WO2020034987A1 - Promédicament renfermant un dérivé de glucuronide en tant qu'inhibiteur jak, son procédé de préparation et ses applications - Google Patents

Promédicament renfermant un dérivé de glucuronide en tant qu'inhibiteur jak, son procédé de préparation et ses applications Download PDF

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WO2020034987A1
WO2020034987A1 PCT/CN2019/100554 CN2019100554W WO2020034987A1 WO 2020034987 A1 WO2020034987 A1 WO 2020034987A1 CN 2019100554 W CN2019100554 W CN 2019100554W WO 2020034987 A1 WO2020034987 A1 WO 2020034987A1
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methyl
general formula
pharmaceutically acceptable
stereoisomer
acceptable salt
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PCT/CN2019/100554
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English (en)
Chinese (zh)
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高鹏
曾蜜
谭松良
孙广俊
包如迪
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江苏豪森药业集团有限公司
上海翰森生物医药科技有限公司
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Priority to CN201980004509.4A priority Critical patent/CN111094314B/zh
Publication of WO2020034987A1 publication Critical patent/WO2020034987A1/fr

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • 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
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of pharmaceutical synthesis, and particularly relates to a prodrug containing a glucuronide derivative JAK inhibitor, a preparation method and application thereof.
  • Janus kinase is an intracellular non-receptor tyrosine kinase that mediates the signaling and activation of various cytokines.
  • the JAK kinase family is divided into four subtypes, JAK1, JAK2, JAK3, and TYK2. Each subtype mediates different types of cytokine signaling pathways.
  • JAK-1, JAK-2, and TYK-2 are found in all tissue cells
  • Expression, JAK-3 is mainly expressed in various hematopoietic cells.
  • the common feature of cytokine receptors is that the receptor itself does not have kinase activity, but the intracellular segment of the receptor has a binding site for the tyrosine kinase JAK.
  • the cytokine receptor When the cytokine receptor binds to its ligand, it activates the receptor-coupled JAKs, which in turn causes the receptor to be phosphorylated.
  • the phosphorylated tyrosine site can bind to the STAT protein containing the SH2 domain. recruited to receptors and phosphorylated by JAKs, followed by phosphotyrosine-mediated STAT dimerization, activated STAT dimers are transferred to the nucleus and activate their target gene transcription, which in turn regulates the growth, activation, Different functions, such as differentiation.
  • the JAK / STAT signaling pathway mediates the signaling of most cytokines in cells and plays a key role in participating in biological processes such as immune regulation and immune cell proliferation.
  • the JAK / STAT signaling pathway has a wide range of functions and is involved in many important biological processes such as cell proliferation, differentiation, apoptosis, and immune regulation, and is associated with a variety of inflammatory diseases such as rheumatoid arthritis, dermatitis, psoriasis, and inflammatory bowel Diseases (ulcerative colitis and Crohn's disease) are closely related; meanwhile, the JAK / STAT signaling pathway is closely related to tumor diseases such as myelofibrosis, polycythemia vera, and primary thrombocytosis, and mutations in the JAK molecule itself It can also cause tumor diseases such as acute myeloid cell leukemia (AML), acute lymphocytic leukemia (ALL), ductal carcinoma of the breast, and non-small cell lung cancer (NSC
  • Inflammatory bowel disease is a chronic intestinal inflammatory disease, including ulcerative colitis and Crohn's disease.
  • the current drugs for treating inflammatory bowel disease are aminosalicylic acid preparations, glucocorticoids, immunosuppressive agents, antibiotics, etc.
  • the main principle of UC treatment is to regulate the immune response and suppress inflammation.
  • sulfasalazine is mainly used in the treatment of mild to moderate UC.
  • Moderate to severe UC currently used drugs include glucocorticoids, but because the risks outweigh the benefits, they will not be used as a long-term treatment.
  • Monoclonal antibodies have problems such as high cost, the production of drug antibodies that affect the safety and effectiveness of drugs, and the inconvenient way of intravenous administration. There are still unmet medical needs in this field. Many patients who have received treatment have not yet responded, and up to 80% of Crohn's disease patients and 30% of UC patients eventually need surgery.
  • Tofacitinib (Xeljanz) is the first oral JAK inhibitor for the treatment of adult patients with moderate to severe active UC. It has significant inhibitory activity on JAK1, 2, 3 subtypes, and its JAK2 / JAK3 selectivity is only 20 times. The activities of JAK1 and JAK2 increase the efficacy of tofacitinib, but also bring more serious side effects. Adverse reactions include infection, tuberculosis, tumors, anemia, liver damage, and increased cholesterol. Tofacitinib's listing carries many black box signs: severe infections (tuberculosis, bacteria, fungi, viruses) and malignancies (lymphomas, etc.).
  • JAK2 activity is related to erythroid cell differentiation and lipid metabolism, some of these adverse reactions are thought to be related to Tofacitinib's insufficient selectivity to JAK-3, which is caused by the non-selective inhibition of the drug.
  • the JAK inhibitors currently on the market and under development mainly compete for the binding of the kinase domain and ADP, so there is a problem of low selectivity, even for selective inhibitors of a certain subtype of JAK. Target-related side effects.
  • JAK inhibitors Due to the good efficacy of JAK inhibitors and the serious side effects associated with multiple targets, the development of a JAK inhibitor drug with higher safety has become an urgent problem. Because inflammatory bowel disease occurs on the surface of the intestinal cavity of the gastrointestinal tract, it can function without the need for drugs to enter the blood system. Therefore, a system was developed to reduce the systemic exposure of the drug in the blood circulation and increase the local exposure of the drug to the site of inflammation. Prodrugs become a good strategy for improving safety.
  • the international application WO2017091544 (A1) reports that Therassemble Company obtained related compounds of its prodrugs by modifying tofacitinib. These compounds show good tissue distribution selectivity, reflecting the feasibility of this strategy and having great clinical application value.
  • An object of the present invention is to provide a compound represented by the general formula (IA), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound represented by the general formula (I) is as follows:
  • M, M 1 or M 2 is O, S or NH;
  • G is a JAK inhibitor, selected from Tofacitinib, Ruxolitinib, Baricitinib, Peficitinib, Pacritinib, Delgocitinib, Pf-04965842, Upadacitinib, Filgotinib, Itacitinib, Fedratinib, Decernotinib, SHR-0302, Delgocitinib, ASN-atin, Bertin PF-06700841, INCB-52793, ATI-502, PF-06651600, AZD-4205, Deuterium-modified ruxolitinib analog, ATI-501, R-348, R-348, NS-018, SHR0302, Jaktinib hydrochloride, Jaktinib hydrochloride or KL-130008;
  • R is -CH 2 OH or -COOPg
  • R 1 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hetero Cyclic, aryl or heteroaryl, wherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and Heteroaryl is optionally further selected from deuterium, alkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy , Hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl with one or more substituents;
  • R 2 and R 3 are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxyl, cyano, alkenyl, Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • Pg is hydrogen or a carboxy protecting group.
  • Pg is a carboxy protecting group, it is selected from -DMB, -Bn, -Allyl, -PfP, -Me, -PMB, -EM, or t-Boc;
  • Pg 1 , Pg 2 and Pg 3 are hydrogen or hydroxyl protecting groups.
  • Pg 1 , Pg 2 and Pg 3 are hydroxyl protecting groups, each is independently selected from -CH 3 , -C (CH 3 ) 3 , -CPh 3 , -CH 2 Ph, -CH 2 OCH 3 , -Si (CH 3 ) 3 , -THP, -SiMe 2 (t-Bu), -Ac or -COPh;
  • n 0, 1, 2, 3, or 4;
  • x 0, 1, 2 or 3.
  • An object of the present invention is to provide a compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound represented by the general formula (I) is as follows:
  • M is O, S or NH
  • G is a JAK inhibitor, selected from Tofacitinib, Ruxolitinib, Baricitinib, Peficitinib, Pacritinib, Delgocitinib, Pf-04965842, Upadacitinib, Filgotinib, Itacitinib, Fedratinib, Decernotinib, SHR-0302, Delgocitinib, ASN-atin, Bertin PF-06700841, INCB-52793, ATI-502, PF-06651600, AZD-4205, Deuterium-modified ruxolitinib analog, ATI-501, R-348, R-348, NS-018, SHR0302, Jaktinib hydrochloride, Jaktinib hydrochloride or KL-130008; preferably SHR-0302;
  • R is -CH 2 OH or -COOPg
  • R 1 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hetero Cyclic, aryl or heteroaryl, wherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and Heteroaryl is optionally further selected from deuterium, alkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy , Hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl with one or more substituents;
  • R 2 and R 3 are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxyl, cyano, alkenyl, Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • Pg is a hydrogen or carboxy protecting group.
  • Pg is a carboxy protecting group, it is selected from -DMB (2,4-dimethoxybenzyl), -Bn (benzyl), -Allyl (allyl), -PfP (Pentafluorophenyl), -Me (methyl), -PMB (p-methylbenzyl), -EME (methoxyethoxymethyl) or t-Boc (tert-butoxycarbonyl);
  • Pg 1 , Pg 2 and Pg 3 are hydrogen or hydroxy protecting groups.
  • Pg 1 , Pg 2 and Pg 3 are hydroxy protecting groups, each is independently selected from -CH 3 (methyl), -C (CH 3 ) 3 (Tert-butyl), -CPh 3 (triphenyl), -CH 2 Ph (benzyl ether), -CH 2 OCH 3 (methoxymethyl), -Si (CH 3 ) 3 (trimethylsilane) Group), -THP (tetrahydrofuryl), -SiMe 2 (t-Bu) (tert-butyldisilyl), -Ac (acetyl) or -COPh (benzoyl);
  • n is an integer of 0, 1, 2, 3, or 4;
  • x is an integer of 0, 1, 2 or 3;
  • M is O
  • Pg 1 , Pg 2 and Pg 3 are hydrogen
  • R is -COOPg
  • Pg is hydrogen
  • R 1 is selected from hydrogen, amino, nitro, halogen, methyl or methoxy
  • R 1 is In the ortho position
  • R 2 and R 3 are both selected from methyl
  • G is not Tofacitinib
  • M is O
  • Pg 1 , Pg 2 and Pg 3 are hydrogen
  • R is -COOPg
  • Pg is hydrogen
  • R 1 is nitro
  • R 1 is Ortho position
  • R 2 and R 3 are selected from methyl at the same time
  • x is 1, G is not Ruxolitinib or Baricitinib .
  • the present invention also relates to a preferred embodiment.
  • the compound represented by the general formula (IA) or (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is characterized in that it is further represented by the general formula (II). Show:
  • M, G, R to R 3 , Pg 1 to Pg 3 , n and x are as described in the general formula (I).
  • the present invention also relates to a preferred embodiment.
  • the compound represented by the general formula (IA) or (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is characterized in that it is further represented by the general formula (IIA). Show:
  • the present invention also relates to a preferred embodiment.
  • the compound represented by the general formula (IA) or (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is characterized in that it is further represented by the general formula (III) Show:
  • M, G, R, R 1 , Pg 1 to Pg 3 and n are as described in the general formula (I).
  • the present invention also relates to a preferred embodiment.
  • the compound represented by the general formula (IA) or (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is characterized in that it is further represented by the general formula (IV) Show:
  • G, R 1 to R 3 , Pg, Pg 1 to Pg 3 and x are as described in the general formula (I).
  • the present invention also relates to a preferred embodiment.
  • the compound represented by the general formula (IA) or (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is characterized in that it is further represented by the general formula (V). Show:
  • M, G, R, R 1 and Pg 1 to Pg 3 are as described in the general formula (I).
  • the present invention also relates to a preferred embodiment.
  • the compound represented by the general formula (IA) or (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is characterized in that it is further represented by the general formula (VI) Show:
  • R, R 1 to R 3 , Pg 1 to Pg 3 and x are as described in the general formula (I).
  • the present invention also relates to a preferred embodiment.
  • the compound represented by the general formula (IA) or (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is characterized in that it is further represented by the general formula (VII) Show:
  • R 1 to R 3 and x are as described in the general formula (I).
  • the present invention also relates to a preferred embodiment.
  • the compound represented by the general formula (IA) or (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is characterized in that it is further represented by the general formula (VIII). Show:
  • R is -CH 2 OH or -COOH
  • G is selected from Tofacitinib or SHR-0302;
  • R 1 is selected from hydrogen, halogen, cyano, nitro, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy,
  • x is an integer selected from 0, 1, 2 or 3, preferably 1;
  • G is Tofacitinib
  • R 1 is selected from nitro
  • R is -CH 2 OH.
  • the present invention also relates to a preferred embodiment.
  • the compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is further characterized by the general formula (IX):
  • R 1 to R 3 and x are as described in the general formula (I).
  • the present invention also relates to a compound represented by the general formula (IB), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • M 1 is O, S or NH
  • G 1 is a JAK inhibitor, selected from Tofacitinib, Ruxolitinib, Baricitinib, Peficitinib, Pacritinib, Delgocitinib, Pf-04965842, Upadacitinib, Filgotinib, Itacitinib, Fedratinib, Decernotinib, SHR-0302, Delgocitinib, ASN-002, CID , PF-06700841, INCB-52793, ATI-502, PF-06651600, AZD-4205, Deuterium-modified ruxolitinib analog, ATI-501, R-348, R-348, NS-018, SHR0302, Jaktinib hydrochloride, Jaktinib hydrochloride Or KL-130008;
  • R ' is -CH 2 OH or -COOPg
  • R 1 ′ is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, Heterocyclyl, aryl or heteroaryl, wherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl And heteroaryl are optionally further selected from deuterium, alkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy Substituted with one or more substituents of aryl, hydroxyalkyl, cycloalkyl, heterocycly
  • R 2 and R 3 are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxyl, cyano, alkenyl, Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • Pg ' is hydrogen or a carboxy protecting group.
  • Pg is a carboxy protecting group, it is selected from -DMB (2,4-dimethoxybenzyl), -Bn (benzyl), -Allyl (allyl),- PfP (pentafluorophenyl), -Me (methyl), -PMB (p-methylbenzyl), -EME (methoxyethoxymethyl) or t-Boc (tert-butoxycarbonyl);
  • Pg 1 ′, Pg 2 ′ and Pg 3 ′ are hydrogen or hydroxy protecting groups.
  • Pg 1 , Pg 2 and Pg 3 are hydroxy protecting groups, each is independently selected from the group consisting of -CH 3 (methyl), -C (CH 3 ) 3 (tert-butyl), -CPh 3 (triphenyl), -CH 2 Ph (benzyl ether), -CH 2 OCH 3 (methoxymethyl), -Si (CH 3 ) 3 (tri (Methylsilyl), -THP (tetrahydrofuryl), -SiMe 2 (t-Bu) (t-butyldisilyl), -Ac (acetyl) or -COPh (benzoyl);
  • n1 is an integer of 0, 1, 2, 3, or 4;
  • x is an integer of 0, 1, 2 or 3.
  • the present invention also relates to a preferred embodiment, the compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the G is selected from the following JAK inhibitors:
  • SHR0302 is Tofacitinib is
  • the present invention also relates to a preferred embodiment, each of the general formulas, stereoisomers, or pharmaceutically acceptable salts thereof described in any one of the features,
  • R 1 is selected from hydrogen, halogen, cyano, nitro, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy;
  • R 2 and R 3 are each independently selected from a C 1-6 alkyl group or a C 1-6 haloalkyl group.
  • the present invention also relates to a method for preparing the compound represented by the general formula (VII) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof, which is characterized by comprising the following steps,
  • the rings R 1 to R 3 , Pg, Pg 1 to Pg 3 and x are as described in the general formula (I).
  • the invention also relates to a method for preparing the compound represented by the general formula (VI) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof, which is characterized by comprising the following steps,
  • the rings R 1 to R 3 , R, Pg 1 to Pg 3 and x are as described in the general formula (I).
  • the present invention also relates to a method for preparing the compound represented by the general formula (VI-2) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof, which is characterized by comprising the following steps,
  • SHR-0302 reacts with general formula (IX) to obtain a compound represented by general formula (VI-2) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof;
  • X is selected from halogen.
  • the invention also relates to a method for preparing a compound represented by the general formula (VII) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof, which is characterized by comprising the following steps:
  • the invention also relates to a method for preparing a compound represented by the general formula (IX) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof, which is characterized by comprising the following steps:
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective dose of a compound of general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmacological agents.
  • the invention also relates to the use of the compound of the general formula (I), its stereoisomers or its pharmaceutically acceptable salts, or the use of the pharmaceutical composition in the preparation of a JAK inhibitor medicament, the application comprising JAK inhibition
  • the agent contains a glucuronide prodrug, which in the application releases a JAK inhibitor, preferably a JAK1, JAK2, JAK3 inhibitor, by cleavage by ⁇ -glucuronidase.
  • the invention also relates to the compound of the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition for preparing a medicine containing a glucuronide derivative JAK inhibitor prodrug Application.
  • the invention also relates to the use of the compound of general formula (I), its stereoisomers or its pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of a medicament for treating inflammatory diseases and tumor diseases.
  • the invention also relates to a method for treating inflammatory diseases and a method for treating tumor diseases, which comprises administering to a patient a therapeutically effective dose of a pharmaceutical composition.
  • the inflammatory diseases mentioned above are selected from rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel disease (ulcerative colitis and Crohn's disease), and the tumor diseases are selected from bone marrow fibrosis and true disease.
  • AML myeloid leukemia
  • ALL acute lymphocytic leukemia
  • NSCLC non-small cell lung cancer
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms Alkyl, most preferably 1 to 3 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 2,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhex
  • lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Methyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl and the like.
  • the alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkane Alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups, methyl, ethyl, isopropyl, tert-butyl, haloalkyl are preferred in the present invention , Deuterated alkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.
  • alkylene means that a hydrogen atom of an alkyl group is further substituted, for example: "methylene” means -CH 2- , "ethylene” means-(CH 2 ) 2- , “propylene” Means-(CH 2 ) 3- , “butylene” means-(CH 2 ) 4- , and the like.
  • alkenyl refers to an alkyl group, as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3 -Butenyl and the like. Alkenyl may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 8 Carbon atoms, most preferably 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • Polycyclocycloalkyl includes spiro, fused and bridged cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl, more preferably cyclopropyl base.
  • spirocycloalkyl refers to a 5- to 20-membered monocyclic polycyclic group that shares one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings have complete conjugation. ⁇ electronic system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. Spirocycloalkyl is divided into monospirocycloalkyl, bisspirocycloalkyl or polyspirocycloalkyl according to the number of common spiro atoms between the rings, preferably monospirocycloalkyl and bisspirocycloalkyl.
  • spirocycloalkyl More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan, or 5 yuan / 6 yuan monospirocycloalkyl.
  • spirocycloalkyl include:
  • Spirocycloalkyl which also contains a single spirocycloalkyl and a heterocycloalkyl spiro atom, non-limiting examples include:
  • fused cycloalkyl refers to a 5- to 20-membered, each ring in the system that shares an adjacent pair of carbon atoms with other rings in the system.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl.
  • fused cycloalkyl include:
  • bridged cycloalkyl refers to a 5- to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a complete Conjugate ⁇ electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic.
  • bridged cycloalkyl include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthalene Radical, benzocycloheptyl and the like.
  • a cycloalkyl group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • groups which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthi
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent that contains 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S (O) A heteroatom of m (where m is an integer from 0 to 2), excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 8 ring atoms; and most preferably 3 to 8 ring atoms.
  • Non-limiting examples of monocyclic heterocyclyl include oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, di Hydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably oxetanyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl , Piperazinyl and pyranyl. More preferred is oxetanyl.
  • Polycyclic heterocyclyls include spiro, fused, and bridged heterocyclic groups; the involved spiro, fused, and bridged heterocyclic groups are optionally connected to other groups through a single bond, or through a ring Any two or more of the above atoms are further ring-connected to other cycloalkyl, heterocyclyl, aryl, and heteroaryl groups.
  • spiroheterocyclyl refers to a 3- to 20-membered monocyclic polycyclic heterocyclic group that shares one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen, or S (O ) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a completely conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan.
  • Spiroheterocyclyl is divided into monospiroheterocyclyl, bisspiroheterocyclyl or polyspiroheterocyclyl according to the number of common spiro atoms between the rings, preferably monospiroheterocyclyl and bisspiroheterocyclyl. More preferred are 3-membered / 5-membered, 4-membered 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclyl.
  • Non-limiting examples of spiroheterocyclyl include:
  • fused heterocyclyl refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system.
  • One or more rings may contain one or more Double bonds, but none of the rings have a completely conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S (O) m (where m is an integer from 0 to 2), and the remaining rings Atoms are carbon. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 3-membered / 5-membered, 4-membered 5-membered, or 5-membered / 6-membered Bicyclic fused heterocyclyl.
  • fused heterocyclyl include:
  • bridged heterocyclyl refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings have a total A y-electron system of a yoke in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S (O) m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan.
  • bridged heterocyclyls include:
  • the heterocyclic ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:
  • the heterocyclic group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • aryl refers to a 6 to 14 membered, all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 members, such as benzene And naphthyl. More preferred is phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include:
  • an aryl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen.
  • Heteroaryl is preferably 5- to 10-membered, more preferably 5- or 6-membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl , Pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl, or pyrimidinyl, thiazolyl; more preferably triazolyl, pyrrolyl, thienyl , Thiazolyl and pyrimidinyl.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or
  • Heteroaryl may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.
  • alkoxy refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.
  • Haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • Haloalkoxy refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
  • Hydroalkyl refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
  • alkenyl refers to alkenyl, also known as alkenyl, where the alkenyl may be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkyl Amino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclothio Radical, carboxyl or carboxylate.
  • Alkynyl means (CH ⁇ C-), wherein the alkynyl may be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, Halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, Carboxy or carboxylate.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • Amino means -NH 2.
  • Cyano refers to -CN.
  • Niro refers to -NO 2.
  • Carboxy refers to -C (O) OH.
  • THF tetrahydrofuran
  • EtOAc means ethyl acetate
  • MeOH means methanol
  • DCM dichloromethane
  • DMF N, N-dimethylformamide
  • DIPEA diisopropylethylamine
  • TFA trifluoroacetic acid
  • DMA refers to N, N-dimethylacetamide.
  • Et 2 O refers to diethyl ether
  • DCE refers to 1,2-dichloroethane.
  • DIPEA N, N-diisopropylethylamine
  • NBS N-bromosuccinimide
  • NIS N-iodosuccinimide
  • Cbz-Cl refers to benzyl chloroformate
  • Pd 2 (dba) 3 refers to tris (dibenzylideneacetone) dipalladium.
  • Dppf refers to 1,1'-bisdiphenylphosphine ferrocene.
  • HATU refers to 2- (7-benzotriazole) -N, N, N ', N'-tetramethylurea hexafluorophosphate.
  • KHMDS refers to potassium hexamethyldisilazide
  • LiHMDS refers to lithium bistrimethylsilylamine.
  • MeLi means methyl lithium
  • N-BuLi refers to n-butyllithium
  • NaBH (OAc) 3 refers to sodium triacetoxyborohydride.
  • X is selected from A, B, or C
  • X is selected from A, B, and C
  • X is A, B, or C
  • X is A, B, or C
  • other terms all express the same Meaning, meaning that X can be any one or several of A, B, and C.
  • the hydrogen atom according to the present invention may be replaced by its isotope deuterium, and any hydrogen atom in the compound of the embodiment according to the present invention may also be replaced by a deuterium atom.
  • Stepoisomerism includes three types of geometric isomerism (cis-trans isomerism), optical isomerism, and conformational isomerism.
  • an heterocyclic group optionally substituted with an alkyl group means that the alkyl group may but need not exist, and this description includes a case where the heterocyclic group is substituted with an alkyl group and a case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted refers to one or more hydrogen atoms in a group, preferably up to 5 and more preferably 1 to 3 hydrogen atoms independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (eg, olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiological / pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as physiological / pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and then exerts the biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the present invention. Such salts are safe and effective when used in mammals, and have due biological activity.
  • the compound structure of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid-mass chromatography (LC-MS). NMR chemical shifts ( ⁇ ) are given in parts per million (ppm).
  • the NMR measurement was performed using Bruker AVANCE-400 nuclear magnetic analyzer. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ). The internal standard was four. Methylsilane (TMS).
  • Liquid chromatography-mass spectrometry LC-MS was performed using an Agilent 1200 Infinity Series mass spectrometer.
  • Agilent 1200 DAD high-pressure liquid chromatography (Sunfire C18 150 ⁇ 4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatography (Gimini C18 150 ⁇ 4.6 mm column) were used.
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specifications adopted by TLC are 0.15mm ⁇ 0.20mm, and the specifications adopted by thin layer chromatography purification products are 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the starting materials in the examples of the present invention are known and commercially available, or they can be synthesized or synthesized according to methods known in the art.
  • Step 5 (2S, 3S, 4S, 5R, 6S) -3,4,5-trihydroxy-6- (4-((((2- (4-(((3aR, 5s, 6aS) -2 -((3-methoxy-1,2,4-thiadiazol-5-yl) carbamoyl) octahydrocyclopentadieno [c] pyrrole-5-yl) (methyl) amino)- N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbooxamido) ethyl) (methyl) carbamoyl) oxo) methyl) -2-nitrophenoxy ) Tetrahydro-2H-pyran-2-carboxylic acid
  • reaction solution was diluted with dichloromethane, and then the reaction solution was washed with saturated brine, and the organic phase was separated and dried over anhydrous sodium sulfate. After filtration, the organic solvent was concentrated under reduced pressure, and the title compound was separated by column chromatography to obtain 255 mg, yield: 33%.
  • Step 5 3-nitro-4-(((2S, 3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-2 -Yl) oxo) benzyl (2- (4-(((3R, 4R) -1- (2-cyanoacetyl) -4-methylpiperidin-3-yl) (methyl) amino ) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbooxalamido) ethyl) (methyl) carbamate
  • Test Example 1 Determination of the inhibitory effect of the compound of the present invention on the activity of JAK kinase
  • the purpose of this test case is to test the compound's inhibitory activity on JAK kinase activity.
  • the centrifuge (5702R) was purchased from Eppendorf;
  • microplate reader was purchased from BioTek, USA, and the model is SynergyH1 full-function microplate reader.
  • TR-FRET test fluorescence resonance energy transfer
  • the kinase reaction was performed in a white 384-well plate (PerkinElmer). Add 1-5 ⁇ L of different concentrations of compounds diluted with DMSO and ddH 2 O to each well, add 1-5 ⁇ L of the corresponding solvent to the positive control well, and then add 1-5 ⁇ L to each well.
  • 0.1-20nM JAK kinase solution diluted with kinase buffer HPES 50-250mM, MgCl 2 5-20mM, etc.
  • kinase buffer HEPES 50-250mM, MgCl 2 5-20mM, etc.
  • the mixed solution was incubated at room temperature for 0.5 to 5 hours, 10 ⁇ L of EDTA and a detection solution containing a labeled antibody were added, and the mixture was incubated at room temperature for 2 to 24 hours.
  • the fluorescence signal values of approximately 615 nm and 665 nm in each well were measured with a BioTek Synergy H1 microplate reader. The signal value calculates the suppression rate.
  • Test Example 2 Determination of the inhibitory effect of the compound of the present invention on cellular JAK1 / TYK2-STAT signaling pathway
  • the purpose of this test case is to test the inhibitory activity of the compound on the cell JAK1 / TYK2-STAT signal pathway.
  • Microplate shaker (88880024) was purchased from Thermo Scientific TM company, centrifuge (5702R) was purchased from Eppendorf company, pipette was purchased from Eppendorf company, microplate reader was purchased from American BioTek company, and the model was SynergyH1. Microplate reader.
  • Test Example 3 Stability of the compound of the present invention in ⁇ -glucuronidase solution
  • the purpose of this test case is to detect whether the compound is cleaved by ⁇ -glucuronidase and the time for complete digestion.
  • the centrifuge (5702R) was purchased from Eppendorf, and the pipette was purchased from Eppendorf or Rainin.
  • LC / MS / MS analysis instrument AB Sciex API 4000.
  • the digestion reaction was performed in a 96-well plate (Corning). Add 50 ⁇ L of ⁇ -glucuronidase (sigma) solution to each well. This solution contains 10 U of enzyme. Add 10 nmol of compound to the corresponding wells and incubate for 0, 5, 10, 20, 30 min. Add 100 ⁇ L at the corresponding time point. ACN stopped the reaction.
  • step A Take 40 ⁇ L of the solution after the digestion in step A, add 160 ⁇ L of acetonitrile to precipitate, mix and centrifuge at 4000 rpm for 10 minutes. Then 100 ⁇ L of the treated supernatant solution was taken for LC / MS / MS analysis of the concentration of the test compound.
  • LC-MS / MS analysis conditions liquid phase conditions: Shimadzu LC-20AD pump; mass spectrometric conditions: AB Sciex API 4000 mass spectrometer; chromatographic column: phenomenex Gemiu 5um C18 50 ⁇ 4.6mm; mobile phase: A liquid is 0.1% formic acid aqueous solution , B liquid is acetonitrile, flow rate: 0.8mL / min, elution time: 0-4 minutes gradient elution.
  • the active metabolite (JAK inhibitor SHR0302) of the prodrug (Example 1) of the preferred embodiment of the present invention can be quickly cut by ⁇ -glucuronidase to release SHR0302.
  • the mechanism of enzyme digestion is shown in the figure above.
  • the sugar part of the structure of Example 42 is a glucose structure, which is different from the gluconic acid of the sugar part of the structure of Example 1. Therefore, under the same experimental conditions, ⁇ -glucuronidase digests Example 42 and releases the active drug Tofacitinib. The rate is extremely slow and cannot be effectively released. However, Example 42 can be quickly digested by ⁇ -D-glucosidase to release the active drug Tofacitinib. The mechanism of the digestion is shown in the following figure:
  • mice To perform a pharmacokinetic test and analysis of blood and gastrointestinal tissues in mice according to a preferred embodiment of the present invention
  • the centrifuge (5702R) was purchased from Eppendorf,
  • mice BALB / c mice were purchased from Shanghai Jiesijie Experimental Animal Co., Ltd.
  • mice BALB / c mice, 3 mice in each group, were administered the compound of the example in a single intragastric administration at a dose of 5 mg / 10 ml / kg, and 0.5, 1, 2, 4, 6, and At 8 and 24 hours, venous blood was collected and the gastrointestinal tissue was collected. The blood was placed in a K 2 EDTA test tube, and the plasma was separated by centrifugation at 1000-3000 ⁇ g for 5-20 minutes at room temperature. The gastrointestinal tissue was removed and rinsed with buffer. The homogenized buffer was added and the tissue was homogenized and frozen or tested. Plasma and tissue homogenate samples were processed by LC / MS / MS to analyze the concentration of test compounds. The obtained pharmacokinetic data are shown in Table 4 below, where AUC 0-t is AUC 0-8 hours :
  • the blood exposure of the active metabolite (Tofacitinib) of the preferred prodrug Example 42 in the present invention is less than that of a single intragastric administration of Tofacitinib; the exposure of the active metabolite (Tofacitinib) of Example 42 in intestinal tissues Greater than the amount of intestinal tissue exposure given to Tofacitinib in a single gavage; the active metabolite SHR0302 of Example 1 had extremely low blood exposure and a higher exposure in intestinal tissue.
  • Example 42 was digested by ⁇ -D-glucosidase after administration to mice by intragastric administration, and the active drug Tofacitinib was released.
  • the molecular weight of Prodrug Examples 1 and 42 is larger than the molecular weight of the corresponding active metabolite. If mice are administered intragastrically with the same molar ratio of prodrug and the corresponding active metabolite, the prodrug (Example 1 and Example 42) ) Can achieve the enrichment of active drugs in target organs (back, colon), and can greatly reduce the exposure of the corresponding active metabolites (SHR0302 and Tofacitinib) in the blood.

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Abstract

Font l'objet de la présente invention un composé de formule I d'un promédicament d'un inhibiteur JAK, sa composition pharmaceutique, un procédé de traitement de maladies inflammatoires et tumeurs avec ledit composé, ainsi qu'un procédé et un intermédiaire pour la préparation dudit composé. Les substituts de formule (I) sont tels que définis dans la description.
PCT/CN2019/100554 2018-08-15 2019-08-14 Promédicament renfermant un dérivé de glucuronide en tant qu'inhibiteur jak, son procédé de préparation et ses applications WO2020034987A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112748203A (zh) * 2020-12-30 2021-05-04 苏州海科医药技术有限公司 一种创新药杰克替尼乳膏临床研究血浆样本中杰克替尼及zg0244浓度的生物分析方法
CN115073543A (zh) * 2022-07-20 2022-09-20 北京普祺医药科技股份有限公司 一种jak抑制剂的化合物前药及其制备与应用

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113943312A (zh) * 2020-07-17 2022-01-18 轶诺(浙江)药业有限公司 一类肠道裂解型共药及其制备和用途

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014194195A2 (fr) * 2013-05-31 2014-12-04 Cerulean Pharma Inc. Polymères à base de cyclodextrine destinés à une administration thérapeutique
WO2017091544A1 (fr) * 2015-11-24 2017-06-01 Theravance Biopharma R&D Ip, Llc Promédicaments d'un composé inhibiteur de jak pour le traitement de maladies inflammatoires gastro-intestinales
WO2018165250A1 (fr) * 2017-03-08 2018-09-13 Theravance Biopharma R&D Ip, Llc Promédicaments à base de glucuronide de tofacitinib
WO2018217700A1 (fr) * 2017-05-23 2018-11-29 Theravance Biopharma R&D Ip, Llc Promédicaments glucuronides d'inhibiteurs de janus kinase
WO2018217699A1 (fr) * 2017-05-23 2018-11-29 Theravance Biopharma R&D Ip, Llc Promédicaments à base de thiocarbamate de tofacitinib

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014194195A2 (fr) * 2013-05-31 2014-12-04 Cerulean Pharma Inc. Polymères à base de cyclodextrine destinés à une administration thérapeutique
WO2017091544A1 (fr) * 2015-11-24 2017-06-01 Theravance Biopharma R&D Ip, Llc Promédicaments d'un composé inhibiteur de jak pour le traitement de maladies inflammatoires gastro-intestinales
WO2018165250A1 (fr) * 2017-03-08 2018-09-13 Theravance Biopharma R&D Ip, Llc Promédicaments à base de glucuronide de tofacitinib
WO2018217700A1 (fr) * 2017-05-23 2018-11-29 Theravance Biopharma R&D Ip, Llc Promédicaments glucuronides d'inhibiteurs de janus kinase
WO2018217699A1 (fr) * 2017-05-23 2018-11-29 Theravance Biopharma R&D Ip, Llc Promédicaments à base de thiocarbamate de tofacitinib

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112748203A (zh) * 2020-12-30 2021-05-04 苏州海科医药技术有限公司 一种创新药杰克替尼乳膏临床研究血浆样本中杰克替尼及zg0244浓度的生物分析方法
CN115073543A (zh) * 2022-07-20 2022-09-20 北京普祺医药科技股份有限公司 一种jak抑制剂的化合物前药及其制备与应用

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