I所示化合物的晶型；药物组合物包含4质量％-55质量％的式I所示化合物的晶型；所述药物组合物包含5质量％-50质量％的式I所示化合物的晶型；所述药物组合物包含7.5质量％-40质量％的式I所示化合物的晶型；所述药物组合物包含10质量％-30质量％的式I所示化合物的晶型。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.
在另一些实施方式中，所述的药物组合物还含有至少一种其他活性成分。In other embodiments, the pharmaceutical composition further comprises at least one other active ingredient.
在另一些实施方式中，所述药物组合物适用于局部给药(局部给药包括外用给药)。In other embodiments, the pharmaceutical composition is suitable for topical administration (topical administration includes topical administration).
在另一些实施方式中，所述药物组合物为软膏剂。In other embodiments, the pharmaceutical composition is an ointment.
在另一些实施方式中，所述药物组合物为乳膏。In other embodiments, the pharmaceutical composition is a cream.
在另一些实施方式中，所述药物组合物为凝胶剂。In other embodiments, the pharmaceutical composition is a gel.
在另一些实施方式中，所述凝胶剂为透明凝胶剂。In other embodiments, the gelling agent is a clear gelling agent.
本申请还提供了上述苯烯莫德晶型或其药物组合物用于制备治疗治疗自身免疫性疾病、炎症性和细胞扩散性疾病的药物的应用。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.
正如科技文献和专利中所报道，有免疫调控活性的化合物是可以用于治疗动物和人的相关疾病。有免疫调控活性的化合物，如本申请在此公开的化合物苯烯莫德晶型是可以用作药 物中的有效成分来治疗与免疫调控活性相关的疾病，如：临床移植的排异(包括器官移植、急性移植、异体移植和同体移植，如利用在烧伤的处理中)，避免缺血性或再灌注损伤，如在器官移植中引起的缺血性和多次灌注的损伤，还可以治疗心急梗死、中风或其它疾病；诱导移植耐受、治疗关节炎(如风湿性关节炎、牛皮癣型关节炎、骨关节炎)；多种硬化症、炎症性肠道疾病，包括溃疡性结肠炎和Crohn’s疾病；狼疮(***性红斑狼疮)；移植物抗宿主病；T细胞超敏反应，包括接触性超敏反应，延迟型超敏反应，麸质过敏性肠病(麸质过敏症)、牛皮癣、接触性皮炎(包括由毒葛导致的)、桥本甲状腺炎、干燥综合症、自体免疫性甲状腺功能亢进，如Grave病、阿狄森病、肾上腺自身免疫性疾病、多腺体自身免疫综合症、免疫性脱发、恶性贫血、白癜风、免疫性垂体机能减退、格林—巴利综合症，还有其他的免疫性疾病，如：肾小球肾炎、血清病、荨麻疹，再有过敏性疾病如呼吸***过敏性疾病(哮喘、花粉热、过敏性鼻炎)或者皮肤过敏；scleracierma；蕈样肉芽肿；急性炎性反应(如急性呼吸窘迫综合症和缺血-再灌注损伤)；皮肌炎；斑秃；慢性光化性皮炎、湿疹、***、掌趾脓疱病、坏疽性脓皮病、塞泽瑞综合症(Sezary’s syndrome)、异位性皮炎、硬皮病,痤疮和酒渣鼻(rosacea)。在一些实施方式中，所述自身免疫性疾病是组织过度增生性疾病、结肠炎或过敏性疾病。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.
在另一些实施方式中，所述组织过度增生性疾病是皮肤病或皮肤肿瘤及其并发症；所述结肠炎是过敏性结肠炎。In other embodiments, the tissue hyperproliferative disorder is a skin disease or a skin tumor and a complication thereof; the colitis is hypersensitivity colitis.
在另一些实施方式中，所述皮肤病包括银屑病、硬皮病和/或湿疹。In other embodiments, the skin condition comprises psoriasis, scleroderma, and/or eczema.
在另一些实施方式中，所述银屑病为轻中度银屑病或寻常型银屑病。In other embodiments, the psoriasis is mild to moderate psoriasis or psoriasis vulgaris.
本申请还进一步提供了苯烯莫德晶型I、II、III和/或IV和上述药物组合物用于抑制白介素-2、白介素-13、白介素-17和/或肿瘤坏死因子的过度表达，或用于抑制T细胞的活化与迁移，或与细胞扩散有关的肿瘤。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.
本申请还进一步提供了一种治疗哺乳动物的自身免疫性疾病的方法，包括对患有自身免疫性疾病的患者施用治疗有效量的苯烯莫德晶型I、II、III和/或IV或上述药物组合物。本申请还进一步提供了一种治疗哺乳动物的组织过度增生性疾病的方法，包括对患有组织过度增生疾病的患者施用治疗有效量的苯烯莫德晶型I、II、III和/或IV或上述药物组合物。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.
在一些实施方式中，所述自身免疫性疾病包括组织过度增生性疾病，结肠炎或过敏性疾病。所述结肠炎是过敏性结肠炎。In some embodiments, the autoimmune disease comprises a tissue hyperproliferative disorder, colitis or an allergic disease. The colitis is allergic colitis.
在一些实施方式中，所述组织过度增生疾病为皮肤病或皮肤肿瘤及其并发症。In some embodiments, the tissue hyperproliferative disorder is a skin disease or a skin tumor and a complication thereof.
在另一些实施方式中，所述皮肤病为银屑病、硬皮病和/或湿疹。In other embodiments, the skin disorder is psoriasis, scleroderma, and/or eczema.
在另一些实施方式中，所述银屑病为轻中度银屑病或寻常型银屑病。In other embodiments, the psoriasis is mild to moderate psoriasis or psoriasis vulgaris.
在另一些实施方式中，所述哺乳动物是人。In other embodiments, the mammal is a human.
本申请还提供了制备苯烯莫德晶型I的方法，所述方法包括：The application also provides a method of preparing phenenyl form I, the method comprising:
a)无定型式I所示化合物溶于正溶剂制得饱和溶液存于容器A中，然后将5到15倍正溶剂体积的反溶剂加到另一容器B中；之后将容器A敞口置于容器B中并于室温下静置至析出晶体且容器B密封；其中，所述正溶剂为乙醇、乙腈、乙酸乙酯或甲基叔丁基醚，所述反溶剂为水或正庚烷；或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)室温下，无定型式I所示化合物溶于溶剂或混合溶剂中制得过饱和溶液，然后加热到30到70℃并搅拌0.2-1小时后，过滤并降温至5℃或以下后静置析晶，其中所述溶剂为甲醇/水的混合物，尤其是混合溶剂的体积比为1:1；或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)室温下，无定型式I所示化合物溶于溶剂或混合溶剂中制得过饱和溶液，然后加热到30到70℃并搅拌0.2-1小时后，过滤并降温至5℃或以下后静置，然后置于室温下挥发析出固体，其中所述溶剂为甲苯，氯仿等单一溶剂，或者乙腈/水，异丙醇/正康烷，乙酸乙酯/正庚烷，2-甲基四氢呋喃/正庚烷，或1,4二氧六环/正庚烷的混合物，尤其是混合溶剂的体积比为1:1；或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)无定型式I所示化合物溶于溶剂或混合溶剂配制成饱和溶液，过滤到新的容器中制得澄清溶液，室温下静置挥发析晶，其中所述溶剂为乙醇，异丙醇，乙腈，乙酸乙酯，或者混合溶剂乙腈/水、1,4二氧六环/水或乙酸异丙酯/正庚烷，尤其体积比为1:1的混合溶剂；或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)无定型式I所示化合物溶于正溶剂制得饱和溶液，过滤得澄清溶液，加入反溶剂直至有固体析出；若加入高到25倍体积的反溶剂仍无固体析出，放置在室温缓慢挥发析晶；所述正溶剂为甲醇、乙醇或丙酮时，反溶剂是水，所述正溶剂是甲苯、氯仿、乙酸乙酯或甲基叔丁基醚时，反溶剂为正庚烷；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)无定型式I所示化合物溶于溶剂/混合溶剂中制得饱和澄清溶液，加入无定型式I所示化合物质量之10-30％的混和高聚物A，即聚乙烯吡咯烷酮，聚乙烯醇，聚氯乙烯，聚醋酸乙烯酯，羟丙基甲基纤维素和甲基纤维素混合物，尤其是等质量混合物，或混和高聚物B，即聚己酸内酯，聚乙二醇，聚甲基丙烯酸甲酯，海藻酸钠和羟乙基纤维素混合物，尤其 是等质量混合；或者甲基纤维素水溶液，或聚乙烯醇水溶液于澄清溶液中，置于室温下挥发析晶体(试验作避光处理)。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).
本申请提供的制备苯烯莫德晶型II的方法包括：The method for preparing phenenyl form II provided by the present application includes:
a)无定型式I所示化合物或晶型I溶于正溶剂四氢呋喃，或者甲苯制得饱和溶液存于容器A中，然后将5到15倍正溶剂体积的反溶剂正庚烷加到另一容器B中；之后将容器A敞口置于容器B中并于室温下静置至析出晶体且容器B密封；或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)室温下，无定型式I所示化合物或晶型I溶于混合溶剂中制得过饱和溶液，然后加热到30到70℃并搅拌0.2-1小时后，过滤并降温至5℃或以下后静置析晶。仍澄清的溶液则置于室温下缓慢挥发析出固体，其中所述溶剂为四氢呋喃/水的混合物，尤其是混合溶剂的体积比为1:1；或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)无定型式I所示化合物或晶型I溶于溶剂或混合溶剂配制成饱和溶液，过滤到新的容器中制得澄清溶液，室温下静置挥发析晶，其中所述溶剂为甲醇，四氢呋喃，或者混合溶剂二氯甲烷/正庚烷，或甲醇/水，尤其体积比为1:1的混合溶剂；或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)无定型式I所示化合物或晶型I溶于正溶剂制得饱和溶液，过滤得澄清溶液，加入反溶剂直至有固体析出；若加入高到25倍体积的反溶剂仍无固体析出，放置在室温缓慢挥发析晶，或先将溶液放置在5℃或以下搅拌过夜，然后放置在室温缓慢挥发析晶；所述正溶剂为异丙醇、乙腈或四氢呋喃时，反溶剂是水；所述正溶剂是乙酸异丙酯、1，4-二氧六环、四氢呋喃或甲苯时，反溶剂为正庚烷；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)无定型式I所示化合物或晶型I溶于四氢呋喃中制得饱和澄清溶液，加入无定型式I所示化合物或晶型I质量之10-30％的离子液体[Bmim]PF6(1-丁基-3-甲基咪唑六氟磷酸盐)，置于室温下挥发析晶体。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.
本申请提供的制备苯烯莫德晶型III的方法包括：The method for preparing phenenyl form III of the present application includes:
a)无定型式I所示化合物或晶型I溶于混合溶剂配制成饱和溶液，过滤到新的容器中制得澄清溶液，室温下静置挥发析晶，其中所述混合溶剂为甲基叔丁基醚/正庚烷，尤其体积比为1:1的混合溶剂；或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)无定型式I所示化合物或晶型I溶于甲基叔丁基醚制得澄清溶液，放置，然后在室温缓慢挥发析晶体；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)无定型式I所示化合物或晶型I溶于二甲亚砜(DMSO)中，过滤得澄清溶液，向该透明溶液中加入反溶剂水至有固体析出；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)无定型式I所示化合物或晶型I溶于甲基叔丁基醚制得澄清溶液，将溶液放置在5℃或以下搅拌过夜，然后放置在室温缓慢挥发析晶，然后在室温缓慢挥发析晶体。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.
本申请提供的制备苯烯莫德晶型IV的方法包括：The method for preparing phenenyl form IV provided by the present application includes:
a)晶型I加入到丙酮/水的混合溶剂中配制成20-30mg/ml的悬浮液，该悬浮液在搅拌下加热到40-60℃，尤其50℃左右，0.2到1个小时，过滤到新的容器中制得澄清溶液，该溶液降温到5℃或以下后，在室温下静置挥发析晶；或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)无定型式I所示化合物或晶型I溶于氯仿或丙酮，过滤制得澄清溶液，然后在室温缓慢挥发析晶体；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)晶型I加入到丙酮/正庚烷，或者乙腈/水的混合溶剂，尤其是1：4的体积比例，配制成10-20mg/ml的浑浊液，该浑浊液在室温下搅拌(试验作避光处理)1到3天后得到晶体；或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)无定型式I所示化合物或晶型I溶于氯仿中，过滤得澄清溶液，向该透明溶液中加入反溶剂正庚烷至有固体析出。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.
本申请提供的苯烯莫德晶型I、晶型Ⅱ、晶型III或晶型IV的纯度≥85％，≥95％，或甚至≥99％或99.5％。The purity of phenenyl Form I, Form II, Form III or Form IV provided herein is ≥85%, ≥95%, or even ≥99% or 99.5%.
本申请披露的晶型可以从含有至少一种溶剂的合适的溶剂体系中结晶，可通过溶剂蒸发、冷却和/或通过加入反溶剂(本申请中所述苯烯莫德溶解性较差的溶剂)，在溶剂体系中达到过饱和实现。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.
如本申请所披露的，结晶可使用或不使用晶种。As disclosed herein, crystals may or may not be seeded.
本申请披露的独特的晶型的结晶与特定条件下结晶过程的动力学和平衡性能有关。因此，本领域的技术人员会意识到，得到的晶型取决于结晶过程的动力学和热力学。在特定条件下(如，溶剂、温度、压力和本申请化合物的浓度)，一种晶型可能要比另一种晶型稳定(或实际上比任何其他晶型稳定)。然而，具有相对较低热力学稳定性的晶型可能动力学上有利。因此动力学之外的因素，例如时间、杂质分布、搅动、晶种的存在与否等也可能影响结晶的形式。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.
另一方面，本申请提供了一种药物组合物，包括治疗有效量的至少一种上述苯烯莫德晶型和至少一种药学上可接受的非活性成分。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.
术语“治疗有效量”是指一个化合物用于治疗对象时对于治疗一种疾病、或一种疾病或病症的至少一种临床症状时，足以影响对疾病、病症或症状的这种治疗的量。“治疗有效量”可以随着化合物，疾病、病症、和/或疾病或病症的症状，疾病、病症、和/或疾病或病症的症状的严重程度，被治疗患者的年龄，和/或被治疗患者的体重等变化。在任意可能的情况下，一个合适的剂量对那些本领域的技术人员可以是显而易见的，也可以是用常规实验确定的。在联合治疗的情况下，“治疗有效量”是指有效治疗疾病、病症或病状的联用对象的总量。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.
所述“药学上可接受的非活性成分”是指适合于期望药物制剂的常规的药用非活性成分。例如：诸如水、各种有机溶剂等的稀释剂；诸如淀粉、蔗糖等的填充剂；诸如纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮(PVP)的黏合剂；诸如甘油的湿润剂；诸如琼脂、碳酸钙和碳酸氢钠的崩解剂；诸如季铵化合物吸收促进剂；诸如十六烷醇的表面活性剂；诸如高岭土和皂黏土的吸收载体；诸如滑石粉、硬脂酸钙、硬脂酸镁和聚乙二醇等的润滑剂。另外还可以在药物组合物中加入其它药学上可接受的非活性成分如分散剂、稳定剂、增稠剂、络合剂、缓冲剂、渗透促进剂、聚合物、芳香剂、甜味剂和染料。优选使用适合期望剂型和期望给药方式的非活性成分。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.
本申请还提供包括至少一种能够以有效量治疗上述病症的式I化合物和一种药学可接受的载体或稀释剂的药物组合物。本申请的组合物可以含有其它为本领域技术人员所公知的试剂，可能通过使用常规的固体或液体载体或稀释剂，以及一类适合于所需要的给药方式的药物添加剂(例如，赋形剂，粘合剂，防腐剂，稳定剂，调味剂等等)根据药物制剂领域众所周知的工艺加以配制。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.
含有活性组分的本申请的药物组合物可为以适合于全身性、口服和/或局部使用的形式。例如，药物组合物可能以无菌注射水溶液或油脂性悬浮液的形式。该悬浮液可能根据已知的技术使用适宜的分散剂或润湿剂和如上所述的悬浮剂配制。无菌注射制剂还可以是一种在无毒的肠胃外可接受的稀释剂或溶剂中的的无菌可注射溶液或悬浮液，例如在1,3-丁二醇中的溶液。在可以使用的可接受的赋形剂和溶剂中可以是水，林格溶液和等渗氯化钠溶液。另外，无菌的，固定油类通常作为溶剂或悬浮介质使用。为此目的可以使用任何温和的固定油，包括合成的甘油单酯或二酯。另外，脂肪酸例如油酸可以应用于注射制剂。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.
对于直肠给药的药物也可以将通式I的化合物以栓剂的形式配制。这些组合物可以通过将药物与一种适宜的无刺激性的赋形剂混合制备，该赋形剂在常规温度下为固体但在直肠温度下为液体，因此在直肠中融化释放出药物。这样的材料为可可脂和聚乙二醇。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.
对于口服的制剂可为片剂，锭剂，糖锭，水溶液或油状悬浮液，可分散性粉剂或粒剂，乳剂，硬的或软的胶囊，或糖浆剂或酏剂。口服用途的组合物可以根据任何本领域已知的制备药物组合物的方法制备。片剂中含有活性组分与适合于制造片剂的无毒药学可接受的赋形剂的混合物。这些赋形剂可以是例如惰性的稀释剂，如碳酸钙，碳酸钠，乳糖，磷酸钙或磷酸钠；造粒和崩解剂，如玉米淀粉或海藻酸；粘合剂，如淀粉，凝胶或***胶，以及润滑剂，如硬脂酸镁，硬脂酸或滑石粉。片剂可能是无包覆的或可能是为了延迟解体和在胃肠道吸收通过已知的技术包衣的，且由此提供比较长的持续作用时间。例如，可以使用一种时间延迟材料例如单硬脂酸甘油酯或二硬脂酸甘油酯。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.
本申请的药物组合物还可以是水包油乳化剂的形式。油相可以是一种植物油，例如橄榄油或花生油，或一种矿物油例如液体石蜡或这些的混合物。适宜的乳化剂可以是天然存在的磷脂，例如大豆，卵磷脂，和来源于脂肪酸和己糖醇酸酐的酯或偏酯，例如单油酸山梨醇酯，和所述偏酯与环氧乙烷的缩合产物，例如聚氧化乙烯单油酸山梨醇酯。乳剂还可能含有甜味剂和调味剂。糖浆剂和酏剂可以与甜味剂例如甘油，丙二醇，山梨糖醇或蔗糖一起制备。这种制剂还可能含有缓和剂，防腐剂和调味剂和着色剂。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.
对于局部使用，可使用含有式I化合物的乳膏，油膏，凝胶物，溶液或悬浮液，等等(对此用药目的，局部用药不仅包括外用给药，还包括洗口药以及含漱剂的给药方式)。这样的局部制剂的制备已经在本领域的药物制剂中较好的描述，例如在Remington’s Pharmaceutical Science，第17版，Mack出版社，Easton，PA中。对于局部用药，这些化合物也可以以粉末或喷雾剂给药，特别是以气雾剂形式。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.
剂量水平在每天约0.01毫克—约140毫克/千克体重，可有效用于治疗上述指明的病症，或者每个患者可以每天约0.5毫克至约7克剂量给药。例如，以每天每公斤体重约0.01至50毫克，或者每患者每天约0.5毫克至约3.5克，优选每患者每天2.5毫克至1克给予本化合物可以有效地治疗炎症。然而可以理解，对于特殊病人的特定剂量水平将取决于多因素，包括年龄，体重，通常的健康状态，性别，饮食，给药时间，给药途径，***速度，药物结合和受到治疗的特定疾病的严重程度。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.
与载体材料相结合以制备单一剂型的活性组分的量将随治疗的主体的改变和特别的给药方式而不同。例如，人的口服制剂可以含有活性剂0.5毫克至5克，并与占组合物总量约百分之5至约95的适当量的载体混合。剂量单元形式通常将含有约1毫克至约500毫克的—活性组分，典型地含有25毫克，50毫克，100毫克，200毫克，300毫克，400毫克，500毫克，600毫克，800毫克，或1000毫克。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.
扩散在一些实施方式中，合适的药物非活性成分选自水、各种有机溶剂和各种惰性稀释剂或填料。如有需要，所述药物组合物可含有一种或多种添加剂，如香料、粘合剂和赋形剂。对于口服给药，片剂可包含至少一种非活性成分选自，例如柠檬酸；诸如淀粉、藻酸及某些复合硅酸盐的各种分解剂；诸如蔗糖、明胶及***胶的各种粘合剂。此外，诸如硬脂酸镁及滑石粉的润滑剂常用于制作片剂的填料。这些成分也可填充于软和硬的明胶胶囊中。当用于口服而且需要是水悬浮液时，其中的活性化合物可与选自各种甜味剂或香味剂、颜料或染料组合的至少一种成分混合。如有需要，可使用各种乳化剂或悬浮剂；还可使用诸如水、乙醇、丙二醇、甘油、或他们的组合的稀释剂。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.
在一些实施方式中，所述药物组合物还包括至少一种其他活性成分。In some embodiments, the pharmaceutical composition further comprises at least one other active ingredient.
包括本申请晶型的药物组合物可通过经皮给药或局部施用的方式对需要治疗的患者给药。经皮给药时，药物组合物可以制成诸如乳膏、凝胶等剂型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.
在一些实施方式中，所述药物组合物，可以诸如膏剂、乳膏或软膏的局部施用的形式给药。In some embodiments, the pharmaceutical composition can be administered in the form of a topical application such as a cream, cream or ointment.
在一些实施方式中，本申请的药物组合物可以通过药学领域的常规方法制备。例如，将活性成分与一种或多种非活性成分混合，然后将其制成所需的剂型。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.
上述晶型主要的特征峰可再现并且在误差限度内(即所述值±0.2°)。The main characteristic peaks of the above crystal forms are reproducible and within the margin of error (i.e., the value is ± 0.2°).
本申请中，“具有如图1所示的X射线粉末衍射图谱”是指X-射线粉末衍射图示出的主要的峰如图1所示，其中主要的峰是指与图1中最高的峰(其相对强度定为100％)相比，相对强度超过10％，优选超过30％的那些峰。同样地，本申请中，具有如图2、图3或图4所示的X-射线粉末衍射图，分别指X-射线衍射图示出的主要的峰如图2、图3及图4所示，其中主要的峰是指与图2、图3及图4中最高的峰(其相对强度定为100％)相比，相对强度超过10％，优选超过30％的那些峰。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%).
附图说明DRAWINGS
图1：式I所示化合物晶型I的X-射线粉末衍射图谱；Figure 1: X-ray powder diffraction pattern of Form I of the compound of Formula I;
图2：式I所示化合物晶型Ⅱ的X-射线粉末衍射图谱；Figure 2: X-ray powder diffraction pattern of Form II of the compound of Formula I;
图3：式I所示化合物晶型III的X-射线粉末衍射图谱；Figure 3: X-ray powder diffraction pattern of Form III of the compound of Formula I;
图4：式I所示化合物晶型IV的X-射线粉末衍射图谱；Figure 4: X-ray powder diffraction pattern of Form IV of the compound of Formula I;
具体实施方式Detailed ways
本申请通过但不限于下述实施例，来进一步说明本申请。在这些实施例中使用的技术或方法，除非另有说明，为本领域的常规技术或方法。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.
XRPD反射模式图在PANalytacal Empyrean(CPE-026)和X’Pert3(CPE-135)X射线粉末衍射分析仪上采集，透射模式在PANalytacal Empyrean(CPE-026)X射线粉末衍射分析仪上采集扫描参数如表1所示。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.
表1Table 1
Figure PCTCN2018108990-appb-000002
Figure PCTCN2018108990-appb-000002
实施例1.晶型I的制备Example 1. Preparation of Form I
晶型I的制备方法一Preparation method of crystal form I
约15毫克的无定型式I所示化合物(简称原料)溶于表1-1中相应的正溶剂制得饱和溶液，并过滤到3毫升小瓶中制得澄清液。20毫升的小瓶中加入4.0毫升的反溶剂(如表1-1所示)，将装有澄清液的3毫升小瓶敞口置于20毫升小瓶后，密封20毫升的小瓶并于室温下静 置(试验作避光及充N 2保护处理)。所有观察到的固体均被分离并经XRPD分析，确认均为晶型I。未析出固体的澄清液体则放置在室温下缓慢挥发析晶，得到的固体经XRPD分析，确认均为晶型I。特别地，带有“*”的晶型I通过温室下缓慢挥发制得。 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.
表1-1Table 1-1
Figure PCTCN2018108990-appb-000003
Figure PCTCN2018108990-appb-000003
晶型I的制备方法二Preparation method 2 of crystal form I
室温下，约25毫克的无定型式I所示化合物(简称原料)在3毫升小瓶中，加入1.0毫升表1-2中相应的溶剂或混合溶剂制得过饱和混悬液。该混悬液加热到50℃并搅拌0.5小时后，过滤到新的小瓶中得到澄清溶液，该澄清溶液降温至5℃后，放置在5℃恒温的生物培养箱中(试验作避光处理)析晶，分别分离所有析出的固体。仍无固体析出的澄清液体则置于室温下缓慢挥发析出固体并分离所得固体。经XRPD分析，确认均为晶型I。特别地，带有“*”的晶型I通过温室下缓慢挥发制得。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.
表1-2Table 1-2
Figure PCTCN2018108990-appb-000004
Figure PCTCN2018108990-appb-000004
Figure PCTCN2018108990-appb-000005
Figure PCTCN2018108990-appb-000005
晶型I的制备方法三Preparation method 3 of crystal form I
约15毫克的无定型式I所示化合物(简称原料)至3毫升小瓶中，分别溶于1.0～1.5mL的表1-3中的溶剂或混合溶剂配制成饱和溶液，过滤到一个新的小瓶制得澄清溶液，用封口膜封住装有澄清溶液的小瓶并在上面扎5～6个小孔后，放置在室温下缓慢挥发(试验作避光处理)。分别收集所得固体，经XRPD分析，确认均为晶型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.
表1-3Table 1-3
原料质量(毫克)Raw material quality (mg) 溶剂，V:VSolvent, V: V 溶剂体积(毫升)Solvent volume (ml) 所得晶型Crystal form
15.015.0 乙醇Ethanol 1.01.0 晶型ICrystal form I
15.015.0 异丙醇Isopropanol 1.01.0 晶型ICrystal form I
14.814.8 乙腈/水，1:1Acetonitrile/water, 1:1 1.51.5 晶型ICrystal form I
14.814.8 1,4二氧六环/水，1:11,4 dioxane / water, 1:1 1.01.0 晶型ICrystal form I
15.115.1 乙酸异丙酯/正庚烷，1:1Isopropyl acetate / n-heptane, 1:1 1.01.0 晶型ICrystal form I
晶型I的制备方法四Preparation method 4 of crystal form I
约15毫克的无定型式I所示化合物(简称原料)至3毫升小瓶中，分别溶于1.0mL表1-4中的溶剂配制成溶液，过滤到新的小瓶制得澄清溶液，敞口放置在室温下挥发(试验作避光处理)。分别分离所得固体并经XRPD分析，确认均为晶型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.
表1-4Table 1-4
原料质量(毫克)Raw material quality (mg) 溶剂Solvent 溶剂体积(毫升)Solvent volume (ml) 所得晶型Crystal form
14.914.9 乙腈Acetonitrile 1.01.0 晶型ICrystal form I
14.914.9 乙酸乙酯Ethyl acetate 1.01.0 晶型ICrystal form I
晶型I的制备方法五Preparation method of crystal form I
约20毫克的无定型式I所示化合物(简称原料)置于3毫升的小瓶内，用适量表1-5中的正溶剂溶解并过滤至20毫升小瓶后，向该澄清溶液中加入的反溶剂，边滴加边搅拌直至有固体析出，分离析出的固体并进行XRPD分析确认。若加入10.0毫升反溶剂仍无固体析出，则将 澄清液放置在室温缓慢挥发析晶(试验作避光处理)。分别收集所得固体，经XRPD分析，确认均为晶型I。特别地，带有“*”的晶型I通过温室下缓慢挥发制得。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.
表1-5Table 1-5
Figure PCTCN2018108990-appb-000006
Figure PCTCN2018108990-appb-000006
晶型I的制备方法六Preparation method of crystal form I
15毫克的无定型式I所示化合物(简称原料)溶于表1-6中相应的溶剂/混合溶剂中制得澄清溶液，加入约2.0毫克混和高聚物A(聚乙烯吡咯烷酮，聚乙烯醇，聚氯乙烯，聚醋酸乙烯酯，羟丙基甲基纤维素和甲基纤维素等质量混合)、混和高聚物B(聚己酸内酯，聚乙二醇，聚甲基丙烯酸甲酯，海藻酸钠和羟乙基纤维素等质量混合)或0.5毫升的水溶性高聚物1(甲基纤维素水溶液，5毫克/毫升)、水溶性高聚物2(98％水解的聚乙烯醇水溶液，5毫克/毫升)于澄清溶液中，用封口膜封住小瓶并在上面扎5～6个小孔，置于室温下挥发(试验作避光处理)。分别收集所得固体，并经XRPD分析，确认均为晶型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.
表1-6Table 1-6
Figure PCTCN2018108990-appb-000007
Figure PCTCN2018108990-appb-000007
Figure PCTCN2018108990-appb-000008
Figure PCTCN2018108990-appb-000008
晶型I的制备方法七Preparation method of crystal form I
室温下，约15毫克的无定型式I所示化合物(简称原料)至3毫升的小瓶内，用表1-7中相应的正溶剂溶解，所得澄清溶液一次性加入到含有4.0毫升相应反溶剂的20毫升小瓶中并搅拌5分钟，分离所得固体。若无固体析出，则将澄清液体放置于室温缓慢挥发(试验作避光处理)。分别收集所得固体，并分别经XRPD分析，确认均为晶型I。特别地，带有“*”的晶型I通过温室下缓慢挥发制得。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.
表1-7Table 1-7
Figure PCTCN2018108990-appb-000009
Figure PCTCN2018108990-appb-000009
实施例2.晶型II的制备Example 2. Preparation of Form II
晶型II的制备方法一 Method 1 for preparing Form II
两份14.9毫克晶型I分别溶于0.4毫升四氢呋喃和1毫升甲苯中，分别过滤取得上清液，均转移至3毫升小瓶。另取两个20毫升的小瓶，均加入4.0毫升的正庚烷，将装有上清液的两个3毫升小瓶分别敞口置于两个20毫升小瓶后，密封20毫升的小瓶并于室温下静置(避光且充N 2保护)一天。然后将澄清液体转移到室温下缓慢挥发析晶。收集所得固体，经XRPD分析，确认均为晶型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.
晶型II的制备方法二Preparation method 2 of crystal form II
称取25.1毫克的晶型I于3毫升小瓶中，加1.0毫升的混合溶剂(四氢呋喃/水,v/v＝1:1)，在50℃下搅拌约0.5小时后过滤取上清液，将所得上清液在室温下缓慢挥发析晶，所得固体经XRPD分析，确认均为晶型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.
晶型II的制备方法三Preparation method 3 of crystal form II
约15毫克的晶型I溶于1.0～1.5mL表2-1所列的溶剂或混合溶剂，过滤后得到澄清液，封住装有澄清溶液的小瓶并在封口上扎5个小孔后，放置在室温下缓慢挥发(试验作避光处理)。分别收集所得固体，并经XRPD分析，确认均为晶型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.
表2-1table 2-1
晶型I样品质量(毫克)Form I sample quality (mg) 溶剂,v:vSolvent, v:v 溶剂体积(毫升)Solvent volume (ml) 所得晶型Crystal form
15.115.1 甲醇Methanol 1.01.0 晶型IIForm II
15.315.3 四氢呋喃Tetrahydrofuran 1.01.0 晶型IIForm II
15.015.0 二氯甲烷/正庚烷,1:1Dichloromethane/n-heptane, 1:1 1.51.5 晶型IIForm II
晶型II的制备方法四Method 4 for preparing Form II
约15毫克的晶型I溶于1毫升表2-2所列的溶剂或混合溶剂，分别过滤后得到澄清液，敞口放置在室温下快速挥发(试验作避光处理)。分别收集所得固体，并经XRPD分析，确认均为晶型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.
表2-2Table 2-2
Figure PCTCN2018108990-appb-000010
Figure PCTCN2018108990-appb-000010
晶型II的制备方法五Preparation method of crystal form II
室温下，约20毫克的晶型I溶于0.4毫升的表2-3所列的溶剂中并过滤至20毫升小瓶后，加入反溶剂，边滴加边搅拌至有固体析出或至反溶剂的体积为10.0毫升，若无固体析出，则将澄清液体于5℃下搅拌过夜，若仍无固体析出，则将澄清液放置在室温缓慢挥发析晶(试验作避光处理)。分别收集所得固体，并经XRPD分析，确认均为晶型II。特别地，其中带有“*”的晶型II通过室温缓慢挥发析晶得到。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.
表2-3Table 2-3
晶型I样品质量(毫克)Form I sample quality (mg) 溶剂Solvent 反溶剂Antisolvent 反溶剂体积(毫升)Antisolvent volume (ml) 所得晶型Crystal form
20.220.2 异丙醇Isopropanol 水water 1.81.8 晶型IIForm II
20.020.0 乙腈Acetonitrile 水water 1.01.0 晶型IIForm II
19.919.9 四氢呋喃Tetrahydrofuran 水water 0.80.8 晶型IIForm II
20.320.3 乙酸异丙酯Isopropyl acetate 正康烷Positive alkane 10.010.0 晶型II*Crystal II*
19.919.9 1,4-二氧六环1,4-dioxane 正康烷Positive alkane 10.010.0 晶型II*Crystal II*
晶型II的制备方法六Method 6 for preparing Form II
15.2毫克的晶型I溶于1.0毫升的四氢呋喃中制得澄清溶液于3-mL玻璃瓶中，然后澄清液中加入0.5毫升的聚环氧乙烷水溶液(5.0毫克/毫升)，置于室温条件下挥发(避光)。收集所得固体并经XRPD分析，确认为晶型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.
晶型II的制备方法七Preparation method of crystal form II
15.2毫克晶型I溶于1mL四氢呋喃中制得澄清溶液于3-mL玻璃瓶中，加入2.5毫克离子液体[Bmim]PF6(1-丁基-3-甲基咪唑六氟磷酸盐)，封住小瓶并在封口膜上扎5～6个小孔，置于室温条件下挥发(试验作避光处理)，收集所得固体，经XRPD分析，确认为晶型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.
晶型II的制备方法八Preparation method of crystal form II
室温下，15.1毫克的晶型I溶于0.4毫升的四氢呋喃制得澄清溶液于3-mL玻璃瓶中。所得澄清溶液一次性加入到含有4.0毫升水(反溶剂)的20毫升小瓶中并搅拌约5分钟，若无固体析出，将澄清液体在5℃搅拌过夜，然后将澄清溶液置于室温缓慢挥发(避光处理)，收集所得固体，并经XRPD分析，确认为晶型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.
实施例3 晶型III的制备Example 3 Preparation of Form III
晶型III的制备方法一Preparation method of crystal form III
200.6毫克的晶型I溶于4.0毫升甲基叔丁基醚/正庚烷(v/v,1:1)中，过滤到小瓶中得到澄清溶液，封住小瓶的瓶口并在封口上扎5个小孔，然后置于室温下缓慢挥发(试验作避光处理)。收集所得固体，并经XRPD分析，确认为晶型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.
晶型III的制备方法二Preparation method 2 of crystal form III
15.1毫克的晶型I溶于1.0毫升混合溶剂甲基叔丁基醚/正庚烷(v/v,1:1)，过滤到3-mL玻璃瓶中制得澄清溶液，封住小瓶的瓶口，并扎5个小孔后，置于室温下缓慢挥发(避光处理)。收集所得固体，经XRPD分析，确认为晶型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.
晶型III的制备方法三Preparation method 3 of crystal form III
称取14.9毫克的晶型I样品置于3毫升玻璃瓶中，另在20毫升小瓶中加入4.0毫升甲基叔丁基醚，将3毫升小瓶敞口置于20毫升小瓶中后，将20毫升小瓶密封(试验避光且N2保护)。室温下静置7天后，将澄清液置于室温缓慢挥发析晶，收集所得固体，并经XRPD分析，确认为晶型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.
晶型III的制备方法四Preparation method 4 of crystal form III
室温下，20.2毫克的晶型I溶于0.4毫升二甲基亚砜(DMSO)中，并过滤至20毫升小瓶制得澄清溶液，向该澄清溶液中加入水(反溶剂)，边滴加边搅拌至有固体析出(水的体积为0.4毫升)，分离所得固体，并经XRPD分析，确认为晶型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.
晶型III的制备方法五Preparation method of crystal form III
室温下，15.2毫克的晶型I溶于0.4毫升的甲基叔丁基醚中制得澄清溶液。该澄清溶液被加入到含有4毫升正庚烷(反溶剂)的20毫升小瓶中并搅拌约5分钟后，该澄清液体降温到5℃并于5℃下搅拌过夜。然后将该澄清液体置于室温下缓慢挥发(避光)，收集所得固体并经XRPD分析，确认为晶型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.
实施例4.晶型IV的制备Example 4. Preparation of Form IV
晶型IV的制备方法一 Method 1 for preparing Form IV
室温下，1.0毫升的混合溶剂丙酮/水(v/v,1:1)中加入25.2毫克的晶型I制得混悬液，该混悬液加热到50℃并搅拌0.5小时后，过滤到新的小瓶制得澄清溶液。所得澄清溶液缓慢地从50℃降温至5℃后，置于室温下缓慢挥发，收集所得固体经XRPD分析，确认为晶型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.
晶型IV的制备方法二Method 2 for preparing Form IV
两份15.0mg晶型I分别溶于1.0mL的氯仿和丙酮中，所得溶液分别过滤后，装有澄清溶液的小瓶分别封口并在封口上扎5个小孔后，均置于室温下缓慢挥发(试验作避光处理)。分别收集所得固体，经XRPD分析，确认均为晶型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.
晶型IV的制备方法三Method 3 for preparing Form IV
约20mg的晶型I至1.5毫升玻璃小瓶中，加入0.3毫升表4-1所列的溶剂，得到的浑浊液置于室温下搅拌2天后(试验避光并充N 2保护)，分离固体并经XRPD分析，确认均为晶型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.
表4-1Table 4-1
晶型I质量(毫克)Form I quality (mg) 溶剂，V:VSolvent, V: V 溶剂体积(毫升)Solvent volume (ml) 所得晶型Crystal form
20.520.5 乙腈/水，1:4Acetonitrile / water, 1:4 0.30.3 晶型IVForm IV
20.120.1 丙酮/正庚烷，1:4Acetone / n-heptane, 1:4 0.30.3 晶型IVForm IV
晶型IV的制备方法四Method 4 for preparing Form IV
19.8毫克的晶型I溶于1.0毫升的氯仿并过滤至20毫升小瓶后，加入正庚烷(反溶剂)，边滴加边搅拌至有固体析出(正庚烷共计4.6mL)，分离析出的固体，经XRPD分析，确认为晶型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.
晶型IV的制备方法五Preparation method of crystal form IV
15.1毫克的晶型I样品溶于1.0毫升的丙酮中得澄清溶液，并加入0.5毫升羟乙基纤维素水溶液(5.0毫克/毫升)，使用封口膜封住小瓶并在上面扎5～6个小孔，置于室温条件下挥发(试验作避光处理)。分离所得固体，并经XRPD分析，确认为晶型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.
实施例5.苯烯莫德晶型I、II、III和IV之固态稳定性Example 5. Solid state stability of phenenic moore crystal forms I, II, III and IV
分别称取适量样品在25℃/60％RH和40℃/75％RH条件下敞口放置一周，同时将另一组样品在80℃条件下密封放置24小时。放置后的样品用XRPD和HPLC进行表征，检测晶型和纯度的变化。测试结果汇总于表2中。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.
表2Table 2
Figure PCTCN2018108990-appb-000011
Figure PCTCN2018108990-appb-000011
Figure PCTCN2018108990-appb-000012
Figure PCTCN2018108990-appb-000012
H:小时；W:周、星期；相对纯度:实验后晶型纯度与原始晶型纯度的比值X100.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结果显示，在RRT＝0.41(0.01％)和1.33(0.05％)处有新的杂质峰出现。*: HPLC results showed that new impurity peaks appeared at RRT = 0.41 (0.01%) and 1.33 (0.05%).
结果表明，在所选测试条件下，晶型I具有较好的物理和化学稳定性。The results show that Form I has good physical and chemical stability under the selected test conditions.
实施例6.苯烯莫德晶型I、II、III和IV之平衡溶解度Example 6. Equilibrium Solubility of Phenylene Mod Forms I, II, III and IV
约10毫克晶型I和2.0毫升去离子水加入到4毫升的离心管中制得悬浊液，然后将所得悬浊液置于旋转孵化器上混合(25转/分钟)，并通过生化培养箱控制温度为25℃。在24小时及48小时分别量取0.8毫升悬浮液，离心分离固体(6000转/分钟，3分钟)，取上清液至HPLC小瓶中进行溶解度测试，固体测XRPD。试验结果汇总于表3。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.
表3table 3
Figure PCTCN2018108990-appb-000013
Figure PCTCN2018108990-appb-000013
--：平衡24小时后观察到转晶，故未收集相关数据；--: After the balance was observed for 24 hours, the crystal was observed, so no relevant data was collected;
N/A：未收集相关数据N/A: No relevant data collected
平衡溶解度测试结果表明：晶型II、III和IV在24小时均已出现转晶现象。而晶型I 48小时未出现转晶现象，且在24小时和48小时的溶解值相似，表明晶型I在水中25℃下的平衡溶解度约为0.019毫克/毫升。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.
上述实施例仅为充分说明本申请而列举的具体实施例，本申请的保护范围以权利要求书的内容为准，而不限于上述具体实施方式。本领域的技术人员在本申请基础上所作的不脱离本申请实质内容的等同替代或变换，亦均在本申请的保护范围之内。因此，本申请的主旨和范围并不局限于本文的具体描述。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.
本申请中公开的所有内容，包括摘要和附图，以及公开的任何方法或过程中的所有步骤，均可以任意组合，除非某些特征和/或步骤是相互排斥的组合。本申请公开的每一种特 征，包括摘要和附图，可以被可达到相同、等同或类似目的的替代特征所替换，除非另有明确阐明。因此，除非另有明确阐明，本申请公开的每一种特征只是一个具有等同或相似特征的通用系列的一个具体实例。除了本文中已描述的之外，对于本领域专业技术人员来讲，基于本文的描述内容基础上的对本申请的各种修饰可以是显而易见的。这些修饰也应落在本附加权利要求的范围内。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.
本文中所引用的每一篇参考文献，均以参考方式全文并入本文中。Each of the references cited herein is hereby incorporated by reference in its entirety.

Claims (18)

  1. 式I所示化合物的晶型，a crystalline form of the compound of formula I,
    Figure PCTCN2018108990-appb-100001
    Figure PCTCN2018108990-appb-100001
  2. 根据权利要求1所述的式I所示化合物的晶型，其特征在于，所述晶型为晶型I，其X射线粉末衍射谱图具有衍射角2θ为15.0°、19.0°、20.1°、21.4°、22.3°和24.4°±0.2°的特征峰。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. 根据权利要求1所述的式I所示化合物的晶型，其特征在于，所述晶型为晶型II，其X射线粉末衍射谱图具有衍射角2θ为7.2°、14.5°、18.0°、19.8°、22.0°和23.5°±0.2°的特征峰。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. 根据权利要求1所述的式I所示化合物的晶型，其特征在于，所述晶型为晶型III，其X射线粉末衍射谱图具有衍射角2θ为5.8°、11.5°、12.5°、14.1°、16.0°和17.3°±0.2°的特征峰。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. 根据权利要求1所述的式I所示化合物的晶型，其特征在于，所述晶型为晶型IV，其X射线粉末衍射谱图具有衍射角2θ为12.1°、13.3°、16.0°、20.0°、24.3°和27.1°±0.2°的特征峰。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. 一种药物组合物，其特征在于，含有治疗有效量的式I所示化合物的晶型I、II、III和/或IV以及药学上可接受的非活性成分。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. 根据权利要求6所述的药物组合物，其特征在于，所述的式I所示化合物的晶型的纯度为≥85质量％。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. 根据权利要求6-7任一项所述的药物组合物，其特征在于，所述药物组合物包含0.01质量％-99质量％的式I所示化合物的晶型。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. 根据权利要求6-8任一项所述的药物组合物，其特征在于，所述药物组合物至少还包含一种除苯烯莫德之外的活性成份。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. 根据权利要求6-9任一项所述的药物组合物，其特征在于，所述药物组合物用于经皮给药、口服给药、胃肠外给药和/或局部给药。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. 根据权利要求6-10任一项所述的药物组合物，其特征在于，所述药物组合物选自软膏剂、乳膏或凝胶剂。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. 权利要求1-5任一项所述的晶型或权利要求6-11任一项所述的药物组合物在制备治疗自身免疫性疾病及其并发症的药物中的应用。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. 根据权利要求12所述的应用，其特征在于，所述自身免疫性疾病是组织过度增生性疾病、结肠炎或过敏性疾病。The use according to claim 12, characterized in that the autoimmune disease is a tissue hyperproliferative disease, colitis or an allergic disease.
  14. 根据权利要求13所述的应用，其特征在于，所述组织过度增生性疾病是皮肤病或皮肤肿瘤及他们的并发症；所述结肠炎是过敏性结肠炎。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. 根据权利要求14所述的应用，其特征在于，所述皮肤病选自银屑病、硬皮病和/或湿疹。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. 根据权利要求12所述的应用，其特征在于，所述疾病选自风湿性关节炎、过敏性鼻炎、II型糖尿病、溃疡性结肠炎、红斑狼疮或肺纤维化。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. 权利要求1-5任一项所述的晶型或权利要求6-11任一项所述的药物组合物在制备用于抑制白介素-2、白介素-13、白介素-17和/或肿瘤坏死因子剂的过度表达，或用于抑制T细胞的活化与迁移的药物中的应用。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. 一种制备式I化合物的晶型I的方法，其特征在于所述方法包括：A method of preparing Form I of a compound of Formula I, characterized in that the method comprises:
    a)无定型式I所示化合物溶于正溶剂制得饱和溶液存于容器A中，然后将5到15倍正溶剂体积的反溶剂加到另一容器B中；之后将容器A敞口置于容器B中并于室温下静置至析出晶体且容器B密封；其中，所述正溶剂为乙醇、乙腈、乙酸乙酯或甲基叔丁基醚，所述反溶剂为水或正庚烷；或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)室温下，无定型式I所示化合物溶于溶剂或混合溶剂中制得过饱和溶液，然后加热到30到70℃并搅拌0.2-1小时后，过滤并降温至5℃或以下后静置析晶，其中所述溶剂为甲醇/水的混合物，尤其是混合溶剂的体积比为1:1；或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)室温下，无定型式I所示化合物溶于溶剂或混合溶剂中制得过饱和溶液，然后加热到30至70℃并搅拌0.2-1小时后，过滤并降温至5℃或以下后静置，然后置于室温下挥发析出固体，其中所述溶剂为单一溶剂甲苯或氯仿，或者乙腈/水，异丙醇/正康烷，乙酸乙酯/正 庚烷，2-甲基四氢呋喃/正庚烷，或1,4二氧六环/正庚烷的混合溶剂，尤其是混合溶剂的体积比为1:1；或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)无定型式I所示化合物溶于溶剂或混合溶剂配制成饱和溶液，过滤到新的容器中制得澄清溶液，室温下静置挥发(试验作避光处理)析晶，其中所述溶剂为乙醇，异丙醇，乙腈，乙酸乙酯，或者混合溶剂乙腈/水、1,4二氧六环/水或乙酸异丙酯/正庚烷，尤其体积比为1:1的混合溶剂；或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)无定型式I所示化合物溶于正溶剂制得饱和溶液，过滤得澄清溶液，加入反溶剂直至有固体析出；若加入高到25倍体积的反溶剂仍无固体析出，放置在室温缓慢挥发析晶；所述正溶剂为甲醇、乙醇或丙酮时，反溶剂是水；所述正溶剂是甲苯、氯仿、乙酸乙酯或甲基叔丁基醚时，反溶剂为正庚烷；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)无定型式I所示化合物溶于溶剂或混合溶剂中制得饱和澄清溶液，加入无定型式I所示化合物质量之10-30％的混和高聚物A，即聚乙烯吡咯烷酮、聚乙烯醇、聚氯乙烯、聚醋酸乙烯酯、羟丙基甲基纤维素和甲基纤维素的混合物，尤其是等质量的混合物，或混和高聚物B，即聚己酸内酯、聚乙二醇、聚甲基丙烯酸甲酯、海藻酸钠和羟乙基纤维素的混合物，尤其是等质量混合，或者甲基纤维素水溶液或聚乙烯醇水溶液于式I化合物的澄清溶液中，置于室温下挥发析晶体。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.
PCT/CN2018/108990 2017-09-30 2018-09-30 Crystal form of benvitimod, and use thereof and preparation method therefor WO2019063002A1 (en)

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