WO2019182322A1 - Nouveau sel, son procédé de préparation et composition pharmaceutique le comprenant - Google Patents

Nouveau sel, son procédé de préparation et composition pharmaceutique le comprenant Download PDF

Info

Publication number
WO2019182322A1
WO2019182322A1 PCT/KR2019/003172 KR2019003172W WO2019182322A1 WO 2019182322 A1 WO2019182322 A1 WO 2019182322A1 KR 2019003172 W KR2019003172 W KR 2019003172W WO 2019182322 A1 WO2019182322 A1 WO 2019182322A1
Authority
WO
WIPO (PCT)
Prior art keywords
tofacitinib
gentisate
anhydride
hydrate
solvate
Prior art date
Application number
PCT/KR2019/003172
Other languages
English (en)
Korean (ko)
Inventor
신희종
기민효
남경완
이순환
이영희
오여준
이은화
김진철
Original Assignee
삼진제약주식회사
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 삼진제약주식회사 filed Critical 삼진제약주식회사
Publication of WO2019182322A1 publication Critical patent/WO2019182322A1/fr

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to a novel salt of tofacitinib, a preparation method thereof, and a pharmaceutical composition comprising the same. More specifically, the present invention relates to a novel salt of tofacitinib with improved solubility and physicochemical properties, a preparation method thereof, and a pharmaceutical composition comprising the same.
  • Tofacitinib ⁇ 3-((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanenitrile ⁇ is a compound represented by the following formula.
  • Tofacitinib is an inhibitor of protein kinases, such as the enzyme Janus kinase 3 (JAK3), which is an organ transplant, xenograft, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and diabetes complications, cancer, asthma , Atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other inhibitors for which immunosuppression is desired are useful therapeutic agents.
  • JK3 Janus kinase 3
  • solubility is an important physicochemical factor in the formulation of the drug and is often dropped from the product development group due to extremely low solubility. Therefore, ensuring proper solubility is an essential factor in the formulation.
  • the stability of the raw material is directly connected to the stability of the product, it is stable under severe conditions such as high temperature conditions or high humidity conditions, so it is essential to secure raw materials having stability in high temperature and high humidity areas.
  • Patent Document 1 International Patent Publication No. 2001/042246
  • Patent Document 2 International Patent Publication No. 2003/048162
  • An object of the present invention is a novel salt of tofacitinib, a method of preparing the same, and a method for preparing the same, which can be easily formulated, can be applied to mass production, and can be obtained in high quality with homogeneous quality while showing excellent physical and chemical properties and solubility. It is to provide a pharmaceutical composition comprising.
  • tofacitinib gentisate a hydrate, anhydride or solvate thereof represented by the following formula (1).
  • Another object of the present invention is to prepare a reaction solution containing tofacitinib; And a method of preparing tofacitinib gentisate, a hydrate, anhydride or solvate thereof, represented by Chemical Formula 1, which comprises reacting tofacitinib with gentis acid by adding gentisic acid to the reaction solution.
  • a reaction solution containing tofacitinib containing tofacitinib
  • An object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising tofacitinib gentisate, a hydrate, anhydride or solvate thereof represented by Formula 1 as an active ingredient.
  • An object of the present invention comprises tofacitinib gentisate, its hydrate, anhydride or solvate as tofacitinib in 5 mg, twice daily to provide a pharmaceutical composition for treating or preventing autoimmune diseases. will be.
  • An object of the present invention comprises tofacitinib gentisate, its hydrate, anhydride or solvate as tofacitinib in 10 mg, twice daily to provide a pharmaceutical composition for treating or preventing autoimmune diseases. will be.
  • the present invention provides a new salt of tofacitinib, tofacitinib gentisate, a hydrate, anhydride or solvate thereof, a preparation method thereof, and a pharmaceutical composition comprising the same as an active ingredient.
  • the term 'hydrate' refers to a new salt of tofacitinib and water that is combined with a non-covalent intermolecular force and may include a stoichiometric or non-stoichiometric amount of water.
  • the hydrate may comprise about 0.25 to about 10 molar ratio of water based on 1 mole of tofacitinib novel salt, and more specifically about 0.5 mole, about 1 mole, about 1.5 mole, about 2 moles of water. Moles, about 2.5 moles, about 3 moles, about 5 moles, and the like.
  • 'anhydride' may be a compound derived by the removal of water molecules in the acid.
  • the term 'solvate' is that a tofacitinib novel salt and a solvent other than water are bound by intermolecular force, and may include a solvent in stoichiometric or non-stoichiometric amounts.
  • the solvate may include a solvent molecule in a ratio of about 0.25 mole to about 10 moles based on 1 mole of tofacitinib novel salt, and more specifically about 0.5 mole, about 1 mole, about 1.5 mole, About 2 moles, about 2.5 moles, about 3 moles, about 5 moles, and the like.
  • the term 'about' refers to a numerical value that is ⁇ 10% of the preceding value.
  • ⁇ pharmaceutically acceptable '' means that when administered to human beings and physiologically acceptable, a medicament of ordinary skill in the art, typically without causing an allergic reaction such as gastrointestinal disorders, dizziness or the like, It may mean that the conventional use in the preparation of the formulation.
  • Tofacitinib Gentisate Hydrates, anhydrides or solvates thereof
  • the present invention provides tofacitinib gentisate, a hydrate, anhydride or solvate thereof.
  • Tofacitinib gentisate of the present invention is a compound represented by the following formula (1).
  • the tofacitinib gentisate, hydrate, anhydride or solvate thereof of the present invention has excellent solubility and excellent physical and chemical properties. Specifically, tofacitinib gentisate, its hydrate, anhydride or solvate according to the present invention shows excellent solubility at various pH conditions, and tofacitinib gentisate, its hydrate, anhydride or solvate according to the present invention has solubility. Because of its superior bioavailability than tofacitinib free base, it has a superior effect on the prevention and treatment of diseases, and side effects including serious infections and malignant tumors are reduced.
  • the tofacitinib gentisate, its hydrate, anhydride or solvate may be crystalline or amorphous, and more specifically, may be crystalline.
  • the term 'crystal form' refers to a solid phase in which the material has an internal structure that is regularly arranged at the molecular level and generates a unique X-ray diffraction pattern with defined peaks.
  • the tofacitinib gentisate may be an anhydride.
  • the hydrate of tofacitinib gentisate may include about 0.25 to about 10 moles of water based on 1 mole of tofacitinib gentisate, and more specifically, about 0.5 moles, about 1 mole, about 1.5 moles, about 2 moles, about 2.5 moles, about 3 moles, about 5 moles, and the like.
  • the solvate of tofacitinib gentisate may include a solvent other than water in a ratio of about 0.25 to about 10 moles based on 1 mole of tofacitinib gentisate, and Specifically, about 0.5 mol, about 1 mol, about 1.5 mol, about 2 mol, about 2.5 mol, about 3 mol, about 5 mol, and the like.
  • Tofacitinib Gentisate Methods for preparing hydrates, anhydrides or solvates thereof
  • the present invention provides a method for preparing tofacitinib gentisate, a hydrate, anhydride or solvate thereof represented by the following Chemical Formula 1.
  • the manufacturing method of the present invention includes the following steps.
  • the preparation method may obtain tofacitinib gentisate, a hydrate, anhydride or solvate thereof represented by Chemical Formula 1 in high purity and high yield.
  • the tofacitinib gentisate prepared according to the present invention, its hydrate, anhydride or solvate has excellent solubility and excellent physical and chemical properties.
  • tofacitinib gentisate prepared according to the present invention, its hydrate, anhydride or solvate shows excellent solubility at various pH conditions, and tofacitinib gentisate, its hydrate, anhydride or solvate according to the present invention.
  • the tofacitinib may be prepared or purchased directly by a known method.
  • the step of preparing a reaction solution containing tofacitinib is a step of preparing a reaction solution containing tofacitinib
  • Suspending or dissolving the tofacitinib may be added to the solvent.
  • the solvent may be a C 1 -C 10 straight or branched chain alcohol, acetone, water or a mixture thereof, and specifically, a C 1 -C 4 straight or branched chain Alcohol, acetone, water or mixtures thereof, and more particularly, straight or branched chain of C 1 -C 4 alcohol (methanol, ethanol, propanol, etc.), acetone or straight chain or branched chain of C 1 -C 4 It may be a mixture of alcohol (methanol, ethanol, propanol, etc.) and water.
  • the solvent may be methanol, acetone, water or a mixture thereof.
  • x in the indication of" C x "of a functional group represents the number of carbon (C)
  • C x -C y means the functional group or main chain which has carbon number x or more and y or less.
  • the solvent when preparing the reaction solution containing tofacitinib, may be added dropwise to about 20 mL to about 150 mL per g of tofacitinib, specifically, about 20 mL To about 130 mL, and more specifically, to about 20 mL to about 120 mL.
  • the methanol per 1 g of tofacitinib may be added dropwise from about 20 mL to about 150 mL, specifically, from about 20 mL to about 120 mL. Can be.
  • the acetone may be added dropwise from about 50 mL to about 150 mL per 1 g of tofacitinib, specifically, from about 80 mL to about 120 mL. Can be.
  • the gentis acid may be added in an amount of about 0.1 to about 5 equivalents based on 1 equivalent of tofacitinib, and specifically about 1 to about 3 equivalents of 1 equivalent of tofacitinib. Can be.
  • the step of reacting tofacitinib and gentisic acid by adding gentisic acid to the reaction solution, by heating the reaction solution to which the gentisic acid is added, tofacitinib and gentic acid may comprise the step of reacting.
  • the temperature increase may be performed by heating the reaction solution to which the gentis acid is added, and the reaction solution to which the gentis acid is added may be raised to a temperature below the boiling point of the solvent used.
  • the reaction solution to which the gentis acid is added may be heated to about 30 ° C. to about 60 ° C., more specifically about 40 ° C. to about 50 ° C.
  • the reaction time for reacting the tofacitinib and gentis acid may be about 1 hour to about 8 hours, specifically about 2 hours to about 6 hours, more specifically about From 2 hours to about 5 hours.
  • the step of reacting the tofacitinib and gentis acid may further include stirring the elevated reaction solution.
  • the method may further comprise depositing a product in a solid state. Specifically, tofacitinib and genisic acid may be reacted to remove the solvent, thereby obtaining a solid product.
  • the solvent may be removed by distillation under reduced pressure.
  • the precipitated solid product is tofacitinib gentisate, which may be crystalline, amorphous, or a mixture thereof, specifically, may be crystalline.
  • the method may further comprise the step of drying the precipitated solid product.
  • the drying may be performed at about 40 ° C. to 80 ° C. for about 6 hours to 24 hours, and specifically, at about 50 ° C. to 70 ° C. for about 8 hours to about 20 hours.
  • the method may further comprise recrystallizing the precipitated solid product.
  • the step of recrystallization is performed in embodiments of the present invention.
  • It may include the step of adding methyl tertiary butyl ether, diethyl ether, cyclohexane, n-hexane, or a mixture thereof to the solid product.
  • methyl tert-butyl ether, diethyl ether, cyclohexane, n-hexane or a mixture thereof added to the solid produced in the recrystallization step is about 1 mL based on 1 g of tofacitinib.
  • the step of recrystallization is performed in embodiments of the present invention.
  • It may include the step of adding methyl tertiary butyl ether, diethyl ether, cyclohexane, n-hexane or a mixture thereof to the solution.
  • the solvent of the recrystallization step may be used in an amount of about 1 mL to about 100 mL per 1 g of tofacitinib, specifically about 2 mL to about 40 mL Can be used as
  • the solvent of the recrystallization step may be a C 1 -C 10 straight or branched chain alcohol, acetone, water or a mixture thereof, specifically C 1 -C 4 Linear or branched alcohol, acetone, water or mixtures thereof, more specifically C 1 -C 4 straight or branched chain alcohols (methanol, ethanol, propanol, etc.), acetone or C 1 -C 4 It may be a mixture of linear or branched alcohol of (methanol, ethanol, propanol, etc.) and water.
  • the solvent may be one of methanol, acetone, water or a mixture thereof.
  • the methanol may be used in an amount of about 1 mL to about 50 mL per 1 g of tofacitinib, specifically, in an amount of about 2 mL to about 10 mL. Can be.
  • the acetone may be used in an amount of about 1 mL to 100 mL per 1 g of tofacitinib, specifically, in an amount of about 5 mL to about 40 mL. have.
  • the methyl tert-butyl ether, diethyl ether, cyclohexane, n-hexane or mixtures thereof in the recrystallization step is about 1 mL to about 500 mL per 1 g of tofacitinib It may be used, specifically about 5 mL to about 200 mL per 1 g of tofacitinib, and more specifically about 10 mL to about 100 mL per 1 g of tofacitinib.
  • the recrystallization of the method may further include the step of depositing tofacitinib gentisate in a solid state.
  • the product in the solid state may be obtained by removing the solvent or cooling after adding methyl tert-butyl ether, diethyl ether, cyclohexane, n-hexane or a mixture thereof in the step of recrystallization.
  • the solvent may be removed by vacuum distillation.
  • the cooling temperature may be about 5 ° C to about 20 ° C, specifically about 5 ° C to about 15 ° C.
  • stirring may be additionally performed during cooling.
  • the method may further include filtering and / or washing the solid state product obtained through the recrystallization.
  • the washing may be performed using methyl tertiary butyl ether, diethyl ether, cyclohexane, n-hexane or a mixture thereof, and specifically, may be performed using methyl tertiary butyl ether.
  • the method may further comprise the step of drying the tofacitinib gentisate in the solid state obtained through the recrystallization step.
  • the drying may be performed at about 40 ° C. to 80 ° C. for about 6 hours to 30 hours, and specifically, at about 50 ° C. to 70 ° C. for about 10 hours to 20 hours.
  • the method may further comprise purifying tofacitinib gentisate, its hydrate, anhydride or solvate thereof. Specifically, preparing a suspension comprising tofacitinib gentisate; Raising the suspension; And precipitation.
  • the solvent in the purification step may be ethyl acetate, isopropyl acetate, butyl acetate.
  • the solvent in preparing the suspension, may be added dropwise to about 3 mL to about 15 mL per g of tofacitinib gentisate, specifically, about 4 mL to about 10 mL It may be added dropwise, more specifically from about 5 mL to about 8 mL.
  • the step of heating the suspension may be performed by adding tofacitinib gentisate to a solvent and then heating, and may be raised to a temperature below the boiling point of the solvent used.
  • the suspension comprising tofacitinib gentisate may be heated to about 30 ° C to about 60 ° C, more specifically about 40 ° C to about 50 ° C.
  • the temperature of the elevated state may be maintained for about 20 hours to about 40 hours after the temperature is raised, specifically about 22 hours to about 36 hours, more specifically about 26 hours to about It can be 32 hours.
  • the precipitation step may remove the solvent to obtain purified tofacitinib gentisate.
  • the solvent may be removed by distillation under reduced pressure.
  • Tofacitinib Gentisate Pharmaceutical composition comprising a hydrate, anhydride or solvate thereof as an active ingredient
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising tofacitinib gentisate, a hydrate, anhydride or solvate thereof represented by the following Formula 1 as an active ingredient.
  • the tofacitinib gentisate, hydrate, anhydride or solvate thereof of the present invention has excellent solubility and excellent physical and chemical properties. Specifically, tofacitinib gentisate, its hydrate, anhydride or solvate according to the present invention shows excellent solubility at various pH conditions, and tofacitinib gentisate, its hydrate, anhydride or solvate according to the present invention has solubility. Because of its excellent bioavailability, it shows an excellent effect in the prevention and treatment of diseases, and side effects including serious infections and malignant tumors are reduced.
  • compositions comprising tofacitinib gentisate, its hydrates, anhydrides, or solvates as active ingredients can exhibit excellent prophylactic or therapeutic effects against autoimmune diseases and are subject to harsh conditions (light, pH, temperature and humidity, etc.). ) Can be stored stably for a long time without any special measures.
  • compositions of the present invention include organ transplantation, xenograft, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and diabetes complications, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease It can exhibit excellent prophylactic or therapeutic effects against Crohn's disease, Alzheimer's disease, leukemia, and other diseases for which immunosuppression is desired.
  • the pharmaceutical composition of the present invention may comprise tofacitinib gentisate, its hydrate, anhydride or solvate in a “therapeutically effective amount”.
  • therapeutically effective amount is an amount of tofacitinib gentisate, its hydrate, anhydride or solvate effective for the prevention or treatment of autoimmune diseases for the purpose of treatment, for example
  • the amount of tofacitinib gentisate, its hydrate, anhydride or solvate administered to a subject to be treated can prevent the occurrence or recurrence of autoimmune diseases, alleviate the symptoms, or provide direct or indirect pathological results.
  • Amount of pharmaceutical composition comprising tofacitinib gentisate, hydrate, anhydride or solvate thereof that inhibits, prevents metastasis, slows progression, alleviates or temporarily alleviates the condition, or improves prognosis It can include both. That is, the therapeutically effective amount may be interpreted to encompass all doses in which the symptoms of autoimmune disease improve or cure by the pharmaceutical composition comprising the tofacitinib gentisate, its hydrate, anhydride or solvate.
  • composition of the present invention can be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage is based on the weight, age, sex and health of the patient. The range varies depending on the diet, the time of administration, the method of administration, the rate of excretion and the severity of the disease.
  • the daily dose of tofacitinib gentisate, hydrate, anhydride or solvate thereof of the present invention is about 0.001 to 100 mg / kg, preferably 0.01 to 10 mg / kg, as tofacitinib, once to several times a day. Can be administered in divided doses.
  • the term 'oral administration' means that the active substance is administered to a substance prepared for digestion, that is, to the gastrointestinal tract for absorption.
  • a substance prepared for digestion that is, to the gastrointestinal tract for absorption.
  • the formulation for oral administration include tablets, troches, lozenges, aqueous suspensions, oily suspensions, prepared powders, granules, emulsions, hard capsules, soft capsules, syrups or elixirs, and the like. Can be mentioned.
  • a binder such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose or gelatin and the like; Excipients such as dicalcium phosphate and the like; Disintegrants such as corn starch or sweet potato starch; Lubricating oils such as magnesium stearate, calcium stearate, sodium stearyl fumarate or polyethylene glycol can be used, and sweeteners, fragrances, syrups and the like can also be used.
  • a liquid carrier such as fatty oil may be additionally used in addition to the above-mentioned materials.
  • parenteral administration means intravenous, intraperitoneal, subcutaneous, intradermal, intramuscular, spinal, spinal or rectal topical administration or infusion.
  • Parenteral administration is by injecting suppository, subcutaneous, intravenous, intramuscular or intrathoracic injections.
  • the composition may be mixed in water with a stabilizer or buffer to prepare a solution or suspension, which may be prepared in a unit dosage form of ampoules or vials.
  • composition of the present invention may further include at least one pharmaceutically acceptable additive in addition to the active ingredient tofacitinib gentisate, its hydrate, anhydride or solvate for administration.
  • pharmaceutically acceptable additives include carriers, excipients, diluents, extenders, antioxidants, stabilizers, solubilizers, buffers, fillers, anticoagulants, lubricants, lubricants, disintegrants, wetting agents, flavorings, emulsifiers, suspending agents, surfactants Preservatives or mixtures thereof.
  • the additive may be a substance that does not react with tofacitinib gentisate, its hydrate, anhydride or solvate, and does not reduce the stability of the composition.
  • Such additives may optionally be included in the pharmaceutical composition in doses in the usual range.
  • the pharmaceutical composition of the present invention may be formulated in a suitable form, specifically, may be formulated into capsules, granules, tablets, injectable formulations, and the like, and specifically, may be formulated into tablets.
  • These formulations may be prepared by conventional methods used in the art for formulation or by methods disclosed in Remington's Pharmaceutical Science (Recent Edition), Mack Publishing Company, Easton PA, and formulated into various formulations depending on the individual disease or component. Can be.
  • the formulation of the present invention may include about 1 mg to about 10 mg of tofacitinib gentisate, a hydrate, anhydride or solvate thereof, based on tofacitinib free base, and specifically, tofa It may be included at about 5 mg based on cytinib free base.
  • the pharmaceutical composition of the present invention may further include one or more substances exhibiting the same or different pharmacological activity in addition to tofacitinib gentisate, its hydrate, anhydride or solvate.
  • active ingredient means a component that can exhibit activity alone or in combination with a carrier having no activity.
  • Preferred dosages of the pharmaceutical compositions of the present invention include the condition and weight of the patient, age, sex, health condition, dietary specificity, nature of the formulation, extent of disease, time of administration of the composition, method of administration, duration or interval of excretion, excretion rate
  • the range may vary depending on the type of drug, drug, and drug type and may be appropriately selected by those skilled in the art. For example, it may range from about 0.1 to 10,000 mg / kg, but is not limited to this, and may be administered once to several times a day.
  • the pharmaceutical composition of the present invention may be for the prevention or treatment of autoimmune diseases.
  • autoimmune disease refers to an allergic disease in which an antibody to its organ tissue or its components is produced.
  • the autoimmune disease may be any one selected from the group consisting of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis.
  • the present invention includes tofacitinib gentisate, its hydrate, anhydride or solvate as 5 mg as tofacitinib, and to provide a pharmaceutical composition for treating or preventing autoimmune diseases by administering twice daily.
  • the present invention comprises tofacitinib gentisate, its hydrate, anhydride or solvate as tofacitinib in 10 mg, and to provide a pharmaceutical composition for treating or preventing autoimmune diseases by administering twice daily.
  • the present invention is to provide a method for preventing or treating autoimmune diseases comprising administering tofacytinib gentisate, its hydrate, anhydride or solvate in a therapeutically effective amount to a subject in need thereof.
  • treatment refers to partially or completely alleviating, ameliorating, alleviating, inhibiting or delaying the onset of a particular disease, disorder and / or disease, reducing severity, or developing one or more symptoms or features. It means to reduce.
  • the term 'prevention' means a delay in the onset of a disease, disorder or disease. Prevention can be considered complete if the onset of the disease, disorder or disease is delayed for a predetermined period of time.
  • the term 'individual' means a mammal, such as a monkey, a cow, a horse, a dog, a cat, a rabbit, a rat, a mouse, and particularly includes a human.
  • the prophylactic or therapeutic method of the present invention includes not only treating the disease itself before the onset of the indication, but also inhibiting or avoiding its manifestation by administering tofacitinib gentisate, its hydrate, anhydride or solvate.
  • the prophylactic or therapeutic dose of a particular active ingredient will vary depending on the nature and severity of the disease or condition and the route by which the active ingredient is administered. Dosage and frequency of dose will vary depending on the age, weight and response of the individual patient. Appropriate dosage regimens can be readily selected by those of ordinary skill in the art that naturally consider such factors.
  • the prophylactic or therapeutic method of the present invention may further comprise the administration of a therapeutically effective amount of tofacitinib gentisate, its hydrate, anhydride or solvate, together with additional active agents to help treat the disease, Additional active agents may exhibit synergistic or additive effects with tofacitinib gentisate, a hydrate, anhydride or solvate thereof.
  • the autoimmune disease may be any one selected from the group consisting of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis.
  • the present invention seeks to provide the use of tofacitinib gentisate, its hydrate, anhydride or solvate for the manufacture of a medicament for the prevention or treatment of autoimmune diseases.
  • the tofacitinib gentisate, hydrate, anhydride or solvate thereof of the present invention for the preparation of a medicament may be mixed with an acceptable pharmaceutically acceptable adjuvant, diluent, carrier and the like, in a complex formulation with other active agents. Can be produced and have a synergistic effect.
  • Tofacitinib Gentisate Use for the manufacture of a medicament for the prevention or treatment of autoimmune diseases of hydrates, anhydrides or solvates thereof
  • the present invention aims to provide a use for the preparation of a medicament for the prevention or treatment of tofacitinib gentisate, its hydrate, anhydride or solvate thereof.
  • the tofacitinib novel salts, hydrates, anhydrides or solvates thereof of the present invention exhibit excellent solubility at various pH conditions, have excellent physicochemical properties, room temperature conditions (25 ° C./60% relative humidity) or harsh conditions (60 ° C.). It shows the excellent stability because it generates less than the standard value in, has the advantage that it can be stored without change for a long time, can be obtained in high purity with homogeneous quality, easy to formulate, mass production is possible, than tofacitinib free base It shows excellent bioavailability and can be more effective in preventing and treating diseases.
  • FIG. 1 shows the 1 H-NMR spectrum of tofacitinib gentisate synthesized according to Example 9.
  • FIG. 1 shows the 1 H-NMR spectrum of tofacitinib gentisate synthesized according to Example 9.
  • Tofacitinib used in the following examples was prepared under the example conditions of WO 2001/042246, and various reagents and solvents mentioned below were purchased from Sigma Aldrich.
  • room temperature is a natural temperature that is warmed or undecreased and may mean a temperature of about 10 ° C to 30 ° C, about 25 ° C or about 23 ° C.
  • Detector ultraviolet absorbance photometer (wavelength, 210 nm)
  • the tofacitinib genitate prepared in Examples 1, 9 and 10 was stored for 4 weeks at room temperature conditions (25 ° C./60% relative humidity) or harsh conditions (60 ° C.), and then as tofacitinib. 20 mg was taken in a 200 mL volumetric flask and dissolved in dilution [0.05% trifluoroacetic acid solution / acetonitrile, (95/5, v / v)] to make the mark. This liquid was filtered through a filter to obtain a sample liquid. 2 ⁇ L of the sample solution was analyzed by the liquid chromatography analysis conditions, and the results are shown in Table 1 below (unit:% of flexible substance).
  • the tofacitinib gentisate prepared in Examples 1, 9 and 10 has a value below the baseline of the flexible material under severe conditions (60 ° C.) as well as room temperature conditions (25 ° C./60% relative humidity). Confirmed.
  • the tofacitinib gentisate prepared in Examples 1, 9, and 10 has excellent chemical stability, is easy to handle and store, and can be very useful for mass production.
  • the tofacitinib novel salts of the present invention are remarkably excellent in solubility, have excellent physicochemical properties and exhibit excellent stability.

Abstract

La présente invention concerne un nouveau sel de tofacitinib ou un hydrate, un anhydride ou un solvate de celui-ci, un procédé de production associé, et une composition pharmaceutique le comprenant. Le nouveau sel de tofacitinib ou un hydrate, anhydride ou solvate de celui-ci, selon la présente invention a une excellente solubilité dans diverses conditions de pH, et le sel de gentisate de tofacitinib ou l'hydrate, l'anhydride, ou le solvate de celui-ci selon la présente invention a une biodisponibilité supérieure à celle de la base libre de tofacitinib en raison d'une excellente solubilité, ce qui permet d'obtenir des effets supérieurs dans la prévention et le traitement de maladies et une réduction des effets secondaires notamment des infections graves et des tumeurs malignes.
PCT/KR2019/003172 2018-03-20 2019-03-19 Nouveau sel, son procédé de préparation et composition pharmaceutique le comprenant WO2019182322A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR20180031880 2018-03-20
KR10-2018-0031880 2018-03-20

Publications (1)

Publication Number Publication Date
WO2019182322A1 true WO2019182322A1 (fr) 2019-09-26

Family

ID=67986303

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2019/003172 WO2019182322A1 (fr) 2018-03-20 2019-03-19 Nouveau sel, son procédé de préparation et composition pharmaceutique le comprenant

Country Status (2)

Country Link
KR (1) KR20190110459A (fr)
WO (1) WO2019182322A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111574522A (zh) * 2020-05-13 2020-08-25 杭州华东医药集团浙江华义制药有限公司 托法替布关键中间体的合成方法
CN112094274A (zh) * 2020-09-08 2020-12-18 杭州华东医药集团新药研究院有限公司 一种改进的托法替布合成方法及杂质制备方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050159434A1 (en) * 2001-12-06 2005-07-21 Pfizer Inc Novel crystalline compound
WO2012135338A1 (fr) * 2011-03-28 2012-10-04 Ratiopharm Gmbh Procédés pour la préparation de sels de tofacitinib
CN104774206A (zh) * 2014-01-14 2015-07-15 江苏柯菲平医药股份有限公司 制备枸橼酸托伐替尼晶型a的新方法
KR20160117596A (ko) * 2014-02-07 2016-10-10 오스펙스 파마슈티칼스, 인코포레이티드 신규 제약 제제
WO2017091544A1 (fr) * 2015-11-24 2017-06-01 Theravance Biopharma R&D Ip, Llc Promédicaments d'un composé inhibiteur de jak pour le traitement de maladies inflammatoires gastro-intestinales
WO2018172821A1 (fr) * 2017-03-23 2018-09-27 Phalanx Labs Private Limited Nouveaux sels d'addition de tofacitinib et leur procédé de préparation

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3463798B2 (ja) 1999-07-28 2003-11-05 日本電気株式会社 光学スキャナ装置
EP1431231B1 (fr) 2001-09-27 2010-12-15 Mitsubishi Denki Kabushiki Kaisha Ascenseur sans local de machinerie

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050159434A1 (en) * 2001-12-06 2005-07-21 Pfizer Inc Novel crystalline compound
WO2012135338A1 (fr) * 2011-03-28 2012-10-04 Ratiopharm Gmbh Procédés pour la préparation de sels de tofacitinib
CN104774206A (zh) * 2014-01-14 2015-07-15 江苏柯菲平医药股份有限公司 制备枸橼酸托伐替尼晶型a的新方法
KR20160117596A (ko) * 2014-02-07 2016-10-10 오스펙스 파마슈티칼스, 인코포레이티드 신규 제약 제제
WO2017091544A1 (fr) * 2015-11-24 2017-06-01 Theravance Biopharma R&D Ip, Llc Promédicaments d'un composé inhibiteur de jak pour le traitement de maladies inflammatoires gastro-intestinales
WO2018172821A1 (fr) * 2017-03-23 2018-09-27 Phalanx Labs Private Limited Nouveaux sels d'addition de tofacitinib et leur procédé de préparation

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111574522A (zh) * 2020-05-13 2020-08-25 杭州华东医药集团浙江华义制药有限公司 托法替布关键中间体的合成方法
CN111574522B (zh) * 2020-05-13 2021-11-23 杭州华东医药集团浙江华义制药有限公司 托法替布关键中间体的合成方法
CN112094274A (zh) * 2020-09-08 2020-12-18 杭州华东医药集团新药研究院有限公司 一种改进的托法替布合成方法及杂质制备方法

Also Published As

Publication number Publication date
KR20190110459A (ko) 2019-09-30

Similar Documents

Publication Publication Date Title
WO2017026718A1 (fr) Nouveau composé 3-(isoxazol-3-yl)-pyrazolo[3,4-d]pyrimidin-4-amine, qui est un inhibiteur de la kinase ret
WO2011083998A2 (fr) Dérivé de biguanide, procédé de préparation de celui-ci et composition pharmaceutique contenant le dérivé de biguanide en tant que substance active
WO2013022243A2 (fr) Nouveau dérivé biphénylé ou sel pharmaceutiquement acceptable de celui-ci, et composition pharmaceutique pour prévenir ou traiter les maladies inflammatoires ou les maladies auto-immunes comprenant ce dérivé ou ce sel comme principe actif
WO2019182322A1 (fr) Nouveau sel, son procédé de préparation et composition pharmaceutique le comprenant
EP2742020A2 (fr) Dérivé de biguanide à substitution n1-amine cyclique-n5, procédés de préparation associés et composition pharmaceutique les comprenant
WO2020256477A1 (fr) Dérivé de pyrimidine inhibant la croissance d'une cellule cancéreuse et son utilisation médicinale
WO2021107657A1 (fr) Nouveau dérivé d'oxydo-réduction de quinazoline et son utilisation en tant qu'inhibiteur de bet
WO2020262998A1 (fr) Nouveau dérivé de quinazoline ayant une activité antitumorale et composition pharmaceutique le comprenant
WO2019231261A1 (fr) Nouveau composé dérivé de biphényle et utilisation associée
WO2022035048A1 (fr) Palmitate d'éther de donépézil ou sel pharmaceutiquement acceptable de celui-ci
WO2021133037A1 (fr) Dérivé de pyrrolidine et composition pharmaceutique de prévention ou de traitement de maladies associées à la protéine bêta-amyloïde ou tau contenant ce dernier
WO2016159666A2 (fr) Forme cristalline et procédé de préparation de celui-ci
WO2013022280A2 (fr) Dérivés de biguanide à substitution n1-amine cyclique-n2, procédés de préparation associés et composition pharmaceutique les comprenant
WO2022149925A1 (fr) Nouvel inhibiteur de tryptophane hydroxylase et son utilisation
WO2018038297A1 (fr) Nouveau sel de (r)- (1-méthylpyrrolidin-3-yl) méthyl (3'-chloro -4'-fluoro- [1,1'-biphényl]-2-yl) carbamate et forme cristalline de celui-ci
WO2020040326A1 (fr) Dérivé d'acide phénylacétique, et composition pour la prévention ou le traitement de maladies auto-immunes le contenant en tant que principe actif
WO2009108017A2 (fr) Nouveaux dérivés de pyruvate avec effet neuroprotecteur, processus de préparation de ceux-ci et composition pharmaceutique comprenant ces dérivés
WO2019231262A1 (fr) Nouveau composé dérivé de biphényle et son utilisation
WO2023113458A1 (fr) Nouveau sel de dérivé de 1-sulfonyle pyrrole, son procédé de préparation et composition pharmaceutique le comprenant
WO2023043197A1 (fr) Nouveau dérivé de canabidiol, son procédé de préparation et composition pour l'amélioration des fonctions cognitives le comprenant
WO2023080741A1 (fr) Nouveau sel d'un dérivé d'acide phénylpropionique, son procédé de production et composition pharmaceutique le contenant
WO2021029450A1 (fr) Nouveau dérivé de pyrimidine sulfonamide et composition pharmaceutique pour prévenir ou traiter le cancer le comprenant en tant que principe actif
WO2023075016A1 (fr) Nouveau composé et composition pour la prévention ou le traitement de maladies cérébrales neuro-inflammatoires comprenant celui-ci en tant que principe actif
WO2023287241A1 (fr) Nouveau composé dérivé de benzoxazolamine et composition pharmaceutique le comprenant pour prévenir ou traiter le cancer
WO2024080793A1 (fr) Nouveau composé hétérobicyclique pour inhiber l'interaction yap-tead et composition pharmaceutique le comprenant

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19772534

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19772534

Country of ref document: EP

Kind code of ref document: A1