WO2022161205A1 - 一种含有jak抑制剂或其盐或其晶型的口服制剂及其制备方法和应用 - Google Patents

一种含有jak抑制剂或其盐或其晶型的口服制剂及其制备方法和应用 Download PDF

Info

Publication number
WO2022161205A1
WO2022161205A1 PCT/CN2022/072415 CN2022072415W WO2022161205A1 WO 2022161205 A1 WO2022161205 A1 WO 2022161205A1 CN 2022072415 W CN2022072415 W CN 2022072415W WO 2022161205 A1 WO2022161205 A1 WO 2022161205A1
Authority
WO
WIPO (PCT)
Prior art keywords
oral preparation
preparation according
correction
compound
under rule
Prior art date
Application number
PCT/CN2022/072415
Other languages
English (en)
French (fr)
Inventor
王征
高鹏
于婷婷
何裕军
沈美月
穆利伟
刘婧婧
石李秀
王德刚
Original Assignee
珠海联邦制药股份有限公司
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 珠海联邦制药股份有限公司 filed Critical 珠海联邦制药股份有限公司
Priority to CA3210023A priority Critical patent/CA3210023A1/en
Priority to JP2023546090A priority patent/JP2024504483A/ja
Priority to CN202280008388.2A priority patent/CN116724039A/zh
Priority to KR1020237026032A priority patent/KR20230129248A/ko
Priority to US18/263,434 priority patent/US20240033255A1/en
Priority to AU2022214702A priority patent/AU2022214702A1/en
Priority to EP22745081.4A priority patent/EP4285899A1/en
Publication of WO2022161205A1 publication Critical patent/WO2022161205A1/zh

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the invention belongs to the field of pharmaceutical preparations, in particular to the oral administration of a class of [1,2,4]triazolo[1,5-a]pyridine compounds and their isomers or their pharmaceutically acceptable salts or their crystal forms.
  • the preparation, its preparation method and application, the oral preparation has the characteristics of rapid dissolution.
  • JAK kinase is a family of intracellular non-receptor tyrosine kinases, which has 4 members: JAK1, JAK2, JAK3, TYK2, of which JAK1, JAK2 and TYK2 are expressed in various tissues and cells of the human body, and JAK3 is mainly Expressed in various hematopoietic cells. JAKs are involved in inflammation, autoimmune diseases, proliferative diseases, transplant rejection (or graft-versus-host disease), diseases involving impaired cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL6. amino acid kinase family.
  • JAK signaling pathway is thought to regulate multiple pathways related to inflammation, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving impaired cartilage turnover, congenital cartilage deformities, and/or hypersecretion of IL6. Signaling pathways in multiple related diseases.
  • JAK-STAT Signal Transducers and Activators of Transcription
  • the JAK-STAT pathway can transmit extracellular signals from a variety of cytokines, interferons, most interleukins and endocrine factors. to the nucleus and is responsible for the expression of protein-coding genes.
  • cytokines bind to their receptors
  • JAK family members autophosphorylate and/or transphosphorylate each other, followed by phosphorylation by STATs, which then migrate into the nucleus to regulate transcription.
  • JAK-STAT pathway is one of the main research directions of the pathogenesis of rheumatoid arthritis (RA). Studies have shown that IFN- ⁇ , TNF- ⁇ , IL-1 ⁇ , IL-2, IL-4, IL-6, IL -7, IL-9, IL-10, IL-15, IL-17, IL-21 and many other cytokines play an important role in the pathogenesis of RA by affecting the JAK-STAT pathway. This signaling pathway plays an important role in the pathogenesis of RA. It is continuously activated and participates in the proliferation of synovial cells and the release of inflammatory cytokines. Therefore, targeted blocking of the JAK-STAT pathway will achieve the purpose of regulating cell activity and improving the pathological process of RA.
  • RA rheumatoid arthritis
  • WO/2020/038457 discloses a series of JAKs satisfying the general formula I of [1,2,4]triazolo[1,5-a]pyridines and isomers or pharmaceutically acceptable salts thereof Kinase inhibitors:
  • JAK kinase inhibitor It is known as a small molecule JAK kinase inhibitor with significant JAK kinase inhibitory activity and high selectivity, and it is expected that these compounds may be used in the treatment of rheumatoid joints. It has not disclosed oral formulations of the JAK kinase inhibitors.
  • the object of the present invention is to provide an oral preparation with rapid dissolution and good stability, and the preparation process of the oral preparation is simple and suitable for large-scale industrial production.
  • the present invention provides an oral preparation comprising a JAK inhibitor and pharmaceutical excipients, wherein the JAK inhibitor comprises a compound of formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof Crystal form:
  • E 1 and E 2 are each independently selected from a single bond, -CH 2 - or -(CH 2 ) 2 -;
  • n 1 or 2;
  • n 1 or 2;
  • g is 1, 2 or 3;
  • h is 1, 2 or 3;
  • R 1 is selected from H, CN, C 1-6 alkyl or 3-6 membered cycloalkyl, wherein the C 1-6 alkyl or 3-6 membered cycloalkyl is optionally surrounded by 1, 2 or 3 Ra replace;
  • R 2 is selected from H, F, Cl, Br, I or C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted with 1, 2 or 3 R b ;
  • R 3 , R 4 and R 5 are each independently selected from H, F, Cl, Br, I or C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted with 1, 2 or 3 Rc ;
  • R 6 , R 7 and R 8 are each independently selected from H, F, Cl, Br, I or C 1-3 alkyl, wherein said C 1-3 alkyl is optionally surrounded by 1, 2 or 3 R d replace;
  • Each R is independently selected from H, F, Cl, Br, I, CN or C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted with 1, 2 or 3 R;
  • each R b is independently selected from F, Cl, Br or I;
  • each R c is independently selected from F, Cl, Br or I;
  • each R d is independently selected from F, Cl, Br or I;
  • each R is independently selected from F, Cl, Br or I;
  • the pharmaceutical excipients include fillers, disintegrants, binders, lubricants or surfactants, or a combination of two or more of them.
  • each R a is independently selected from H, F, Cl, Br, I or CN.
  • the compound of formula (I), its isomer or its pharmaceutically acceptable salt wherein, R 1 is selected from H, CN, C 1-3 alkyl or 3- 5-membered cycloalkyl, wherein the C 1-3 alkyl and 3-5 membered cycloalkyl are optionally substituted with 1, 2 or 3 Ra.
  • the compound of formula (I), its isomer or its pharmaceutically acceptable salt wherein, R 1 is selected from H, CN, CH 3 , wherein the CH 3 , Optionally substituted with 1, 2 or 3 Ra.
  • the compound of formula (I), its isomer or its pharmaceutically acceptable salt wherein, R 1 is selected from H, CN, CF 3 , CHF 2 ,
  • the compound of formula (I), its isomer or its pharmaceutically acceptable salt wherein, R 2 is selected from H, F, Cl, Br or I.
  • the compound of formula (I), its isomer or its pharmaceutically acceptable salt wherein, R 3 , R 4 and R 5 are independently selected from H, F, Cl, Br or I.
  • the compound of formula (I), its isomer or a pharmaceutically acceptable salt thereof wherein R 6 , R 7 and R 8 are independently selected from H, F, Cl, Br or I.
  • the compound of formula (I), its isomer or its pharmaceutically acceptable salt wherein, the structural unit selected from
  • the compound of formula (I), its isomer or its pharmaceutically acceptable salt wherein, the structural unit selected from
  • the compound of formula (I), its isomer or its pharmaceutically acceptable salt wherein, the structural unit selected from
  • the compound of formula (I), its isomer or its pharmaceutically acceptable salt is selected from
  • L1 is as defined in claim 1 or 9;
  • R 1 is as defined in claims 1 to 5;
  • R 2 is as defined in claim 1 or 6;
  • R 3 , R 4 and R 5 are as defined in claim 1 or 7;
  • R 6 , R 7 and R 8 are as defined in claim 1 or 8.
  • the compound of formula (I), its isomer or its pharmaceutically acceptable salt is selected from
  • L1 is as defined in claim 1 or 9;
  • Ra is as defined in claim 1 or 2;
  • R 2 is as defined in claim 1 or 6;
  • R 3 , R 4 and R 5 are as defined in claim 1 or 7;
  • R 6 , R 7 and R 8 are as defined in claim 1 or 8.
  • JAK inhibitors include the following compounds, isomers or pharmaceutically acceptable salts thereof
  • the compound of formula (I), its isomer or its pharmaceutically acceptable salt is selected from
  • the oral preparation includes one or more fillers.
  • the oral preparation includes one or more disintegrants.
  • the oral preparation includes one or more binders.
  • the oral preparation further includes one or more lubricants.
  • the oral preparation further includes one or more surfactants.
  • the oral preparation includes one or more fillers and one or more disintegrants.
  • the oral preparation includes one or more fillers, one or more disintegrants and one or more binders.
  • the oral preparation includes one or more fillers, one or more disintegrants, one or more binders and one or more lubricant.
  • the oral preparation includes one or more fillers, one or more disintegrants, one or more binders, one or more lubricant and one or more surfactants.
  • the filler is selected from microcrystalline cellulose, lactose, pregelatinized starch or anhydrous calcium hydrogen phosphate, or a combination of two or more thereof.
  • the disintegrant is selected from croscarmellose sodium, sodium starch glycolate, crospovidone or dry starch, or a combination of two or more of them .
  • the binder is selected from carboxypropylmethylcellulose, hydroxypropylcellulose, povidone, methylcellulose or ethylcellulose, or two or both of them more than one combination.
  • the lubricant is selected from magnesium stearate, micropowder silica gel, talc, hydrogenated vegetable oil, polyethylene glycols or sodium lauryl sulfate, or two or both of them combination of the above.
  • the surfactant is selected from sodium lauryl sulfate.
  • the invention provides an oral preparation comprising a compound of formula (II) (S)-N-(5-(2-(2,2-difluorocyclopropanecarbonyl)-2-azaspiro[3.5]nonan-7-yl) )-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof, and one or more fillers, one or more disintegrants, one or more binders, one or more lubricants, and one or more surfactants.
  • the XRPD spectrum analysis data of the A crystal form of the compound of the formula (II) is as follows:
  • the XRPD spectrum analysis data of the B crystal form of the compound of the formula (II) is as follows:
  • the XRPD spectrum analysis data of the C crystal form of the compound of the formula (II) is as follows:
  • the XRPD spectrum analysis data of the D crystal form of the compound of the formula (II) are as follows:
  • the XRPD pattern of the A crystal form of the compound of formula (II) is shown in FIG. 6 .
  • the XRPD pattern of the B crystal form of the compound of formula (II) is shown in FIG. 8 .
  • the XRPD pattern of the C crystal form of the compound of formula (II) is shown in FIG. 11 .
  • the XRPD pattern of the D crystal form of the compound of formula (II) is shown in FIG. 13 .
  • the pharmacologically acceptable salt of the active ingredient can be selected from (S)-N-(5-(2-(2,2-difluorocyclopropanecarbonyl)-2- Azaspiro[3.5]non-7-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof, active ingredient
  • the content of the composition is 1% to 50% of the total weight of the composition, preferably 5% to 40%, more preferably 6% to 30%, more preferably 8% to 25%, as an example, it can be 10%, 11% , 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20%.
  • fillers may also be included in the oral formulations provided in the present invention.
  • fillers may include but are not limited to lactose, microcrystalline cellulose, pregelatinized starch, anhydrous calcium hydrogen phosphate, calcium sulfate, calcium carbonate, dextrin, maltose, mannitol, sorbitol , trehalose and xylitol, etc.
  • the filler is selected from one or more of lactose, microcrystalline cellulose, pregelatinized starch, and anhydrous calcium hydrogen phosphate.
  • the filler is a mixture of lactose and microcrystalline cellulose.
  • the content of the filler can be 0%-78.5% of the total weight of the pharmaceutical composition, preferably 10%-70%, more preferably 20%-60%, more preferably 30%- 50%, by way of example, can be 30%, 31.75%, 37.25%, 39.25%, 41.75%, 42.25%, 43.75%.
  • the weight ratio of lactose and microcrystalline cellulose is 0:1, 5:3, 3:1, 1:1, 1:0; preferably 1:1.
  • the disintegrating agent may include, but is not limited to, croscarmellose sodium, sodium starch glycolate, crospovidone, dry starch, low-substituted hydroxypropyl cellulose, alginic acid , chitosan, corn starch.
  • the disintegrant in the composition may include, but is not limited to, one or more of croscarmellose sodium, sodium starch glycolate or crospovidone.
  • the disintegrant is croscarmellose sodium.
  • the content of the disintegrant may be 1%-25% of the total weight of the pharmaceutical composition, preferably 2%-16%, more preferably 4%, 8%, or 12%.
  • the binder can include but is not limited to hypromellose, hydroxypropyl cellulose, povidone, pregelatinized starch, sodium carboxymethyl cellulose, methyl cellulose one or more of them.
  • the content of the binder is based on the total weight of the composition, and the content of the binder is about 0.1%-5%, preferably 1%-4%, more preferably 2%-3%, The most preferred is 1.5% (calculated as an example of 20 mg, containing 3 mg of binder).
  • the oral preparation provided in the present invention may also contain one or more lubricants, such as magnesium stearate, micropowder silica gel, talc, hydrogenated vegetable oil, polyethylene glycols, sodium lauryl sulfate, the lubricants
  • the content is 0.1% to 5% of the total weight of the composition, preferably 0.5% to 3%, more preferably 1%.
  • the oral preparation provided by the present invention may also contain one or more surfactants, such as sodium dodecyl sulfate (SDS), based on the total weight of the composition, the content of the surfactant is about 0.1% to 5% ; preferably 1% to 3%; most preferably 2%.
  • SDS sodium dodecyl sulfate
  • composition comprising the following components by weight:
  • fillers selected from one or both of lactose and microcrystalline cellulose
  • 1% to 25% disintegrant selected from one or more of croscarmellose sodium, sodium starch glycolate and crospovidone;
  • binder selected from one or more of hypromellose, hydroxypropyl cellulose and povidone;
  • lubricant selected from magnesium stearate
  • surfactant selected from sodium dodecyl sulfate (SDS).
  • composition comprising the following components by weight:
  • disintegrant selected from one or more of croscarmellose sodium, sodium starch glycolate and crospovidone;
  • binder selected from one or more of hypromellose, hydroxypropyl cellulose, and povidone;
  • lubricant selected from magnesium stearate
  • surfactant selected from sodium dodecyl sulfate (SDS).
  • the oral preparation of the present invention can be prepared by a preparation method commonly used in the art, such as wet granulation, dry granulation, one-step granulation, etc., to prepare pharmaceutical composition granules, and then perform tablet compression.
  • the pharmaceutical composition of the present invention can also be prepared into tablets by the method of powder direct compression.
  • the filler, disintegrant, binder, lubricant or surfactant can be added in an internal or external manner; as an exemplary illustration, the filler can be The disintegrating agent can be internal or external; the binder can be internal or external; the lubricant can be internal or external; The surfactant is in the form of internal addition or external addition.
  • the oral preparation of the present invention dissolves very rapidly and completely.
  • 0.01mol/L hydrochloric acid solution is used as the dissolution medium, preferably 900ml of 0.01mol/L hydrochloric acid solution, at 37
  • the composition of the present invention is subjected to a dissolution test at a paddle speed of 50 rpm at ⁇ 0.5°C, and the dissolution rate is greater than or equal to 80% in 10 minutes or 15 minutes, preferably greater than 90% in 15 minutes or 20 minutes, and more preferably in 30 minutes or 45 minutes. greater than or equal to 95%.
  • the oral preparation of the present invention is placed in a watch glass, and the stability is investigated under the conditions of high temperature (60° C.), high humidity (relative humidity 75% ⁇ 1%, 15.5-60° C.) and light (illuminance is 4500lx ⁇ 500lx), Samples were taken on 5 days, 10 days and 30 days respectively, and the HPLC method was used to measure the changes of related substances, content and dissolution rate.
  • the results showed that the composition provided by the present invention was stable in nature, and the influencing factors 5 days, 10 days and 30 days results were the same as the results. Compared with 0 days, there was no significant difference in related substances, dissolution rate and content.
  • the oral preparation of the present invention is placed in an environment with a temperature of 40° C. ⁇ 2° C. and a relative humidity of 75% ⁇ 5% for stability investigation, and is placed for 1 month, and then the changes of related substances, content and dissolution rate are measured by HPLC method respectively. , the results show that the composition provided by the present invention has stable properties, and compared with the 0-day accelerated results, there is no significant difference in related substances, dissolution rates and contents.
  • Figure 1 shows the dissolution curves of the tablets of Examples 1 to 7 in 0.01 mol/L hydrochloric acid solution.
  • Figure 2 shows the dissolution profiles of the tablets of Examples 1, 8 and 9 in 0.01 mol/L hydrochloric acid solution.
  • Figure 3 shows the dissolution curves of the tablets of Examples 1 and 10-13 in 0.01 mol/L hydrochloric acid solution.
  • Figure 4 shows the dissolution curves of the tablets of Examples 1 and 14-18 in 0.01 mol/L hydrochloric acid solution.
  • Figure 5 shows the dissolution curves of the tablets of Examples 1 and 19 in 0.01 mol/L hydrochloric acid solution.
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues use without undue toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting the neutral forms of such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids; also include salts of amino acids such as arginine, etc. , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base
  • compositions for oral administration may further contain sweetening, flavoring, coloring, coating and/or preservative agents to provide a palatable preparation.
  • the pharmaceutical composition is in the form of a tablet.
  • Tablets can be prepared by compression or molding.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent or preservative .
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. Tablets may optionally be coated or scored.
  • “Pharmaceutical formulation” as used herein refers to a process in which different chemical substances, including active drugs, are combined to produce a final medicinal product.
  • Pharmaceutical formulations include enteral formulations (tablets, capsules), parenteral formulations (liquid, lyophilized powder) or topical formulations (dermal, inhalable).
  • the "pharmaceutically acceptable excipient, carrier or diluent" of the present invention includes, but is not limited to, any adjuvant, carrier, excipient, retention aid approved by the relevant governmental regulatory authority as acceptable for human or livestock use Agents, additives, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers, etc.
  • fillers refers to a substance that can improve the compression moldability of the drug and improve the content uniformity. Fillers include starch, sucrose, dextrin, lactose, pregelatinized starch, microcrystalline cellulose, corn starch, dextrose, ethyl cellulose, fructose, maltodextrin, maltose, medium chain triglycerides, anhydrous Calcium hydrogen phosphate, calcium sulfate, calcium carbonate, sugar alcohols erythritol, isomalt, lactitol, mannitol, sorbitol, trehalose, xylitol.
  • disintegrant refers to an auxiliary material that promotes the rapid disintegration of the tablet into fine particles in gastrointestinal fluids, and is mainly used to eliminate the binding force due to adhesion and/or high compression, thereby causing the tablet to disintegrate in water.
  • Disintegrants include dry starch, sodium starch glycolate, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, microcrystalline cellulose, alginic acid, sodium alginate, and the like.
  • binder refers to an adjuvant that is inherently viscous and can impart appropriate viscosity to non-viscous or insufficiently viscous materials, promotes solid powders to bond into larger particles, and helps to make stronger dosage forms. Binders include starch pulp, cellulose derivatives, methyl cellulose, hypromellose, hypromellose, sodium carboxymethyl cellulose, povidone, gelatin, 50% to 70% sucrose solution, alginic acid sodium solution, etc.
  • Lubricant refers to materials that prevent material from agglomerating and adhering to the punch and punch surfaces, or to the capsule filling machine. Lubricants can improve the surface properties of particles, such as improving the electrostatic distribution of the particle surface, improving the roughness of the particle surface, reducing friction, improving the selective adsorption of gases, and weakening the van der Waals forces between particles.
  • Lubricants include magnesium stearate, micronized silica gel, talc, hydrogenated vegetable oils, polyethylene glycols, sodium lauryl sulfate, hydrogenated castor oil, cottonseed oil, glyceryl behenate, glyceryl monostearate, Glyceryl palmitate, medium chain triglycerides, mineral oil, light mineral oil, octyldodecanol, poloxamer, polyethylene glycol, polyoxyethylene stearate, polyvinyl alcohol, etc.
  • the autoimmune diseases mentioned in the present invention refer to rheumatoid arthritis, inflammatory bowel disease (ulcerative colitis, Crohn's disease), systemic lupus erythematosus, dermatomyositis, ankylosing spondylitis, multiple sclerosis , Type I diabetes, psoriasis, vitiligo, Sjogren's syndrome, etc., or other inflammatory skin diseases such as atopic dermatitis, eczema, lichen planus, lichen glossy, lichen atrophicus, panniculitis, acne, suppurative sweat glands inflammation, etc.
  • the pulverized TUL01101, lactose, microcrystalline cellulose, croscarmellose sodium, carboxymethyl starch sodium, crospovidone, and substituted hydroxypropyl cellulose were mixed according to the proportions in Table 1, using a high-efficiency wet method.
  • the granulator carries out wet granulation, using 3.4% hypromellose and 2.3% sodium lauryl sulfate aqueous solution as the granulation liquid, after granulation, wet granulation and drying are carried out, and then the dried granules (water ⁇ 3%) dry granules, add croscarmellose sodium or sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and magnesium stearate, mix evenly and press into tablets.
  • the dissolution test of the tablets in Examples 1 to 7 was carried out.
  • the results show that the compound TUL01101 in Example 4, Example 6 and Example 7 dissolves slowly and fails to dissolve completely within 45 minutes, while the compound TUL01101 in the other examples can be completely dissolved and the dissolution behavior is similar.
  • croscarmellose sodium, sodium carboxymethyl starch and crospovidone are preferred as disintegrants.
  • TUL01101 is sensitive to moisture, croscarmellose with relatively low hygroscopicity is most preferred.
  • Sodium is used as disintegrant; since increasing the amount of disintegrant does not significantly improve the dissolution behavior, the preferred amount of disintegrant is 8.0%.
  • the dissolution data are shown in Table 2, and the dissolution profile is shown in Figure 1.
  • Example 1 The tablet of Example 1 was placed in a watch glass, and the stability was investigated under the conditions of high temperature (60 ° C), high humidity (relative humidity 75% ⁇ 1%, 15.5 ⁇ 60 ° C) and light (illuminance is 4500lx ⁇ 500lx), Samples were taken on 5 days, 10 days and 30 days respectively, and the changes of related substances, content and dissolution rate were determined by HPLC method. The results showed that: the properties of the tablet in Example 1 were stable, and the results of influencing factors on 5 days, 10 days and 30 days were the same as 0. There is no significant difference in the related substances, dissolution rate and content, and the data are shown in Table 3.
  • Example 1 The tablet of Example 1 was placed in a temperature of 40 ° C ⁇ 2 ° C, and the relative humidity was 75% ⁇ 5% to investigate the stability, placed for 1 month, and then the HPLC method was used to measure the related substances, content and dissolution. Changes, the results show that: the tablet properties of Example 1 are stable, and the results of accelerated 1 month are compared with 0 days, and there is no significant difference in related substances, dissolution rate and content. The data are shown in Table 4.
  • the pulverized TUL01101, lactose, microcrystalline cellulose, and croscarmellose sodium were wet granulated by a high-efficiency wet mixing granulator according to the proportions in Table 5, and 3.4% hypromellose or Hydroxypropyl cellulose, povidone and 2.3% sodium lauryl sulfate aqueous solution are used as granulation liquid. After granulation, wet granulation and drying are carried out, and then the dried granules (moisture ⁇ 3%) are dried and granulated. , add croscarmellose sodium and magnesium stearate, mix well and press into tablet.
  • the dissolution rate of the tablets in Example 1 and Examples 8 to 9 was determined.
  • the type of binder has no significant effect on the dissolution behavior of the preparation.
  • the dissolution data are shown in Table 6, and the dissolution profile is shown in Figure 2.
  • the pulverized TUL01101, lactose, microcrystalline cellulose, pregelatinized starch, anhydrous calcium hydrogen phosphate, and croscarmellose sodium were wet granulated by a high-efficiency wet mixing granulator according to the proportions in Table 7. , using 3.4% hypromellose and 2.3% sodium lauryl sulfate aqueous solution as granulation solution, wet granulation and drying treatment after granulation, and then dry granules after drying (moisture ⁇ 3%) granules, add croscarmellose sodium and magnesium stearate, mix well and press into tablets.
  • the dissolution rate of the tablets in Example 1 and Examples 10 to 13 was determined.
  • the results show that, in Example 12, the compound TUL01101 was dissolved slowly and could not be completely dissolved, while the compound TUL01101 in the other examples could be completely dissolved.
  • the type and dosage of fillers will affect the dissolution behavior of the preparation.
  • the dissolution data is shown in Table 8, and the dissolution curve is shown in Figure 3.
  • the pulverized TUL01101, lactose, microcrystalline cellulose, and croscarmellose sodium were wet granulated by a high-efficiency wet mixing granulator according to the proportions in Table 9, and 3.4% hypromellose and 2.3% sodium lauryl sulfate aqueous solution is used as granulation liquid, wet granulation and drying treatment are carried out after granulation, then the dried granules (moisture ⁇ 3%) are dried and granulated, and croscarmellose sodium is added. and magnesium stearate, mix well and press into tablets.
  • the dissolution rate of the tablets in Example 1 and Examples 14 to 18 was determined.
  • the dissolution data is shown in Table 10 below, and the dissolution profile is shown in Figure 4.
  • the pulverized TUL01101, lactose, microcrystalline cellulose, sodium lauryl sulfate, croscarmellose sodium, and magnesium stearate were mixed uniformly and directly pressed into tablets according to the proportions in Table 11.
  • the dissolution test of the tablets in Example 1 and Example 19 was carried out.
  • the dissolution data is shown in Table 12 below, and the dissolution profile is shown in Figure 5.
  • the results show that in Example 19, the compound TUL01101 was dissolved slowly and could not be completely dissolved. Based on the research results of the above examples, the wet granulation process was preferred.
  • Step 1 To a solution of compound 1-1 (10.2 g, 42.6 mmol) in THF (150 mL) was added dropwise LiHMDS (1 M, 51.2 mL) at -78°C. The reaction solution was stirred at -78°C for 1 hour, and then 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (16.7 g, 46.9 mmol) in THF ( 150 mL) solution was added to the reaction solution, followed by stirring at 15°C for 12 hours.
  • LiHMDS 1 M, 51.2 mL
  • reaction was quenched with 250 mL of saturated ammonium chloride, diluted with 200 mL of water, and then extracted with ethyl acetate (200 mL*3). The organic phases were combined, washed with saturated brine, dried over sodium sulfate, filtered and concentrated to obtain compound 1-2. The crude product was used directly in the next reaction without purification.
  • Step 2 To a solution of compound 1-2 (16 g, 43.1 mmol) and pinacol diboronate (12.0 g, 47.4 mmol) in DMF (100 mL) was added potassium acetate (12.7 g, 129.3 mmol) and Pd ( dppf) Cl2.CH2Cl2 (3.5 g, 4.3 mmol), replaced 3 times with nitrogen and kept stirring at 70°C for 3 hours under nitrogen.
  • the reaction solution was dispersed in a mixed solution of 300 mL of water and 400 mL of ethyl acetate. The organic phase was separated, washed with saturated brine, dried over sodium sulfate, filtered and concentrated to obtain the crude product.
  • the crude product was purified by silica gel column chromatography to obtain compound 1-3.
  • Step 3 Under nitrogen atmosphere, dissolve compound 1-3 (3.5 g, 10.0 mmol) and N-(5-bromo-[1,2,4]triazolo[1,5-a]pyridine-2 -yl)cyclopropanecarboxamide (2.6 g, 9.1 mmol) in dioxane (60 mL) and water (15 mL) was added potassium carbonate (3.8 g, 27.3 mmol) and Pd(dppf)Cl 2 .CH 2 Cl2 (744 mg , 911.0 ⁇ mol). The reaction solution was stirred at 90°C for 3 hours. The reaction solution was concentrated, and the obtained crude product was separated and purified by column chromatography to obtain compound 1-4.
  • Step 4 To a solution of compound 1-4 (3.5 g, 8.2 mmol) in dichloromethane (10 mL) was added hydrochloric acid/ethyl acetate (4 M, 30 mL), and the reaction solution was stirred at 25 °C for 0.5 h. A solid precipitated out, filtered and dried to give compound 1-5 (3.3 g hydrochloride, crude), which was used directly in the next reaction without purification.
  • Step 5 To a solution of compound 1-5 (3.0 g, 8.34 mmol, hydrochloride) in methanol (100 mL) was added Pd/C (1 g, 10%) under nitrogen atmosphere. The suspension was replaced with hydrogen 3 times and then stirred under a hydrogen atmosphere (30 psi) at 30°C for 12 hours. The reaction solution was filtered and concentrated to obtain compound 1-6 (3 g hydrochloride, crude product), which was directly used in the next reaction without purification.
  • Step 6 Compound 1-6 (0.87 g, 2.40 mmol, hydrochloride) was dissolved in N,N-dimethylformamide (10 mL), HOBt (487 mg, 3.6 mmol, ) and EDCI (691 mg, 3.6 mmol), then (1S)-2,2-difluorocyclopropylcarboxylic acid (323 mg, 2.6 mmol) and diisopropylethylamine (621 mg, 4.8 mmol) were added, and the reaction solution was reacted at 15° C. for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to preparative HPLC (neutral system) to obtain the compound of formula (II).
  • sample B crystal form into a sample bottle, and then add 1.0 mL of different solvents [pure water, SGF (simulated gastric fluid), FaSSIF (simulated intestinal fluid in fasting state), FeSSIF (simulated intestinal fluid in fed state) )], shake well. Shake at 37°C on a constant temperature shaker. After shaking for 24 hours, the solution was centrifuged, and the obtained supernatant was tested for its solubility. After diluting the supernatant (diluent ACN/H2O (1/1)) by a certain number (the compound has low solubility, the supernatant is diluted twice except for SGF, and SGF is diluted by 10 times), and its concentration is determined by HPLC.
  • solvents pure water, SGF (simulated gastric fluid), FaSSIF (simulated intestinal fluid in fasting state), FeSSIF (simulated intestinal fluid in fed state)
  • Diluent acetonitrile: water 1:1.
  • Mobile phase A 0.1% TFA aqueous solution, for example: Pipette 1 mL of TFA into 1 L of pure water, mix well, and ultrasonically degas.
  • Mobile phase B 100% acetonitrile.
  • STD solution Form B was used as the reference substance. Weigh about 5 mg of the reference substance in a glass bottle, dissolve with 10 mL of diluent, ultrasonicate for about 10 minutes to fully dissolve the sample, cool to room temperature and shake well. Duplicates were prepared in parallel, labelled the corresponding STD1, STD2. The corresponding STD1 was diluted 10, 100, 1000 and 2000 times with diluent, and the standard curve was used for testing.
  • sample solution Dilute the supernatant (diluent ACN/H2O (1/1)) by a certain number (the compound has a low solubility, and the supernatant is diluted twice except for SGF, and SGF is diluted by 10 times), shake well, It was placed in a 1.5mL liquid phase vial to be tested, and its concentration was determined by HPLC.
  • Form B has good solubility in simulated biological media, which is beneficial to obtain good in vivo bioavailability.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

提供了一种口服制剂，所述口服制剂含有JAK抑制剂和药用辅料，其中所述JAK抑制剂包括式(Ⅰ)化合物、其异构体或其药学上可接受的盐或它们的晶型。所述口服制剂具有溶出迅速的特点，制备工艺简单，适合工业化大生产。

Description

一种含有JAK抑制剂或其盐或其晶型的口服制剂及其制备方法和应用
本申请主张如下优先权：CN202110114769.6，申请日2021.01.29。
技术领域
本发明属于药物制剂领域，具体涉及一类[1,2,4]三唑并[1,5-a]吡啶类化合物及其异构体或其药学上可接受的盐或其晶型的口服制剂及其制备方法和应用，该口服制剂具有溶出迅速的特点。
背景技术
JAK激酶是一类胞内非受体酪氨酸激酶家族，该激酶家族有4个成员：JAK1，JAK2，JAK3，TYK2，其中JAK1、JAK2和TYK2在人体各组织细胞中均有表达，JAK3主要表达于各造血组织细胞中。JAK参与炎症、自身免疫疾病、增殖性疾病、移植排斥(或移植物抗宿主病)、涉及软骨更新(turnover)受损的疾病、先天软骨畸形和/或与IL6分泌过多相关的疾病的酪氨酸激酶家族。有研究证实，抑制JAK信号通路被认为可以调控多条与炎症、自身免疫性疾病、增殖性疾病、移植排斥、涉及软骨更新(turnover)受损的疾病、先天软骨畸形和/或与IL6分泌过多相关疾病的信号通路。
JAK激酶的四个家族成员选择性结合在不同的细胞因子受体上，发挥不同的生理学作用。JAKs的下游是信号转录与转录激活因子家族(Signal Transducers and Activators of Transcription，STAT)，JAK-STAT通路能将来自多种细胞因子、干扰素、大多数白细胞介素和内分泌因子等细胞外信号传导到细胞核，并负责蛋白质编码基因的表达。当细胞因子与其受体结合时，JAK家族成员自磷酸化和/或彼此转磷酸化，随后STATs磷酸化，然后迁移至细胞核内以调节转录。
JAK-STAT通路是类风湿性关节炎(RA)发病机制的主要研究方向之一，研究表明，IFN-γ、TNF-α、IL-1β、IL-2、IL-4、IL-6、IL-7、IL-9、 IL-10、IL-15、IL-17、IL-21等诸多细胞因子都是通过影响JAK-STAT通路在RA发病中起到重要作用，此信号通路在RA发病中呈持续激活状态，参与滑膜细胞的增殖、炎性细胞因子的释放等过程，因此，针对性阻断JAK-STAT通路将能达到调节细胞活动，改善RA病理过程的目的。
WO/2020/038457公开了[1,2,4]三唑并[1,5-a]吡啶类化合物及其异构体或其药学上可接受的盐的一系列满足式I通式的JAK激酶抑制剂：
Figure PCTCN2022072415-appb-000001
已知其为小分子JAK激酶抑制剂，具有显著的JAK激酶抑制活性和高度选择性，并预期这些化合物可能用于类风湿性关节的治疗。其尚未公开所述JAK激酶抑制剂的口服制剂。
这些化合物包括如下式II所示的化合物，其化学名为(S)-N-(5-(2-(2,2-二氟环丙烷羰基)-2-氮螺环[3.5]壬-7-基)-[1,2,4]三唑[1,5-a]吡啶-2-基)环丙烷甲酰胺：
Figure PCTCN2022072415-appb-000002
上述文献同样没有公开如何获得溶出迅速且完全的口服制剂，因此，需要更深入研究发现溶出良好并且稳定的口服制剂，并且该口服制剂制备工艺简单，适合工业化大生产。
发明内容
本发明的目的在于提供一种溶出迅速、稳定性好的口服制剂，并且该口服制剂制备工艺简单，适合工业化大生产。
本发明提供一种口服制剂，所述口服制剂包括含有JAK抑制剂和药用辅料，其中所述JAK抑制剂包括式(Ⅰ)化合物、其异构体或其药学上可接受的盐或它们的晶型：
Figure PCTCN2022072415-appb-000003
其中，
E 1和E 2分别独立地选自单键、-CH 2-或-(CH 2) 2-；
L 1选自单键、-(CH 2)g-、-C(＝O)-或-C(＝O)-(CH 2)h-；
m为1或2；
n为1或2；
g为1、2或3；
h为1、2或3；
R 1选自H、CN、C 1-6烷基或3～6元环烷基，其中所述C 1-6烷基或3～6元环烷基任选被1、2或3个Ra取代；
R 2选自H、F、Cl、Br、I或C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R b取代；
R 3、R 4和R 5分别独立地选自H、F、Cl、Br、I或C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个Rc取代；
R 6、R 7和R 8分别独立地选自H、F、Cl、Br、I或C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R d取代；
每一个R a分别独立地选自H、F、Cl、Br、I、CN或C 1-3烷基，其中 所述C 1-3烷基任选被1、2或3个R取代；
每一个R b分别独立地选自F、Cl、Br或I；
每一个R c分别独立地选自F、Cl、Br或I；
每一个R d分别独立地选自F、Cl、Br或I；
每一个R分别独立地选自F、Cl、Br或I；
所述药用辅料包括填充剂、崩解剂、粘合剂、润滑剂或表面活性剂，或它们中两种或两种以上的组合。
本发明中，作为实施方案之一，所述式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其中，每一个R a分别独立地选自H、F、Cl、Br、I或CN。
本发明中，作为实施方案之一，所述式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其中，R 1选自H、CN、C 1-3烷基或3～5元环烷基，其中所述C 1-3烷基和3～5元环烷基任选被1、2或3个Ra取代。
本发明中，作为实施方案之一，所述式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其中，R 1选自H、CN、CH 3、
Figure PCTCN2022072415-appb-000004
其中所述CH 3、
Figure PCTCN2022072415-appb-000005
任选被1、2或3个Ra取代。
本发明中，作为实施方案之一，所述式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其中，R 1选自H、CN、CF 3、CHF 2、
Figure PCTCN2022072415-appb-000006
Figure PCTCN2022072415-appb-000007
本发明中，作为实施方案之一，所述式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其中，R 2选自H、F、Cl、Br或I。
本发明中，作为实施方案之一，所述式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其中，R 3、R 4和R 5分别独立地选自H、F、Cl、Br或I。
本发明中，作为实施方案之一，所述式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其中，R 6、R 7和R 8分别独立地选自H、F、Cl、Br 或I。
本发明中，作为实施方案之一，所述式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其中，L 1选自单键、-CH 2-、-(CH 2) 2-、-C(＝O)-或-C(＝O)-(CH 2)-。
本发明中，作为实施方案之一，所述式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其中，结构单元
Figure PCTCN2022072415-appb-000008
选自
Figure PCTCN2022072415-appb-000009
Figure PCTCN2022072415-appb-000010
本发明中，作为实施方案之一，所述式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其中，结构单元
Figure PCTCN2022072415-appb-000011
选自
Figure PCTCN2022072415-appb-000012
Figure PCTCN2022072415-appb-000013
本发明中，作为实施方案之一，所述式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其中，结构单元
Figure PCTCN2022072415-appb-000014
选自
Figure PCTCN2022072415-appb-000015
Figure PCTCN2022072415-appb-000016
本发明中，作为实施方案之一，所述式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其选自
Figure PCTCN2022072415-appb-000017
其中，
L 1如权利要求1或9所定义；
R 1如权利要求1～5所定义；
R 2如权利要求1或6所定义；
R 3、R 4和R 5如权利要求1或7所定义；
R 6、R 7和R 8如权利要求1或8所定义。
本发明中，作为实施方案之一，所述式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其选自
Figure PCTCN2022072415-appb-000018
其中，
L 1如权利要求1或9所定义；
R a如权利要求1或2所定义；
R 2如权利要求1或6所定义；
R 3、R 4和R 5如权利要求1或7所定义；
R 6、R 7和R 8如权利要求1或8所定义。
本发明中，作为实施方案之一，JAK抑制剂包括下列化合物、其异构体或其药学上可接受的盐
Figure PCTCN2022072415-appb-000019
Figure PCTCN2022072415-appb-000020
本发明中，作为实施方案之一，所述式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其选自
Figure PCTCN2022072415-appb-000021
本发明中，作为实施方案之一，所述口服制剂包括一种或多种的填充剂。
本发明中，作为实施方案之一，所述口服制剂包括一种或多种的崩解剂。
本发明中，作为实施方案之一，所述口服制剂包括一种或多种的粘合剂。
本发明中，作为实施方案之一，所述口服制剂还包括一种或多种的润滑剂。
本发明中，作为实施方案之一，所述口服制剂还包括一种或多种的表面活性剂。
本发明中，作为实施方案之一，所述口服制剂包括一种或多种的填充剂和一种或多种的崩解剂。
本发明中，作为实施方案之一，所述口服制剂包括一种或多种的填充剂、一种或多种的崩解剂和一种或多种的粘合剂。
本发明中，作为实施方案之一，所述口服制剂包括一种或多种的填充剂、一种或多种的种崩解剂、一种或多种的粘合剂和一种或多种的润滑剂。
本发明中，作为实施方案之一，所述口服制剂包括一种或多种的填充剂、一种或多种的种崩解剂、一种或多种的粘合剂、一种或多种的润滑剂和一种或多种的表面活性剂。
本发明中，作为实施方案之一，所述填充剂选自微晶纤维素、乳糖、预胶化淀粉或无水磷酸氢钙，或它们两种或两种以上的组合。
本发明中，作为实施方案之一，所述崩解剂选自交联羧甲基纤维素钠、羧甲淀粉钠、交联聚维酮或干淀粉，或它们两种或两种以上的组合。
本发明中，作为实施方案之一，所述粘合剂选自羧丙甲纤维素、羟丙基纤维素、聚维酮、甲基纤维素或乙基纤维素，或它们中两种或两种以上的组合。
本发明中，作为实施方案之一，所述润滑剂选自硬脂酸镁、微粉硅胶、滑石粉、氢化植物油、聚乙二醇类或十二烷基硫酸钠，或它们两种或两种以上的组合。
本发明中，作为实施方案之一，所述表面活性剂选自十二烷基硫酸钠。
本发明提供一种口服制剂包括式(Ⅱ)化合物(S)-N-(5-(2-(2,2-二氟环丙烷羰基)-2-氮螺环[3.5]壬-7-基)-[1,2,4]三唑[1,5-a]吡啶-2-基)环丙烷甲酰胺或其药学上可接受的盐，以及一种或多种填充剂、一种或多种崩解剂、一种或多种粘合剂、一种或多种润滑剂和一种或多种表面活性剂。
本发明中，作为实施方案之一，所述(Ⅱ)的化合物或其药学上可接受的盐的晶型
Figure PCTCN2022072415-appb-000022
为A、B、C或D型结晶。
本发明中，作为实施方案之一，所述式(Ⅱ)化合物的A晶型XRPD图谱解析数据如下：
Figure PCTCN2022072415-appb-000023
Figure PCTCN2022072415-appb-000024
本发明中，作为实施方案之一，所述式(Ⅱ)化合物的B晶型XRPD图谱解析数据如下：
Figure PCTCN2022072415-appb-000025
本发明中，作为实施方案之一，所述式(Ⅱ)化合物的C晶型XRPD图谱解析数据如下：
Figure PCTCN2022072415-appb-000026
本发明中，作为实施方案之一，所述式(Ⅱ)化合物的D晶型XRPD图谱解析数据如下：
Figure PCTCN2022072415-appb-000027
本发明中，作为实施方案之一，所述式(Ⅱ)化合物的A晶型的XRPD图如图6所示。
本发明中，作为实施方案之一，所述式(Ⅱ)化合物的B晶型的XRPD图如图8所示。
本发明中，作为实施方案之一，所述式(Ⅱ)化合物的C晶型的XRPD图如图11所示。
本发明中，作为实施方案之一，所述式(Ⅱ)化合物的D晶型的XRPD图如图13所示。
本发明中提供的口服制剂中，所述活性成分的药理学上可接受的盐可以选自(S)-N-(5-(2-(2,2-二氟环丙烷羰基)-2-氮螺环[3.5]壬-7-基)-[1,2,4]三唑[1,5-a]吡啶-2-基)环丙烷甲酰胺或其药学上可接受的盐，活性成分的含量为组合物总重量的1％～50％，优选5％～40％，进一步优选6％～30％，更优选8％～25％，作为示例性的说明，可以为10％、11％、12％、13％、14％、15％、16％、17％、18％、19％、或20％。
本发明中提供的口服制剂中还可以包括填充剂、崩解剂、粘合剂、润滑剂及表面活性剂中的一种或多种。
本发明中提供的口服制剂中，填充剂可以包括但不限于乳糖、微晶纤维素、预胶化淀粉、无水磷酸氢钙、硫酸钙、碳酸钙、糊精、麦芽糖、甘露醇、山梨醇、海藻糖和木糖醇等。在本发明优选的实施方案中，所述填充剂选自乳糖、微晶纤维素、预胶化淀粉、无水磷酸氢钙中的一种或几种。在更优选的实施方案中，所述填充剂为乳糖和微晶纤维素的混合物。
本发明中提供的口服制剂中，填充剂的含量可以为所述药物组合物的总重量的0％～78.5％，优选10％～70％，进一步优选20％～60％，更优选30％～50％，作为示例性的说明，可以为30％、31.75％、37.25％、39.25％、41.75％、42.25％、43.75％。其中乳糖和微晶纤维素的重量比例为0:1、5:3、3:1、1:1、1:0；优选1:1。
本发明中提供的口服制剂中，崩解剂可以包括但不限于交联羧甲基纤维素钠、羧甲淀粉钠、交联聚维酮、干淀粉、低取代羟丙基纤维素、海藻酸、壳聚糖、玉米淀粉。在本发明优选的实施方案中，组合物中崩解剂可以包括但不限于交联羧甲基纤维素钠、羧甲淀粉钠或交联聚维酮 中的一种或多种。在本发明优选的实施方案中，崩解剂是交联羧甲基纤维素钠。
本发明中提供的口服制剂中，崩解剂的含量可以为所述药物组合物的总重量的1％～25％，优选2％～16％，更优选4％、8％、或12％。
本发明中提供的口服制剂中，粘合剂可以包括但不限于羟丙甲纤维素、羟丙基纤维素、聚维酮、预胶化淀粉、羧甲基纤维素钠、甲基纤维素中的一种或几种。
本发明中提供的口服制剂中，粘合剂的含量基于组合物的总重量，所述粘合剂含量为约0.1％～5％，优选1％～4％，更优选2％～3％，最优选1.5％(20mg为例计算，含粘合剂3mg)。
本发明中提供的口服制剂还可以含有一种或多种润滑剂，例如硬脂酸镁、微粉硅胶、滑石粉、氢化植物油、聚乙二醇类、十二烷基硫酸钠，所述润滑剂含量为组合物的总重量的0.1％～5％，优选0.5％～3％，更优选1％。
本发明提供的口服制剂还可以含有一种或几种表面活性剂，例如十二烷基硫酸钠(SDS)，基于组合物的总重量，所述表面活性剂的含量为约0.1％～5％；优选1％～3％；最优选2％。
本发明优选的实施方案中，提供了一种药物组合物，包括含有以重量计的如下成分：
1)1％～50％的(S)-N-(5-(2-(2,2-二氟环丙烷羰基)-2-氮螺环[3.5]壬-7-基)-[1,2,4]三唑[1,5-a]吡啶-2-基)环丙烷甲酰胺或其药学上可接受的盐；
2)0％～78.5％的填充剂，选自乳糖和微晶纤维素的一种或两种；
3)1％～25％的崩解剂，选自交联羧甲基纤维素钠、羧甲淀粉钠、交联聚维酮的一种或多种；
4)0.1％～5％的粘合剂，选自羟丙甲纤维素、羟丙基纤维素、聚维酮的一种或多种；
5)0.1％～5％的润滑剂，选自硬脂酸镁；
6)0.1％～5％的表面活性剂，选自十二烷基硫酸钠(SDS)。
本发明优选的另一实施方案中，提供了一种药物组合物，包括含有以重量计的如下成分：
1)8％～25％的(S)-N-(5-(2-(2,2-二氟环丙烷羰基)-2-氮螺环[3.5]壬-7-基)-[1,2,4]三唑[1,5-a]吡啶-2-基)环丙烷甲酰胺或其药学上可接受的盐；
2)30～50％的填充剂，选自乳糖和微晶纤维素的一种或两种；
3)2％～16％的崩解剂，选自交联羧甲基纤维素钠、羧甲淀粉钠、交联聚维酮的一种或多种；
4)1％～4％的粘合剂，选自羟丙甲纤维素、羟丙基纤维素、聚维酮的一种或多种；
5)0.5％～3％的润滑剂，选自硬脂酸镁；
6)1％～3％的表面活性剂，选自十二烷基硫酸钠(SDS)。
本发明的口服制剂可以采用本领域常用的制备方法制备，如湿法制粒、干法制粒、一步制粒等方法制备药物组合物颗粒，再进行压片。本发明的药物组合物也可采用粉末直压的方法，制备成片剂。本发明中，作为实施方案之一，所述填充剂、崩解剂、粘合剂、润滑剂或表面活性剂添加方式可以为内加或外加方式；作为示例性的说明，所述填充剂可以为内加或外加的方式；所述崩解剂可以为内加或外加的方式；所述粘合剂可以为内加或或外加的方式，所述润滑剂可以为内加或外加的方式；所述表面活性剂为内加或外加的方式。
本发明的口服制剂溶出十分迅速且完全，根据中国药典2015年版四部通则0931第二法(桨法)，以0.01mol/L盐酸溶液为溶出介质，优选900ml的0.01mol/L盐酸溶液，在37±0.5℃下以50rpm的桨速对本发明组合物进行溶出试验，10分钟或15分钟溶出度大于等于80％，优选15分钟或20分钟溶出度大于90％，更优选30分钟或45分钟溶出度大于等于95％。
本发明的口服制剂置于表面皿中，于高温(60℃)、高湿(相对湿度75％士1％,15.5～60℃)及光照(照度为4500lx士500lx)条件下进行稳定性考察，分别于5天、10天、30天取样，采用HPLC法测定有关物质、 含量及溶出度的变化，结果表明：本发明提供的组合物性质稳定，影响因素5天、10天、30天结果与0天比较，有关物质、溶出度与含量均无显著差异。
本发明的口服制剂置于温度40℃±2℃，相对湿度为75％±5％的环境下进行稳定性考察，放置1个月，然后分别采用HPLC法测定有关物质、含量及溶出度的变化，结果表明本发明提供的组合物性质稳定，加速1月结果与0天比较，有关物质、溶出度与含量均无显著差异。
附图说明
图1显示实施例1～7的片剂在0.01mol/L盐酸溶液中的溶出曲线。
图2显示实施例1、8、9的片剂在0.01mol/L盐酸溶液中的溶出曲线。
图3显示实施例1、10～13的片剂在0.01mol/L盐酸溶液中的溶出曲线。
图4显示实施例1、14～18的片剂在0.01mol/L盐酸溶液中的溶出曲线。
图5显示实施例1、19的片剂在0.01mol/L盐酸溶液中的溶出曲线。
图6：A晶型的XRPD图谱。
图7：A晶型的DSC图谱。
图8：B晶型的XRPD图谱
图9：B晶型的DSC图谱。
图10：B晶型的TGA图谱。
图11：C晶型的XRPD图谱。
图12：C晶型的DSC图谱。
图13：D晶型的XRPD图谱。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的 或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应商品或其活性成分。
本发明所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明所述的“药物组合物”通常用于口服给药。用于口服给药的药物组合物可进一步包含甜味剂、调味剂、着色剂、包衣剂和/或防腐剂，以提供适口的制剂。在一个实施方案中，药物组合物是片剂的形式。片剂可通过压制或模塑制备。压制片剂可以通过在合适的机器中压制自由流动形式的活性成分来制备，该自由流动形式的活性成分例如粉末或颗粒，任选地与粘合剂、润滑剂、惰性稀释剂或防腐剂混合。模制片剂可以通过在合适的机器中模制，用惰性液体稀释剂润湿的粉末状活性成分的混合物来制备。片剂可任选地包衣或刻痕。
本发明所述的“药物制剂”是指其中组合不同化学物质(包括活性药物)以产生最终药用产品的方法。药物制剂包括肠内制剂(片剂，胶囊)，肠胃外制剂(液体，冻干粉末)或局部制剂(皮肤，可吸入)。
本发明的“药学上可接受的赋形剂、载体或稀释剂”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助留剂、增添剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂等。
术语“填充剂”是指能够改善药物的压缩成型性，提高含量均匀度的物质。填充剂包括淀粉、蔗糖、糊精、乳糖、预胶化淀粉、微晶纤维素、玉米淀粉、右旋糖、乙基纤维素、果糖、麦芽糊精、麦芽糖、中链甘油三酯、无水磷酸氢钙、硫酸钙、碳酸钙、糖醇类赤藓糖醇、异麦芽酮糖醇、乳糖醇、甘露醇、山梨醇、海藻糖、木糖醇。
术语“崩解剂”是指促使片剂在胃肠液中迅速碎裂成细小颗粒的辅料，主要用于消除因黏合及或高度压缩而产生的结合力，从而使片剂在水中瓦解。崩解剂包括干淀粉、羧甲淀粉钠、低取代羟丙纤维素、交联羧甲纤维素钠、交联聚维酮、微晶纤维素、海藻酸、海藻酸钠等。
术语“粘合剂”是指本身具有粘性并能赋予无粘性或粘性不足的物料以适宜粘性的辅料，促使固体粉末粘结成更大的粒子，有助于制成较为坚固的剂型。粘合剂包括淀粉浆、纤维素衍生物、甲基纤维素、羟丙纤维素、羟丙甲纤维素、羧甲纤维素钠、聚维酮、明胶、50％～70％蔗糖溶液、海藻酸钠溶液等。
术语“润滑剂”是指防止物料聚集并粘附于冲头与冲头表面，或粘附胶囊填充机的物料。润滑剂可以改善颗粒的表面特性，如改善粒子表面的静电分布、改善粒子表面的粗糙度、减少摩擦力、改善气体的选择性吸附，减弱粒子间的范德华力等。润滑剂包括硬脂酸镁、微粉硅胶、滑石粉、氢化植物油、聚乙二醇类、十二烷基硫酸钠、氢化蓖麻油，棉籽油，山嵛酸甘油酯，单硬脂酸甘油酯，棕榈酸甘油酯，中链甘油三酯，矿物油，轻质矿物油，辛基十二烷醇，泊洛沙姆，聚乙二醇，聚氧乙烯 硬脂酸酯，聚乙烯醇等。
本发明所述的自身免疫性疾病是指类风湿性关节炎、炎性肠病(溃疡性结肠炎、克罗恩病)、系统性红斑狼疮、皮肌炎、强直性脊柱炎、多发性硬化、I型糖尿病、银屑病、白癜风、干燥综合症等，或其它炎症性皮肤病如特应性皮炎、湿疹、扁平苔藓、光泽苔藓、硬化萎缩性苔藓、脂膜炎、痤疮、化脓性汗腺炎等。
具体实施方式
通过以下实施例进一步详细说明本发明。这些实施例仅用于说明性目的，而并不用于限制本发明的范围。
实施例1～7
将粉碎处理过的TUL01101、乳糖、微晶纤维素、交联羧甲纤维素钠、羧甲淀粉钠、交联聚维酮、取代羟丙纤维素按表1的比例，采用高效湿法混合制粒机进行湿法制粒，以3.4％的羟丙甲纤维素和2.3％的十二烷基硫酸钠水溶液作为制粒液，制粒后进行湿整粒及干燥处理，然后将干燥后颗粒(水分＜3％)干整粒，加入外加交联羧甲纤维素钠或羧甲淀粉钠、交联聚维酮、低取代羟丙纤维素以及硬脂酸镁，混合均匀后压片。
表1
Figure PCTCN2022072415-appb-000028
Figure PCTCN2022072415-appb-000029
实验例1溶出实验
根据中国药典2020年版四部通则0931第二法(桨法)，对实施例1～7中的片剂进行溶出度测定。使用900ml 0.01mol/L盐酸溶液为溶出介质，在37±0.5℃下以50rpm的桨速进行溶出试验。结果表明，实施例4、实施例6和实施例7中化合物TUL01101溶出缓慢，45分钟未能完全溶出，其余实施例中化合物TUL01101均能完全溶出且溶出行为相似。综合以上实施例研究结果，优选交联羧甲纤维素钠、羧甲淀粉钠及交联聚维酮作为崩解剂，因TUL01101对湿敏感，最优选吸湿性相对较低的交联羧甲纤维素钠作为崩解剂；因增加崩解剂用量对溶出行为改善不明显，故崩解剂用量优选8.0％。溶出数据如表2所示，溶出曲线见图1。
表2
Figure PCTCN2022072415-appb-000030
Figure PCTCN2022072415-appb-000031
实验例2：稳定性研究
(1)影响因素试验
将实施例1片剂置表面皿中，于高温(60℃)、高湿(相对湿度75％±1％,15.5～60℃)及光照(照度为4500lx±500lx)条件下进行稳定性考察，分别于5天、10天、30天取样，采用HPLC法测定有关物质、含量及溶出度的变化，结果表明：实施例1片剂性质稳定，影响因素5天、10天、30天结果与0天比较，有关物质、溶出度与含量均无显著差异，数据如表3所示。
表3
Figure PCTCN2022072415-appb-000032
(2)加速试验
将实施例1片剂置于温度40℃±2℃，相对湿度为75％±5％的环境下进行稳定性考察，放置1个月，然后分别采用HPLC法测定有关物质、含量及溶出度的变化，结果表明：实施例1片剂性质稳定，加速1月结果与0天比较，有关物质、溶出度与含量均无显著差异，数据如表4所示。
表4
检验项目 0月 1月
有关物质(总杂质) 0.3％ 0.3％
溶出度(30min) 99.1％ 94.9％
含量测定 99.7％ 100.0％
实施例8～9
将粉碎处理过的TUL01101、乳糖、微晶纤维素、交联羧甲纤维素钠按表5的比例，采用高效湿法混合制粒机进行湿法制粒，以3.4％的羟丙甲纤维素或羟丙基纤维素、聚维酮和2.3％的十二烷基硫酸钠水溶液作为制粒液，制粒后进行湿整粒及干燥处理，然后将干燥后颗粒(水分＜3％)干整粒，加入外加交联羧甲纤维素钠及硬脂酸镁，混合均匀后压片。
表5
Figure PCTCN2022072415-appb-000033
实验例3溶出实验
根据中国药典2020年版四部通则0931第二法(桨法)，对实施例1和实施例8～9中的片剂进行溶出度测定。使用900ml 0.01mol/L盐酸溶液为溶出介质，在37±0.5℃下以50rpm的桨速进行溶出试验。结果表明，实施例1、实施例8和实施例9中，TUL01101均能完全溶出且溶出行为相似。综合以上实施例研究结果，粘合剂种类对于制剂溶出行为无显著性影响。溶出数据如表6所示，溶出曲线见图2。
表6
Figure PCTCN2022072415-appb-000034
实施例10～13
将粉碎处理过的TUL01101、乳糖、微晶纤维素、预胶化淀粉、无水磷酸氢钙、交联羧甲纤维素钠按表7的比例，采用高效湿法混合制粒机进行湿法制粒，以3.4％的羟丙甲纤维素和2.3％的十二烷基硫酸钠水溶液作为制粒液，制粒后进行湿整粒及干燥处理，然后将干燥后颗粒(水分＜3％)干整粒，加入外加交联羧甲纤维素钠及硬脂酸镁，混合均匀后压片。
表7
成分 实施例(mg/片)
  1 10 11 12 13
TUL01101 20.0 20.0 20.0 20.0 20.0
乳糖 78.5 0 — — 157.0
无水磷酸氢钙 — — 78.5 — —
预胶化淀粉 — — — 78.5 —
微晶纤维素 78.5 157.0 78.5 78.5 0
交联羧甲纤维素钠(內加) 8.0 8.0 8.0 8.0 8.0
羟丙甲纤维素 3.0 3.0 3.0 3.0 3.0
十二烷基硫酸钠 2.0 2.0 2.0 2.0 2.0
交联羧甲纤维素钠(外加) 8.0 8.0 8.0 8.0 8.0
硬脂酸镁 2.0 2.0 2.0 2.0 2.0
片重 200 200 200 200 200
实验例4溶出实验
根据中国药典2020年版四部通则0931第二法(桨法)，对实施例1和实施例10～13中的片剂进行溶出度测定。使用900ml 0.01mol/L盐酸溶液为溶出介质，在37±0.5℃下以50rpm的桨速进行溶出试验。结果表明，实施例12中，化合物TUL01101溶出缓慢，未能完全溶出，其余实施例中化合物TUL01101均能完全溶出。综合以上实施例研究结果，填充剂的种类及用量会影响制剂的溶出行为，溶出数据如表8所示，溶出曲线见图3。
表8
Figure PCTCN2022072415-appb-000035
Figure PCTCN2022072415-appb-000036
实施例14～18
将粉碎处理过的TUL01101、乳糖、微晶纤维素、交联羧甲纤维素钠按表9的比例，采用高效湿法混合制粒机进行湿法制粒，以3.4％的羟丙甲纤维素和2.3％的十二烷基硫酸钠水溶液作为制粒液，制粒后进行湿整粒及干燥处理，然后将干燥后颗粒(水分＜3％)干整粒，加入外加交联羧甲纤维素钠及硬脂酸镁，混合均匀后压片。
表9
Figure PCTCN2022072415-appb-000037
实验例5溶出实验
根据中国药典2020年版四部通则0931第二法(桨法)，对实施例1和实施例14～18中的片剂进行溶出度测定。使用900ml 0.01mol/L盐酸溶液为溶出介质，在37±0.5℃下以50rpm的桨速进行溶出试验。结果表明，实施例18中，化合物TUL01101溶出缓慢，原因是由于实施例18中制剂单剂量含主药量过大，主药溶解度限制所致溶出行为变慢，其余规格制剂溶出行为均相似。溶出数据如下表10所示，溶出曲线见图4。
表10
Figure PCTCN2022072415-appb-000038
实施例19
将粉碎处理过的TUL01101、乳糖、微晶纤维素、十二烷基硫酸钠、交联羧甲纤维素钠、硬脂酸镁按表11的比例，混合均匀后直接压片。
表11
Figure PCTCN2022072415-appb-000039
Figure PCTCN2022072415-appb-000040
实验例6溶出实验
根据中国药典2020年版四部通则0931第二法(桨法)，对实施例1和实施例19中的片剂进行溶出度测定。使用900ml 0.01mol/L盐酸溶液为溶出介质，在37±0.5℃下以50rpm的桨速进行溶出试验。溶出数据如下表12所示，溶出曲线见图5。结果表明，实施例19中，化合物TUL01101溶出缓慢，未能完全溶出，综合以上实施例研究结果，优选湿法制粒工艺。
表12
Figure PCTCN2022072415-appb-000041
实施例20式(Ⅱ)化合物的制备
Figure PCTCN2022072415-appb-000042
步骤1:在-78℃下，向溶有化合物1-1(10.2g,42.6mmol)的THF(150mL)溶液中滴加LiHMDS(1M,51.2mL)。该反应液在-78℃下搅拌1小时后将1,1,1-三氟-N-苯基-N-(三氟甲基磺酰基)甲磺酰胺(16.7g,46.9mmol)的THF(150mL)溶液加入到该反应液中,然后在15℃下搅拌12小时。用250mL饱和氯化铵淬灭反应，用200mL水稀释，然后用乙酸乙酯(200mL*3)萃取。合并有机相，经饱和食盐水洗涤，硫酸钠干燥，过滤浓缩得到化合物1-2。粗品未经纯化直接用于下一步反应。
1H NMR(400MHz,CDCl3)δ5.63(br s,1H),3.50-3.65(m,4H),2.34(br s,4H),1.88(br t,J＝5.90Hz,2H),1.37(s,9H)。
步骤2：向溶有化合物1-2(16g,43.1mmol)和联硼酸频那醇酯(12.0g,47.4mmol)的DMF(100mL)溶液中加入醋酸钾(12.7g,129.3mmol)和Pd(dppf)Cl2.CH2Cl2(3.5g,4.3mmol)，用氮气置换3次并保持在氮气氛围中70℃下搅拌3小时。将反应液分散在300mL水和400mL乙酸乙酯混合液中。将有机相分离并经饱和食盐水洗涤，硫酸钠干燥，过滤浓缩得到粗品。粗品经硅胶色谱柱法纯化得到化合物1-3。
1H NMR(400MHz,CDCl 3)δ6.46(br s,1H),3.71-3.53(m,4H),2.31(br d,J＝3.0Hz,2H),2.24-2.16(m,2H),1.74(t,J＝6.3Hz,2H),1.44(s,9H),1.26(s,12H)。
步骤3：在氮气氛围中，向溶有化合物1-3(3.5g,10.0mmol)和N-(5-溴-[1,2,4]三唑并[1,5-a]吡啶-2-基)环丙烷甲酰胺(2.6g,9.1mmol)的二氧六环(60mL)和水(15mL)的溶液中加入碳酸钾(3.8g,27.3mmol)和Pd(dppf)Cl 2.CH 2Cl 2(744mg,911.0μmol)。该反应液在90℃下搅拌3小时。将反应液浓缩，所得粗品经柱色谱分离纯化得到化合物1-4。LCMS(ESI)m/z:424.3[M+H]+。
步骤4：向溶有化合物1-4(3.5g,8.2mmol)的二氯甲烷(10mL)溶液中加入盐酸/乙酸乙酯(4M,30mL)，该反应液在25℃下搅拌0.5小时。固体析出，过滤并干燥，得到化合物1-5(3.3g盐酸盐，粗品)，未经纯化，直接用于下一步反应。
LCMS(ESI)m/z:324.1[M+H]+。
步骤5：在氮气氛围中，向溶有化合物1-5(3.0g,8.34mmol,盐酸盐)的甲醇(100mL)溶液中加入Pd/C(1g,10％)。该悬浊液用氢气置换3次，然后在氢气氛围(30psi)30℃下搅拌12小时。将反应液过滤，浓缩得到化合物1-6(3g盐酸盐，粗品)，未经纯化，直接用于下一步反应。
LCMS(ESI)m/z:326.2[M+H]+。
步骤6：将化合物1-6(0.87g,2.40mmol,盐酸盐)溶解在N,N-二甲基甲酰胺(10mL)中，加入HOBt(487mg,3.6mmol,)和EDCI(691mg,3.6mmol)，之后加入(1S)-2,2-二氟环丙基甲酸(323mg,2.6mmol)和二异丙基乙胺(621mg,4.8mmol)，反应液在15℃反应12小时。反应液减压浓缩，残余物经由制备型HPLC(中性体系)得到式(Ⅱ)化合物。
1H NMR(400MHz,CD3OD)δ7.32-7.73(m,2H),6.95(br s,1H),3.62-4.22(m,4H),3.45(br s,1H),3.18-3.37(m,1H),2.61(br s,1H),1.45-2.27(m,10H),0.78-1.17(m,4H)。LCMS(ESI)m/z:430.0[M+H]+。
实施例21各晶型的制备方法
称取50mg式(Ⅱ)化合物加入到2.0mL玻璃小瓶中，加入0.4mL甲醇和水的溶剂混合物(体积比1:1)，所得悬浊液，加入磁子后，将上 述样品置于加热磁力搅拌器上(40℃)进行搅拌。搅拌100小时后混悬的样品离心后置于35℃真空干燥箱过夜。干燥后的样品经检测XRPD(如图6所示)，判断为式(Ⅱ)化合物的A晶型，同时检测DSC(如图7所示)。
称取大约50mg式(Ⅱ)化合物加入到2.0mL玻璃小瓶中，加入0.4mL乙酸乙酯。加入磁子后，将上述样品置于加热磁力搅拌器上(40℃)进行搅拌。搅拌100小时后混悬的样品离心后置于35℃真空干燥箱过夜。干燥后的样品经检测XRPD(如图8所示)，判断为式(Ⅱ)化合物的B晶型，同时检测DSC(如图9所示)和TGA(如图10所示)。
式(Ⅱ)化合物的A晶型加热至170℃，经检测XRPD(图11所示)，晶型发生改变，得到的新晶型为式(Ⅱ)化合物的C晶型，同时检测DSC(如图12所示)。
称取大约50mg式(Ⅱ)化合物加入到2.0mL玻璃小瓶中，加入0.4mL乙醇和水的溶剂混合物(体积比1:1)所得悬浊液。加入磁子后，将上述样品置于加热磁力搅拌器上(40℃)进行搅拌。搅拌100小时后混悬的样品离心后置于35℃真空干燥箱过夜。干燥后的样品经检测XRPD(如图13所示)，判断为式(Ⅱ)化合物的D晶型。
实施例22式(Ⅱ)化合物的B晶型的固体稳定性研究
准确称重B晶型约5mg置于干燥洁净的玻璃瓶中，摊成薄薄一层，作为正式供试样品，放置于影响因素试验条件下(60℃，92.5％RH)和加速条件下(40℃/75％RH和60℃/75％RH)，其样品为完全暴露放样，用铝箔纸盖上，扎上小孔。在5天，10天取样分析。光照(可见光1200000Lux，紫外200W)条件下放置的样品为室温完全暴露放样。
实验结果表明，在影响因素条件(高温-60℃、高湿-92.5％RH、光照)和加速条件(40℃/75％RH和60℃/75％RH)下晶型均未发生变化。
实施例23式(Ⅱ)化合物的B晶型的生物媒介溶解度研究
1.B晶型的生物媒介溶解度实验
分别称取样品B晶型约2mg于样品瓶中，然后向其分别加入各1.0mL不同的溶媒【纯水，SGF(模拟胃液)，FaSSIF(禁食状态模拟肠液)，FeSSIF(进食状态模拟肠液)】，振荡摇匀。置于恒温振荡仪上于37℃条件下振荡。振荡24小时后离心分离，所得上清液测试其溶解度大小。将上清液稀释(稀释剂ACN/H2O(1/1))一定倍数后(化合物溶解度较小，上清液除SGF均稀释两倍，SGF稀释10倍)，用HPLC测定其浓度。
2.稀释剂及流动相的配制
稀释剂：乙腈：水1:1。流动相A：0.1％TFA水溶液，例：移取1mL的TFA于1L的纯水中，混合均匀，超声脱气。流动相B：100％乙腈。
3.对照品和样品液的配制
STD溶液配制：将B晶型作为对照品。分别称取5mg左右的对照品于玻璃瓶中，用10mL稀释剂使其溶解，超声10分钟左右使样品充分溶解，冷却至室温摇匀。平行配制两份，标记为相应的STD1，STD2。将对应的STD1用稀释剂稀释10、100、1000和2000倍，做标准曲线进行测试。
样品液的配制：将上清液稀释(稀释剂ACN/H2O(1/1))一定倍数后(化合物溶解度较小，上清液除SGF均稀释两倍，SGF稀释10倍)，摇匀，置于1.5mL液相小瓶中待测，用HPLC测定其浓度。
4.生物媒介溶解度结果(如表13所示)
表13 B晶型的生物媒介溶解度结果
Figure PCTCN2022072415-appb-000043
Figure PCTCN2022072415-appb-000044
实验结论：B晶型的在模拟的生物媒介溶解度良好，这一特性有利于获得良好的体内生物利用度。

Claims (62)

  1. 一种含有JAK抑制剂的口服制剂，其特征在于，所述口服制剂包括JAK抑制剂和药用辅料，其中所述JAK抑制剂包括式(Ⅰ)化合物、其异构体或其药学上可接受的盐或它们的晶型：
    Figure PCTCN2022072415-appb-100001
    其中，
    E 1和E 2分别独立地选自单键、-CH 2-或-(CH 2) 2-；
    L 1选自单键、-(CH 2) g-、-C(＝O)-或-C(＝O)-(CH 2)h-；
    m为1或2；
    n为1或2；
    g为1、2或3；
    h为1、2或3；
    R 1选自H、CN、C 1-6烷基或3～6元环烷基，其中所述C 1-6烷基或3～6元环烷基任选被1、2或3个Ra取代；
    R 2选自H、F、Cl、Br、I或C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R b取代；
    R 3、R 4和R 5分别独立地选自H、F、Cl、Br、I或C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R c取代；
    R 6、R 7和R 8分别独立地选自H、F、Cl、Br、I或C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R d取代；
    每一个Ra分别独立地选自H、F、Cl、Br、I、CN或C1-3烷基，其中所述C 1-3烷基任选被1、2或3个R取代；
    每一个R b分别独立地选自F、Cl、Br或I；
    每一个R c分别独立地选自F、Cl、Br或I；
    每一个R d分别独立地选自F、Cl、Br或I；
    每一个R分别独立地选自F、Cl、Br或I；
    所述药用辅料包括的填充剂、崩解剂、粘合剂、润滑剂或表面活性剂，或它们中的两种或两种以上的组合。
  2. 根据权利要求1所述的口服制剂，其特征在于，所述式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其中，每一个Ra分别独立地选自H、F、Cl、Br、I或CN。
  3. 根据权利要求1或2所述的口服制剂，其特征在于，所述式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其中，R1选自H、CN、C 1-3烷基或3～5元环烷基，其中所述C 1-3烷基和3～5元环烷基任选被1、2或3个Ra取代。
  4. 根据权利要求3所述的口服制剂，其特征在于，所述式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其中，R 1选自H、CN、CH 3、
    Figure PCTCN2022072415-appb-100002
    Figure PCTCN2022072415-appb-100003
    其中所述CH 3、
    Figure PCTCN2022072415-appb-100004
    任选被1、2或3个Ra取代。
  5. 根据权利要求4所述的口服制剂，其特征在于，所述式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其中，R 1选自H、CN、CF 3、CHF 2、
    Figure PCTCN2022072415-appb-100005
  6. 根据权利要求1所述的口服制剂，其特征在于，所述式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其中，R 2选自H、F、Cl、Br或I。
  7. 根据权利要求1所述的口服制剂，其特征在于，所述式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其中，R 3、R 4和R 5分别独立地选自H、F、Cl、Br或I。
  8. 根据权利要求1所述的口服制剂，其特征在于，所述式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其中，R 6、R 7和R 8分别独立地选自H、F、Cl、Br或I。
  9. 根据权利要求1所述的口服制剂，其特征在于，所述式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其中，L 1选自单键、-CH 2-、-(CH 2) 2-、-C(＝O)-或-C(＝O)-(CH 2)-。
  10. 根据权利要求1所述的口服制剂，其特征在于，所述式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2022072415-appb-100006
    选自
    Figure PCTCN2022072415-appb-100007
    Figure PCTCN2022072415-appb-100008
  11. 根据权利要求1所述的口服制剂，其特征在于，所述式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2022072415-appb-100009
    选自
    Figure PCTCN2022072415-appb-100010
    Figure PCTCN2022072415-appb-100011
  12. 根据权利要求1所述的式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2022072415-appb-100012
    选自
    Figure PCTCN2022072415-appb-100013
    Figure PCTCN2022072415-appb-100014
  13. 根据权利要求1～9任意一项所述的口服制剂，其特征在于，所述式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其选自
    Figure PCTCN2022072415-appb-100015
    Figure PCTCN2022072415-appb-100016
    其中，
    L 1如权利要求1或9所定义；
    R 1如权利要求1～5所定义；
    R 2如权利要求1或6所定义；
    R 3、R 4和R 5如权利要求1或7所定义；
    R 6、R 7和R 8如权利要求1或8所定义。
  14. 根据权利要求13所述的口服制剂，其特征在于，所述式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其选自
    Figure PCTCN2022072415-appb-100017
    其中，
    L 1如权利要求1或9所定义；
    R a如权利要求1或2所定义；
    R 2如权利要求1或6所定义；
    R 3、R 4和R 5如权利要求1或7所定义；
    R 6、R 7和R 8如权利要求1或8所定义。
  15. 一种含有JAK抑制剂的口服制剂，其特征在于，JAK抑制剂包 括下列化合物、其异构体或其药学上可接受的盐
    Figure PCTCN2022072415-appb-100018
    Figure PCTCN2022072415-appb-100019
  16. 根据权利要求15所述的口服制剂，其特征在于，所述式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其选自
    Figure PCTCN2022072415-appb-100020
  17. 根据权利要求1～16任一所述口服制剂，其特征在于，所述口服制剂包括一种或多种的填充剂。
  18. 根据权利要求1～16任一所述口服制剂，其特征在于，所述口服制剂包括一种或多种的崩解剂。
  19. 根据权利要求1～16任一所述口服制剂，其特征在于，所述口服制剂包括一种或多种的粘合剂。
  20. 根据权利要求1～16任一所述口服制剂，其特征在于，所述口服制剂还包括一种或多种的润滑剂。
  21. 根据权利要求1～16任一所述口服制剂，其特征在于，所述口服制剂还包括一种或多种的表面活性剂。
  22. 根据权利要求1～16任一所述口服制剂，其特征在于，所述口服制剂包括一种或多种的填充剂和一种或多种的崩解剂。
  23. 根据权利要求1～16任一所述口服制剂，其特征在于，所述口服制剂包括一种或多种的填充剂、一种或多种的崩解剂和一种或多种的粘合剂。
  24. 根据权利要求1～16任一所述口服制剂，其特征在于，所述口服制剂包括一种或多种的填充剂、一种或多种的种崩解剂、一种或多种的粘合剂和一种或多种的润滑剂。
  25. 根据权利要求1～16任一所述口服制剂，其特征在于，所述口服制剂包括一种或多种的填充剂、一种或多种的种崩解剂、一种或多种的粘合剂、一种或多种的润滑剂和一种或多种的表面活性剂。
  26. 根据权利要求17～25所述的口服制剂，其特征在于，所述填充剂选自微晶纤维素、乳糖、预胶化淀粉或无水磷酸氢钙，或它们两种或两种以上的组合。
  27. 根据权利要求18～29所述的口服制剂，其特征在于，所述崩解剂选自交联羧甲基纤维素钠、羧甲淀粉钠、交联聚维酮或干淀粉，或它们两种或两种以上的组合。
  28. [根据细则91更正 08.02.2022]　
    根据权利要求19～25所述的口服制剂，其特征在于，所述粘合剂选自羧丙甲纤维素、羟丙基纤维素、聚维酮、甲基纤维素或乙基纤维 素，或它们中两种或两种以上的组合。
  29. [根据细则91更正 08.02.2022]　
    根据权利要求20～25所述的口服制剂，其特征在于，所述润滑剂选自硬脂酸镁、微粉硅胶、滑石粉、氢化植物油、聚乙二醇类或十二烷基硫酸钠，或它们两种或两种以上的组合。
  30. [根据细则91更正 08.02.2022]　
    根据权利要求20～25所述的口服制剂，其特征在于，所述表面活性剂十二烷基硫酸钠。
  31. [根据细则91更正 08.02.2022]　
    根据权利要求1～30任一所述口服制剂，其特征在于，所述口服制剂包括JAK抑制剂、一种或多种填充剂、一种或多种崩解剂、一种或多种粘合剂、一种或多种润滑剂和一种或多种表面活性剂，所述JAK抑制剂是结构式(II)的化合物或其药学上可接受的盐或其晶型。
    Figure PCTCN2022072415-appb-100021
  32. [根据细则91更正 08.02.2022]　
    根据权利要求31所示的口服制剂，其特征在于，JAK抑制剂的含量为组合物总重量的1％～50％，优选5％～40％，进一步优选6％～30％，更优选8％～25％，最优选10％、15％、20％。
  33. [根据细则91更正 08.02.2022]　
    根据权利要求31所示的口服制剂，其特征在于，所述一种或多种填充剂选自微晶纤维素、乳糖、预胶化淀粉、无水磷酸氢钙中的至少一项。
  34. [根据细则91更正 08.02.2022]　
    根据权利要求33所示的口服制剂，其特征在于，所述填充剂微晶纤维素的含量为组合物总重量的0％～78.5％，优选10％～70％，进一步优选20％～60％，更优选30％～50％，最优选31.75％、37.25％、39.25％、41.75％、42.25％、43.75％。
  35. [根据细则91更正 08.02.2022]　
    根据权利要求33所示的口服制剂，其特征在于，所述填充剂乳糖的含量为组合物总重量的0％～78.5％，优选10％～70％，进一步优选 20％～60％，更优选30％～50％，最优选31.75％、37.25％、39.25％、41.75％、42.25％、43.75％。
  36. [根据细则91更正 08.02.2022]　
    根据权利要求33所示的口服制剂，其特征在于，所述填充剂预胶化淀粉的含量为组合物总重量的0％～78.5％，优选10％～70％，进一步优选20％～60％，更优选30～50％，最优选39.25％。
  37. [根据细则91更正 08.02.2022]　
    根据权利要求33所示的口服制剂，其特征在于，所述填充剂无水磷酸钙的含量为组合物总重量的0％～78.5％，优选10％～70％，进一步优选20％～60％，更优选30～50％，最优选39.25％。
  38. [根据细则91更正 08.02.2022]　
    根据权利要求33所示的口服制剂，其特征在于，所述填充剂可以为乳糖和微晶纤维素的混合物，乳糖和微晶纤维素的重量比例为0:1、5:3、3:1、1:1、1:0；优选1:1。
  39. [根据细则91更正 08.02.2022]　
    根据权利要求32所示的口服制剂，其特征在于，所述一种或多种崩解剂选自交联羧甲基纤维素钠、羧甲淀粉钠、交联聚维酮、干淀粉的至少一项。
  40. [根据细则91更正 08.02.2022]　
    根据权利要求39所示的口服制剂，其特征在于，所述崩解剂交联羧甲基纤维素钠的含量为组合物总重量的2％～16％，优选4％、8％、12％。
  41. [根据细则91更正 08.02.2022]　
    根据权利要求39所示的口服制剂，其特征在于，所述崩解剂羧甲淀粉钠的含量为组合物总重量的2％～16％，优选8％。
  42. [根据细则91更正 08.02.2022]　
    根据权利要求39所示的口服制剂，其特征在于，所述崩解剂交联聚维酮的含量为组合物总重量的2％～16％，优选8％。
  43. [根据细则91更正 08.02.2022]　
    根据权利要求32所示的口服制剂，其特征在于，所述一种或多种粘合剂选自羧丙甲纤维素、羟丙基纤维素、聚维酮、甲基纤维素、乙基纤维素中的至少一种。
  44. [根据细则91更正 08.02.2022]　
    根据权利要求43所示口服制剂，其特征在于，所述粘合剂羟丙甲纤维素的含量为组合物总重量的0.1％～5％，优选1％～4％，更优选2％～3％，最优选1.5％。
  45. [根据细则91更正 08.02.2022]　
    根据权利要求43所示的口服制剂，其特征在于，所述粘合剂羟丙基纤维素的含量为组合物总重量的0.1％～5％，优选1％～4％，更优选 2％～3％，最优选1.5％。
  46. [根据细则91更正 08.02.2022]　
    根据权利要求43所示的口服制剂，其特征在于，所述粘合剂聚维酮的含量为组合物总重量的0.1％～5％，优选1％～4％，更优选2％～3％，最优选1.5％。
  47. [根据细则91更正 08.02.2022]　
    根据权利要求32所示的口服制剂，其特征在于，所述一种或多种润滑剂选自硬脂酸镁、微粉硅胶、滑石粉、氢化植物油、聚乙二醇类、十二烷基硫酸钠。
  48. [根据细则91更正 08.02.2022]　
    根据权利要求47所示的口服制剂，其特征在于，所述润滑剂的含量为组合物的总重量的0.1％～5％，优选0.5％～3％，更优选1％。
  49. [根据细则91更正 08.02.2022]　
    根据权利要求32所示的口服制剂，其特征在于，所述表面活性剂选自十二烷基硫酸钠。
  50. [根据细则91更正 08.02.2022]　
    根据权利要求49所示的口服制剂，其特征在于，所述表面活性剂的含量为总重量的0.1％～5％；优选1％～3％；最优选2％。
  51. [根据细则91更正 08.02.2022]　
    根据权利要求1～50所述的口服制剂，其特征在于，所述(Ⅱ)的化合物或其药学上可接受的盐的晶型
    Figure PCTCN2022072415-appb-100022
    为A、B、C或D型结晶。
  52. [根据细则91更正 08.02.2022]　
    根据权利要求51所述的口服制剂，其特征在于，所述式(Ⅱ)化合物的A晶型的XRPD特征峰包括
    Figure PCTCN2022072415-appb-100023
    Figure PCTCN2022072415-appb-100024
  53. [根据细则91更正 08.02.2022]　
    根据权利要求51所述的口服制剂，其特征在于，所述式(Ⅱ)化合物的B晶型的XRPD特征峰包括
    Figure PCTCN2022072415-appb-100025
    Figure PCTCN2022072415-appb-100026
  54. [根据细则91更正 08.02.2022]　
    根据权利要求51所述的口服制剂，其特征在于，所述式(Ⅱ)化合物的C晶型的XRPD特征峰包括
    Figure PCTCN2022072415-appb-100027
  55. [根据细则91更正 08.02.2022]　
    根据权利要求51所述的口服制剂，其特征在于，所述式(Ⅱ)化合物的D晶型的XRPD特征峰包括
    Figure PCTCN2022072415-appb-100028
    Figure PCTCN2022072415-appb-100029
  56. [根据细则91更正 08.02.2022]　
    根据权利要求52所述的口服制剂，其特征在于，所述式(Ⅱ)化合物的A晶型的XRPD图如图6所示。
  57. [根据细则91更正 08.02.2022]　
    根据权利要求53所述的口服制剂，其特征在于，所述式(Ⅱ)化合物的B晶型的XRPD图如图8所示。
  58. [根据细则91更正 08.02.2022]　
    根据权利要求54所述的口服制剂，其特征在于，所述式(Ⅱ)化合物的C晶型的XRPD图如图11所示。
  59. [根据细则91更正 08.02.2022]　
    根据权利要求52所述的口服制剂，其特征在于，所述式(Ⅱ)化合物的D晶型的XRPD图如图13所示。
  60. [根据细则91更正 08.02.2022]　
    根据权利要求1～59任意一项所述的口服制剂的制备方法，所述制备方法选自湿法制粒、干法制粒工艺和粉末直压工艺中的一种，优选湿法制粒。
  61. [根据细则91更正 08.02.2022]　
    根据权利要求60所述的制备方法，所述填充剂、崩解剂、粘合剂、润滑剂或表面活性剂为内加或外加方式。
  62. [根据细则91更正 08.02.2022]　
    根据权利要求1～59任意一项所述的口服制剂在制备治疗自身免疫性疾病的药物中的用途，所述自身免疫性疾病优选类风湿性关节炎、炎性肠病、特应性皮炎。
PCT/CN2022/072415 2021-01-29 2022-01-17 一种含有jak抑制剂或其盐或其晶型的口服制剂及其制备方法和应用 WO2022161205A1 (zh)

Priority Applications (7)

Application Number Priority Date Filing Date Title
CA3210023A CA3210023A1 (en) 2021-01-29 2022-01-17 Oral preparation containing jak inhibitors or salts or crystal forms thereof, and preparation method and application thereof
JP2023546090A JP2024504483A (ja) 2021-01-29 2022-01-17 Ｊａｋ阻害剤またはその塩もしくは結晶形を含有する経口製剤、並びにその製造方法及び用途
CN202280008388.2A CN116724039A (zh) 2021-01-29 2022-01-17 一种含有jak抑制剂或其盐或其晶型的口服制剂及其制备方法和应用
KR1020237026032A KR20230129248A (ko) 2021-01-29 2022-01-17 Jak 억제제 또는 이의 염 또는 결정형을 함유하는 경구제제, 및 이의 제조 방법 및 응용
US18/263,434 US20240033255A1 (en) 2021-01-29 2022-01-17 Oral preparation containing jak inhibitor or salt thereof or crystal form thereof, preparation method therefor, and application thereof
AU2022214702A AU2022214702A1 (en) 2021-01-29 2022-01-17 Oral preparation containing jak inhibitor or salt thereof or crystal form thereof, preparation method therefor, and application thereof
EP22745081.4A EP4285899A1 (en) 2021-01-29 2022-01-17 Oral preparation containing jak inhibitor or salt thereof or crystal form thereof, preparation method therefor, and application thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202110114769.6 2021-01-29
CN202110114769 2021-01-29

Publications (1)

Publication Number Publication Date
WO2022161205A1 true WO2022161205A1 (zh) 2022-08-04

Family

ID=82653047

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/072415 WO2022161205A1 (zh) 2021-01-29 2022-01-17 一种含有jak抑制剂或其盐或其晶型的口服制剂及其制备方法和应用

Country Status (8)

Country Link
US (1) US20240033255A1 (zh)
EP (1) EP4285899A1 (zh)
JP (1) JP2024504483A (zh)
KR (1) KR20230129248A (zh)
CN (1) CN116724039A (zh)
AU (1) AU2022214702A1 (zh)
CA (1) CA3210023A1 (zh)
WO (1) WO2022161205A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20230091250A1 (en) * 2020-02-21 2023-03-23 Zhuhai United Laboratories Co., Ltd. Crystalline form of jak inhibitor and application thereof

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018019223A1 (zh) * 2016-07-26 2018-02-01 张文燕 作为选择性jak抑制剂化合物，该化合物的盐类及其治疗用途
CN108341814A (zh) * 2017-01-23 2018-07-31 上海翔锦生物科技有限公司 Jak激酶抑制剂及其应用
WO2020038457A1 (zh) 2018-08-23 2020-02-27 珠海联邦制药股份有限公司 作为JAK抑制剂的[1，2，4]三唑并[1，5-a]吡啶类化合物及其应用
CN111892592A (zh) * 2019-08-06 2020-11-06 江苏柯菲平医药股份有限公司 Jak激酶抑制剂及其用途
WO2021159372A1 (zh) * 2020-02-13 2021-08-19 珠海联邦制药股份有限公司 Jak抑制剂在制备治疗jak激酶相关疾病药物中的应用
WO2021164786A1 (zh) * 2020-02-21 2021-08-26 珠海联邦制药股份有限公司 Jak抑制剂的晶型及其应用

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018019223A1 (zh) * 2016-07-26 2018-02-01 张文燕 作为选择性jak抑制剂化合物，该化合物的盐类及其治疗用途
CN108341814A (zh) * 2017-01-23 2018-07-31 上海翔锦生物科技有限公司 Jak激酶抑制剂及其应用
WO2020038457A1 (zh) 2018-08-23 2020-02-27 珠海联邦制药股份有限公司 作为JAK抑制剂的[1，2，4]三唑并[1，5-a]吡啶类化合物及其应用
CN111892592A (zh) * 2019-08-06 2020-11-06 江苏柯菲平医药股份有限公司 Jak激酶抑制剂及其用途
WO2021159372A1 (zh) * 2020-02-13 2021-08-19 珠海联邦制药股份有限公司 Jak抑制剂在制备治疗jak激酶相关疾病药物中的应用
WO2021164786A1 (zh) * 2020-02-21 2021-08-26 珠海联邦制药股份有限公司 Jak抑制剂的晶型及其应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHINESE PHARMACOPOEIA, 2020

Also Published As

Publication number Publication date
EP4285899A1 (en) 2023-12-06
JP2024504483A (ja) 2024-01-31
US20240033255A1 (en) 2024-02-01
KR20230129248A (ko) 2023-09-07
CN116724039A (zh) 2023-09-08
CA3210023A1 (en) 2022-08-04
AU2022214702A1 (en) 2023-08-03

Similar Documents

Publication Publication Date Title
CN104781239B (zh) 用于治疗病毒感染和另外的疾病的烷基嘧啶衍生物
CN110088105B (zh) Jak家族激酶的小分子抑制剂
CN102264743B (zh) Mlk抑制剂及其使用方法
CN101925603B (zh) 囊性纤维化跨膜通道调节因子的调节剂
CN102421784B (zh) 作为gsk-3抑制剂的7-环烷基氨基喹诺酮
TW201944994A (zh) 用於治療囊腫纖化症之醫藥組合物
JP2021527031A (ja) セピアプテリンの薬学的に許容される塩
KR20170095896A (ko) 페놀성 trpv1 작용제의 프로드러그
TW201116276A (en) Glycine compounds
CN109952304A (zh) 一类抑制并降解cdk的化合物
KR20170123694A (ko) 그렐린 o-아실 트랜스퍼라제 억제제
TW202016110A (zh) Ｊａｋ激酶家族之小分子抑制劑
WO2022161205A1 (zh) 一种含有jak抑制剂或其盐或其晶型的口服制剂及其制备方法和应用
CN102219783A (zh) 盐酸维拉佐酮及其组合物
WO2018233437A1 (zh) 巴瑞克替尼的晶型及其制备方法
CN109937203A (zh) 一类具有抑制并降解酪氨酸蛋白激酶jak1或jak2活性的化合物
CN113045494B (zh) 吡啶酮衍生物及其在制备预防和/或治疗结核分枝杆菌所引起的结核病的药物中的用途
TWI616447B (zh) 巴瑞克替尼（Ｂａｒｉｃｉｔｉｎｉｂ）磷酸鹽晶型Ｄ及其藥物組合物
KR20240006641A (ko) Tyk2 억제제로서의 헤테로아릴 화합물, 이의 조성물 및 용도
CN109963853A (zh) 一类具有降解酪氨酸蛋白激酶jak3活性的化合物
WO2021104363A1 (zh) 含无定型态芳杂环化合物的组合物、其制备方法及用途
CN114644642A (zh) 一种噻吩并吡啶化合物的晶型a、制备方法及其药物组合物
CA2907921C (en) Inhibition of il-2 production
JP2022507558A (ja) チエノピリドン誘導体のカリウム塩一水和物及びその調製方法
CN114605408B (zh) 5-羟基-1,3-二取代苯基吡啶并[2,3-d]嘧啶类化合物及其制法和应用

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: 22745081

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 202280008388.2

Country of ref document: CN

ENP Entry into the national phase

Ref document number: 20237026032

Country of ref document: KR

Kind code of ref document: A

Ref document number: 3210023

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2023546090

Country of ref document: JP

Ref document number: 18263434

Country of ref document: US

ENP Entry into the national phase

Ref document number: 2022214702

Country of ref document: AU

Date of ref document: 20220117

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2022745081

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2022745081

Country of ref document: EP

Effective date: 20230829