WO2019057103A1 - Inhibiteur de jak, procédé de préparation de celui-ci et application dans le domaine de la médecine - Google Patents

Inhibiteur de jak, procédé de préparation de celui-ci et application dans le domaine de la médecine Download PDF

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WO2019057103A1
WO2019057103A1 PCT/CN2018/106647 CN2018106647W WO2019057103A1 WO 2019057103 A1 WO2019057103 A1 WO 2019057103A1 CN 2018106647 W CN2018106647 W CN 2018106647W WO 2019057103 A1 WO2019057103 A1 WO 2019057103A1
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compound
trans
cis
acid
cancer
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许昕
张瑱
李云飞
王贯
朱伟波
***
瞿敏凯
张林丽
宋锦乾
刘磊
陈海继
刘强
王艺瑾
葛建
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上海华汇拓医药科技有限公司
浙江华海药业股份有限公司
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Definitions

  • the invention belongs to the field of medical chemistry, and relates to a novel class of JAK kinase inhibitors and a preparation method thereof, and the use thereof in the prevention and treatment of diseases related to Janus kinase (JAK), wherein the JAK-related diseases include inflammatory diseases and autoimmune diseases. Wait.
  • JAK Janus kinase
  • Protein kinases are a class of enzymes that catalyze the phosphorylation of proteins. They transfer gamma-phosphate from adenosine triphosphate (ATP) to amino acid residues of protein molecules such as serine, threonine, and tyrosine. Residues such as histidine, thereby altering the conformation and activity of the protein. Phosphorylation of proteins is an important part of many signaling pathways, and most important life processes in cells are inseparable from protein phosphorylation.
  • ATP adenosine triphosphate
  • Protein kinases are primarily responsible for the control of intracellular signal transduction processes, including regulation of a variety of important biological processes such as cell growth, survival and differentiation, organ formation and morphogenesis, neovascularization, tissue repair and regeneration, and many diseases and diseases. Aberrant regulation of protein kinases is associated with abnormal intracellular responses.
  • Janus kinase is a type of intracellular non-receptor tyrosine kinase.
  • the human JAK family has four members, namely JAK1, JAK2, JAK3 and non-receptor tyrosine kinase 2 (TYK2).
  • JAK1, JAK2, and TYK2 are widely distributed, while JAK3 is only distributed in the bone marrow and lymphatic system.
  • Members of the JAK family have a molecular weight of about 120-140 kDa and are composed of more than 1000 amino acid residues (Leonard, W., O'Shea, JJ, JAKS and STATS: Biological implications. Annu. Rev. Immunol. 1998, 16, 293-322.
  • JH JAK homology domains
  • JH2 domain is a "pseudo" kinase domain, which regulates the activity of JH1
  • JH4-JH7 constitutes a four-in-one domain, which regulates JAK Binding to cytokine receptors (Kisseleva, T., Bhattacharya, S., Braunstein, J., Schindler, CW Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene. 2002, 285 (1–2) , 1–24.).
  • STAT Signal transducer and activator of transcription
  • the STAT protein family includes STAT1 and STAT2. 7 members including STAT3, STAT4, STAT5a, STAT5b and STAT6.
  • the interaction between JAK and STAT plays an important role in the cytokine receptor signaling pathway (O'Sullivan, LA, Lionue, C., Lewis, RS, Stephenson, SEM, Ward, ACCytokine receptor signaling through the Jak Stat Pathway in disease. Mol. lmmunol, 2007, 44 ⁇ 10): 2497-2506.).
  • the subunit of the receptor dimerizes or multimerizes, and the JAK bound to each subunit is phosphorylated due to proximity to each other, and the activated JAK catalyzes the receptor itself. Phosphorylation of the amino acid residue forms a "docking site" where the corresponding STAT binds to the receptor complex. STAT binds to the phosphotyrosine residue on the receptor molecule through its SH2 domain and phosphorylates its C-terminal tyrosine residue under the action of JAK.
  • the phosphorylated STAT interacts with the same/ The heterodimer enters the nucleus and binds to the promoter region of the corresponding gene, thereby regulating gene transcription and expression.
  • the JAK-STAT pathway may interact with other signal transduction pathways, participate in the development, differentiation, maturation, apoptosis and functional expression of various immune and hematopoietic cells, and regulate the immune response, immune cell differentiation and inflammation of the body.
  • JAK is a very important drug target.
  • JAK inhibitors some studies have been carried out (eg Norman, P. Selective JAK inhibitors in development for rheumatoid arthritis. Expert Opin. Investig. Drugs, 2014, 23, 1067- 1077), JAK inhibitors can be used in the treatment of diseases such as rheumatoid arthritis, polycythemia vera, psoriasis, essential thrombocythemia and myelofibrosis, such as Ruxolitinib as a selective inhibitor of JAK1 and JAK2 In 2011, it was approved by the US FDA for the treatment of myelofibrosis; Baricitinib is also a selective inhibitor of JAK1 and JAK2 (see CN102026999), and the European EMA and the Japanese Ministry of Health, Labor and Welfare have approved it for the treatment of moderate to severe rheumatoid Arthritis, but was temporarily rejected by the US FDA for listing; the JAK1 selective inhibitors
  • Tofacitinib is currently the only FDA approved for sale in the US market for the treatment of rheumatoid arthritis JAK1 and JAK3 selective inhibitors (Kremer, JM, et al., "The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase Ila trial of three dosage levels of CP-690,550 Versatile placebo.Arthritis & Rheumatology, 2009, 60 (7), 1895-1905), however, patients taking tofatinib may have some adverse reactions, such as possible serious infections and increased risk of cancer and heart failure (FDA will be seriously infected Black box warnings with malignant tumors).
  • JAK inhibitors listed above, there are also related patents such as WO2008109943, WO2011112662, WO2013091539, WO2014128591, WO2016027195 and the like all also disclose JAK inhibitors.
  • JAK inhibitors Although a series of JAK inhibitors have been disclosed, these JAK inhibitors that are on the market or in the research stage still have room for improvement in efficacy and safety, and there is still a need to develop new JAKs with better efficacy and safety. Inhibitors to provide better efficacy and reduce adverse reactions in patients.
  • the present invention relates to a novel class of small molecule JAK inhibitors which provide a class of compounds of the formula II or tautomers, meso, racemates, enantiomers, diastereoisomers thereof Isomers, mixtures thereof, and pharmaceutically acceptable salts, polymorphs, solvates, prodrugs, metabolites, isotopic derivatives thereof, and pharmaceutical compositions comprising the same, for use in prevention Or treating JAK-related indications,
  • R is -OH, -methylalkyl, -methoxy, hydroxy-substituted C 1-2 alkyl, halogen-substituted methylalkyl, halogen-substituted methaneoxy, halogen, amino, mono(C 1-3 alkyl) -amino-, bis(C 1-3 alkyl)-amino-, nitrile, -C 5-6 cycloalkyl or phenyl;
  • the halogen is preferably a fluorine atom, and the halogen-substituted methylalkyl group is preferably a trifluoro-substituted methylalkyl group;
  • R 0 is fluorine, methyl, vinyl, formyl, acetyl, methoxycarbonyl, decyloxycarbonyl, decyloxycarbonyl, carbamoyl, oxazolyl, thiadiazolyl,
  • Y 4 is carbon and Y 8 is -NH-;
  • Y 1 is carbon
  • Y 2 is carbon
  • Y 3 is nitrogen
  • Y 5 is nitrogen
  • Y 6 is nitrogen
  • Y 7 is carbon
  • Y 6 is carbon
  • Y 7 is nitrogen
  • Y 1 is nitrogen
  • Y 2 is carbon
  • Y 3 is nitrogen
  • Y 5 is carbon
  • Y 6 is carbon
  • Y 7 is nitrogen or carbon.
  • the present invention provides a process for the preparation of a compound of the formula II, which is prepared by the following scheme,
  • the compound II-Ia reacts with triethylphosphorylacetate under the action of an organic base or an inorganic base to form a trans compound II-Ib, and the trans compound II-Ib is reacted with N-(methoxymethyl)- N-(trimethylsilylmethyl)benzylamine reacts to form trans compound II-Ic, and trans compound II-Ic is hydrolyzed under base to form trans compound II-Id;
  • Compound II-Iaa is reacted under a palladium catalyst under hydrogen atmosphere or formate to form cis compound II-Ib, and cis compound II-Ib is reacted with N-(methoxymethyl)- N-(trimethylsilylmethyl)benzylamine is reacted to form cis compound II-Ic, and cis compound II-Ic is hydrolyzed by acid to form cis compound II-Id.
  • the cis/trans compound II-Id forms a cis/trans compound II-Ie under the action of diphenylphosphoryl azide, a cis/trans compound II-Ie under the action of a palladium catalyst, in a hydrogen atmosphere or formic acid
  • the cis/trans compound II-If is formed under salt hydrogen supply, and the cis/trans compound II-If is reacted with trifluoroethylamine under the action of carbonyl diimidazole to form a cis/trans compound II-Ig, cis /trans compound II-Ig reacts under acid to form cis/trans compound II-Ih,
  • the compound IIc-a reacts with ammonia water under the action of an activator to form an amide IIc-b
  • the compound IIc-b reacts with trifluoroacetic anhydride in the presence of a base to form a compound IIc-c
  • the compound IIc-c is in the presence of a base with benzene Sulfonyl chloride reacts to form compound IIc-d, which reacts with cis/trans compound II-Ih under the action of a palladium catalyst and a ligand or a base to form compound IIc-e.
  • Compound IIc-e is in the presence of a base.
  • Hydrogen peroxide H 2 O 2
  • compound IIc-f Hydrogen peroxide (H 2 O 2 ) is hydrolyzed to form compound IIc-f
  • compound IIc-f is deprotected in the presence of a base to form compound IIc
  • the activator is preferably carbonyldiimidazole, N,N'-dicyclohexyl a carbodiimide, 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) or a combination thereof
  • the ligand is three Ethylamine, diisopropylethylamine, 1,8-diazabicycloundec-7-ene or a combination thereof;
  • the compound II-Id is reacted under the action of a palladium catalyst under a hydrogen atmosphere or a hydrogenate to form a compound II-Ig, and the compound II-Ig reacts with a benzyl chloroformate under a base to form a cis/trans group.
  • Compound II-Ik is reacted under the action of a palladium catalyst under a hydrogen atmosphere or a hydrogenate to form a compound II-Ig, and the compound II-Ig reacts with a benzyl chloroformate under a base to form a cis/trans group.
  • compound IIa-a is reacted with trimethylsilylacetylene under the catalysis of a palladium catalyst in the presence of a cuprous salt (preferably CuI) and a base under inert gas to form compound IIa-b, and compound IIa-b is present in the base
  • a cuprous salt preferably CuI
  • compound IIa-b is present in the base
  • the reaction is followed by reaction with p-toluenesulfonyl chloride to form compound IIa-c.
  • the compound IIa-c is reacted with zinc cyanide under the catalysis of a palladium catalyst and under inert gas to form compound IIa-d.
  • the compound IIa-d acts on the palladium catalyst.
  • the compound IIa-i is reacted with trifluoroethylamine under the action of carbonyldiimidazole or triphosgene to form a compound IIa-j, compound IIa -j removes the protective compound in the presence of a base IIa;
  • compound IIb-a is reacted with benzenesulfonyl chloride in the presence of a base to form compound IIb-b
  • compound IIb-b is reacted with tetrabutylammonium nitrate in the presence of trifluoromethanesulfonic anhydride to form compound IIb-c
  • compound IIb-c Reaction with cis/trans compound II-Ih in the presence of a base to form compound IIb-d
  • compound (IIb-d) under the action of ammonium chloride or acid (such as acetic acid or dilute hydrochloric acid) with iron powder, zinc powder or Combining to form compound IIb-e
  • compound IIb-e is reacted with formic acid, formate, trimethyl orthoformate or triethyl orthoformate or a combination thereof to form compound IIb-f
  • compound IIb-f is removed in the presence of a base Protection to form compound IIb;
  • the base is, for example, NaH, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide, triethylamine , diisopropylethylamine, 1,8-diazabicycloundec-7-ene, butyl lithium, lithium diisopropylamide, lithium hexamethyldisilazide or a combination thereof
  • An acid such as formic acid, acetic acid, benzoic acid, trifluoroacetic acid, trichloroacetic acid, hydrogen chloride, hydrogen bromide, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, sulfuric acid, phosphoric acid or a combination thereof
  • said palladium catalyst such as palladium Carbon, palladium oxide, palladium hydro
  • the present invention also provides a compound of the formula (II) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, and a mixture thereof. a method of form, and a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound (II-Ia) is reacted with triethylphosphorylacetate in a suitable solvent (such as tetrahydrofuran, etc.) at 0 ° C to room temperature for 1 to 24 hours under the action of a base such as NaH to form a trans compound (II). -Ib).
  • a suitable solvent such as tetrahydrofuran, etc.
  • Compound (II-Ib) is reacted with an acid (such as trifluoroacetic acid) at 0 ° C to room temperature in a suitable solvent (such as dichloromethane) and N-(methoxymethyl)-N- (trimethyl)
  • an acid such as trifluoroacetic acid
  • a suitable solvent such as dichloromethane
  • the silylmethyl)benzylamine is reacted for 1 to 24 hours to form the trans compound (II-Ic).
  • the compound (II-Ic) is reacted with a base such as sodium hydroxide at 0 ° C to room temperature in a suitable solvent (such as methanol) for 1 to 24 hours to be hydrolyzed to give the trans compound (II-Id).
  • a base such as sodium hydroxide at 0 ° C to room temperature
  • a suitable solvent such as methanol
  • the compound (II-Id) is reacted with diphenylphosphoryl azide at room temperature to 120 ° C in a suitable solvent (such as t-butanol, etc.) for 1 to 24 hours to form a trans compound (II-Ie). .
  • a suitable solvent such as t-butanol, etc.
  • the compound (II-Ie) is reacted by a Pd catalyst (such as Pd/C, Pd(OH) 2 or the like) at a temperature of from room temperature to 100 ° C under a hydrogen atmosphere in a suitable solvent (such as methanol). At 24 hours, a trans compound (II-If) was produced.
  • a Pd catalyst such as Pd/C, Pd(OH) 2 or the like
  • the compound (II-If) is reacted with trifluoroethylamine in a suitable solvent (such as dichloromethane) at a temperature of from room temperature to 100 ° C for 1 to 24 hours to form a trans compound (II-Ig). .
  • a suitable solvent such as dichloromethane
  • the compound (II-Ig) is reacted with an acid (such as HCl, TFA, etc.) at 0 ° C to room temperature in a suitable solvent (such as dichloromethane) for 1 to 24 hours to form a trans compound (II-Ih). ).
  • an acid such as HCl, TFA, etc.
  • a suitable solvent such as dichloromethane
  • the compound (II-Iaa) is reacted by a partially poisoned Pd catalyst (such as a Linda catalyst, etc.) at a temperature of from room temperature to 100 ° C under a hydrogen atmosphere in a suitable solvent (such as tetrahydrofuran) for 1 to 24 hours. , the cis compound (II-Ib) is produced.
  • a partially poisoned Pd catalyst such as a Linda catalyst, etc.
  • a suitable solvent such as tetrahydrofuran
  • the compound (II-Ic) is reacted with an acid (such as hydrochloric acid) at room temperature to 100 ° C in a suitable solvent (such as 1,4-dioxane, etc.) for 1 to 24 hours to hydrolyze to form a cis compound. (II-Id).
  • an acid such as hydrochloric acid
  • a suitable solvent such as 1,4-dioxane, etc.
  • the compound (II-Id) is reacted under the action of a Pd catalyst (such as Pd/C, Pd(OH) 2 or the like) at a temperature of from room temperature to 100 ° C in a hydrogen atmosphere in a suitable solvent (such as methanol).
  • a Pd catalyst such as Pd/C, Pd(OH) 2 or the like
  • a suitable solvent such as methanol
  • the compound (II-Ig) is reacted with a benzyl chloroformate in a suitable solvent (such as dichloromethane, tetrahydrofuran, etc.) at 0 ° C to room temperature for 1 to 24 hours under the action of a base such as triethylamine.
  • a suitable solvent such as dichloromethane, tetrahydrofuran, etc.
  • Compound (IIa-a) is catalyzed by a palladium catalyst (such as Pd(dppf)Cl 2 , Pd(PPh 3 ) 4 , Pd(OAc) 2 , etc.) in the presence of CuI and a base (such as triethylamine). Between room temperature and 120 ° C, in a suitable solvent (such as 1,4-dioxane or N, N'-dimethylformamide, etc.) and inert gas (such as nitrogen, argon, etc.) and the top three The silyl acetylene is reacted for 1 to 24 hours to form a compound (IIa-b).
  • a palladium catalyst such as Pd(dppf)Cl 2 , Pd(PPh 3 ) 4 , Pd(OAc) 2 , etc.
  • a base such as triethylamine
  • Compound (IIa-b) is reacted in the presence of a base (such as NaH, etc.) at 0 ° C to room temperature in a suitable solvent (such as N, N'-dimethylformamide, etc.) for 0.25 to 1 hour, and then with The toluenesulfonyl chloride is reacted for 1 to 24 hours to give the compound (IIa-c).
  • a base such as NaH, etc.
  • a suitable solvent such as N, N'-dimethylformamide, etc.
  • Compound (IIa-c) is catalyzed by a palladium catalyst (such as Pd(dppf)Cl 2 , Pd(PPh 3 ) 4 , Pd(OAc) 2 , etc.) at room temperature to 120 ° C in a suitable solvent (eg 1 , 4-dioxane or N,N'-dimethylformamide, etc.) and an inert gas (such as nitrogen, argon, etc.) and zinc cyanide for 1 to 24 hours under protection, to form compound (IIa-d) .
  • a palladium catalyst such as Pd(dppf)Cl 2 , Pd(PPh 3 ) 4 , Pd(OAc) 2 , etc.
  • a suitable solvent eg 1 , 4-dioxane or N,N'-dimethylformamide, etc.
  • an inert gas such as nitrogen, argon, etc.
  • the compound (IIa-d) is reacted by a Pd catalyst (such as Pd/C, Pd(OH) 2 or the like) at a temperature of from room temperature to 100 ° C under a hydrogen atmosphere in a suitable solvent (such as methanol).
  • a Pd catalyst such as Pd/C, Pd(OH) 2 or the like
  • a suitable solvent such as methanol
  • Compound (IIa-f) is reacted by Lawesson's reagent in a suitable solvent (such as 1,4-dioxane, etc.) at room temperature to 100 ° C for 1 to 24 hours to form compound (IIa-g). .
  • a suitable solvent such as 1,4-dioxane, etc.
  • Compound (IIa-g) is reacted by Lawesson's reagent in a suitable solvent (such as 1,4-dioxane, etc.) at room temperature to 100 ° C for 1 to 24 hours to form compound (IIa-h). .
  • a suitable solvent such as 1,4-dioxane, etc.
  • the compound (IIa-h) is reacted with HBr in a suitable solvent (e.g., 1,4-dioxane) at a temperature of from room temperature to 100 ° C for 1 to 24 hours to give a compound (IIa-i).
  • a suitable solvent e.g., 1,4-dioxane
  • the compound (IIa-i) is reacted with trifluoroethylamine in a suitable solvent (such as dichloromethane) at a temperature of from room temperature to 100 ° C for 1 to 24 hours under the action of CDI to give a compound (IIa-j).
  • a suitable solvent such as dichloromethane
  • the compound (IIa-j) is reacted in the presence of a base (e.g., NaOH or the like) at 0 ° C to room temperature in a suitable solvent (e.g., methanol/water, etc.) for 1 to 24 hours to remove the compound (IIa).
  • a base e.g., NaOH or the like
  • a suitable solvent e.g., methanol/water, etc.
  • the compound (IIb-d) is reacted with dilute hydrochloric acid under an action of iron powder at 0 ° C to room temperature in a suitable solvent (such as methanol) for 1 to 24 hours to give a compound (IIb-e).
  • the compound (IIb-e) is reacted with triethyl orthoformate in a suitable solvent (for example, toluene or the like) at a temperature of from room temperature to 120 ° C for 1 to 24 hours to give a compound (IIb-f).
  • a suitable solvent for example, toluene or the like
  • the compound (IIb-f) is reacted in the presence of a base (e.g., NaOH or the like) at 0 ° C to room temperature in a suitable solvent (e.g., methanol/water, etc.) for 1 to 24 hours to remove the compound (IIb).
  • a base e.g., NaOH or the like
  • a suitable solvent e.g., methanol/water, etc.
  • the compound (IIc-a) is reacted with aqueous ammonia in a suitable solvent (e.g., tetrahydrofuran, dichloromethane, etc.) at 0 ° C to room temperature for 1 to 24 hours under the action of CDI to give an amide (IIc-b).
  • a suitable solvent e.g., tetrahydrofuran, dichloromethane, etc.
  • the compound (IIc-b) is reacted with trifluoroacetic anhydride in the presence of a base (such as triethylamine) at 0 ° C to room temperature in a suitable solvent (such as dichloromethane) for 1 to 24 hours to give a compound (IIc). -c).
  • a base such as triethylamine
  • a suitable solvent such as dichloromethane
  • the compound (IIc-d) is subjected to a palladium catalyst (such as Pd 2 (dba) 3 or the like) and a ligand (such as Xant Phos, etc.) at room temperature to 120 ° C in a suitable solvent (such as 1.4-dioxane, Toluene or the like is reacted with the cis or trans intermediate (II-Ih) for 1 to 24 hours to give the compound (IIc-e).
  • a palladium catalyst such as Pd 2 (dba) 3 or the like
  • a ligand such as Xant Phos, etc.
  • the compound (IIc-e) is reacted with hydrogen peroxide (H 2 O 2 ) in the presence of a base (e.g., K 2 CO 3 , etc.) at 0 ° C to room temperature in a suitable solvent (e.g., dimethyl sulfoxide, etc.). Hydrolysis gives the compound (IIc-f) from 1 to 24 hours.
  • a base e.g., K 2 CO 3 , etc.
  • a suitable solvent e.g., dimethyl sulfoxide, etc.
  • the compound (IIc-f) is reacted in the presence of a base (e.g., NaOH or the like) at 0 ° C to room temperature in a suitable solvent (e.g., methanol/water, etc.) for 1 to 24 hours to remove the compound (IIc).
  • a base e.g., NaOH or the like
  • a suitable solvent e.g., methanol/water, etc.
  • the pharmaceutically acceptable salts of the compounds of the present invention include the acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts, examples including, but not limited to, hydrochloride, sulfate/hydrogen sulfate, nitrate, phosphate/hydrogen phosphate/dihydrogen phosphate, hydrobromic acid Salt, hydroiodide, acetate, lactate, methanesulfonate, citrate, malate, maleate, fumarate, tartrate, salicylate, stearate , and similar salts.
  • Suitable base addition salts are formed from bases which form non-toxic salts, for example as alkali metal salts, alkaline earth metal salts or as ammonium salts, examples including, but not limited to, sodium, potassium, calcium, magnesium, or with ammonia Or an organic amine such as ethylamine, ethanolamine, triethanolamine or a salt of an amino acid.
  • bases which form non-toxic salts, for example as alkali metal salts, alkaline earth metal salts or as ammonium salts, examples including, but not limited to, sodium, potassium, calcium, magnesium, or with ammonia Or an organic amine such as ethylamine, ethanolamine, triethanolamine or a salt of an amino acid.
  • the invention also includes internal salts or betaines (zwitterions) in addition to the salt forms mentioned.
  • the compound of formula (II) may exist in crystalline or amorphous form. Furthermore, certain crystalline forms of the compounds of formula (II) may exist in polymorphic form and are included within the scope of the invention.
  • Many conventional analytical techniques can be used including, but not limited to, single crystal X-ray powder diffraction (XRPD) patterns, infrared (IR) spectroscopy, Raman spectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and solids.
  • XRPD single crystal X-ray powder diffraction
  • IR infrared
  • Raman spectroscopy Raman spectroscopy
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • solidssNMR Nuclear magnetic resonance
  • the compounds of the invention also include tautomeric forms.
  • Tautomeric forms result from the exchange of a single bond with an adjacent double bond and the accompanying proton transfer.
  • Tautomeric forms include proton transfer tautomers which are isomeric protonated states having the same empirical formula and total charge.
  • Examples of proton transfer tautomers include keto-enol pairing, amide-imidate pairing, lactam-lactam pairing, enamine-imine pairing, and two wherein protons can occupy a heterocyclic ring system Or a cyclic form at multiple positions, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1, 2,4 triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyridyl Oxazole.
  • the tautomeric form can be balanced or spatially fixed to one form by appropriate substitution.
  • the present invention also relates to a compound of the formula (II) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, a mixture thereof, and Use of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for inhibiting JAK kinase;
  • the JAK kinase is preferably JAK1, JAK2 or JAK3.
  • the present invention also relates to a compound of the formula (II) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, a mixture thereof, and Use of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for inhibiting JAK kinase, wherein the medicament optionally contains one or more other agents which modulate the immune system of the mammal, an anticancer agent Or an anti-inflammatory agent.
  • the present invention also relates to a compound of the formula (II) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, a mixture thereof, and Use of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for inhibiting JAK kinase, wherein the medicament is for treating or preventing a disorder or a disease of the immune system including, for example, organ transplant rejection (such as allogeneic rejection and graft versus host disease); autoimmune diseases including, for example, lupus, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriasis, ulcerative colitis, Crohn's Disease, autoimmune thyroid disease, etc.; skin diseases, including, for example, psoriasis, rash, atopic dermatitis, etc.; allergic conditions, including, for example, asthma, rhinitis, etc.; viral diseases including, for example
  • the invention further relates to a compound of the formula (II) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, and Use of a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same for the preparation of a medicament for inhibiting JAK kinase, wherein the medicament optionally comprises another one or more agents, anticancer agents or anti-inflammatory agents which modulate the immune system of the mammal Agent for the treatment or prevention of diseases or diseases of the immune system including, for example, organ transplant rejection (such as allogeneic inhibition and graft versus host disease); autoimmune diseases including, for example, lupus, multiple sclerosis, rheumatoid Arthritis, juvenile arthritis, psoriasis, ulcerative colitis, Crohn's disease, autoimmune thyroid disease, etc.; skin diseases including, for example, psoriasis, rash, atopic dermatitis, etc.;
  • the invention further relates to a compound of the formula (II) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, and A pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, which is a drug for inhibiting JAK kinase.
  • the JAK kinase is preferably JAK1, JAK2 or JAK3.
  • the invention further relates to a compound of the formula (II) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, and A pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, which is further used in combination with another one or more agents, anticancer agents or anti-inflammatory agents which modulate the immune system of the mammal.
  • the invention further relates to a compound of the formula (II) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, and A pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same for use in the treatment or prevention of diseases or diseases of the immune system including, for example, organ transplant rejection (such as allogeneic inhibition and graft versus host disease); autoimmune Diseases including, for example, lupus, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriasis, ulcerative colitis, Crohn's disease, autoimmune thyroid disease, etc.; skin diseases including, for example, psoriasis, Rash, atopic dermatitis, etc.; allergic conditions, including, for example, asthma, rhinitis, etc.; viral diseases including, for example, hepatitis B, hepatitis C, varicella-zoster virus, etc.; type I diabetes
  • the invention further relates to a compound of the formula (II) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, and A pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, which is further used in combination with another one or more agents, anticancer agents or anti-inflammatory agents which modulate the immune system of the mammal for treating or preventing the following disorders or diseases: Diseases of the immune system, including, for example, organ transplant rejection (such as allogeneic inhibition and graft versus host disease); autoimmune diseases including, for example, lupus, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriasis, Crohn's colitis, Crohn's disease, autoimmune thyroid disease, etc.; skin diseases, including, for example, psoriasis, rash, atopic dermatitis, etc.; allergic conditions, including, for example, asthma, rhinitis,
  • the present invention relates to a method of inhibiting JAK kinase comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula (II) or a tautomer, a mesogen, a racemate thereof, Enantiomers, diastereomers, mixtures thereof, and pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same.
  • the compound represented by the formula (II) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, a mixture thereof, and the like is used in combination with one or more other agents, anticancer agents or anti-inflammatory agents that modulate the immune system of the mammal.
  • the invention also relates to a method of treating or preventing a disorder or disease of the immune system comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula (II) or a tautomer thereof, a mesogen, or an external a racemate, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the immune system disorder or disease is selected from the group consisting of: immunization Systemic diseases including, for example, organ transplant rejection (such as allogeneic inhibition and graft versus host disease); autoimmune diseases including, for example, lupus, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriasis, ulceration Sick colitis, Crohn's disease, autoimmune thyroid disease, etc.; skin diseases including, for example, psoriasis, rash, atopic dermatitis, etc.; allergic conditions including
  • the invention also relates to a method of treating or preventing a disorder or disease of the immune system comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula (II) or a tautomer thereof, a mesogen, or an external Racemates, enantiomers, diastereomers, mixtures thereof, and pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, and one or more additional mammalian immune systems a reagent, an anticancer agent or an anti-inflammatory agent, wherein the immune system disorder or disease is selected from the group consisting of diseases of the immune system, including, for example, organ transplant rejection (such as allogeneic inhibition and graft versus host disease); autoimmune diseases, These include, for example, lupus, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriasis, ulcerative colitis, Crohn's disease, autoimmune thyroid disease, etc.; skin diseases including, for example, psorias
  • compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers.
  • the active compounds of the invention may be formulated for oral, buccal administration, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) or rectal administration, or for administration by inhalation or insufflation.
  • the dosage form of the drug may also be formulated in sustained release dosage forms.
  • compositions can be formulated into various types of dosage unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions and suspensions), depending on the purpose of the treatment. Or it is suitable for a dosage form administered by inhalation or insufflation.
  • any excipient known and widely used in the art can be used.
  • carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silicic acid; binders such as water, ethanol, propanol, ordinary syrup, dextrose solution, starch Solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.; disintegrating agents such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, carbonic acid Fatty acid esters of calcium, polyethylene sorbitan, sodium lauryl sulfate, monoglyceryl stearate, starch and lactose; disintegration inhibitors such as white sugar, glyceryl tristearate, coconut oil and hydrogenation Oil; adsorption promoters such as quaternary
  • any excipient known in the art and widely used may be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc.; Such as gum arabic powder, gum tragacanth powder, gelatin and ethanol, etc.; disintegrating agents such as agar and kelp powder.
  • any of the excipients known and widely used in the art can be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides. Wait.
  • the solution or suspension may be sterilized (preferably by adding an appropriate amount of sodium chloride, glucose or glycerin, etc.) to prepare an isotonic injection with blood.
  • Any of the commonly used carriers in the art can also be used in the preparation of the injection.
  • water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid esters of polyethylene sorbitan can be added.
  • the active compound of the invention is suitably released in the form of a solution or suspension from a pump spray container that is received or squeezed or aspirated, or in the form of a spray.
  • the pressurized container or sprayer is released and released using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit can be determined by providing a metered release valve.
  • the pressurized container or nebulizer may contain a solution or suspension of the active compound.
  • a capsule or cartridge (e.g., made of gelatin) for use in an inhaler or insufflator can be formulated as a powder mixture containing a compound of the invention and a suitable powder
  • stereoisomer denotes an isomer formed by at least one asymmetric center.
  • compounds having one or more (eg, one, two, three or four) asymmetric centers which can produce racemates, racemic mixtures, meso-forms, single enantiomers , mixtures of diastereomers and individual diastereomers.
  • Specific individual molecules can also exist as geometric isomers (cis/trans).
  • solvate refers to a form of a compound that is physically associated with a solvent, typically by a solvolysis reaction. This physical bond involves hydrogen bonding.
  • solvents include water, ethanol, methanol, acetic acid, and the like.
  • the compound of formula (II) can be prepared in crystalline form and can be in the form of a solvate (e.g., hydrated form).
  • Suitable solvates comprise pharmaceutically acceptable solvates (e.g., hydrates), and further comprise stoichiometric solvates and non-stoichiometric solvates. In certain instances, such as when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid, the solvate will be capable of dissociating.
  • “Solvate” encompasses both solution and dissociable solvates. Representative solvates include hydrates, ethanolates, methanolates, and the like.
  • prodrug means a derivative which is converted into a compound of the present invention by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, for example, by oxidation, reduction, hydrolysis or the like which is each carried out under an enzyme catalysis.
  • metabolite refers to all molecules derived from any compound of the invention in a cell or organism, preferably a human.
  • isotopic derivative refers to a compound which comprises one or more atoms of a compound and which contains an isotope in a non-natural proportion.
  • hydrazine 2 H or D
  • hydrazine 3 H or T
  • carbon-13 13 C
  • nitrogen-15 15 N
  • oxygen-18 18 O
  • pharmaceutical composition means a mixture comprising one or more compounds of the invention or a physiological/pharmaceutically acceptable salt or prodrug thereof and other chemical components, such as physiologically/pharmaceutically acceptable Carrier and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • the carrier includes all pharmaceutical preparations which can be used in the pharmaceutical field for the preparation of injection and non-injection routes, such as diluents, wetting agents, fillers, binders, slip agents, disintegrating agents, absorption enhancers, Surfactants, retarders, adsorbents, suspending agents, flocculants, deflocculating agents, emulsifiers, common substrates, solubilizers, solubilizers, latent solvents, preservatives, flavoring agents, colorants, antioxidants , buffer, bacteriostatic agent, isotonicity regulator, pH adjuster, metal ion complexing agent, hardener, thickener, and the like.
  • pharmaceutical preparations which can be used in the pharmaceutical field for the preparation of injection and non-injection routes, such as diluents, wetting agents, fillers, binders, slip agents, disintegrating agents, absorption enhancers, Surfactants, retarders, adsorbents, suspending agents, flocculants,
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR chemical shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • the solvent was determined to be deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and internal standard was tetramethylsilane (TMS).
  • reaction was monitored by thin layer chromatography (TLC) or LC-MS.
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm. ⁇ 0.5mm.
  • the developing solvent systems used were: petroleum ether and ethyl acetate systems, n-hexane and ethyl acetate systems, dichloromethane and methanol systems.
  • the volume ratio of the solvent is adjusted depending on the polarity of the compound.
  • the system of the eluent for column chromatography and the developer system for thin layer chromatography using the purified compound include: petroleum ether and ethyl acetate systems, n-hexane and ethyl acetate systems, dichloromethane and methanol systems.
  • the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid.
  • the temperature of the reaction was room temperature (20 ° C to 30 ° C) unless otherwise specified.
  • Trifluoroethylamine (93 mg, 0.94 mmol) was dissolved in dichloromethane (5 mL), triethylamine (237 mg, 2.30 mmol) was added, and phosgene (138 mg, 0.47 mmol) was added at 0 ° C and stirred at 0 ° C 2
  • the compound (trans)-8-(4-ethylpyrrolidin-3-yl)-3H-bisimidazo[1,2-a:4',5'-e]pyrazine 1i 120 mg, After stirring at room temperature for 6 hours, the reaction was completed by LCMS.
  • Step 5 (cis)-3-(3H-bisimidazo[1,2-a:4',5'-e]pyrazine-8-yl)-4-ethyl-N-(2,2 Preparation of 2-trifluoroethyl)pyrrolidine-1-carboxamide H02
  • Trifluoroethylamine 80 mg, 0.81 mmol was dissolved in dichloromethane (5 mL), triethylamine (410 mg, 4.06 mmol) was added, and the mixture was stirred at 0 ° C (120 mg, 0.40 mmol) and stirred at 0 ° C 2
  • the compound (cis)-8-(4-ethylpyrrolidin-3-yl)-3H-bisimidazo[1,2-a:4',5'-e]pyrazine 2d 104 mg, After stirring at room temperature for 6 hours, the reaction was completed by LCMS.
  • the second step is the preparation of 3,6-dibromopyrazine-2-carbaldehyde 3c
  • the third step is the preparation of 5-bromo-1H-pyrazolo[3,4-b]pyrazine 3d
  • Example 7 The same procedure as in Example 7 was carried out, and 7a in Example 7 was replaced with 9a to obtain Compound H09.
  • LCMS (ESI) m / z: 381 [M + H] +.
  • Example 1 Inhibition test of JAK kinase by a compound of the present invention
  • JAK1 developed by PerkinElmer Ultra assay, JAK2 Ultra assay, JAK3 The Ultra assay method was tested.
  • JAK1 The Ultra assay enzyme reaction system included 2 nM JAK1 (Invitrogen, PV4775), 50 nM ULightTM-JAK-1 peptide (substrate, PerkinElmer, TRF0121-M) and 38 uM ATP (Sigma, A7699).
  • JAK2 The Ultra assay enzyme reaction system included 0.03 nM JAK2 (Invitrogen, PV4288), 50 nM ULightTM-JAK-1 peptide (substrate, PerkinElmer, TRF0121-M) and 12 uM ATP (Sigma, A7699).
  • the Ultra assay enzyme reaction system included 0.08 nM JAK3 (Invitrogen, PV4080), 50 nM ULightTM-JAK-1 peptide (substrate, PerkinElmer, TRF0121-M) and 4 uM ATP (Sigma, A7699).
  • the above reaction system also included: detection solution, 2 nM Eu-W1024 anti-phosphotyrosine (PerkinElmer, AD0069); stop solution, 10 mM EDTA (Invitrogen, 1842C505).
  • the enzymatic reaction buffer contained 50 mM HEPES (pH 7.5) (Invitrogen, 15630130), 10 mM MgCl 2 (Sigma, 63020), 1 mM EDTA (Invitrogen, 1842 C505), 2 mM DTT (Sigma, 43815), 0.01% BRIJ-35 (Sigma, B4184). JAK1 kinase, JAK2 kinase, JAK3 kinase, ATP, and substrate were all diluted in buffer.
  • Test compounds H01-H12 were separately dissolved in DMSO. In the experiments for each compound, the compounds were diluted 3-fold such that the final concentration of the test compound ranged from 0.017 nM to 1 uM for a total of 11 gradient concentrations.
  • the maximum value is the control value of DMSO added to the well plate, the minimum value is the value obtained by blank, and the conversion value is the value obtained for each compound hole.
  • the fitting was carried out by the XLFit fitting tool in excel to obtain the semi-inhibitory concentration (IC 50 ) of the corresponding compound.
  • the IC 50 for inhibition of JAK1-3 kinase activity by the compounds of the invention is shown in the table below.
  • the compound of the present invention has different inhibitory effects on JAK1-3 kinase, and JAK1 has a lower IC50 value and a better inhibitory activity against JAK1 than JAK2 and JAK3, and thus the compound of the present invention is JAK1 has good selectivity. Since JAK kinase is involved in various important physiological processes in vivo, extensive inhibition of different subtypes may bring adverse reactions in addition to therapeutic benefit. Therefore, JAK1 selective inhibition provided by the present invention Agents will have the advantage of being safer.
  • Example 2 Inhibition test of cell proliferation by the compound of the present invention
  • the inhibition test of the proliferation of Blast T cells and TF-1 cells by the compounds of the present invention was carried out by the following method.
  • the tested compounds H01, H04, H8, H9, H11, H12 were dissolved in DMSO.
  • the compound solution was diluted in a 4-fold gradient so that the final concentration of the compound solution was from 0.0006 to 10 uM.
  • the DMSO control solution was the correspondingly diluted DMSO solution.
  • the medium used contained: RPM1640 (GibcoTM-11875093), 10% FBS (Ausbina, 0986180), 1% penicillin-streptomycin (Gibco, 1902242).
  • Human erythroid leukemia cell line TF-1 cells (ATCC, Cat. No. CC) were cultured in a medium containing 2 ng/mL GM-CSF (granulocyte-macrophage colony-stimulating factor, also known as sagstatin, Biosource, F3039). -Y1652), after reaching a density of 4.0 ⁇ 10 5 cells/mL, starved for 24 hours in a medium containing no GM-CSF, and resuspended the cells in a medium containing 2 ng/mL GM-CSF at 5,000 cells/well.
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • the IC50 of the inhibition of proliferation of Blast T cells and TF-1 cells by the compounds of the present invention is shown in the following table.
  • mice Male ICR mice (Shanghai Xipuer-Beikai Experimental Animal Co., Ltd.) at 8 weeks of age and weighing 22-24 g were used as experimental animals.
  • the H01 compound, H04 compound, H09 compound, H11 compound and H12 compound were administered by intragastric administration.
  • the effect of swelling of the mouse foot The anti-inflammatory pharmacodynamics of the inventive compounds are explored.
  • H01 compound, H04 compound, H09 compound, H11 compound, H12 compound is H01 compound, H04 compound, H09 compound, H11 compound, H12 compound.
  • mice A certain amount of the compound was weighed and dissolved in an aqueous solution of 4% Tween 80/0.5% hydroxypropylmethylcellulose. The volume of the mice was 10 ml/kg.
  • the base foot volume represents the volume of the foot prior to administration.
  • 10 mg/kg of the compound of the present invention can alleviate the swelling rate of the mouse foot caused by carrageenan, especially within 1-2 hours after administration, indicating that the compound of the present invention has certain anti-acute inflammation.
  • the effect, and the swelling rate of the foot at 2 hours is better than methotrexate.
  • Example 4 Effect of the compound of the present invention on swelling of rat foot
  • H01 compound, H04 compound, H09 compound, H11 compound, H12 compound is H01 compound, H04 compound, H09 compound, H11 compound, H12 compound.
  • Rats were given H01 compound, H04 compound, H09 compound, H11 compound, H12 compound or the usual dose of methotrexate according to the dosage shown in the table below.
  • the foot was injected subcutaneously with 0.1 ml of 0.03%. (W/V) concanavalin (sigma, C2010).
  • W/V concanavalin
  • the base foot volume represents the volume of the foot prior to administration.
  • 10 mg/kg of the compound of the present invention can alleviate concanavalin-induced rat paw swelling, indicating that the compound of the present invention has an anti-acute inflammation effect, and some compounds are resistant to acute inflammation after 2 or 4 hours. The effect is better than methotrexate.
  • Example 5 Effect test of the compound of the present invention on rat rheumatoid arthritis
  • Lewis female rats (Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.) aged 5-6 weeks and weighing 160g (experimental) were used as experimental animals to measure the compound of H01, H09, H11 and H12 after long-term administration to rats.
  • the anti-inflammatory pharmacodynamics of the inventive compounds are explored.
  • H01 compound, H09 compound, H11 compound, H12 compound is H01 compound, H09 compound, H11 compound, H12 compound.
  • a certain amount of the compound was weighed and dissolved in an aqueous solution (solvent) of 4% Tween 80/0.5% hydroxypropylmethylcellulose.
  • the intragastric volume of the rats was 10 ml/kg.
  • Type II collagen (Sigma, C7806) was dissolved in 0.1 M acetic acid, overnight at 4 ° C in a refrigerator, and the collagen concentration was 4 mg/mL.
  • IFA incomplete Freund's adjuvant
  • the rats were immunized with collagen emulsion twice, and 0.1 ml of a single injection of the collagen emulsion prepared above was applied to the base of the tail, and two injections were made in the back skin, 0.2 per injection. Ml. Animals were clinically scored and tested for foot volume from day 10 to day 14 after modeling. Animals with successful modeling (average ⁇ 3 points/animal according to the following scoring standard clinical scores) were randomly assigned to each of the administration groups, 10 animals in each group, and the above compounds or methylamine were intragastrically administered twice a day at a dose of 10 mg/kg.
  • the pterygium (at a dose of 4 mg/kg) was administered to the model control group only by intragastric administration until the 27th day.
  • the experiment was scored twice a week during the experiment, the foot volume was measured twice, and the body weight was weighed twice.
  • the score was scored according to the standard of 0-4, the highest score of each limb was 4 points, and the highest score of each animal was 16 points.
  • the scoring criteria are as follows: 0, no redness; 1, medium foot (tibia) or slight swelling of the ankle joint; 2, slight swelling from the ankle to the midfoot (tibia); 3, from the ankle to the tibia joint Degree of bloating; 4, severe redness from the toes or fingers to the ankle or wrist.
  • the 10 mg/kg dose of the compound of the present invention can alleviate the clinical score of arthritis in rats, reduce the swelling volume of the toes, and alleviate the progression of arthritis.
  • mice Male SD rats aged 7-8 weeks and weighing 180-220 g were used as experimental animals. LC/MS/MS method was used to determine the plasma in the plasma at different time points after H01, H04, H08, H09, H11 and H12. concentration. The pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.
  • a certain amount of the compound was weighed and dissolved in 50% PEG400/water to prepare a uniform solution.
  • Rats were intragastrically administered with a dose of 5 mg/kg, and 0.2 ml of blood was collected from the eyelids before and after the administration of 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, 24.0 hours.
  • plasma was separated by centrifugation at 6000 rpm for 10 minutes at 4 ° C, and stored at -80 ° C.
  • the LC system is the LC-20AD UFLC High Performance Liquid Chromatography System (Shimadzu, LC-20AD).
  • the mass spectrometry system was equipped with an electrospray ionization source (ESI) (Applied Biosystems, Canada) for the AB Sciex API4000 tertiary quadrupole mass spectrometer.
  • ESI electrospray ionization source
  • the software used to control the LC/MS and quantitative analysis was Analyst 1.6 (Applied Biosystems, Canada) and the pharmacokinetic parameters were analyzed using WinNonlin (version 5.2, Pharsight, Mountain View, CA) non-compartmental models.
  • the liquid chromatography was separated using a Synergi Fusion-RP C 18 column (50 x 2.0 mm, inner diameter 4 ⁇ m). The column temperature was maintained at room temperature. The composition and gradient of the mobile phase are shown in the table below.
  • test compound was dissolved in DMSO to prepare a stock solution with a concentration of 1 mg/mL, and diluted with 50% acetonitrile to obtain a series of standard working solutions at concentrations of 10, 3, 1, 0.3, 0.1, 0.03 and 0.01 ⁇ g/mL. , and a series of standard quality control solutions (8, 0.5 and 0.03 ⁇ g / mL).
  • a standard solution 1000, 500, 200, 100, 10, 5, 2, and 1 ng/mL
  • a quality control standard solution plasma sample 800
  • the internal standard tolbutamide solid powder was dissolved in DMSO to prepare a 1 mg/mL stock solution.
  • the stock solution was diluted with 100% acetonitrile to give a 200 ng/mL solution as a protein precipitant.
  • the pharmacokinetic parameters of the compounds of the invention are as follows:
  • Example 7 Test for inhibition of hERG potassium channel current by compound
  • the electrocardiology manual patch clamp was used to detect the effects of H01, H04, H08, H09, H11, H12 compounds on hERG potassium channels, and the initial cardiac safety of the compounds of the present invention was investigated.
  • test compound was dissolved in DMSO and placed in a mother liquor of 10 mM, 3.3 mM, 1.1 mM, 0.37 mM. Next, the extracellular solution was used for secondary dilution, and the final test solution concentrations were 30 uM, 10 uM, 3.3 uM, 1.1 uM, and 0.37 uM.
  • the extracellular fluid contained: 130 mM NaCl, 4 mM KCl, 1.8 mM CaCl 2 , 1 mM MgCl 2 , 10 mM glucose, 10 mM HEPES (pH 7.4).
  • the intracellular fluid contained: 130 mM KCl, 1 mM MgCl 2 , 5 mM EGTA, 5 mM MgATP, and 10 Mg ATP HEPES (pH 7.2).
  • Cell culture medium composition DMEM (Gibco, 11330032), 15% fetal bovine serum (PAA, A15-101), 1% penicillin-streptomycin (Biowest, L0022-100).
  • HEK293 cells overexpressing the hERG potassium channel were cultured in medium consisting of DMEM/15% fetal calf serum/1% penicillin-streptomycin 37 ° C, 5% CO 2 incubator. During the experiment, the cells were transferred to a cell bath embedded in an inverted microscope platform, and the extracellular fluid was perfused, and the cells were allowed to stand for 5 minutes to start the experiment. Membrane currents were recorded using a HEKA EPC-10 patch clamp amplifier and a PATCHMASTER acquisition system (HEKA Instruments, Inc., D-67466, Lambrcht, Pfalz, Germany).
  • the experiment was performed using the whole cell recording mode, and the current value was recorded according to the electrophysiological stimulation protocol below.
  • the membrane voltage was clamped at -80 mV, and the cells were given 2 s, +20 mV voltage stimulation, activated hERG potassium channel, and then repolarized to -50 mV for 5 s, generating an outward tail current, and the stimulation frequency was once every 15 s.
  • the current value is the peak value of the tail current.
  • the channel current was recorded in the whole cell recording mode in the experiment. First, perfusate the extracellular fluid (about 2 ml per minute) and keep recording, waiting for the current to stabilize (current-down less than 5% in 5 minutes), at which point the peak current is the control current value.
  • the extracellular fluid containing the drug to be tested is perfused and continuously recorded until the inhibition of the hERG current reaches a steady state, and the peak current is the current value after dosing. After reaching a steady state, if the hERG current is recovered after flushing with extracellular fluid, the perfusion can be continued to test other concentrations or drugs.
  • the solution containing the drug to be tested is perfused and recorded in the order of concentration from low to high. Data were collected using PATCHMASTER V2X60 (HEKA Instruments, D-67466 Lambrecht, Pfalz, Germany) and analyzed and statistically performed using Origin 8.5 (OriginLab, Northampton, MA) software.
  • the IC50 of the current inhibition of hERG by the compounds of the present invention is shown in the following table. It can be seen from the data in the table below that the compound of the present invention has a weak current inhibition effect on hERG and is safe.

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Abstract

La présente invention se rapporte au domaine de la chimie médicale, et concerne un inhibiteur de JAK, son procédé de préparation et une application dans le domaine de la médecine. La présente invention concerne un nouvel inhibiteur de JAK de petite molécule, ayant une structure telle que représentée par la formule générale II. Le présent composé tel que représenté par la formule générale II a un meilleur effet de médicament et est plus sûr dans la prévention ou le traitement d'indications associées à JAK.
PCT/CN2018/106647 2017-09-21 2018-09-20 Inhibiteur de jak, procédé de préparation de celui-ci et application dans le domaine de la médecine WO2019057103A1 (fr)

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CN111072543B (zh) * 2019-11-13 2021-06-04 北京海美桐医药科技有限公司 一种(3r,4s)-4-乙基吡咯烷-3-羧酸类化合物的制备方法及其应用
CN114478346A (zh) * 2021-12-31 2022-05-13 和鼎（南京）医药技术有限公司 一种制备乌帕替尼中间体的方法

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WO2007077949A1 (fr) * 2005-12-28 2007-07-12 Astellas Pharma Inc. Inhibiteurs heterocycliques de la janus kinase 3
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