WO2020173364A1 - Composition pharmaceutique orale contenant un dérivé d'azétidine en tant que principe actif, son procédé de préparation et son utilisation - Google Patents

Composition pharmaceutique orale contenant un dérivé d'azétidine en tant que principe actif, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2020173364A1
WO2020173364A1 PCT/CN2020/075913 CN2020075913W WO2020173364A1 WO 2020173364 A1 WO2020173364 A1 WO 2020173364A1 CN 2020075913 W CN2020075913 W CN 2020075913W WO 2020173364 A1 WO2020173364 A1 WO 2020173364A1
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Prior art keywords
pharmaceutical composition
active ingredient
oral pharmaceutical
alkyl
pharmaceutically acceptable
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PCT/CN2020/075913
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English (en)
Chinese (zh)
Inventor
李岩
蔡孟锬
王梦馨
宋宏梅
蔡家强
赵曦
周丹
赵栋
吴灵静
舒路川
闫海霞
唐超
王英
薛彤彤
王晶翼
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Priority to CN202080007400.9A priority Critical patent/CN113508114B/zh
Publication of WO2020173364A1 publication Critical patent/WO2020173364A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This application relates to an oral pharmaceutical composition with azetidine derivative as an active ingredient, and a preparation method and application thereof.
  • Background of the invention relates to an oral pharmaceutical composition with azetidine derivative as an active ingredient, and a preparation method and application thereof.
  • JAK is an intracellular non-receptor tyrosine protein kinase and belongs to the protein kinase family. In mammals, the JAK family has four members: JAK1 (also known as Janus kinase-1), JAK2 (also known as Janus kinase-2), JAK3 (also known as Janus kinase-3) and TYK2 (also known as protein-tyrosine Acid kinase 2). JAK plays a key role in cytokine signal transduction.
  • the downstream substrates of JAK family kinases include signal transduction and activation of transcription (STAT) proteins.
  • JAK JAK/STAT pathway
  • the interaction between JAK and STAT plays an important role in the cytokine receptor signaling pathway and is widely involved in cell proliferation, differentiation, apoptosis, and inflammation.
  • the activation of JAK/STAT pathway promotes the occurrence and development of various diseases, including various solid tumors, lymphomas, leukemias, and inflammatory diseases.
  • Cisoka new type of azetidine derivative which is a small molecule drug that can be administered orally, which can selectively target the key node in the disease progression of rheumatoid arthritis (Rheumatoid Arthritis, RA).
  • JAK1 and JAK2 kinases and hinder the phosphorylation of the downstream transcription factor STAT, eventually leading to the interruption of the signal transduction of the JAK/STAT signal axis, a key link in the course of rheumatoid arthritis, resulting in the inability of cytokine signals to be transmitted to the nucleus for regulation and transcription. It plays a role in reducing the release of inflammatory factors, inhibiting abnormal proliferation of immune cells, etc., which is beneficial to improving the course of rheumatoid arthritis, achieving the purpose of improving the pathological process and exerting a significant therapeutic effect.
  • azetidine derivatives have obvious therapeutic effects on rat collagen-induced arthritis (CIA) models. It can achieve the equivalent exposure level and efficacy of the same target drug Baricitinib at a dose of 10 mg/kg. In addition, the pharmacokinetic properties of such azetidine derivatives are good.
  • the systemic drugs mainly exist in their original form, do not accumulate after repeated administration, have no significant binding to red blood cells, are widely distributed in the body, are mainly excreted in feces, and have no CYP enzyme. Inhibition.
  • the results of toxicological studies are similar to those reported in the literature of the same target drug Baricitinib. The toxic effect can be restored or there is a trend of recovery, and repeated administration does not accumulate. In view of this, such azetidine derivatives have broad application prospects and high clinical development value for the clinical treatment of rheumatoid arthritis.
  • Chinese Patent Application No. 201680059396.4 discloses oral pharmaceutical compositions of such azetidine derivatives.
  • the preparation process of these compositions is complicated, and there are many influencing factors, resulting in poor process repeatability, which is not conducive to industrialized scale-up production. Therefore, there is an urgent clinical need to provide a new method that can make oral pharmaceutical compositions containing such novel azetidine derivatives have excellent dissolution, and the preparation process is stable and simple, and the prepared method has excellent dissolution properties.
  • Oral pharmaceutical composition Summary of the invention
  • An object of the present application is to provide a method for preparing an oral pharmaceutical composition
  • an active ingredient is a compound of formula I, a pharmaceutically acceptable salt thereof, Stereoisomers, polymorphs, solvates, metabolites or prodrugs,
  • R 2 and R 3 are each independently selected from H, CN, halogen and Q_ 6 alkyl;
  • R 4 and R 5 are each independently selected from H, halogen and CN;
  • X is selected from N and CR 6 ;
  • Y is selected from N and CR 9 ;
  • Z is selected from N and CR 7;
  • W is selected from N and CR 8 ;
  • R 6 , R 7 and are each independently selected from H, halogen, CN, Q_ 6 alkyl, Q_ 6 alkoxy and C(0)NR 12 R 13;
  • R HJ and Ru are each independently selected from Q- 6 alkyl, C 3-1D cycloalkyl, 3-10 membered heterocyclic group, C 6-14 aryl, 5-14 membered heteroaryl, C7-20 arylalkene Base and NR12R13;
  • R 12 and R 13 are each independently selected from H and Q_ 6 alkyl
  • alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and arylalkyl are each optionally substituted with 1, 2 or 3 substituents independently selected from halogen, CN and Q_ 4 alkyl substituents ,
  • the method includes:
  • D v (90) is 1 ⁇ 500 ⁇ m
  • D v (50) is 1 ⁇ 100 ⁇ m
  • D[4,3] is 1 ⁇ 50 ⁇ m
  • the active ingredient is mixed with the carrier, passed through a 40-60 mesh sieve and mixed again.
  • this application provides a method for preparing an oral pharmaceutical composition comprising an active ingredient and at least one pharmaceutically acceptable carrier, which further comprises:
  • Another object of the present application is to provide an oral pharmaceutical composition
  • an active ingredient comprising an active ingredient and at least one pharmaceutically acceptable carrier, wherein the active ingredient is the compound of formula I as shown above, which is pharmaceutically acceptable Salts, stereoisomers, polymorphs, solvates, metabolites or prodrugs of, in accordance with the "Chinese Pharmacopoeia” (2015 edition) basket method, at a rotation speed of 75 rpm, a temperature of 37 ° C, at 900 ml
  • the dissolution rate of the oral pharmaceutical composition measured in a pH 3.0 disodium hydrogen phosphate/citric acid buffer is: at least 80% by weight of the active ingredient is dissolved within 30 minutes; preferably, at least 88 weight % Of the active ingredient is dissolved within 45 minutes, and at least 93% by weight of the active ingredient is dissolved within 60 minutes.
  • the application provides an oral pharmaceutical composition, which is a capsule or tablet.
  • the application provides an oral pharmaceutical composition, which is prepared by the method of the application.
  • Another object of the present application is to provide the use of the oral pharmaceutical composition of the present application in the preparation of drugs for treating JAK-related diseases.
  • the JAK-related diseases are preferably selected from inflammatory diseases, autoimmune diseases or cancers, and more preferably rheumatoid joints.
  • Another object of this application is to provide a method for treating JAK-related diseases, including those in need Of individuals administer the oral pharmaceutical composition of this application.
  • Another objective of the present application is to provide the oral pharmaceutical composition of the present application, which is used to treat JAK-related diseases.
  • alkyl is defined to include saturated aliphatic hydrocarbons, which include straight and branched chains.
  • the alkyl group has 1 to 6, for example 1 to 4 carbon atoms.
  • CM alkyl refers to a linear or branched group of 1 to 6 carbon atoms (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isopropyl).
  • CM alkyl refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (ie methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl Or tert-butyl).
  • alkyloxy refers to a linear, branched, or cyclic saturated monovalent hydrocarbon group of the formula -0-alkyl, wherein the term “alkyl” is as defined above or as defined below "Cycloalkyl", such as methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, Cyclobutoxy, pentyloxy, isopentyloxy or n-hexyloxy, or their isomers.
  • cycloalkyl refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic ring, such as cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic ring, including spirocyclic, fused or bridged systems (such as bicyclic [1.1] pentyl, bicyclic [2.2.1] heptyl, bicyclic [ 3.2.1] octyl or bicyclic [5.2.0] nonyl, decalinyl, etc.), which are optionally substituted with 1 or more (such as 1 to 3) suitable substituents.
  • monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl,
  • C 3-1Q cycloalkyl refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 10 ring-forming carbon atoms ( For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bicyclo[11.1]pentyl), which are optionally substituted by one or more (such as 1 to 3) suitable substituents, such as methyl Group substituted cyclopropyl.
  • suitable substituents such as methyl Group substituted cyclopropyl.
  • a 3-10 membered heterocyclic group is a group having 3-10 carbon atoms and heteroatoms in the ring, such as but not limited to oxiranyl group, aziridinyl group, azetidinyl group ( azetidinyl), oxetanyl (oxetanyl), tetrahydrofuranyl, dioxolinyl (dioxolinyl), pyrrolidinyl, pyrrolidone, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydrofuranyl Hydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl.
  • aryl refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugate 7: electron system.
  • (: 6-14 aryl) means an aromatic group containing 6 to 14 carbon atoms, such as phenyl or naphthyl.
  • the aryl group is optionally substituted by 1 or more (Such as 1 to 3) suitable substituents are substituted.
  • heteroaryl refers to a monovalent monocyclic, bicyclic or tricyclic aromatic ring system, which has 5, 6, 8, 9, 10, 11, 12, 13, or 14 ring atoms, Especially 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and it contains at least one heteroatom (the heteroatom is for example oxygen, nitrogen or sulfur) which may be the same or different, and, in addition It can be benzo-fused in each case.
  • the heteroaryl group is selected from the group consisting of thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiol Diazolyl, etc. and their benzo derivatives; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives.
  • aralkyl preferably denotes an aryl-substituted alkyl group, wherein the aryl group and the alkyl group are as defined herein. Generally, the aryl group may have 6-14 carbon atoms, and the alkyl group may have 1-6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
  • generation or “prime” group is defined to include F, Cl, Br, or I.
  • substituted means that one or more (eg, one, two, three, or four) hydrogens on the specified atom are replaced by a selection from the indicated group, provided that no more than the specified atom is The normal valence in the current situation and the substitution forms a stable compound. Combinations of substituents and/or variables are only allowed when such combinations form stable compounds.
  • optionally substituted refers to optionally substituted with a specific group, atomic group or part.
  • the compounds of the application may also contain one or more (for example, one, two, three, or four) isotope substitutions.
  • H can be any isotopic form, including 1 H, 2 H (D or deuterium), and 3 H (T or tritium);
  • C can be any isotopic form, including 12 C, 13 C, and 14 C;
  • 0 can be any isotope Forms, including 160 and 180 etc.
  • stereoisomer means an isomer due to at least one asymmetric center.
  • compounds with one or more (for example, one, two, three or four) asymmetric centers it can produce racemates, racemic mixtures, single enantiomers, and diastereomers Conformer mixtures and individual diastereomers.
  • Certain individual molecules can also exist as geometric isomers (cis/trans).
  • the compounds of the present application can exist in a mixture of two or more structurally different forms (commonly referred to as tautomers) that are in rapid equilibrium.
  • tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. It should be understood that the scope of this application covers all such arbitrary ratios (for example, 60%, 65%, 70% > 75%, 80%, 85%, 90%, 95%, 96%, 97% > 98%, 99%). %) isomers or mixtures thereof.
  • This application covers all possible crystalline forms or polymorphs of the compounds of this application, which can be a single polymorph or a mixture of more than one polymorph in any ratio.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, solvates, metabolites, or prodrugs, which can be directly or directly or after being administered to patients in need thereof Indirectly provide the compound of the present application or its metabolites or residues.
  • the pharmaceutically acceptable salt of the compound of the present application includes its acid addition salt and base addition salt.
  • Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include aspartate, bicarbonate/carbonate, bisulfate, borate, camphorsulfonate, citrate, cyclamate, ethanedisulfonate, ethanesulfonate , Fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydroiodide/iodide, isethionate, lactate, methyl sulfate , Naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate /Dihydrogen phosphate, pyroglutamate, saccharate, stearate, tannate and xinofoate.
  • Suitable base addition salts are formed from bases that form non-toxic salts. Examples include aluminum salt, arginine salt, benzathine penicillin salt, calcium salt, choline salt, diethylamine salt, diethanolamine salt, glycinate, lysine salt, magnesium salt, meglumine salt, ethanolamine salt, Potassium, sodium, tromethamine and zinc salts.
  • the compound of the present application may exist in the form of a hydrate or a solvate, wherein the compound of the present application contains a polar solvent as a structural element of the crystal lattice of the compound, especially, for example, water, methanol or ethanol.
  • a polar solvent as a structural element of the crystal lattice of the compound, especially, for example, water, methanol or ethanol.
  • the amount of polar solvent, especially water can be present in a stoichiometric or non-stoichiometric ratio.
  • the metabolites of the compounds of the present application are also included in the scope of the present application, that is, compounds formed in the body when the drug is administered.
  • prodrugs of the present application can be used, for example, by using certain groups known to those skilled in the art (for example, "pro-moieties” described in H. Bundgaard's Design of Prodrugs (Elsevier, 1985)) To replace appropriate functional groups present in the compound of formula I to produce.
  • the term “content uniformity” refers to the degree to which the content of each tablet (unit) of a small-dose or single-dose solid preparation, semi-solid preparation, and heterogeneous liquid preparation meets the label weight.
  • particle size refers to the size of the particles, where D v (50) represents the median particle size of the distribution, that is, 50% of the particles are smaller than the size and 50% of the particles are larger than the size. D v (10) represents the particle size of 10% of all particles smaller than the stated size. Similarly, D v (90) represents a particle size of 90% of all particles smaller than the stated size. D[4, 3] refers to the volume-weighted average particle size. D[3,2] refers to the surface area weighted average particle size.
  • pulverization refers to the process of pulverizing large-sized solid materials to a suitable degree by mechanical force or airflow, which includes dry pulverization, wet pulverization, cryogenic pulverization, and ultrafine pulverization.
  • the crushing equipment includes mortar, universal crusher, ball mill and jet mill.
  • sieving refers to pulverized particles or powders, etc., to meet the needs of preparing the formulation, and have a mixing effect to ensure the uniformity of the components.
  • Screening equipment includes shaking screens, vibrating screens, rotating screens and drum screens.
  • the term "gradient mixing” refers to mixing the active ingredient with a certain amount of excipients (a single excipient or a pre-mix of multiple excipients) to obtain a first mixture, and then adding the first mixture to a certain weight ratio (Eg 4 times, 5 times, 6 times, etc.)
  • the auxiliary materials (a single auxiliary material or a pre-mix of multiple auxiliary materials) are mixed to obtain a second mixture, and the auxiliary materials are continued to be added according to the same method until all the auxiliary materials are added.
  • an oral pharmaceutical composition comprising an active ingredient of an azetidine derivative and at least one pharmaceutically acceptable carrier.
  • the oral pharmaceutical composition has excellent dissolution and stability, and its preparation process is stable and simple, and its various indicators meet the requirements of the Chinese Pharmacopoeia, and meet the needs of clinical and commercial use.
  • the active ingredient contained in the oral pharmaceutical composition of the present application is the compound of formula I, its pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, metabolite or prodrug,
  • R 2 and R 3 are each independently selected from H, CN, halogen and Q_ 6 alkyl;
  • R 4 and R 5 are each independently selected from H, halogen and CN;
  • X is selected from N and CR 6 ;
  • Y is selected from N and CR 9 ;
  • Z is selected from N and CR 7;
  • W is selected from N and CR 8 ;
  • R 6 , R 7 and are each independently selected from H, halogen, CN, Q_ 6 alkyl, Q_ 6 alkoxy and C(0)NR 12 R 13;
  • RHJ and Ru are each independently selected from Q- 6 alkyl, C 3-1D cycloalkyl, 3-10 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, C7-20 arylalkyl And NR12R13;
  • R 12 and R 13 are each independently selected from H and Q_ 6 alkyl
  • alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl are each optionally substituted with 1, 2 or 3 substituents independently selected from halogen, CN and alkyl.
  • 11 2 and 11 3 are each independently selected from H, CN, F, and methyl.
  • 114 and 115 are each independently selected from H, F, C1, and CN.
  • X is CR 6 .
  • X, Y, Z or W are each independently selected from N and CH.
  • X is CH
  • Y, Z or W are each independently selected from > ⁇ PCH.
  • R 6 , R 7 are each independently selected from H, F, Cl, CN, methyl, ethyl, methoxy and C(0)NH 2 .
  • R 1D and R u are each independently selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, aziridine Ridinyl, pyrrolidinyl, phenyl, benzyl, and N(CH 3 ) 2 , wherein the above groups are each optionally substituted with 1, 2 or 3 substituents independently selected from F, CN and methyl.
  • R 12 and R 13 are each independently selected from H, methyl, and ethyl.
  • the active ingredient contained in the oral pharmaceutical composition of the present application is the compound of formula II, its pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, metabolism Substance or prodrug,
  • the active ingredient contained in the oral pharmaceutical composition of the present application is the compound of formula III, its pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, metabolism Substance or prodrug,
  • W or Z is N; or W is CR 8 , Z is CR 7 , and R 2 , R 4, R 5 and not are H at the same time.
  • the active ingredient contained in the oral pharmaceutical composition of the present application is a compound of formula IV, its pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, metabolism Substance or prodrug,
  • R 10 and Ru are each independently selected from Q- 6 alkyl, C 3-1 () cycloalkyl, 3-10 membered heterocyclic group, C 6-14 aryl, 5-14 membered heteroaryl, C 7- 20 Aralkyl and NR 12 R 13 , wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group and aralkyl group are each optionally 1, 2 or 3 independently selected from halogen , CN and Q_ 4 alkyl substituents are substituted.
  • the active ingredient contained in the oral pharmaceutical composition of the present application is a compound of formula V, its pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, metabolism Substance or prodrug,
  • the active ingredients contained in the oral pharmaceutical composition of this application are compounds of formula VI, their pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, metabolism Substance or prodrug,
  • the active ingredient is a compound selected from the following, a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, metabolite, or prodrug thereof:
  • the active ingredients are as follows:.
  • the amount of the active ingredient is 0.01-30% by weight of the oral pharmaceutical composition, preferably 0.05-10% by weight, preferably 0.1-30% by weight, more preferably 0.5- 10% by weight.
  • the oral pharmaceutical composition of the present application contains 0.1-10 mg, preferably 0.1-5 mg, preferably 1-10 mg, more preferably 1-5 mg of the active ingredient.
  • the oral pharmaceutical composition of the present application may also include one or more additional therapeutic or preventive agents, including but not limited to: chemotherapeutic agents or anti-proliferative agents, anti-inflammatory agents, immunotherapy Regulators or immunosuppressive agents, neurotrophic factors, drugs for the treatment of cardiovascular diseases, drugs for the treatment of destructive bone disorders, drugs for the treatment of liver diseases, antiviral agents, drugs for the treatment of blood diseases, Drugs used to treat diabetes or drugs used to treat immunodeficiency diseases.
  • the one or more additional therapeutic or preventive agents are selected from efalizumab, mycophenolate sodium, etanercept, methotrexate and the like.
  • the pharmaceutically acceptable carriers used in the oral pharmaceutical composition of the present application include but are not limited to fillers, disintegrants, lubricants and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).
  • the filler includes, but is not limited to, one or more of the following: mannitol, microcrystalline cellulose, starch, pregelatinized starch, lactose, calcium dihydrogen phosphate, calcium hydrogen phosphate, calcium phosphate, calcium carbonate Wait.
  • the filler is mannitol, microcrystalline cellulose or lactose. More preferably, the filler is microcrystalline cellulose.
  • the amount of the filler is 1-99.99% by weight of the oral pharmaceutical composition, preferably 20-99.99%, more preferably 70-99.99%.
  • the weight ratio of microcrystalline cellulose used in the oral pharmaceutical composition of the present application to the active ingredient is 20:1 ⁇ 1300:1, preferably 20:1 ⁇ 200:1, more preferably 25:1 ⁇ 150:1.
  • the disintegrant includes, but is not limited to, one or more of the following: low-substituted hydroxypropyl cellulose, low-substituted hypromellose, sodium carboxymethyl cellulose, croscarmellose sodium, carboxymethyl cellulose Sodium methyl starch and so on.
  • the disintegrant is croscarmellose sodium.
  • the amount of the disintegrant is 0-20%, preferably 0-10% of the weight of the oral pharmaceutical composition.
  • the oral pharmaceutical composition of the present application may not contain a disintegrant.
  • the lubricant includes, but is not limited to, one or more of the following: stearic acid, magnesium stearate, calcium stearate, hydrogenated vegetable oil, sodium lauryl sulfate, magnesium lauryl sulfate, talc, Polyethylene glycol, sodium stearyl fumarate, silicon dioxide, etc.
  • the lubricant is magnesium stearate, sodium stearyl fumarate or silicon dioxide.
  • the amount of the lubricant is 0-10% by weight of the oral pharmaceutical composition, preferably 0-5%.
  • the oral pharmaceutical composition of the present application comprises the above-mentioned active ingredient and microcrystalline cellulose, wherein the weight ratio of the microcrystalline cellulose to the active ingredient is 20:1 to 1300:1, Preferably it is 20:1 ⁇ 200:1, more preferably 25:1 ⁇ 150:1.
  • the oral pharmaceutical composition of the present application contains 0.01-30% by weight, preferably 0.05-10% by weight of the active ingredient as described above and 1-99.99%, preferably 20-99.99%, more preferably 70-99.99% of the micro Crystalline cellulose, wherein the weight ratio of microcrystalline cellulose to the active ingredient is 20:1 ⁇ 1300:1, preferably 20:1 ⁇ 200:1, preferably 25:1 ⁇ 150:1, more preferably 60 : 1 ⁇ 140: 1.
  • the dosage form of the oral pharmaceutical composition of the present application includes, but is not limited to, tablets, capsules, lozenges, hard candy, powders, granules, solutions, aromatic liquids, elixirs, suspensions, elixirs, and syrups Wait.
  • the oral pharmaceutical composition of the present application is a capsule.
  • the capsule shell of the capsule is gelatin hollow capsules, hypromellose hollow capsules, etc., preferably gelatin hollow capsules.
  • the oral pharmaceutical composition of the present application is a tablet, preferably a coated tablet, more preferably a gastric-soluble coated tablet, such as a gastric-soluble film-coated tablet.
  • the measurement is carried out in 900 ml of disodium hydrogen phosphate/citric acid buffer with a pH of 3.0 at a rotation speed of 75 rpm and a temperature of 37 ° C.
  • the obtained dissolution rate of the oral pharmaceutical composition is: at least 80% by weight of the active ingredient is dissolved within 30 minutes. Preferably, at least 88% by weight of the active ingredient is dissolved within 45 minutes, At least 93% by weight of the active ingredient dissolves within 60 minutes.
  • At least 55% by weight of the active ingredient is dissolved within 10 minutes
  • At least 60% by weight of the active ingredient is dissolved within 15 minutes
  • At least 80% by weight of the active ingredient is dissolved within 30 minutes
  • a method for preparing the oral pharmaceutical composition of the present application which includes:
  • D v (90) is 1 ⁇ 500 ⁇ m, preferably 1-100 ⁇ m;
  • the active ingredient is mixed with the carrier, passed through a 40-60 mesh sieve and mixed again.
  • the method further includes:
  • step ii) in the method is: gradiently mixing the active ingredient and the carrier, sieve H 40-60 mesh and mixing again.
  • the preparation method provided in this application is used to prepare oral pharmaceutical compositions with small specifications (for example, containing 0.1-5 mg > 0.5 mg > 1-5 mg of active ingredients).
  • the preparation method provided in this application is simple and stable, the API content and mixing uniformity of the intermediate materials in the preparation process are good, and the finished preparations obtained have fast dissolution and stable quality, and are suitable for industrial scale-up production.
  • the use of the oral pharmaceutical composition of the present application in the preparation of drugs for treating JAK-related diseases is provided.
  • a method for treating JAK-related diseases includes administering the oral pharmaceutical composition of the present application to an individual in need thereof.
  • the oral pharmaceutical composition of the present application which is used to treat JAK-related diseases.
  • the JAK-related diseases are selected from but not limited to diseases of the immune system (such as organ transplant rejection), autoimmune diseases (such as multiple sclerosis, rheumatoid arthritis, juvenile arthritis, Psoriatic arthritis, type I diabetes, lupus, psoriasis), allergic conditions (such as asthma, food allergy, atopic dermatitis and rhinitis), skin diseases (such as psoriasis, atopic dermatitis, rash), Solid and hematological malignancies (such as prostate cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, malignant glioma, leukemia, lymphoma, multiple myeloma) and bone marrow Proliferative disorders (including polycythemia, idiopathic thrombocythemia, chronic spontaneous myelofibrosis, extramyelofibrosis with myelofibrosis
  • autoimmune diseases such as multiple
  • the application also provides the use of the oral pharmaceutical composition of the application for simultaneous, separate and sequential use in combination with another therapeutic or preventive agent (for example, the additional therapeutic or preventive agent as described above) .
  • another therapeutic or preventive agent for example, the additional therapeutic or preventive agent as described above
  • the dosage range of the active ingredient contained in the oral pharmaceutical composition of the present application is about 0.0001 to about 50 mg/kg body weight/day, For example, about 0.01 to about 10 mg/kg body weight/day (single or divided administration).
  • the doctor determines the precise dose needed to treat the patient according to the stage and severity of the disease and the specific needs and responses of the individual patient.
  • treating means to reverse, reduce, inhibit the disease or condition to which such term is applied, or the progression of one or more symptoms of such disease or condition, or prevent Such a disorder or condition or one or more symptoms of such a disorder or condition.
  • “Individual” as used herein includes human or non-human animals.
  • Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from diseases such as the diseases described herein.
  • “Non-human animals” in this application include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (such as sheep, dogs). , Cats, cows, pigs, etc.).
  • Example 1 Basic formulation formulation and dissolution measurement
  • Preparation process 1grind and sieve the raw material; 2weigh the prescription amount of the raw material and auxiliary materials and mix them for 10 minutes; 3the mixed materials pass through a 60-mesh sieve once; 4the materials are mixed again for 10 minutes; 5fill the capsules.
  • the dissolution test method is the "Chinese Pharmacopoeia” (2015 edition) basket method, rotating speed 75 rpm, temperature 37 ° C, medium volume 900 ml, in a hydrochloric acid solution at pH 1.0, disodium hydrogen phosphate/citric acid buffer at pH 3.0, The results of the dissolution investigation under pH 4.5 sodium acetate/acetic acid buffer are shown in Table 1-2.
  • the preparation process of prescription 2-1 and prescription 2-2 is the same as that of prescription 1 in Example 1.
  • the dissolution test method is the "Chinese Pharmacopoeia” (2015 edition) basket method, the rotating speed is 75 rpm, the temperature is 37 ° C, and the dissolution medium is 900 ml of pH 3.0 disodium hydrogen phosphate/citric acid buffer.
  • the dissolution investigation results are shown in Table 2. -2.
  • the dissolution measurement method is the basket method of the Chinese Pharmacopoeia (2015 edition), the rotation speed is 75 rpm, the temperature is 37 ° C, and the dissolution medium is 900 ml of pH 3.0 disodium hydrogen phosphate/citric acid buffer.
  • the investigation results are shown in Table 3-2.
  • Table 4-1 The prescription composition of different filler (microcrystalline cellulose) dosage
  • Preparation process 1 The crude drug passes through 80 mesh sieve once; 2Weighs the prescription amount of crude drug and auxiliary materials and mixes for 10 minutes; 3The mixed material passes through 60 mesh sieve once; 4Mixes again for 10 minutes; 5Fill the capsule.
  • the dissolution measurement method is the basket method of the Chinese Pharmacopoeia (2015 edition), the rotation speed is 75 rpm, the temperature is 37 ° C, and the dissolution medium is 900 ml of pH 3.0 disodium hydrogen phosphate/citric acid buffer.
  • the survey results are shown in Table 4-2.
  • the capsules were prepared according to the prescription shown in Table 5-1, and the influence of the particle size distribution of the drug substance on the dissolution of the preparation was investigated. Table 5-1. Dosage of each ingredient in prescription 5
  • Preparation process 1Use optional methods (such as grinding, sieving, mechanical pulverization or jet pulverization, etc.) to pulverize the API to different particle sizes, see Table 5-2 for particle size information; 2Gradient mixing of raw and auxiliary materials; 50 mesh sieve once; 4mix again; 5fill the capsule. Obtain four batches of products with different particle diameters of APIs, which are represented by prescription 5-1 (screening), prescription 5-2 (jet pulverization), prescription 5-3 (jet pulverization) and prescription 5-4 (jet pulverization) .
  • the dissolution determination method is the "Chinese Pharmacopoeia” (2015 edition) basket method, the rotating speed is 75 rpm, the temperature is 37 ° C, and the medium is 900 ml of pH 3.0 disodium hydrogen phosphate/citric acid buffer. The investigation results are shown in Table 5-3.
  • 1 mg, 2 mg, and 5 mg capsules were prepared according to the prescription shown in Table 6-1, and the content and mixing uniformity of the intermediate materials were investigated.
  • Raw material drug pretreatment Take the raw material drug for mechanical crushing, and carry out particle size testing. The results are shown in Table 6-2;
  • step (4) Pass the powder obtained in step (4) through a 20-mesh sieve to obtain the intermediate material after sieving;
  • step (6) Add the mixture material obtained in step (5) to a three-dimensional motion mixer and mix for 10 min to obtain a total mixed intermediate material;
  • Capsule filling Choose 3# gelatin hollow capsule, calculate the theoretical filling amount and control range according to the intermediate result, and then fill the capsule.
  • Table 6-2 API particle size data Table 6-3. Mixing uniformity of API content of intermediate materials
  • step (6) The mixture material obtained in step (5) is added to a three-dimensional motion mixer and mixed for 10 min;
  • Capsule filling Select 3# gelatin hollow capsule, calculate the theoretical filling volume and control range according to the intermediate result, set the host frequency to 15Hz, and start the capsule filling.
  • Table 7-2 API particle size data Table 7-3. API content and mixing uniformity of intermediate materials
  • the dissolution test method is the "Chinese Pharmacopoeia” (2015 edition) basket method, the rotating speed is 75 rpm, the temperature is 37 ° C, and the dissolution medium is 900 ml of pH 3.0 disodium hydrogen phosphate/citric acid buffer. The results are shown in Table 7-4.
  • composition of the present application can achieve rapid dissolution in vitro, the dissolution rate can reach more than 80% within 15 minutes, and the dissolution rate can reach more than 90% within 30 minutes. It has the effects of rapid dissolution and absorption in vivo, which is convenient for better Effectively play the medicine. Influencing factors test results
  • the dissolution test method is the "Chinese Pharmacopoeia” (2015 edition) basket method, the rotating speed is 75 rpm, the temperature is 37 ° C, and the dissolution medium is 900 ml of pH 3.0 disodium hydrogen phosphate/citric acid buffer, and the sample is measured at 30 min Dissolution.
  • the above results show that, without packaging, the composition of the present application has stable properties under conditions of light, high humidity and high temperature, no significant changes in impurities, dissolution and content in compliance with regulations, and the formulation has good stability. Results of stability investigation
  • the oral solid pharmaceutical high-density polyethylene heat-sealed gasket bottle was used as the inner packaging, and the stability was investigated. The results are shown in Table 7-6.
  • the dissolution test method is the "Chinese Pharmacopoeia” (2015 edition) basket method, the rotating speed is 75 rpm, the temperature is 37 ° C, and the dissolution medium is 900 ml of pH 3.0 disodium hydrogen phosphate/citric acid buffer, and the sample is measured at 30 min Dissolution.
  • the above results show that the composition of the present application has stable properties under accelerated, intermediate and long-term conditions, with no significant changes in impurities, and the dissolution rate is stable under accelerated, intermediate and long-term conditions when the oral solid high-density polyethylene heat-sealed gasket bottle is used as the inner packaging.
  • the content is in compliance with the regulations, and the preparation has good stability.
  • the preparation process of the oral pharmaceutical composition of the present application is simple and stable, the API content and mixing uniformity of the intermediate materials are good, and the obtained finished preparations dissolve quickly and have stable quality, and are suitable for industrial scale-up production.
  • the foregoing embodiments do not limit the solution of the application in any way.
  • various modifications of the present application will be apparent to those skilled in the art. Such modifications are also intended to fall within the scope of the appended claims. All references cited in this application (including all patents, patent applications, journal articles, books and any other publications) are incorporated herein by reference in their entirety.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

La présente invention concerne une composition pharmaceutique orale contenant un dérivé d'azétidine en tant que principe actif, son procédé de préparation et son utilisation. Le procédé de préparation de la composition pharmaceutique orale est simple et stable ; la teneur en API et l'uniformité de mélange des matériaux intermédiaires sont satisfaisantes ; et la préparation obtenue se dissout rapidement, est de qualité stable, et est appropriée pour une production à l'échelle industrielle.
PCT/CN2020/075913 2019-02-27 2020-02-20 Composition pharmaceutique orale contenant un dérivé d'azétidine en tant que principe actif, son procédé de préparation et son utilisation Ceased WO2020173364A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112159394A (zh) * 2020-10-09 2021-01-01 嘉兴特科罗生物科技有限公司 一种作为jak激酶抑制剂的小分子化合物及其用途
EP3976612A4 (fr) * 2019-05-28 2023-04-26 Mankind Pharma Ltd Nouveaux composés pour l'inhibition de la janus kinase 1
CN116444529A (zh) * 2023-06-16 2023-07-18 北京科翔中升医药科技有限公司 一种氘代氮杂环丁烷类jak抑制剂及其用途
WO2023174314A1 (fr) * 2022-03-18 2023-09-21 四川科伦博泰生物医药股份有限公司 Utilisation et procédé de traitement d'un dérivé d'azétidine
US20230404925A1 (en) * 2020-10-23 2023-12-21 Elanco Us Inc. Jak inhibitors having a specific particle size distribution

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101568330A (zh) * 2006-06-30 2009-10-28 伊休蒂卡有限公司 用于制备纳米粒形式的生物活性化合物的方法
WO2010039939A1 (fr) * 2008-10-02 2010-04-08 Incyte Corporation Inhibiteurs des janus kinases pour le traitement du syndrome de l’œil sec et autres maladies de l’œil
CN102026999A (zh) * 2008-03-11 2011-04-20 因塞特公司 作为jak抑制剂的氮杂环丁烷和环丁烷衍生物
WO2013173506A2 (fr) * 2012-05-16 2013-11-21 Rigel Pharmaceuticals, Inc. Procédé de traitement d'une dégradation musculaire
RU2601410C1 (ru) * 2015-11-13 2016-11-10 ЗАО "Р-Фарм" {3-[(7H-ПИРРОЛО[2,3-d]ПИРИМИДИН-4-ИЛ)АЗОЛИЛ]АЗЕТИДИН-3-ИЛ}АЦЕТОНИТРИЛЫ В КАЧЕСТВЕ ИНГИБИТОРОВ ЯНУС КИНАЗ
CN106551912A (zh) * 2015-09-29 2017-04-05 南京优科制药有限公司 一种提高难溶性药物溶出度的方法
WO2017097224A1 (fr) * 2015-12-11 2017-06-15 四川科伦博泰生物医药股份有限公司 Dérivé d'azétidine, son procédé de préparation et son utilisation

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103705485B (zh) * 2013-12-31 2015-07-22 广州帝奇医药技术有限公司 一种用于治疗骨髓增生异常综合症的组合物及其制备方法

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101568330A (zh) * 2006-06-30 2009-10-28 伊休蒂卡有限公司 用于制备纳米粒形式的生物活性化合物的方法
CN102026999A (zh) * 2008-03-11 2011-04-20 因塞特公司 作为jak抑制剂的氮杂环丁烷和环丁烷衍生物
WO2010039939A1 (fr) * 2008-10-02 2010-04-08 Incyte Corporation Inhibiteurs des janus kinases pour le traitement du syndrome de l’œil sec et autres maladies de l’œil
WO2013173506A2 (fr) * 2012-05-16 2013-11-21 Rigel Pharmaceuticals, Inc. Procédé de traitement d'une dégradation musculaire
CN106551912A (zh) * 2015-09-29 2017-04-05 南京优科制药有限公司 一种提高难溶性药物溶出度的方法
RU2601410C1 (ru) * 2015-11-13 2016-11-10 ЗАО "Р-Фарм" {3-[(7H-ПИРРОЛО[2,3-d]ПИРИМИДИН-4-ИЛ)АЗОЛИЛ]АЗЕТИДИН-3-ИЛ}АЦЕТОНИТРИЛЫ В КАЧЕСТВЕ ИНГИБИТОРОВ ЯНУС КИНАЗ
WO2017097224A1 (fr) * 2015-12-11 2017-06-15 四川科伦博泰生物医药股份有限公司 Dérivé d'azétidine, son procédé de préparation et son utilisation

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3976612A4 (fr) * 2019-05-28 2023-04-26 Mankind Pharma Ltd Nouveaux composés pour l'inhibition de la janus kinase 1
CN112159394A (zh) * 2020-10-09 2021-01-01 嘉兴特科罗生物科技有限公司 一种作为jak激酶抑制剂的小分子化合物及其用途
US20230404925A1 (en) * 2020-10-23 2023-12-21 Elanco Us Inc. Jak inhibitors having a specific particle size distribution
WO2023174314A1 (fr) * 2022-03-18 2023-09-21 四川科伦博泰生物医药股份有限公司 Utilisation et procédé de traitement d'un dérivé d'azétidine
CN116444529A (zh) * 2023-06-16 2023-07-18 北京科翔中升医药科技有限公司 一种氘代氮杂环丁烷类jak抑制剂及其用途
CN116444529B (zh) * 2023-06-16 2023-12-05 药康众拓(江苏)医药科技有限公司 一种氘代氮杂环丁烷类jak抑制剂及其用途

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